Therapeutic use of glucokinase activators in combination with insulin or insulin analogs

Abstract

The invention relates to therapeutic use of a glucokinase activator in combination with insulin or an insulin analogue. Methods of using glucokinase (GK) activators, particularly in combination with insulin or insulin analogs, are generally disclosed herein. In certain aspects, the disclosure provides methods of treating type 1 diabetes mellitus comprising administering a GK activator in combination with insulin or an insulin analogue. Also disclosed herein are uses of GK activators as medicaments, and the preparation of medicaments for such uses.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of June 10, 2019, an application number of 201980028636.8, and an invention title of "Therapeutic Use of a Glucokinase Activator in Combination with Insulin or an Insulin Analogue" (the application date of the corresponding PCT application is June 10, 2019, and the application number is PCT / US2019 / 036227). Technical Field

[0002] The present disclosure generally discloses methods of using a glucokinase (GK) activator, particularly in combination with insulin or an insulin analogue. In certain aspects, the present disclosure provides methods of treating type 1 diabetes that comprise administering a combination of a GK activator and insulin or an insulin analogue. In certain other aspects, the present disclosure provides methods of treating related conditions and improving glycemic control, such as increasing the percentage of time a subject is within a target blood glucose range, decreasing the percentage of time a subject is within a hypoglycemic or hyperglycemic range, decreasing body weight, decreasing glycated hemoglobin levels, reducing the occurrence of diabetic ketoacidosis, decreasing mean daily blood glucose levels, reducing the total daily rapid-acting insulin dose, reducing the total daily basal insulin dose, reducing the total daily insulin dose, reducing the total number of daily insulin injections, reducing the total number of daily basal insulin injections, reducing the total number of insulin boluses, reducing the total daily rapid-acting insulin dose at each meal, reducing the number of hypoglycemic events over a period of time, and reducing the number of severe hypoglycemic events over a period of time. The present disclosure also discloses the use of a GK activator as a medicament and the preparation of a medicament for such use. Background Art

[0003] Type 1 diabetes (T1D) is a chronic disease caused by the autoimmune destruction of insulin-producing β-cells in the pancreas. As a result, people with T1D do not produce enough insulin to allow them to properly regulate their blood glucose levels. Thus, if left untreated, they are likely to suffer from acute illnesses due to extremely high blood glucose. However, even with treatment, people with T1D still experience fluctuations in blood glucose levels, which can lead to acute illnesses (such as hyperglycemia and hypoglycemia) and ultimately increase the risk of chronic diseases (such as heart disease, stroke, blindness (due to diabetic retinopathy), kidney failure, and poor blood circulation in the limbs (which can lead to the need for amputation of limbs that no longer benefit from adequate blood circulation)).

[0004] Type 1 diabetes is typically only controllable by administering insulin or insulin analogs. In recent decades, the development of various available insulins has been witnessed, including rapid-acting insulin, short-acting insulin, intermediate-acting insulin, and long-acting insulin. Additionally, recently marketed devices provide continuous glucose monitoring and are equipped with pumps for real-time adjustment of insulin dosage. Many pharmaceutical therapies for treating non-insulin-dependent diabetes have shown inefficiency or no effect in treating type 1 diabetes. That is because many pharmaceutical therapies rely on the body's ability to produce endogenous insulin. Therefore, such therapies are of little use in treating type 1 diabetes as patients with type 1 diabetes have little or no ability to produce and secrete endogenous insulin.

[0005] Accordingly, there is a continuing need to develop effective pharmaceutical compounds that can help control type 1 diabetes without relying on endogenous insulin production. SUMMARY OF THE INVENTION

[0006] The present disclosure generally provides methods for treating type 1 diabetes and related conditions using a combination of a liver-selective glucokinase (GK) activator and insulin or an analog thereof. It has surprisingly been found that activation of GK in the liver (relative to GK in the pancreas or brain) can improve the efficacy of insulin therapy, improve glycemic control, and / or simplify the treatment regimen for type 1 diabetes. Accordingly, it has been found that in certain aspects, these results can be achieved by combining insulin administration with administration of a liver-selective GK activator.

[0007] Glucokinase (GK) is an enzyme that, among other things, helps phosphorylate glucose to glucose-6-phosphate. In vertebrates, GK-mediated glucose phosphorylation typically occurs in the cells of the liver, pancreas, intestine, and brain. In each of these organs, GK can regulate carbohydrate metabolism by acting as a glucose sensor, thereby triggering a shift in metabolism or cellular function in response to an increase and / or decrease in blood glucose levels. Small molecule GK activators are useful because they can increase the rate of glucose phosphorylation, thereby reducing the amount of glucose in the blood.

[0008] METHODS OF TREATMENT

[0009] In a first aspect, the present invention provides a method for treating type 1 diabetes, the method comprising administering to a subject in need a combination of a liver-selective glucokinase activator and insulin or an analog thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, the present invention provides a method of increasing the percentage of time in a target blood glucose range in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, the present invention provides a method of reducing the total daily rapid-acting insulin dose in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, the present invention provides a method of reducing the mean daily blood glucose in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, the present invention provides a method of reducing the blood glucagon level in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0014] In another aspect, the present invention provides a method of reducing the glycated hemoglobin level in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0015] In another aspect, the present invention provides a method for reducing the percentage of time in the hypoglycemic range in a subject with type 1 diabetes, the method comprising administering to a subject in need a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0016] In another aspect, the present invention provides a method for reducing the percentage of time in the hyperglycemic range in a subject with type 1 diabetes, the method comprising administering to a subject in need a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0017] In another aspect, the present invention provides a method for reducing the incidence, duration or likelihood of diabetic ketoacidosis in a subject with type 1 diabetes, the method comprising administering to a subject in need a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0018] In another aspect, the present invention provides a method for reducing the incidence, duration or likelihood of diabetic ketosis in a subject with type 1 diabetes, the method comprising administering to a subject in need a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0019] In another aspect, the present invention provides a method for reducing one or more metabolic ketones in a subject with type 1 diabetes, the method comprising administering to a subject in need a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0020] In another aspect, the present invention provides a method of reducing body weight in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0021] In another aspect, the present invention provides a method of reducing the total daily basal insulin dose in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0022] In another aspect, the present invention provides a method of reducing the total daily insulin dose in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0023] In another aspect, the present invention provides a method of reducing the total number of daily insulin injections in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0024] In another aspect, the present invention provides a method of reducing the total number of daily basal insulin injections in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0025] In another aspect, the present invention provides a method for reducing the total number of daily insulin boluses in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0026] In another aspect, the present invention provides a method for reducing the total daily bolus insulin dose at each meal in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0027] In another aspect, the present invention provides a method for reducing the number of hypoglycemic events over a period of time in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0028] In another aspect, the present invention provides a method for reducing the number of severe hypoglycemic events over a period of time in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0029] In another aspect, the present disclosure provides a treatment method to achieve any previous improvement in glycemic control in a subject with type 1 diabetes (e.g., reducing the time in the hypoglycemic range or reducing the number of hypoglycemic events or severe hypoglycemic events), while not reducing the HbA1c level in the subject or only slightly increasing the HbA1c (0.1%, 0.2% or 0.3%), the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0030] Use of a combination

[0031] In another aspect, the present invention provides the use of a combination of a liver-selective glucokinase activator and insulin or an analogue thereof for the treatment of type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0032] In another aspect, the present invention provides the use of a combination of a liver-selective glucokinase activator and insulin or an analogue thereof for increasing the percentage of time within a target blood glucose range in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0033] In another aspect, the present invention provides the use of a combination of a liver-selective glucokinase activator and insulin or an analogue thereof for reducing the total daily rapid-acting insulin dose in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0034] In another aspect, the present invention provides the use of a combination of a liver-selective glucokinase activator and insulin or an analogue thereof for reducing the mean daily blood glucose in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0035] In another aspect, the present invention provides the use of a combination of a liver-selective glucokinase activator and insulin or an analogue thereof for reducing the blood-glucagon level in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0036] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for reducing the glycated hemoglobin level in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0037] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for reducing the percentage of time in the hypoglycemic range in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0038] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for reducing the percentage of time in the hyperglycemic range in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0039] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for reducing the incidence, duration or likelihood of diabetic ketoacidosis in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0040] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for reducing the incidence, duration or likelihood of diabetic ketoacid in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0041] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for reducing one or more metabolic ketones in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0042] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for reducing body weight in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0043] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for reducing the total daily basal insulin dose in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0044] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for reducing the total daily insulin dose in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0045] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for reducing the total number of daily insulin injections in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0046] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for reducing the total number of daily basal insulin injections in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0047] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for reducing the total number of daily rapid insulin boluses in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0048] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for reducing the total daily rapid insulin bolus dose per meal in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0049] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for reducing the number of hypoglycemic events over a period of time in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0050] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in combination with insulin or an analogue thereof for a method of reducing the number of severe hypoglycemic events over a period of time in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0051] On the other hand, the present invention provides the use of a combination of a liver-selective glucokinase activator and insulin or an analogue thereof to achieve any prior improvement in glycemic control in a subject with type 1 diabetes (e.g., reducing the time of hypoglycemia or reducing the number of hypoglycemic or severe hypoglycemic events), without reducing the HbA1c level in the subject or with only a slight increase in HbA1c, the method comprising administering to a subject in need a combination of a liver-selective glucokinase activator and insulin or an analogue thereof. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0052] Drug preparation

[0053] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for combination with insulin or an analogue thereof for the treatment of type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0054] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for combination with insulin or an analogue thereof to increase the percentage of time within a target blood glucose range in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0055] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for combination with insulin or an analogue thereof to reduce the total daily rapid-acting insulin dose in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0056] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for combination with insulin or an analogue thereof to reduce the mean daily blood glucose in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0057] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for combination with insulin or an analogue thereof to reduce the blood-glucagon level in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0058] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the glycated hemoglobin level in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0059] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the percentage of time in the hypoglycemic range in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0060] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the percentage of time in the hyperglycemic range in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0061] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the incidence, duration or likelihood of diabetic ketoacidosis in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0062] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the incidence, duration or likelihood of diabetic ketosis in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0063] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce one or more metabolic ketones in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0064] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce body weight in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0065] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the total daily basal insulin dose in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0066] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the total daily insulin dose in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0067] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the total number of daily insulin injections in a subject with type 1 diabetes. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0068] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the total number of daily basal insulin injections in a subject with type 1 diabetes. In some embodiments thereof, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0069] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the total number of daily rapid insulin boluses in a subject with type 1 diabetes. In some embodiments thereof, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0070] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the total daily rapid insulin bolus dose at each meal in a subject with type 1 diabetes. In some embodiments thereof, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0071] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the number of hypoglycemic events over a period of time in a subject with type 1 diabetes. In some embodiments thereof, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0072] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the number of severe hypoglycemic events over a period of time in a subject with type 1 diabetes. In some embodiments thereof, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0073] On the other hand, the present invention provides the use of a liver-selective glucokinase activator in the preparation of a medicament for combination with insulin or an analogue thereof to achieve any prior improvement in blood glucose control in a subject with type 1 diabetes (e.g., reducing the time in the hypoglycemic range or reducing the number of hypoglycemic events or severe hypoglycemic events), without reducing the HbA1c level in the subject or with only a slight increase in HbA1c. In some of its embodiments, the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0074] Other aspects and embodiments are set forth in the above drawings, detailed description of the invention, and claims. Brief Description of the Drawings

[0076] Figure 1 Shows the percentage of time that the blood glucose level of each subject was between 70 and 180 mg / dL at each dose (400, 800, and 1200 mg / day of UT-1) and at baseline, where each data point represents the median for each subject over four days (days 3-6) at each dose.

