GPR84 agonists for use in the treatment of diabetes

Abstract

A composition for use in increasing insulin secretion, appetite suppression, increasing circulating glucagon-like peptide 1 (GLP-1), reducing plasma glucose levels, or treating diabetes. The composition has a compound having the formula (I) wherein: R1 and R2 are each individually H or OH; R3 is optionally substituted C1-6 alkyl or optionally substituted carbocyclyl.

Description

GPR84 AGONISTS FOR USE IN THE TREATMENT OF DIABETESField of the Invention

[0001] The invention relates to compositions for the treatment of diabetes.Background

[0002] More than 450 million people live with diabetes worldwide. The alarming increase in type 2 diabetes (T2DM) incidence coupled with the failure of established anti-diabetic drugs to tightly manage diabetes demonstrates the market need for innovation. Targeting free fatty-acid (FA) G-protein-coupled receptors (GPCRs) can be used to counteract defective insulin secretion, low beta cell mass, insulin resistance and inflammation.

[0003] Only 36% of people with diabetes achieve the targets recommended to reduce their risk of developing diabetic complications. There is a need for therapies that provide a combination of benefits, with fewer side effects. Cardiovascular disease (CVD) is a major cause of death and disability in diabetes, accounting for 52% of fatalities in those with T2DM. New treatments are necessary due to the increasing prevalence of diabetes and related complications. Extensive studies have been conducted on GPCRs in the Diabetes Research Group at Ulster University. Based on the extensive clinical evidence of enhancing Glucagon-Like Peptide-1 (GLP-1) GPCR activation, our studies have shown GPCR-based therapies can target pancreatic and intestinal cells, with anti-diabetic, anti-inflammatory and anti-obesity effects. As the endocrine pancreas is key in regulating glucose homeostasis and insulin secretion, the pancreatic islets are an important target for anti-diabetic therapies.

[0004] The GPR84 receptor has been identified as an exciting new therapeutic target for diabetes and obesity, with agonists showing restoration of pancreatic islet architecture with enhanced beta cell proliferation and beta cell mass. Our research has focused on the agonists due to the spectrum of beneficial effects that they offer including anti-tumour, and anti-oxidant properties.

[0005] To date, GPCR agonists have had considerable success as an effective treatment strategy for obesity and type 2 diabetes. GLP-1 receptor is just one of arange of GPCRs that enable drugs to target tissues of relevance for type 2 diabetes and obesity. The GLP-1 receptor, GLP1 R, is probably the best characterised GPCR to have been harnessed to date for the treatment of diabetes. It is targeted by administered GLP-1 mimetics as well as by raised circulating active GLP-1 achieved following dipeptidyl peptidase 4 (DPP4) inhibition. The global success of GLP1 R- based therapeutics has highlighted the benefits of targeting the gut-pancreatic axis, as well as the potential effectiveness of drugs that activate Gas-coupled receptors in pancreatic beta cells.

[0006] Ligands to other GPCRs, including free fatty acid receptor 1 (FFAR1 , also known as GPR40), GPR119 and the glucose-dependent insulinotropic polypeptide (GIP) receptor, have progressed recently through to clinical trials in humans. FA receptor agonism is considered to be an important clinical target for T2D treatment. GPR119 agonists include GSK1292263 (GSK, Ph2), MBX-2982 (Metabolex / Sanofi, Ph2), PSN821 (Astella / AstraZeneca, Ph2), APD597 and APD668 (Arena Pharma, Ph1), ZYG19 (Zydus Cadila, Ph1).

[0007] GPCRs comprise a large family of cell membrane proteins that have recently attracted significant pharmaceutical interest for diabetes treatment as GPCRs account for approximately 40% of FDA approved drugs. The growth in market size of diabetes therapeutics is driven by increasing disease prevalence and potential for better patient outcomes. Identifying a new GPCR in the pancreas and establishing an important islet function for this GPR84 receptor is a unique discovery that has the potential to be developed into therapeutics for obesity and type 2 diabetes worth >£500 million.

[0008] The present invention seeks to obviate or mitigate the problem treating diabetes.Summary of the Invention

[0009] According to an aspect of the invention there is provided a composition, the composition comprising a compound having the formula:wherein:RI and R2 are each individually H or OH;R3 is optionally substituted C1-6 alkyl, optionally substituted carbocyclyl, or C1-6 alkyl carbocyclyl.

[0010] Optionally, R1 is OH and R2 is H.

[0011] Optionally, R3 is butyl, and optionally n-butyl.

[0012] Optionally, R3 is Ci , C2, C3, C4, C5 or Ce alkyl. Optionally, R3 is Ci , C2, C3, C4, C5 or Ce alkyl carbocyclyl. Optionally, R3 is methyl, ethyl, propyl, butyl, pentyl or hexyl.

[0013] Optionally, R3 is optionally substituted benzene.

[0014] Optionally, R3 is benzene substituted with halo.

[0015] Optionally, R3 is bromobenzene.

[0016] Optionally, the compound has the formula:

[0017] Optionally, the compound has the formula:

[0018] Optionally, the concentration of the compound in the composition is between 10'10to 10'4M. Optionally, the concentration of the compound in the composition is between 10'9to 10'5M. Optionally, the concentration of the compound in the composition 10'8to 10'6M.

