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Uses of glycerokinase as glucose metabolism disorder treatment target

A technology of glycerol kinase and glucose metabolism, which can be used in metabolic diseases, gene therapy, endocrine system diseases, etc., and can solve the problems of unreported effects of glycerol kinase

Active Publication Date: 2017-11-03
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the prior art, there is no report on the role of glycerol kinase in type 2 diabetes and the regulation of hepatic gluconeogenesis and blood glucose homeostasis by regulating the AKT-FOXO-PEPCK / G6Pase pathway

Method used

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  • Uses of glycerokinase as glucose metabolism disorder treatment target
  • Uses of glycerokinase as glucose metabolism disorder treatment target
  • Uses of glycerokinase as glucose metabolism disorder treatment target

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] Example 1. The expression of glycerol kinase in the liver of diabetic model mice increases, and inhibiting the expression of glycerol kinase can significantly improve the hyperglycemia and insulin sensitivity of mice

[0108] Glycerol kinase is involved in gluconeogenesis by catalyzing glycerol to 3-phosphate glycerol. Glycerol kinase is mainly expressed in the liver, followed by the kidney, with a small amount expressed in adipose tissue and skeletal muscle. The inventors found in the diabetic mouse model induced by high-fat diet that the expression of glycerolkinase (glycerolkinase, Gyk) in the liver was significantly higher than that of the mice fed with the control diet ( figure 1 A).

[0109] The inventors used adenovirus-mediated RNA interference to inhibit the expression of Gyk in the liver of diabetic model mice ( figure 1 B). It was found that after RNA interference Gyk expression, can significantly reduce the blood glucose and fasting blood glucose ( figur...

Embodiment 2

[0114] Example 2. Glycerol kinase regulates gluconeogenesis and blood glucose homeostasis by regulating glycerol metabolism and AKT-FOXO1-mediated gluconeogenesis gene expression

[0115]In this example, the function and mechanism of Gyk in liver gluconeogenesis and blood glucose homeostasis were explored in normal mice.

[0116] 1. The effect of overexpression of Gyk

[0117] The present inventors utilized adenovirus-mediated overexpression of Gyk in the liver of normal mice ( figure 2 A), a significant decrease in blood glycerol concentration was found ( figure 2 B), the increase of blood glucose when the mice were free to eat ( figure 2 C), gluconeogenesis with glycerol as precursor was significantly enhanced ( figure 2 D). These results indicated that Gyk regulates gluconeogenesis by regulating glycerol metabolism at the overall level, confirming the role of Gyk in regulating gluconeogenesis with glycerol as precursor.

[0118] Pyruvate tolerance experiments showe...

Embodiment 3

[0128] Embodiment 3, drug screening

[0129] 1. Drug screening with cells expressing glycerol kinase

[0130] Primary cultured hepatocytes from mice can express glycerol kinase endogenously. The cell is used as a cell model for screening, improving or treating disorders of glucose metabolism.

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Abstract

The present invention relates to uses of glycerokinase as a glucose metabolism disorder treatment target. According to the present invention, the results show that glycerokinase can catalyze glycerol to generate 3-phosphoglycerol so as to participate in gluconeogenesis, can regulate the expressions of gluconeogenesis enzyme glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (PEPCK) through an AKT-FOXO1 signaling pathway so as to regulate gluconeogenesis, and can provide important effects in the maintaining of the blood glucose homeostasis, such that the glycerokinase and the regulator thereof are the new target for blood glucose regulation and diabetes treatment.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, and more specifically, the invention relates to the use of glycerol kinase as a therapeutic target for disorders of glucose metabolism. Background technique [0002] Hepatic glucose metabolism (including blood glucose absorption, glycogen synthesis and breakdown, gluconeogenesis and output) plays an important role in maintaining blood glucose homeostasis. Hepatic gluconeogenesis hyperactivity is an important pathological mechanism of type 2 diabetes mellitus. Increased hepatic glucose output leads to elevated blood sugar. Correcting hyperglucose production is beneficial to control the pathogenesis of diabetes and secondary diseases. Therefore, research on inhibitors targeting glycogen production is of great significance for the control and treatment of diseases related to glucose metabolism disorders, including metabolic syndrome and type 2 diabetes. [0003] Glycerol kinase can catalyze the ph...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K48/00A61K31/7088A61P3/10A61P5/50A61P3/08C12Q1/48
CPCA61K31/7088A61K45/00C12Q1/485
Inventor 乐颖影卓鉥
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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