[0077] Figure 2 Shows the percentage of time that the blood glucose level of each subject was between 54 and 70 mg / dL at each dose (400, 800, and 1200 mg / day of UT-1) and at baseline, where each data point represents the median for each subject over four days (days 3-6) at each dose.

[0078] Figure 3 Shows the percentage of time that the blood glucose level of each subject was below 54 mg / dL at each dose (400, 800, and 1200 mg / day of UT-1) and at baseline, where each data point represents the median for each subject over four days (days 3-6) at each dose.

[0079] Figure 4 Shows the percentage of time that the blood glucose level of each subject was greater than 180 mg / dL at each dose (400, 800, and 1200 mg / day of UT-1) and at baseline, where each data point represents the median for each subject over four days (days 3-6) at each dose.

[0080] Figure 5 Shows the average daily rapid-acting insulin dose (U) at each dose (400, 800, and 1200 mg / day of UT-1) and at baseline, where each data point represents the average for each subject over four days (days 3-6) at each dose.

[0081] Figure 6 Shows the mean daily basal insulin dose (U) for each dose (400, 800, and 1200 mg / day of UT-1) and at baseline, where each data point represents the mean for each subject over four days (days 3-6) at each dose. DETAILED DESCRIPTION OF THE INVENTION

[0083] The following description details various aspects and embodiments of the invention disclosed herein. Specific embodiments are not intended to limit the scope of the invention. Rather, the embodiments provide non-limiting examples of various combinations and methods included within the scope of the claimed invention. The description should be read from the perspective of one of ordinary skill in the art. Thus, information well known to one of ordinary skill in the art is not necessarily included.

[0084] DEFINITIONS

[0085] Unless otherwise indicated herein, the following terms and phrases have the meanings set forth below. The present disclosure may employ other terms and phrases not explicitly defined herein. These other terms and phrases shall have the meaning that they would have to one of ordinary skill in the art in the context of the present disclosure. In some cases, a term or phrase may be defined in either the singular or the plural form. In such cases, it should be understood that any term in the singular form may include its plural counterpart, and vice versa, unless explicitly stated to the contrary.

[0086] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to "a substituent" includes a single substituent as well as two or more substituents, and the like.

[0087] As used herein, "for example," "for instance," "such as," or "including" are intended to introduce examples that further illustrate a more general subject. These examples are for illustrative purposes only and are not meant to be limiting in any way, unless otherwise explicitly stated. These phrases also do not denote any preference for the disclosed embodiments.

[0088] As used herein, "administer" or "administration" means introducing, for example, a compound or composition to a subject. The term is not limited to any particular mode of delivery and can include, for example, subcutaneous delivery, intravenous delivery, intramuscular delivery, intracisternal delivery, delivery by infusion techniques, transdermal delivery, oral delivery, nasal delivery, and rectal delivery. In addition, depending on the mode of delivery, the administration can be performed by various individuals, including, for example, healthcare professionals (such as doctors, nurses, etc.), pharmacists, or the subject (such as self-administration).

[0089] As used herein, "treat" or "treating" or "treatment" can refer to one or more of the following: delaying the progression of a disease, disorder or condition; controlling a disease, disorder or condition; ameliorating one or more symptoms of a disease, disorder or condition; or delaying the recurrence of a disease, disorder or condition or its characteristic symptoms, depending on the nature of the disease, disorder or condition and its characteristic symptoms.

[0090] As used herein, "subject" refers to any mammal, such as but not limited to a human, horse, cow, sheep, pig, mouse, rat, dog, cat, and primates such as chimpanzee, gorilla, and rhesus monkey. In some embodiments, the "subject" is a human. In some embodiments, the "subject" is a human who exhibits one or more characteristic symptoms of a disease, disorder or condition. The term "subject" does not require any special status with respect to a hospital, clinic or research institution (such as being a diagnosed patient, research participant, etc.).

[0091] As used herein, the terms "blood glucose level", "blood sugar level", "plasma glucose level", and "blood glucose concentration" refer to the amount of glucose present in the blood of a subject, and these terms may be used interchangeably. Blood glucose levels are typically measured in mg / dL or mmol / L.

[0092] As used herein, the term "metabolic ketone" refers to any compound produced by fatty acid metabolism (such as by hepatic enzymes), and includes but is not limited to acetoacetic acid (AcAc), β-hydroxybutyric acid (BHB), and acetone.

[0093] As used herein, the term "hypoglycemia" refers to a blood glucose level in a subject that is lower than the normal level. In humans, hypoglycemia can be defined as a blood glucose level below 70 mg / dL. In one embodiment, hypoglycemia in a human is a blood glucose level less than 70 mg / dL and greater than or equal to 54 mg / dL.

[0094] As used herein, the term "severe hypoglycemia" refers to a blood glucose level in a subject that is significantly lower than the normal level. In humans, severe hypoglycemia can be defined as a blood glucose level below 54 mg / dL.

[0095] As used herein, the term "hypoglycemic event" refers to a subject's blood glucose level being below the normal level for a period of time. In one embodiment, a hypoglycemic event can occur when self - monitoring of blood glucose (SMBG) shows a single measured blood glucose level below the normal level. In other embodiments, in the case of continuous monitoring of blood glucose levels, a hypoglycemic event can occur over a period of time, such as when the blood glucose level remains below the normal level for at least 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 15, 20, 25, 30, 60, or 120 minutes. In one embodiment, in humans, a hypoglycemic event can be defined as a blood glucose level less than 70 mg / dL over a period of time or at a single SMBG measurement. In another embodiment, in humans, a hypoglycemic event can be defined as a blood glucose level less than 70 mg / dL and greater than or equal to 54 mg / dL over a period of time or in a single SMBG measurement. The end of a hypoglycemic event may occur after the subject's blood glucose level has been elevated above a threshold for a period of time. For example, the blood glucose level may need to be continuously above the threshold for at least 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 15, 20, 25, 30, 60, or 120 minutes to mark the end of the hypoglycemic event. In one embodiment, in humans, the end of a hypoglycemic event can be defined as a blood glucose level greater than 70 mg / dL over a period of time or at a single SMBG measurement.

[0096] As used herein, the term "severe hypoglycemic event" refers to a subject's blood glucose level being significantly below the normal level for a period of time. In one embodiment, a severe hypoglycemic event can occur when self - monitoring of blood glucose (SMBG) shows a single measured blood glucose level significantly below the normal level. In other embodiments, in the case of continuous monitoring of blood glucose levels, a severe hypoglycemic event can occur over a period of time, such as when the blood glucose level remains continuously below the normal level for at least 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 15, 20, 25, 30, 60, or 120 minutes. In one embodiment, in humans, a severe hypoglycemic event can be defined as a blood glucose level less than 54 mg / dL over a period of time or at a single SMBG measurement. The end of a severe hypoglycemic event may occur after the subject's blood glucose level has been elevated above a threshold for a period of time or in a single SMBG measurement. For example, the blood glucose level may need to be continuously above the threshold for at least 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 15, 20, 25, 30, 60, or 120 minutes to mark the end of the hypoglycemic event. In one embodiment, in humans, the end of a severe hypoglycemic event can be defined as a blood glucose level greater than or equal to 54 mg / dL over a period of time or at a single SMBG measurement.

[0097] As used herein, the term "hyperglycemia" refers to a blood glucose level in a subject that is above the normal level. In humans, hyperglycemia can be defined as a blood glucose level greater than 180 mg / dL. In one embodiment, hyperglycemia in a human is a blood glucose level greater than 180 mg / dL and less than or equal to 250 mg / dL.

[0098] As used herein, the term "severe hyperglycemia" refers to a blood glucose level in a subject that is significantly above the normal level. In humans, severe hyperglycemia can be defined as a blood glucose level greater than 250 mg / dL.

[0099] As used herein, the term "hyperglycemic event" refers to a blood glucose level in a subject that is above the normal level over a period of time. In one embodiment, a hyperglycemic event can occur when self - monitoring of blood glucose (SMBG) measures a blood glucose level above the normal level in a single measurement. In other embodiments, in the case of continuous monitoring of blood glucose levels, a hyperglycemic event can occur over a period of time, such as when the blood glucose level remains above the normal level for at least 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 15, 20, 25, 30, 60, or 120 minutes. In one embodiment, in humans, a hyperglycemic event can be defined as a blood glucose level greater than 180 mg / dL over a period of time or in a single SMBG measurement. In another embodiment, in humans, a hyperglycemic event can be defined as a blood glucose level greater than 180 mg / dL and less than or equal to 250 mg / dL over a period of time or in a single SMBG measurement. The end of a hyperglycemic event may occur after the subject's blood glucose level has remained below a threshold for a period of time. For example, the blood glucose level may need to be continuously below the threshold for at least 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 15, 20, 25, 30, 60, or 120 minutes to mark the end of a hyperglycemic event. In one embodiment, in humans, the end of a hyperglycemic event can be defined as a blood glucose level less than 180 mg / dL over a period of time or in a single SMBG measurement.

[0100] As used herein, the term "severe hyperglycemic event" refers to a subject's blood glucose level being significantly higher than the normal level over a period of time. In one embodiment, it occurs when, through self - monitoring of blood glucose (SMBG), the blood glucose level in a single measurement is significantly higher than the normal level, and a severe hypoglycemic event may occur. In other embodiments, in the case of continuous monitoring of blood glucose levels, a severe hyperglycemic event may occur over a period of time, such as when the blood glucose level continuously remains higher than the normal level for at least 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 15, 20, 25, 30, 60, or 120 minutes. In one embodiment, in humans, a severe hyperglycemic event can be defined as a blood glucose level greater than 250 mg / dL over a period of time or in a single SMBG measurement. The end of a severe hyperglycemic event may occur after the subject's blood glucose level has decreased to below a threshold over a period of time or in a single SMBG measurement. For example, the blood glucose level may need to be continuously below the threshold for at least 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 15, 20, 25, 30, 60, or 120 minutes to mark the end of the hyperglycemic event. In one embodiment, in humans, the end of a severe hyperglycemic event can be defined as a blood glucose level less than or equal to 250 mg / dL over a period of time or in a single SMBG measurement.

[0101] As used herein, the term "bolus insulin dose" is an insulin dose specifically administered to a subject immediately before or after a meal time or near a meal time to control the blood glucose level after the meal. The bolus insulin dose should act rapidly, so short - acting insulin, rapid - acting insulin, or a combination thereof is often used in the bolus insulin dose.

[0102] As used herein, the term "basal insulin dose" is an insulin dose given to a subject during fasting (such as between meals or during sleep) to keep the blood glucose level within an acceptable range. The basal insulin dose is usually administered once or twice a day, but may be administered more frequently. The basal insulin dose needs to act over a relatively long period of time (such as several hours), so the basal insulin dose usually contains long - acting insulin, intermediate - acting insulin, or a mixture of long - acting and intermediate - acting insulin.

[0103] As used herein, the term "baseline" refers to the period before treatment and the relevant level or value of the item being measured during that pre - treatment period. In one embodiment, the pre - treatment period can be a continuous period of 1, 2, 3, 4, 5, 6 days or more before treatment. The pre - treatment period can end immediately before the start of treatment, or the pre - treatment period can be a continuous time period that ends at least 1, 2, 3 days or more before the start of treatment.

[0104] As used herein, the term "pharmaceutical composition" is used to denote a composition that can be administered to a mammalian host in unit dosage form, such as orally, topically, parenterally, by inhalation spray or rectally, containing conventional non-toxic carriers, diluents, excipients, vehicles, etc. The term "parenteral" as used herein includes subcutaneous injection, intravenous, intramuscular, intracisternal injection or by infusion techniques.

[0105] As used herein, the term "pharmaceutically acceptable salt" refers to salts of a compound, which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, ethanedisulfonate, estolate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, naphthalenesulfonate, nitrate, N-methylglucamine salt, oxalate, pamoate (pamoate), palmitate, pantothenate, phosphate / hydrogen phosphate, polygalacturonate, potassium salt, salicylate, sodium salt, stearate, subacetate, succinate, tannate, tartrate, theophyllinate, tosylate, triethiodide, trimethylammonium salt and valerate. When acidic substituents are present, such as -COOH, ammonium salts, morpholinium salts, sodium salts, potassium salts, barium salts, calcium salts, etc. can be formed for use in dosage forms. When basic groups are present, such as amino or basic heteroaryl such as pyridyl, acidic salts such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartrate, fumarate, mandelate, benzoate, cinnamate, mesylate, esylate, picrate, etc. can be formed. In certain embodiments, the GK activator is in the form of a hydrochloride salt. In other embodiments, the GK activator is in the free acid form.

[0106] As used herein, the unit term "mg / kg" refers to the mass of a compound (in mg) administered to a subject per unit mass of the subject (measured in kg). For example, "administering 1.0 mg / kg to a subject per day" means administering 170 mg per day to a subject with a mass of 170 kg.

[0107] As used herein, "mix" or "mixed" or "mixture" generally refers to any combination of two or more compositions. The two or more compositions do not need to have the same physical state; thus, a solid can be "mixed" with a liquid, for example, to form a slurry, suspension, or solution. Additionally, these terms do not require any degree of homogeneity or uniformity of the compositions. Such a "mixture" can be homogeneous or heterogeneous, or can be uniform or non-uniform. Further, the term does not require the use of any specific equipment for mixing, such as an industrial mixer.

[0108] As used herein, "optionally" means that the subsequently described event may or may not occur. In some embodiments, the optional event does not occur. In some other embodiments, the optional event does occur one or more times.

[0109] As used herein, "comprise" or "comprises" or "comprising" or "comprised of" refers to an open group, meaning that the group can include additional members in addition to those specifically listed. For example, the phrase "comprising A" means that A must be present, but other members can also be present. The terms "include", "have", and "composed of" and their grammatical variants have the same meaning. In contrast, "consist of" or "consists of" or "consisting of" refers to a closed group. For example, the phrase "consisting of A" means that A is present and only A is present.

[0110] As used herein, "or" shall be given its broadest reasonable interpretation and is not limited to any one / or meaning. Thus, the phrase "comprising A or B" means that A can be present without B, or B can be present without A, or both A and B can be present. Additionally, if A, for example, defines a class that can have multiple members, such as A 1 and A 2 , then one or more members of the class can be present simultaneously.

[0111] As used herein, a "GK activator" is a compound that activates GK in a subject (e.g., a human) in direct or indirect response to the presence of a compound (or its metabolite) in the subject. WO 2005 / 066145 provides a non-limiting list of compounds that are GK activators. In addition, a GK activator can activate GK anywhere GK is present, but some can selectively activate GK in certain systems or organs. For the treatment of lowering blood glucose levels, it is generally associated with GK activation in the pancreas and / or liver. When the GK activator is a liver-selective GK activator, the GK activator directly or indirectly increases glucose utilization in the liver (hepatocytes), and the dose does not cause a substantial increase in pancreatic (β-cell) insulin secretion in response to glucose (e.g., less than a 25% increase, or less than a 15% increase, or less than a 10% increase, or less than a 5% increase, or less than a 3% increase in insulin secretion in the pancreas in response to glucose), or does not induce a substantial increase in GK activity in other systems or organs (e.g., the brain or central nervous system). In some embodiments, the liver-selective GK activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0112] Other terms are defined elsewhere in this specification, even if not included in this subsection.

[0113] Combination of a GK activator and insulin

[0114] In one or more of the above aspects, the present invention provides a method of administering a GK activator (or in some embodiments, a liver-selective GK activator) to a subject in need thereof. Generally, the method comprises administering to the subject in need thereof a combination of a GK activator and insulin or an analogue thereof.

[0115] Any suitable GK activator or liver-selective GK activator can be used. In some embodiments, the liver-selective GK activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof. In some other embodiments, the liver-selective GK activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid. In some other embodiments, the liver-selective GK activator is a pharmaceutically acceptable salt of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid.

[0116] The GK activator can be administered in any suitable manner, including subcutaneous delivery, intravenous delivery, intramuscular delivery, intrathecal delivery, delivery by infusion techniques, transdermal delivery, oral delivery, nasal delivery, and rectal delivery. In some embodiments of any of the foregoing embodiments, the administration includes oral administration of a liver-selective GK activator. Suitable oral dosage forms are described in further detail below.

[0117] The liver-selective GK activator is administered in combination with insulin or an analogue thereof. As used herein, "in combination with" does not necessarily mean that the agents are administered on the same schedule or as part of a common dosage form. In some cases, these drugs can be administered once daily or once weekly and can be administered by different means.

[0118] Insulin

[0119] Insulin or an analogue thereof can be administered in any suitable manner, including but not limited to oral administration (via the intestine or lung), subcutaneous administration (such as continuous subcutaneous insulin infusion), and injection administration. In some other embodiments, insulin or an analogue thereof is administered subcutaneously or by injection. In another embodiment, insulin or an analogue thereof is administered by two different routes.

[0120] Any suitable form of insulin or its analogs can be used. These include, but are not limited to, rapid-acting insulin, regular or short-acting insulin, intermediate-acting insulin, and long-acting insulin. When injected subcutaneously, rapid-acting insulin typically reaches the bloodstream within about 15 minutes after injection and is effective for 2 - 4 hours. Types of rapid-acting insulin include: insulin lispro (Apidra), insulin aspart (Humalog), and insulin glulisine (NovoLog). When injected subcutaneously, regular or short-acting insulin typically reaches the bloodstream within 30 minutes after injection and is effective for about 3 to 6 hours. Types of regular or short-acting insulin include: Humulin R, Novolin R. When injected subcutaneously, intermediate-acting insulin typically reaches the bloodstream about 2 to 4 hours after injection and is effective for about 12 to 18 hours. Types of intermediate-acting insulin include: NPH (Humulin N, Novolin N). When injected subcutaneously, long-acting insulin typically reaches the bloodstream several hours after injection and is effective within 24 hours. Types of long-acting insulin include: insulin detemir (Levemir) and insulin glargine (Lantus). In certain embodiments, the administration comprises administering to a subject in need a combination of a liver-selective glucokinase activator and insulin, such as rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, or a combination of insulins. In some embodiments, the combination of insulin administered can comprise rapid-acting insulin and short-acting insulin. In other embodiments, the combination of insulin administered can comprise intermediate-acting insulin and long-acting insulin. In other embodiments, the combination of insulin administered can include any combination of two, three, or four types of insulin. In some other embodiments, the administration comprises administering to a subject in need a combination of a liver-selective glucokinase activator and insulin lispro, insulin aspart, insulin glulisine, isophane insulin, insulin zinc, insulin glargine, insulin detemir, or any combination thereof.

[0121] subject

[0122] The disclosed methods can be performed on any suitable subject, including humans, horses, cows, sheep, pigs, mice, rats, dogs, cats, and primates, such as chimpanzees, gorillas, and rhesus monkeys. In some embodiments, the subject is a human.

[0123] In the methods disclosed herein, the subject is a subject in need of the treatment. In some embodiments, this includes a subject exhibiting one or more of the following symptoms: (i) a fasting blood glucose concentration greater than 100 mg / dL, or greater than 110 mg / dL, or greater than 100 or 110 mg / mL and less than 125 mg / dL; (ii) a plasma glucose level greater than 140 mg / dL two hours after a meal or a plasma glucose level greater than 140 mg / dL three hours after a meal; (iv) an HbA1c value equal to or greater than 5.7%, 6.5%, 7.0%, 7.5% or 8.0%; (v) persistent presence of two or more islet antibodies.

[0124] The nature of the subject's need depends on the treatment goal. In some embodiments of any of the foregoing embodiments, the subject shows an elevated glycated hemoglobin level in their blood, such as an elevated HbA1c level in their blood. In some such embodiments, administration of a liver-selective GK activator in combination with insulin or an analogue thereof is carried out to reduce the glycated hemoglobin level of the subject, such as the HbA1c level of the subject. In some embodiments, other blood glucose control measures are achieved (such as reducing the time in the hypoglycemic range or reducing the number of hypoglycemic or severe hypoglycemic events), with or without a reduction in HbA1c or a slight increase in HbA1c level.

[0125] In some other embodiments, the subject has one or more symptoms consistent with type 1 diabetes. In some such embodiments, a combination of a liver-selective GK activator and insulin or an analogue thereof is administered to treat type 1 diabetes (including treating one or more symptoms associated therewith). In some other embodiments, the subject has elevated body weight, or in some cases, obesity. In some such embodiments, a combination of the liver-selective GK activator and insulin or an analogue thereof is administered to reduce body weight. In some other embodiments, the subject is based on one or more symptoms consistent with poor glycemic control, such as a greater percentage of time outside of a target blood glucose range (e.g., in a hypoglycemic range or in a hyperglycemic range). In some such embodiments, a combination of the liver-selective GK activator and insulin or an analogue thereof is administered to increase the percentage of time within the target blood glucose range, reduce the percentage of time within the hyperglycemic range, reduce the percentage of time within the hypoglycemic range, or reduce the number of hypoglycemic or severe hypoglycemic events over a period of time. Thus, in some such embodiments, a combination of a liver-selective glucokinase activator and insulin or an analogue thereof is administered to reduce one or more rapid bolus insulin doses, the rapid bolus insulin dose per meal, one or more basal insulin doses, or the total insulin dose over a period of time. In some embodiments, the subject shows an elevated daily average blood glucose level. Thus, in some such embodiments, a combination of a liver-selective glucokinase activator and insulin or an analogue thereof is administered to reduce the daily average blood glucose level. In some embodiments, the subject experiences an increased risk of diabetic ketoacidosis. Thus, in some embodiments, a combination of a liver-selective glucokinase activator and insulin or an analogue thereof is administered to reduce the incidence, duration, or likelihood of ketoacidosis.

[0126] Administration of the GK activator

[0127] Any suitable dose and dosing regimen of a liver-selective GK activator can be used. In some embodiments, the methods disclosed herein include administering 1 to 30 mg / kg of a liver-selective GK activator per day. These amounts can be administered in any suitable regimen throughout the day. In some embodiments, the administration includes administering the liver-selective GK activator one or more times a day, such as once a day, twice a day, three times a day, etc. In some other such embodiments, the administration includes administering the liver-selective GK activator twice a day. The administration can be with or without food. In some embodiments, the administration includes administering the liver-selective GK activator one or more times a day, with at least one of the one or more times being with food. In some such embodiments, the administration includes administering the liver-selective GK activator twice a day, with food. In some embodiments, the two or more daily doses contain equal amounts of the liver-selective GK activator. In other embodiments, the method includes administering 1 to 30 mg / kg of a liver-selective GK activator every other day, or every two days, or every three days, or every four days, every five days. The dosage form for a single administration can contain 1 - 75 mg, 75 - 100 mg, 75 - 150 mg, 100 - 150 mg, 125 - 175 mg, 150 - 200 mg, 175 - 225 mg, 200 - 250 mg, 225 - 275 mg, 250 - 300 mg, 275 - 325 mg, 300 - 350 mg, 325 - 375 mg, 350 - 400 mg, 375 - 425 mg, 400 - 450 mg, 425 - 475 mg, 450 - 500 mg, 475 - 525 mg, 500 - 550 mg, 525 - 575 mg, 550 - 600 mg, 575 - 625 mg, 600 - 650 mg, 625 - 675 mg, 675 - 725 mg, 700 - 750 mg, 725 - 800 mg, or 775 - 825 mg of the liver-selective GK activator. In other embodiments, the liver-selective GK activator is administered in one or more doses in an amount ranging from 100 mg / day to 2000 mg / day, or 200 mg / day to 1500 mg / day, or 400 mg / day to 1200 mg / day, or 500 mg / day to 1200 mg / day, or 800 mg / day to 1200 mg / day.

[0128] The duration of the methods disclosed herein can be carried out for any suitable period of time depending on the treatment objective. Since type 1 diabetes and its related diseases are chronic conditions, in some embodiments, the administration can be carried out indefinitely, such as for several years or longer. In some embodiments, the administration includes administering the liver-selective GK activator for a period of at least one week, or at least two weeks, or at least three weeks, or at least six weeks, or at least 9 weeks, or at least 12 weeks.

[0129] Administration of insulin or its analogs can be carried out using any suitable method. For example, in some embodiments, insulin or its analogs are co-administered with continuous glucose monitoring such that insulin or its analogs are administered as needed based on glucose levels.

[0130] Other antidiabetic drugs

[0131] In some embodiments of any of the foregoing aspects and embodiments, the liver-selective GK activator and insulin or its analogs can also be co-administered with one or more other antidiabetic drugs. As used herein, the term "co-administered" does not necessarily mean that the antidiabetic drug is administered on the same schedule as the liver-selective GK activator or insulin or its analogs. After all, in some cases, these drugs may be administered once a day or once a week. Thus, as used herein, the term "co-administered" means that the drugs are administered in such a way that at the time of administration of the liver-selective GK activator, one or more other antidiabetic drugs have a non-zero concentration in the subject's blood. In some embodiments, the liver-selective GK activator and one or more antidiabetic drugs are formulated into the same dosage form, such as a tablet or capsule for oral administration. In other embodiments, they are formulated separately and administered in a manner suitable for the respective dosage forms.

[0132] Any suitable anti - diabetic drug can be used. For example, in some embodiments, the one or more anti - diabetic drugs are selected from: biguanides (including metformin, phenformin, and butformin), thiazolidinediones (including rosiglitazone, pioglitazone, and troglitazone), sulfonylureas (including tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, gliquidone, and glipizide), meglitinides (including repaglinide and nateglinide), α - glucosidase inhibitors (including miglitol, acarbose, and voglibose), glucagon - like peptide analogs and agonists (including exenatide, liraglutide, semaglutide, taspoglutide, lixisenatide, albiglutide, and dulaglutide), gastric inhibitory peptide analogs, dipeptidyl peptidase - 4 (DPP - 4) inhibitors (including vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin, teneligliptin, and gemigliptin), amylin agonist analogs, sodium / glucose cotransporter inhibitors (such as dual SGLT1 and SGLT2 inhibitors or selective SGLT2 inhibitors), and glucagon - like peptide (GLP) analogs and agonists. In some such embodiments, the one or more anti - diabetic drugs are metformin. In another such embodiment, the one or more anti - diabetic drugs are sodium / glucose cotransporter inhibitors such as sotagliflozin, empagliflozin, dapagliflozin, canagliflozin, or ertugliflozin.

[0133] In embodiments where metformin is co - administered in combination with the liver - selective GK activator, the co - administration includes orally co - administering 1 to 30 mg / kg of metformin per day to a subject or co - administering 1 mg to 2,500 mg of metformin per day to a subject. The co - administration can be carried out at any suitable dose. In some embodiments, the co - administration includes co - administering metformin once or more times a day, such as once a day, twice a day, three times a day, four times a day, etc. In some embodiments, the co - administration includes co - administering metformin twice a day. In some other embodiments, the co - administration includes co - administering metformin twice a day with food. In some embodiments, two or more daily doses contain equal amounts of metformin. In some other embodiments of any of the above aspects and embodiments, co - administering metformin includes administering 1 to 25 mg / kg of metformin per day to a subject in need. In some other such embodiments, co - administering metformin includes co - administering 100 to 2000 mg of metformin per day to a human subject in need.

[0134] In some other such embodiments of co - administration of an SGLT inhibitor and a liver - selective GK activator, the co - administration comprises orally administering the SGLT inhibitor at a daily dose that is equal to or lower than the daily dose of the SGLT inhibitor provided in the relevant product label.

[0135] Use for reducing glycated hemoglobin

[0136] The above - mentioned methods are described as general methods. In some embodiments of any of the above - mentioned aspects and embodiments, the method is a method for reducing the glycated hemoglobin level in a subject. In some other such embodiments, reducing the glycated hemoglobin level comprises reducing the HbA1c level in a subject. For example, in some embodiments, reducing the glycated hemoglobin level comprises reducing the HbA1c level in a subject by an absolute amount of at least 0.1%, at least 0.3%, or an absolute amount of at least 0.5%, or an absolute amount of at least 0.7%, or an absolute amount of at least 0.9%, or an absolute amount of at least 1.0%, where the HbA1c level is measured as a percentage according to the National Glycohemoglobin Standardization Program (NGSP) protocol.

[0137] In some other embodiments of any of the above - mentioned aspects and embodiments, the present invention provides the use of a combination of a liver - selective GK activator and insulin or an analogue thereof for reducing an elevated glycated hemoglobin level in a subject according to any of the above - mentioned embodiments. In some other embodiments of any of the above - mentioned aspects and embodiments, the present invention provides the use of a liver - selective GK activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce an elevated glycated hemoglobin level in a subject, wherein the medicament is prepared for administration to the subject according to any of the above - mentioned methods.

[0138] In other embodiments herein, measures for improving glycemic control can be achieved without reducing the HbA1c level or even while increasing the HbA1c level.

[0139] Use for treating diabetes

[0140] The above - mentioned methods are described as general methods. In some embodiments of any of the above - mentioned aspects and embodiments, the method is a method for treating type 1 diabetes. In other embodiments of any of the above - mentioned aspects and embodiments, the method is a method for treating type 2 diabetes in a subject who uses insulin to regulate blood glucose levels with or without another antidiabetic drug.

[0141] In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in combination with insulin or an analogue thereof for the treatment of type 1 diabetes. In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in the preparation of a medicament for use in combination with insulin or an analogue thereof for the treatment of type 1 diabetes, wherein the medicament is prepared for administration to a subject according to any of the above methods.

[0142] In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in combination with insulin or an analogue thereof for the treatment of type 2 diabetes in a subject who also uses insulin, with or without another antidiabetic drug, to regulate blood glucose levels according to any of the above embodiments. In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in the preparation of a medicament for use in combination with insulin or an analogue thereof for the treatment of type 2 diabetes in a subject who also uses insulin, with or without another antidiabetic drug, to regulate blood glucose levels, wherein the medicament is prepared for administration to a subject according to any of the above methods.

[0143] Use for reducing body weight

[0144] The above methods are described as general methods. In some embodiments of any of the above aspects and embodiments, the method is a method for reducing body weight. In some other such embodiments, the method comprises reducing the body mass index (BMI) of a subject having an elevated BMI level by an absolute amount of at least 0.5, or at least 1.0, or at least 1.5, or at least 2.0. In other embodiments, the body weight of the subject may be reduced by at least 0.1, or 0.2, or 0.3, or 0.4, or 0.5, or 0.6, or 0.7, or 0.8, or 0.9, or 1.0, or 1.5, or 2.0 kg. In another embodiment, the reduction in the subject's BMI or body weight is for a period of 1, 2, 3, 4, 5, 6, 7 or 8 weeks, or 3, 4, 5 or 6 months.

[0145] In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in combination with insulin or an analogue thereof for reducing body weight. In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in the preparation of a medicament for use in combination with insulin or an analogue thereof for reducing body weight, wherein the medicament is prepared for administration to a subject according to any of the above methods.

[0146] Use for improving blood glucose control

[0147] The above method is described as a general method. In some embodiments of any of the above aspects and embodiments, the method is a method for improving blood glucose control.

[0148] In some embodiments, the method is a method for increasing the percentage of time within a target blood glucose range, i.e., for a human, in the range of 70 mg / dL to 180 mg / dL per unit time. In some such embodiments, the method comprises increasing the percentage of time within the target blood glucose range by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, or at least 8%, or at least 10%, or at least 12%, or at least 14% in absolute percentage, based on the absolute difference in the percentage of time within the target blood glucose range over a period of time, relative to a baseline (such as administering only insulin or its analog).

[0149] In other embodiments, the method is a method for increasing the percentage of time within the blood glucose range of 80 - 130 mg / dL (pre-meal range) between meals (e.g., 2 hours after the previous meal and immediately before the next meal). In other embodiments, the method is a method for increasing the percentage of time when the blood glucose level is less than or equal to 180 mg / dL at the start and end of 2 hours after a meal. The percentage increase in time in these methods can be at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, or at least 8%, or at least 10%, or at least 12%, or at least 14% in absolute percentage, based on the percentage difference in time within the target blood glucose range, relative to a baseline (such as administering only insulin or its analog).

[0150] In some embodiments, the method is a method for reducing the percentage of time within a hypoglycemic range or a severe hypoglycemic range. In some such embodiments, the method comprises reducing the percentage of time within the hypoglycemic range or the severe hypoglycemic range by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, or at least 8%, or at least 10%, or at least 12%, or at least 14% in absolute percentage, based on the absolute difference in the percentage of time within the target blood glucose range over a period of time, relative to a baseline (such as administering only insulin or its analog).

[0151] In some embodiments, the method is a method of reducing the percentage of time in a hyperglycemic range or a severely hyperglycemic range. In some such embodiments, the method comprises reducing the percentage of time in a hyperglycemic range or a severely hyperglycemic range by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, or at least 8%, or at least 10%, or at least 12%, or at least 14% absolute percentage, based on the absolute difference in the percentage of time in a target blood glucose range, relative to a baseline (such as administration of insulin or its analogs alone).

[0152] In some embodiments, the method is a method of reducing the number of hypoglycemic events or severe hypoglycemic events over a period of time. In some such embodiments in which the subject uses a CGM, the method comprises reducing the number of hypoglycemic events or severe hypoglycemic events over a period of time by at least 1 event or 2 events in absolute amount. In other such embodiments in which the subject uses SMBG, the method comprises reducing the number of hypoglycemic events or severe hypoglycemic events over a period of time by at least 1 event, 2 events, 10 events, 20 events, 30 events, 50 events, 70 events in absolute amount. In some embodiments, the period of time can be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days.

[0153] In other embodiments, the method comprises the number of hyperglycemic events or severe hyperglycemic events over a period of time. In some such embodiments in which the subject uses a CGM, the method comprises reducing the number of hyperglycemic events or severe hyperglycemic events over a period of time by at least 1 event or 2 events in absolute amount. In other such embodiments in which the subject uses SMBG, the method comprises reducing the number of hyperglycemic events or severe hyperglycemic events over a period of time by at least 1 event, 2 events, 10 events, 20 events, 30 events, 50 events, 70 events in absolute amount. In some embodiments, the period of time is 1 day, or 2 days, 3 days, 4 days, 5 days, 6 days or 7 days.

[0154] In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in combination with insulin or an analogue thereof for increasing the percentage of time within the target blood glucose range, reducing the percentage of time within the hypoglycemic range, reducing the percentage of time within the hyperglycemic range, reducing the time within the severe hypoglycemic range, reducing the number of hyperglycemic events, or reducing the number of severe hypoglycemic events, according to any of the above embodiments. In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to increase the percentage of time within the target blood glucose range, reduce the percentage of time within the hypoglycemic range, reduce the percentage of time within the hyperglycemic range, reduce the time within the severe hypoglycemic range, reduce the number of hyperglycemic events, or reduce the number of severe hypoglycemic events, wherein the medicament is prepared for administration to a subject according to any of the above methods.

[0155] Use for reducing insulin dose

[0156] The above method is described as a general method. In some embodiments of any of the above aspects and embodiments, the method is a method for reducing the dose of insulin (or an analogue thereof) in a subject, for example, on a per-dose basis, a daily basis, a weekly basis, or other time periods. In some other such embodiments, the method comprises reducing the insulin (or an analogue thereof) dose by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, or at least 25%, or the absolute amount of reduction is at least 1 unit, 2 units, 3 units, 4 units, 5 units, 6 units, 7 units, 8 units, 9 units, or 10 units, based on the baseline insulin (or an analogue thereof) dose (such as when treated with insulin or an analogue thereof alone).

[0157] Use for reducing the total daily rapid-acting insulin dose

[0158] In some embodiments, the method is a method for reducing the total daily rapid-acting insulin dose. In some such embodiments, the method comprises reducing the total daily rapid-acting insulin (or an analogue thereof) dose by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, or at least 25%, or the absolute amount of reduction is at least 1 unit, 2 units, 3 units, 4 units, 5 units, 6 units, 7 units, 8 units, 9 units, or 10 units, based on the baseline total daily rapid-acting insulin (or an analogue thereof) dose (such as when treated with insulin or an analogue thereof alone).

[0159] Use for reducing the total daily basal insulin dose

[0160] In some embodiments, the method is a method of reducing the total daily basal insulin dose. In some such embodiments, the method comprises reducing the total daily basal insulin (or an analogue thereof) dose by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, or at least 25%, or by an absolute amount of at least 1 unit, 2 units, 3 units, 4 units, 5 units, 6 units, 7 units, 8 units, 9 units, or 10 units, based on the baseline total daily basal insulin (or an analogue thereof) dose (such as when treated with insulin or an analogue thereof alone).

[0161] Use for reducing the total daily insulin dose

[0162] In some embodiments, the method is a method of reducing the total daily insulin dose. In some such embodiments, the method comprises reducing the total daily insulin (or an analogue thereof) dose by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, or at least 25%, or by an absolute amount of at least 1 unit, 2 units, 3 units, 4 units, 5 units, 6 units, 7 units, 8 units, 9 units, or 10 units, based on the baseline total daily insulin (or an analogue thereof) dose (such as when treated with insulin or an analogue thereof alone).

[0163] Use for reducing the number or dose of insulin injections

[0164] In some embodiments, the method is a method of reducing the number of insulin injections over a period of time, where the period of time can be 1 day, 1 week, or 1 month. In some embodiments, the total number of insulin injections can be reduced by 1, 2, 3, or more. In other embodiments, the method is a method of reducing the number of daily basal insulin injections, where the number of injections can be reduced by 1, 2, 3, or more. In other embodiments, the method is a method of reducing the number of daily rapid insulin bolus injections, where the number of injections can be reduced by 1, 2, 3, or more. In another embodiment, the number of daily insulin injections does not exceed 1 or 2 or 3.

[0165] In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in combination with insulin or an analogue thereof according to any of the above embodiments for reducing insulin dose or injection. In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce insulin dose or injection, wherein the medicament is prepared for administration to a subject according to any of the above methods.

[0166] Use for reducing daily average blood glucose

[0167] The above method is described as a general method. In some embodiments of any of the above aspects and embodiments, the method is a method for reducing the daily average blood glucose level. In some other such embodiments, the method comprises reducing the daily average blood glucose level by at least 5 mg / dL, or at least 7 mg / dL, or at least 10 mg / dL, or at least 15 mg / dL, or at least 20 mg / dL, or at least 25 mg / dL, or at least 30 mg / dL, or at least 35 mg / dL, relative to baseline treatment (such as using only insulin or its analog).

[0168] In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in combination with insulin or its analog according to any of the above embodiments for reducing the daily average blood glucose level. In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in the preparation of a medicament for use in combination with insulin or its analog for reducing the daily average blood glucose level, wherein the medicament is prepared for administration to a subject according to any of the above methods.

[0169] Use for reducing glucagon level

[0170] Glucagon is a polypeptide hormone produced by the alpha cells of the pancreas. It is a hyperglycemic agent that mobilizes glucose by activating hepatic glycogenolysis (glycogen is especially broken down into glucose). However, an overly high glucagon level may cause temporary changes in blood pressure, increased heart rate, nausea, vomiting, and / or hyperglycemia, and certain antidiabetic drugs (such as SGLT2 inhibitors) may cause excessive glucagon secretion.

[0171] The above method is described as a general method. In some embodiments of any of the above aspects and embodiments, the method is a method for reducing the plasma glucagon level and / or not increasing the plasma glucagon level. In some other such embodiments, the method comprises reducing the glucagon level by at least 5 pg / mL, or at least 10 pg / mL, or at least 25 pg / mL, or at least 30 pg / mL, or at least 35 pg / mL, or at least 50 pg / mL, or at least 75 pg / mL, relative to baseline treatment (such as using only insulin or its analog), or reducing the glucagon level to below 200 pg / mL, or below 150 pg / mL, or below 100 pg / mL.

[0172] In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in combination with insulin or an analogue thereof for reducing plasma glucagon levels. In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in the preparation of a medicament for use in combination with insulin or an analogue thereof for reducing plasma glucagon levels, wherein the medicament is prepared for administration to a subject according to any of the above methods.

[0173] Use for reducing the incidence, duration or likelihood of diabetic ketoacidosis

[0174] The above method is described as a general method. In some embodiments of any of the above aspects and embodiments, the method is a method for reducing the incidence, duration or likelihood of diabetic ketoacidosis. In one embodiment, diabetic ketoacidosis is defined as a subject having elevated levels of one or more metabolic ketones such as serum or urinary ketones (greater than the upper limit of the normal range), and having a blood pH of 7.3 or lower and a serum bicarbonate level of 18 mmol / L or lower. In another embodiment, diabetic ketoacidosis is defined as a subject having elevated plasma, serum or urinary ketones (greater than the upper limit of the normal range) or a blood pH less than 7.3 or a serum bicarbonate level of 18 mmol / L or lower, or 15 mmol / L or lower or equivalent mEq / L measure, or a blood glucose level greater than 250 mg / dL, or any combination of the above measures. In one embodiment, the metabolic ketones are selected from acetoacetic acid (AcAc), β-hydroxybutyric acid (BHB) and acetone. In another embodiment, the level of AcAc is measured in the serum of the subject. In another embodiment, the level of BHB is measured in the urine of the subject. In another embodiment, the level of BHB is measured in the blood of the subject. In another embodiment, the level of one or more metabolic ketones is 0.3 to 0.5 mM, or greater than 0.5 mM, or 0.5 to 1.0 mM, or 1.0 to 3.0 mM, or greater than 3.0 mM, or 4.0 mM, or 5.0 mM, 10 mM, or 15 mM, or 20 mM. In some other such embodiments, the method comprises reducing the incidence of diabetic ketoacidosis by at least 5%, or at least 10%, or at least 15% over a relevant time period (such as 1 week, one month, two months, three months, etc.) relative to baseline treatment (such as using only insulin or an analogue thereof).

[0175] In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in combination with insulin or an analogue thereof in reducing the incidence, duration or likelihood of diabetic ketoacidosis. In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the incidence, duration or likelihood of diabetic ketoacidosis, wherein the medicament is prepared for administration to a subject according to any of the above methods.

[0176] Use in reducing the incidence, duration or likelihood of diabetic ketosis

[0177] The above method is described as a general method. In some embodiments of any of the above aspects and embodiments, the method is a method for reducing the incidence, duration, or likelihood of diabetic ketoacidosis. In one embodiment, diabetic ketoacidosis is defined as a subject having elevated metabolic ketones, such as serum or urinary ketones (greater than the upper limit of the normal range), and blood glucose and / or blood pH within the normal range. For example, diabetic ketoacidosis may occur when the subject's blood pH is equal to or higher than 7.3 and / or the serum bicarbonate level is greater than 15 mmol / L, 18 mmol / L, or 20 mmol / L. In other embodiments, the subject's blood glucose level is less than 250 mg / dL or less than 200 mg / dL, or less than 180 mg / dL. In one embodiment, the metabolic ketones indicative of the incidence of diabetic ketoacidosis are selected from acetoacetic acid (AcAc), β-hydroxybutyric acid (BHB), and acetone. In another embodiment, the level of AcAc is measured in the subject's blood or urine. In another embodiment, the level of BHB is measured in a sample collected from the subject's blood or urine. In another embodiment, the level of acetone is measured in the subject's breath sample. In another embodiment, the level of one or more metabolic ketones indicative of diabetic ketoacidosis is 0.3 to 0.5 mM, or greater than 0.5 mM, or 0.5 to 1.0 mM, or 1.0 to 3.0 mM, or 3.0 mM to 6.0 mM, or 6.0 mM to 10 mM, or greater than 5 mM or 10 mM or 15 mM or 20 mM or 25 mM. In some other such embodiments, the method comprises reducing the incidence of diabetic ketoacidosis by at least 5%, or at least 10%, or at least 15% over a relevant time period (such as 1 week, one month, two months, three months, etc.) relative to baseline treatment (such as using only insulin or its analogs). In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in combination with insulin or its analogs according to any of the above embodiments in reducing the incidence, duration, or likelihood of diabetic ketoacidosis. In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in the preparation of a medicament for use in combination with insulin or its analogs to reduce the incidence, duration, or likelihood of diabetic ketoacidosis, wherein the medicament is prepared for administration to a subject according to any of the above methods.

[0178] Use for reducing metabolic ketones

[0179] The above method is described as a general method. In some embodiments of any of the above aspects and embodiments, the method is a method for reducing the level of metabolic ketones in a subject. In one embodiment, the reduced metabolic ketones are selected from acetoacetate (AcAc), β-hydroxybutyrate (BHB), and acetone. In another embodiment, the level of AcAc is reduced. In another embodiment, the level of BHB is reduced. In another embodiment, the level of one or more metabolic ketones is reduced by at least 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, or 0.9 mM, or by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, or 50%, relative to a baseline measurement, such as before treatment. In another embodiment, the level of BHB is reduced by at least 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, or 0.9 mM, or by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, or 50%, relative to a baseline measurement, such as before treatment. In another embodiment, the level of AcAc is reduced by at least 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, or 0.9 mM, or by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, or 50%, relative to a baseline measurement, such as before treatment. In another embodiment, the level of acetone is reduced by at least 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, or 0.9 mM, or by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, or 50%, relative to a baseline measurement, such as before treatment. In some other such embodiments, the method comprises reducing the level of one or more metabolic ketones over a relevant period of time (such as 1 week, one month, two months, three months, etc.), relative to baseline treatment (such as using only insulin or an analogue thereof).

[0180] In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in combination with insulin or an analogue thereof according to any of the above embodiments for reducing the level of metabolic ketones. In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in the preparation of a medicament for use in combination with insulin or an analogue thereof to reduce the level of metabolic ketones, wherein the medicament is prepared for administration to a subject according to any of the above methods.

[0181] Use for reducing the incidence, duration or likelihood of diabetic lactic acidosis

[0182] The above method is described as a general method. In some embodiments of any of the above aspects and embodiments, the method is a method for reducing the incidence, duration or likelihood of diabetic lactic acidosis. In one embodiment, diabetic lactic acidosis is defined as a subject having an elevated lactate level such as greater than 1.0 mM, 1.5 mM, 2.0 mM, 2.5 mM, 3.0 mM, 3.5 mM, 4.0 mM, 4.5 mM, 5.0 mM, 10 mM, or 15 mM. In another embodiment, diabetic lactic acidosis is defined as a subject having an elevated arterial blood lactate concentration (e.g., higher than 14.4 mg / dL or 1.6 mM) or venous blood lactate concentration (e.g., higher than 19.8 mg / dL or 2.2 mM), or an equivalent capillary blood lactate concentration. In some other such embodiments, the method comprises reducing the incidence of diabetic lactic acidosis by at least 5%, or at least 10%, or at least 15% relative to baseline treatment (such as using only insulin or its analogs) over a relevant time period, such as one week, one month, two months, three months, etc.

[0183] In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in combination with insulin or its analogs according to any of the above embodiments in reducing the incidence, duration or likelihood of diabetic lactic acidosis. In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in the preparation of a medicament for use in combination with insulin or its analogs to reduce the incidence, duration or likelihood of diabetic lactic acidosis, wherein the medicament is prepared for administration to a subject according to any of the above methods.

[0184] Use for reducing lactate

[0185] The above method is described as a general method. In some embodiments of any of the above aspects and embodiments, the method is a method for reducing lactate levels in a subject. In one embodiment, the lactate level is reduced by at least 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.5 mM, 2.0 mM, or reduced by at least 1 mg / dL, or 2 mg / dL, or 3 mg / dL, or 4 mg / dL or 5 mg / dL or 10 mg / dL, or reduced to below 3.0 mM, or reduced to below 2.5 mM, or reduced to below 2.0 mM, or reduced to below 1.5 mM, or reduced to below 1.0 mM, or reduced by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, or 50%, relative to a baseline measurement, such as before treatment. In another embodiment, the lactate level is measured in arterial blood. In another embodiment, the lactate level is measured in venous blood. In some other such embodiments, the method comprises reducing the lactate level over a relevant period of time, such as one week, one month, two months, three months, etc., relative to baseline treatment (such as using only insulin or its analogue).

[0186] In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in combination with insulin or its analogue according to any of the above embodiments for reducing lactate levels. In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a liver-selective GK activator in the preparation of a medicament for use in combination with insulin or its analogue for reducing lactate levels, wherein the medicament is prepared for administration to a subject according to any of the above methods.

[0187] Test

[0188] The treatment methods disclosed herein may include the step of measuring one or more biomarkers before, during, and / or after certain periods of treatment. In one embodiment, the method may further comprise obtaining or having obtained one or more biological samples from a subject over a period of time, and performing or having performed a body fluid test on the biological sample. The body fluid test can be used to determine the percentage of time within a target blood glucose range, the level of glycated hemoglobin, the percentage of time within a hypoglycemic range, the percentage of time within a hyperglycemic range, the incidence or number of occurrences of diabetic ketoacidosis, the incidence or number of occurrences of diabetic ketosis, the number of hypoglycemic or severe hypoglycemic events over a period of time, the number of hyperglycemic or severe hyperglycemic events over a period of time.

[0189] The biological sample or body fluid to be tested may include fluids produced by the human body, such as saliva or parts thereof, mucus secretions, tears, sweat, bile, semen, urine, vaginal secretions, exhaled breath, anal secretions, blood, plasma, serum, and mixtures thereof. In one embodiment, the biological sample or body fluid may be saliva, mucus secretion, tears, sweat, urine, exhaled breath, blood, or serum.

[0190] Biomarkers that can be measured in the biological sample or body fluid include glucose, metabolic ketones, glucagon, glycated hemoglobin, lactate, and pH. In some embodiments, the method may include measuring the blood glucose level, serum pH level or serum bicarbonate level of a subject, one or more metabolic ketones in the subject's blood, breath or urine, measuring the glucagon hormone level in the subject's blood, the lactate level in the subject's blood, and / or measuring the level of glycated hemoglobin in the subject's blood, such as the HbA1c level in the subject's blood.

[0191] Biomarkers can be measured by any method known in the art. For example, glucose can be measured by using a continuous glucose monitoring device or a glucose test strip. Blood pH can be measured by pH test paper, a calibrated pH meter. Glucagon can be measured by radioimmunoassay or ELISA assay. Urinary ketone concentration can be measured using an over-the-counter reagent strip that determines the presence of AcAc after reacting with nitroprusside. Blood ketone concentration can be measured using an electrochemical capillary blood monitor and a corresponding individually foil-packaged BHB test strip. Glycated hemoglobin can be assayed using high performance liquid chromatography, immunoassay, enzymatic assay, capillary electrophoresis, or boronate affinity chromatography. Lactate can be measured using a blood gas analyzer. Lactate can be measured by a portable / point-of-care analyzer (such as those using an enzymatic (lactate oxidase) amperometric detection method), or by a device using an amperometric metabolite sensor or an ion-selective electrode.

[0192] In another embodiment, the method may include the step of selecting a subject for treatment. In some embodiments, it is determined whether a subject is at risk of developing diabetic ketoacidosis by measuring the subject's blood glucose, blood pH, serum pH, serum bicarbonate, and / or the level of one or more metabolic ketones, and thus the subject is selected for treatment. If it is determined that the subject has diabetic ketoacidosis, for example, by an increase in the level of one or more metabolic ketones without an abnormal blood glucose level and / or a blood pH below 7.3, then the subject may be at risk of developing diabetic ketoacidosis. In an embodiment, if it is determined that the subject is at risk of developing diabetic ketoacidosis, the method further includes administering to the subject a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0193] In other embodiments, a subject may be selected for treatment when the subject is in need of a therapeutically reduced level of metabolic ketones, a therapeutically reduced level of glucagon, a therapeutically reduced level of lactate, a therapeutically reduced level of blood glucose, a therapeutically reduced level of HbA1c, or a therapeutically increased level of plasma pH. Thus, the method may first comprise determining whether a subject is in need of a therapeutically reduced level of metabolic ketones, a therapeutically reduced level of glucagon, a therapeutically reduced level of lactate, a therapeutically reduced level of blood glucose, a therapeutically reduced level of HbA1c, or a therapeutically increased level of plasma pH. In one embodiment, the subject is identified for treatment after obtaining or having obtained a biological sample from the subject and having performed or having had performed a body fluid test on the biological sample to determine whether the level of one or more biomarkers is associated with a need for therapeutic modulation of its level.

[0194] In other embodiments, a subject may be selected for treatment when a combination of clinical symptoms, clinical events, and / or biomarker levels is identified. For example, if a subject has more than 1, 2, 3, 4, or 5 hyperglycemic events, severe hyperglycemic events, hypoglycemic events, or severe hypoglycemic events over a period of time, the subject may be selected for treatment. If a subject has elevated levels of one or more metabolic ketones, has euglycemic ketoacidosis, has a blood pH equal to or less than 7.3, has an HbA1c higher than 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, or 9.0%, has elevated levels of lactate such as higher than 1.0 mM, or 2.0 mM, or 3.0 mM, or 4.0 mM and / or has a glucagon level higher than 100 pg / mL, 130 pg / mL, 150 pg / mL, or 200 pg / mL or any combination thereof, the subject may also be selected for treatment. In any of the foregoing methods, the method may further comprise obtaining or having obtained a biological sample from the subject over a period of time and having performed or having had performed a body fluid test on the biological sample to determine whether the level of one or more biochemical markers is increasing or decreasing, and if the level of one or more biochemical markers is not trending in the desired direction, administering a greater dose of the liver-selective glucokinase activator.

[0195] Dosage forms of pharmaceutical compositions

[0196] The liver-selective GK activator can be formulated into any suitable pharmaceutical composition. As used herein, the term "pharmaceutical composition" refers to a composition (e.g., a granular powder or a liquid) that contains a pharmaceutically active ingredient (e.g., a liver-selective GK activator) and a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable" refers to a substance that is not biologically undesirable, generally at the dosage administered.

[0197] The single-dose formulation of the liver-selective GK activator may comprise 1-75 mg, 75-100 mg, 75-150 mg, 100-150 mg, 125-175 mg, 150-200 mg, 175-225 mg, 200-250 mg, 225-275 mg, 250-300 mg, 275-325 mg, 300-350 mg, 325-375 mg, 350-400 mg, 375-425 mg, 400-450 mg, 425-475 mg, 450-500 mg, 475-525 mg, 500-550 mg, 525-575 mg, 550-600 mg, 575-625 mg, 600-650 mg, 625-675 mg, 675-725 mg, 700-750 mg, 725-800 mg, or 775-825 mg of a liver-selective GK activator.

[0198] In some embodiments, the liver-selective GK activator is included in a pharmaceutical composition separate from any co-administered anti-diabetic drug (e.g., metformin or an SGLT2 inhibitor), wherein each pharmaceutical composition further comprises a pharmaceutically acceptable carrier. In other embodiments, the liver-selective GK activator and one or more co-administered anti-diabetic drugs (e.g., metformin or an SGLT2 inhibitor) are included in the same pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier.

[0199] The pharmaceutical compositions described herein can be packaged in a form suitable for oral administration as discrete units (i.e., dosage forms), such as capsules, tablets, sachets, etc. Preparing solid compositions in oral form is within the ability of those skilled in the art, including selecting other pharmaceutically acceptable ingredients from the groups listed above to provide a medicinally useful and palatable formulation. Such pharmaceutical compositions can be prepared by methods known in the art of pharmaceutical formulation, e.g., see Remington's Pharmaceutical Sciences, 18th Edition, (Mack Publishing Company, Easton, Pa., 1990).

[0200] The present invention provides, but is not limited to, the following embodiments:

[0201] 1. A method for treating type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0202] 2. A method for increasing the percentage of time within a target blood glucose range in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0203] 3. The method according to Embodiment 2, wherein the target blood glucose range is from 70 mg / dL to 180 mg / dL.

[0204] 4. The method according to Embodiment 2 or 3, wherein the method comprises increasing the percentage of time within the target blood glucose range by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, or at least 8%, or at least 10%, or at least 12%, or at least 14% of the absolute percentage, based on the absolute difference in the percentage of time within the target blood glucose range over a period of time.

[0205] 5. A method for reducing the total daily rapid bolus insulin dose in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0206] 6. The method according to Embodiment 5, wherein the total daily rapid bolus insulin dose is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, or at least 25%, or the absolute amount of reduction is at least 1 unit, 2 units, 3 units, 4 units, 5 units, 6 units, 7 units, 8 units, 9 units, or 10 units, relative to the baseline total daily rapid bolus insulin (or analogue thereof) dose.

[0207] 7. A method for reducing the daily average blood glucose in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0208] 8. The method according to Embodiment 7, wherein the method comprises reducing the daily average blood glucose in the subject by at least 5 mg / dL, or at least 10 mg / dL, or at least 15 mg / dL, based on the daily average blood glucose.

[0209] 9. A method for reducing the glycated hemoglobin level in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0210] 10. The method according to Embodiment 9, wherein the glycated hemoglobin is HbA1c, and wherein the method comprises reducing the absolute amount of the HbA1c level in the subject by at least 0.1%, at least 0.3%, at least 0.5%, at least 0.7%, at least 0.9%, or at least 1.0%, wherein the HbA1c level is measured as a percentage according to the National Glycohemoglobin Standardization Program (NGSP) protocol.

[0211] 11. A method for reducing the percentage of time in the hypoglycemic range in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0212] 12. The method according to embodiment 11, wherein the absolute percentage reduction in the amount of time in the hypoglycemic range relative to baseline is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, or at least 8%, or at least 10%, or at least 12%, or at least 14%, based on the absolute difference in the percentage of time in the target blood glucose range over a period of time.

[0213] 13. A method for reducing the percentage of time in the hyperglycemic range in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0214] 14. The method according to embodiment 13, wherein the absolute percentage reduction in the amount of time in the hyperglycemic range relative to baseline is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, or at least 8%, or at least 10%, or at least 12%, or at least 14%, based on the absolute difference in the percentage of time in the target blood glucose range over a period of time.

[0215] 15. A method for reducing the incidence of diabetic ketoacidosis in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0216] 16. The method according to embodiment 15, wherein the method comprises reducing the incidence of diabetic ketoacidosis by at least 5%, or at least 10%, or at least 15% relative to baseline.

[0217] 17. A method for reducing body weight in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0218] 18. The method according to embodiment 17, wherein the method comprises reducing the body mass index of a subject with an elevated body mass index (BMI) by at least 0.5, or at least 1.0, or at least 1.5, or at least 2.0.

[0219] 19. The method according to embodiment 17, wherein the method comprises reducing the weight of the subject by at least 0.1, or 0.2, or 0.3, or 0.4, or 0.5, or 0.6, or 0.7, or 0.8, or 0.9, or 1.0, or 1.5, or 2.0 kg.

[0220] 20. A method for reducing the total daily basal insulin dose in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0221] 21. The method according to embodiment 20, wherein the total daily basal insulin dose is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, or at least 25%, or the absolute amount of reduction is at least 1 unit, 2 units, 3 units, 4 units, 5 units, 6 units, 7 units, 8 units, 9 units, or 10 units, relative to the baseline total daily basal insulin (or its analogue) dose.

[0222] 22. A method for reducing the total daily insulin dose in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0223] 23. The method according to embodiment 22, wherein the total daily insulin dose is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, or at least 25%, or the absolute amount of reduction is at least 1 unit, 2 units, 3 units, 4 units, 5 units, 6 units, 7 units, 8 units, 9 units, or 10 units, relative to the baseline total daily insulin (or its analogue) dose.

[0224] 24. A method for reducing the total number of daily insulin injections in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0225] 25. The method according to embodiment 24, wherein the number of daily basal insulin injections is reduced.

[0226] 26. The method according to embodiment 24, wherein the number of rapid insulin boluses is reduced.

[0227] 27. The method according to embodiment 24, wherein the number of rapid insulin boluses and basal injections is reduced.

[0228] 28. The method according to any one of embodiments 24-27, wherein the number of injections is reduced by 1, 2, or 3 relative to the baseline.

[0229] 29. A method for reducing the daily rapid insulin bolus dose at each meal in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0230] The method according to embodiment 29, wherein the daily rapid bolus insulin dose at each meal is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, or at least 25%, or the absolute amount of reduction is at least 1 unit, 2 units, 3 units, 4 units, 5 units, 6 units, 7 units, 8 units, 9 units, or 10 units, relative to the baseline total daily rapid bolus insulin (or its analogue) dose at each meal.

[0231] 31. A method for reducing the number of hypoglycemic events or severe hypoglycemic events in a subject with type 1 diabetes over a period of time, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0232] 32. The method according to embodiment 31, wherein the subject uses continuous glucose monitoring and the number of hypoglycemic events or severe hypoglycemic events is reduced relative to the baseline over a period of time.

[0233] 33. The method according to embodiment 32, wherein the absolute amount by which the number of hypoglycemic events or severe hypoglycemic events is reduced over the period of time is at least 1 event or 2 events.

[0234] 34. The method according to embodiment 31, wherein the subject uses self-monitoring of blood glucose and the number of hypoglycemic events or severe hypoglycemic events is reduced relative to the baseline over a period of time.

[0235] 35. The method according to embodiment 34, wherein the absolute amount by which the number of hypoglycemic events or severe hypoglycemic events is reduced over the period of time is at least 1 event, 2 events, 10 events, 20 events, 30 events, 50 events, or 70 events.

[0236] 36. The method according to any one of embodiments 31-35, wherein the period of time is 1 day, or 2 days, 3 days, 4 days, 5 days, 6 days or 7 days.

[0237] 37. A method for reducing or not increasing plasma glucagon levels in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0238] 38. The method according to embodiment 37, wherein the glucagon level is reduced by at least 5 pg / mL or reduced to less than 200 pg / mL.

[0239] 39. A method for reducing the incidence, duration, or likelihood of diabetic ketoacidosis in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0240] 40. The method according to embodiment 39, wherein the method comprises reducing the incidence of diabetic ketoacidosis by at least 5%, or at least 10%, or at least 15% relative to a baseline.

[0241] 41. A method for reducing one or more metabolic ketones in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0242] 42. The method according to embodiment 41, wherein the level of the one or more metabolic ketones is reduced by at least 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, or 0.9 mM, or by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, or 50% as measured relative to a baseline.

[0243] 43. A method for reducing the incidence, duration, or likelihood of diabetic lactic acidosis in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0244] 44. The method according to embodiment 43, wherein the method comprises reducing the incidence of diabetic lactic acidosis by at least 5%, or at least 10%, or at least 15% relative to a baseline.

[0245] 45. A method for reducing lactic acid levels in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

[0246] 46. The method according to embodiment 45, wherein the lactic acid level is reduced by at least 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.5 mM, or 2.0 mM, or reduced by at least 1 mg / dL, or 2 mg / dL, or 3 mg / dL, or 4 mg / dL or 5 mg / dL or 10 mg / dL, or reduced to less than 3.0 mM, or reduced to less than 2.5 mM, or reduced to less than 2.0 mM, or reduced to less than 1.5 mM, or reduced to less than 1.0 mM, or reduced by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, or 50%, relative to the baseline measurement.

[0247] 47. The method of any of the foregoing embodiments, wherein the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid or a pharmaceutically acceptable salt thereof.

[0248] 48. The method according to embodiment 47, wherein the liver-selective glucokinase activator is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid.

[0249] 49. The method according to embodiment 47, wherein the liver-selective glucokinase activator is a pharmaceutically acceptable salt of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid.

[0250] 50. The method of any of the foregoing embodiments, wherein the administration comprises oral administration of the liver-selective glucokinase activator.

[0251] 51. The method of any of the foregoing embodiments, wherein the administration comprises oral, subcutaneous or injection administration of insulin or an analogue thereof.

[0252] 52. The method according to any one of embodiments 1-50, wherein the administration comprises subcutaneous or injection administration of insulin or an analogue thereof.

[0253] 53. The method of any of the foregoing embodiments, wherein the subject is a human.

[0254] 54. The method of any of the foregoing embodiments, wherein the administration comprises administering the liver-selective glucokinase activator once or multiple times a day, such as once a day, twice a day, three times a day, etc.

[0255] The method according to embodiment 54, wherein at least one of the one or more times is with food.

[0256] 56. The method according to embodiment 54, wherein the administration comprises administering the liver-selective glucokinase activator twice a day.

[0257] 57. The method according to embodiment 54, wherein the administration comprises administering the liver-selective glucokinase activator twice a day with food.

[0258] 58. The method according to any one of the foregoing embodiments, wherein the administration comprises administering the liver-selective glucokinase activator for a period of not less than 1 week, or not less than 2 weeks, or not less than 3 weeks, or not less than 6 weeks, or not less than 9 weeks, or not less than 12 weeks.

[0259] 59. The method according to any one of the foregoing embodiments, wherein the insulin or its analogue comprises insulin, insulin lispro, insulin aspart, insulin glulisine, isophane insulin, insulin zinc, insulin glargine, insulin detemir, or any combination thereof.

[0260] 60. The method according to any one of the foregoing embodiments, wherein the insulin is rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, or a combination of any two, three, or four types of insulin.

[0261] 61. The method according to any one of the foregoing embodiments, wherein the administration comprises administering to a subject in need a combination of a liver-selective glucokinase activator and insulin lispro, insulin aspart, insulin glulisine, isophane insulin, insulin zinc, insulin glargine, insulin detemir, or any combination thereof.

[0262] 62. The method according to any one of the foregoing embodiments, wherein the administration further comprises co-administering to a subject in need other anti-diabetic drugs in combination with the liver-selective glucokinase activator and insulin or its analogue.

[0263] 63. The method according to any one of the foregoing embodiments, wherein the method further comprises the step of selecting a subject for treatment.

[0264] 64. The method according to embodiment 63, wherein the step of selecting the subject for treatment comprises the steps of: obtaining or having obtained a biological sample from the subject, and performing or having performed a body fluid test on the biological sample to determine whether the subject has biomarker levels related to the need for therapeutic reduction of metabolic ketone levels, therapeutic reduction of lactate levels, therapeutic reduction of glucagon levels, therapeutic reduction of blood glucose levels, therapeutic reduction of HbA1c levels, or therapeutic elevation of plasma pH levels.

[0265] The method of any of the foregoing embodiments, wherein the method further comprises the steps of

[0266] obtaining or having obtained a biological sample from a subject over a period of time, and

[0267] performing or having performed a body fluid test on the biological sample to determine whether the level of one or more biochemical markers has increased or decreased, and

[0268] administering a greater dose of a liver-selective glucokinase activator or a pharmaceutically acceptable salt thereof if the level of one or more biochemical markers does not progress in the desired direction. Examples

[0269] Example 1 - Research Design

[0270] An open-label, weekly dose-escalation study was conducted with up to 3 dose escalations. Five adult patients with type 1 diabetes mellitus (T1DM) who used a continuous glucose monitoring (CGM) device and received insulin via continuous subcutaneous insulin infusion (CSII) received a daily dose of 400, 800, or 1200 mg of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylthio}-acetic acid (UT-1) once daily for 7 days at each dose level.

[0271] The first 7 days of the study (days -7 to -1) were used to obtain baseline laboratory samples and record the baseline insulin dose and blood glucose levels in the patients' usual insulin, diet, and activity regimens. The once-daily treatment dose of UT-1 was administered at breakfast. Safety labs were collected on days -7, 1, 8, 15, 21, and 28. Insulin pump data and CGM data were collected on days 1, 8, 15, 21, and 28 for each dosing period. The patients adjusted their insulin as needed to maintain glycemic control. Data from days 3 to 6 of each dosing period or baseline period were used for data analysis.

[0272] Results

[0273] No harmful effects on liver function or plasma lipids were observed during the study. As shown in the following data and associated figures, a trend was also seen towards improved glycemic control while reducing the insulin dose. Further trends towards improved glycemic control were observed in the increase in the ratio of average daily carbohydrate intake to average daily rapid bolus insulin dose from baseline to the 400 mg dose and from the 400 mg dose to the 800 mg dose. Pharmacokinetic data indicated that the UT-1 concentration was lower in the 1200 mg group than in the 800 mg group in three out of five subjects.

[0274] In Figure 1 it, the median percentage of time with blood glucose levels in the range of 70 - 180 mg / dL increased from baseline (52.0%) to the 400 mg dose (67.9%), and from the 400 mg dose (67.9%) to the 800 mg dose (75.7%). The data for preparing Figure 1 are provided in Table 1 below.

[0275] Table 1 - Percentage of time with blood glucose levels in the range of 70 - 180 mg / dL for each subject at baseline and each dose (using CGM).

[0276]

[0277] Each data point in Table 1 represents the median for each subject over four days (days 3 - 6) at each dose.

[0278] The data for preparing Figure 2 are provided in Table 2.

[0279] Table 2 - Percentage of time with blood glucose levels between 54 and 70 mg / dL for each subject at baseline and each dose (using CGM).

[0280]

[0281] Each data point in Table 2 represents the median for each subject over four days (days 3 - 6) at each dose.

[0282] The data for preparing Figure 3 are provided in Table 3.

[0283] Table 3 - Percentage of time with blood glucose levels below 54 mg / dL for each subject at baseline and each dose (using CGM).

[0284]

[0285] Each data point in Table 3 represents the median for each subject over four days (days 3 - 6) at each dose.

[0286] In Figure 4 it, the median percentage of time with blood glucose levels greater than 180 mg / dL (hyperglycemia) decreased from baseline (37%) to the 400 mg dose (30.92%), and from the 400 mg dose (30.92%) to the 800 mg dose (20.46%). The data for preparing Figure 4 are provided in Table 4 below.

[0287] Table 4 – Percentage of time with blood glucose levels > 180 mg / dL for each subject at baseline and each dose (using CGM).

[0288]

[0289] Each data point in Table 4 represents the median for each subject over four days (days 3 - 6) at each dose.

[0290] At Figure 5 the mean bolus insulin dose per day (mean U / day) decreased from baseline (27.1 mean U / day) to 400 mg (25 mean U / day), and from 400 mg to 800 mg (20 mean U / day).

[0291] Data for the preparation of Figure 5 are provided in Table 5.

[0292] Table 5 – Mean units of bolus insulin administered per day for each subject at baseline and each dose.

[0293]

[0294] Each data point in Table 5 represents the mean for each subject over four days (days 3 - 6) at each dose.

[0295] Data for the preparation of Figure 6 are provided in Table 6.

[0296] Table 6 – Mean units of basal insulin administered per day for each subject at baseline and each dose.

[0297]

[0298] Each data point in Table 6 represents the mean for each subject over four days (days 3 - 6) at each dose.

[0299] Example 2 - Research Design

[0300] A multicenter, double-blind, placebo-controlled study was conducted with a 2-week single-blind placebo run-in period to evaluate UT-1 as a potential adjunctive therapy to insulin treatment in T1DM. This study examined the responses of 20 adult patients with T1DM who used a continuous glucose monitoring (CGM) device and received insulin via continuous subcutaneous insulin infusion (CSII) once daily with either placebo or 800 mg of UT-1 for up to 12 weeks. The once-daily treatment was taken with breakfast. Safety and assessment laboratory tests were collected before the placebo run-in period, on day 1 before blinded study drug administration, at week 2, week 4, week 6, week 8, week 12, and approximately week 13. Insulin pump data and CGM data were collected from the single-blind placebo run-in period through the end of dosing. Quality of life and treatment satisfaction questionnaires were also used. Patients adjusted their insulin as needed to maintain glycemic control.

[0301] Results

[0302] The baseline mean HbA1c in the UT-1 and placebo treatment groups was 7.3% and 7.4%, respectively. Patients receiving UT-1 treatment (n = 8) showed a statistically significant mean decrease in HbA1c of 0.6% at 12 weeks (ending with HbA1c of 6.7 - 6.8% at 12 weeks), while the group treated with placebo (n = 11) showed a mean increase in HbA1c of 0.1% (ending with HbA1c of 7.5% at week 12), resulting in a mean difference of 0.7% in the UT-1 group relative to the placebo group (p = 0.03). At the same time, a trend of reduced insulin use was observed in the group treated with UT-1.

[0303] Patients in this study received insulin adjustments to optimize glucose levels. Therefore, the primary analysis included responder analysis, where a "treatment responder" was defined as a patient in whom a decrease in HbA1c was detected in blood or urine at week 12 during the study period, without abnormal lactate (greater than 20 mg / dL) or abnormal metabolic ketones (greater than 4.17 mg / dL BHB), and with no increase in the time of grade 2 hypoglycemia (blood glucose < 54 mg / dl). Among all study patients, the proportion of responders was higher in the group treated with UT-1 (75%) compared to the placebo group (9%) (p = 0.006). Consistent with the results of the treatment responders, abnormal levels of metabolic ketones were observed in plasma or urine in 63% of patients in the placebo group, compared with 13% of patients treated with UT-1.

[0304] Overall and by system organ class, tolerance to UT-1 was good, and the incidence of treatment-emergent adverse events was similar. No serious adverse events were reported in this study. There were also no reports of diabetic ketoacidosis or severe hypoglycemia in this study.

Claims

1. A method for treating type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

2. A method for increasing the percentage of time within a target blood glucose range in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

3. A method for reducing the total daily rapid-acting insulin dose in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

4. A method for reducing the mean daily blood glucose in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

5. A method for reducing the glycated hemoglobin level in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

6. A method for reducing the percentage of time within a hypoglycemic range in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

7. A method for reducing the percentage of time within a hyperglycemic range in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

8. A method for reducing the incidence of diabetic ketoacidosis in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

9. A method for reducing body weight in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

10. A method for reducing the total daily basal insulin dose in a subject with type 1 diabetes, the method comprising administering to a subject in need thereof a combination of a liver-selective glucokinase activator and insulin or an analogue thereof.

Images