[0019] Optionally, the composition further comprises a GLP-1 R agonist. Optionally, the GLP-1 R agonist is semaglutide. The molar concentration of the compound to semaglutide may be in the range of 25-75:1 , 40-60:1 , or 50:1. Optionally, the concentration of semaglutide in the composition is between 2 x 10'12to 2 x 10'6M. Optionally, the concentration of semaglutide in the composition is between 2 x 10'11to 2 x 10-7M. Optionally, the concentration of semaglutide in the composition is 2 x 10'10to 2 x 10’8M.

[0020] The composition may be for use in increasing insulin secretion, increasing circulating GLP-1 , reducing plasma glucose, promoting weight loss, increasing pancreatic islet growth and proliferation, or treating diabetes.

[0021] According to a further aspect of the invention there is provided a method of increasing insulin secretion, increasing circulating glucagon-like peptide 1 (GLP-1), reducing plasma glucose, promoting weight loss, improving pancreatic islet growth and proliferation, or treating diabetes, the method involving the steps of administering a composition comprising a compound having the formula:wherein:Ri and R2 are each individually H or OH;R3 is optionally substituted C1-6 alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.

[0022] The method may involve the step of administering a pharmaceutically acceptable amount of the composition.

[0023] The method may involve administering a composition wherein the concentration of the compound in the composition is 0.005 - 0.3 pmol I kg body weight. The method may involve administering a composition wherein the concentration of the compound in the composition is 0.01 - 0.2 pmol I kg body weight. The method may involve administering a composition wherein the concentration of the compound in the composition is 0.05 - 0.15 pmol I kg body weight. The method may involve administering a composition wherein the concentration of the compound in the composition is 0.1 pmol I kg body weight.

[0024] The method may involve administering a composition wherein the concentration of GLP-1 R agonist in the composition is 0.5 - 4 nmol I kg body weight. The method may involve administering a composition wherein the concentration of the GLP-1 R agonist in the composition is 1 - 3 nmol I kg body weight. The method may involve administering a composition wherein the concentration of the GLP-1 R agonist in the composition is 1.5 - 2.5 nmol I kg body weight. The method may involve administering a composition wherein the concentration of the GLP-1 R agonist in the composition is 2 nmol / kg body weight. The GLP-1 R agonist may be semaglutide.

[0025] The features of the compound described in relation to one aspect of the invention may be used interchangeably with the features described in relation to another or further aspect of the invention.List of Figures

[0026] Specific implementations of the present disclosure will now be described, by way of example only, and with reference to the accompanying drawings in which:

[0027] Figure 1. Effects of exendin-4, embelin (2, 5-dihydroxy-3-undecylcyclohexa-2, 5-diene-1 , 4-dione), and two compounds according to the present invention (labelled 45 and 46 respectively) on insulin secretion in pancreatic clonal BRIN-BD11 beta cells. Results are Mean ± SEM (n=8) for insulin secretion at 16 mM glucose **p<0.01 , ***p<0.001 , compared to glucose.Ap<0.05, compared to embelin.

[0028] Figure 2. Effects of exendin, embelin, and two compounds according to the present invention (labelled 45 and 46 respectively) on pancreatic BRIN-BD11 cell proliferation. Results are Mean ± SEM (n=8) ***p<0.001 , compared to standard media.

[0029] Figure 3. Effects of new GPR84-based compounds on beta cell viability. Cells were incubated with compounds for 18 h prior to addition of MTT. Values are Mean ± SEM (n=8) **p<0.01 and ***p<0.001 , compared to media alone.

[0030] Figure 4. Effects of new GPR84-based compounds on cytokine-induced apoptosis in pancreatic BRIN-BD11 cells. Cells were incubated in cytokine mix (I L-113: 100U / ml, IFNy: 20U / ml and TNFcc 200U / ml) with test compounds for 18 h prior to staining for TLINEL. Values are Mean ± SEM (n=8) *p<0.05, **p<0.01 and ***p<0.001 , compared to media alone orAAp<0.01 andAAAp<0.001 , compared to cytokine mix.

[0031] Figure 5. Effects of saline, sitagliptin, embelin, and two compounds according to the present invention (labelled NED-59245 and NED-49246 respectively) on food intake in lean C57BI / 6 mice. *p<0.05, **p<0.01 and ***p<0.001 , compared to saline.

[0032] Figure 6. Effects of embelin, and two compounds according to the present invention (labelled 45 and 46 respectively) and semaglutide on (A) blood glucose with (B) associated AUC in high fat fed (HFF) C57BI / 6 mice. GPR84 compounds (0.1 mol / kg body weight, oral) and semaglutide (2nmol / kg body weight,intraperitoneal) were administered once daily for 21 days. Values are Mean ± SEM. Changes deemed significant when *p<0.05, **p<0.01 and ***p<0.001 , compared to HFF control mice.

[0033] Figure 7. Effects of embelin, two compounds according to the present invention (labelled 45 and 46 respectively) and semaglutide on (C) plasma insulin with (D) associated AUC in HFF C57BI / 6 mice. GPR84 compounds (0.1 mol / kg body weight, oral) and semaglutide (2nmol / kg body weight, intraperitoneal) were administered once daily for 21 days. Values are Mean ± SEM. Changes deemed significant when *p<0.05, **p<0.01 and ***p<0.001 , compared to HFF control,Ap<0.05 compared to semaglutide.

[0034] Figure 8. Effects of embelin, two compounds according to the present invention (labelled 45 and 46 respectively) and semaglutide on (A) plasma GLP-1 and (B) cell proliferation from HFF C57BI / 6 mice. GPR84 compounds (0.1 mol / kg body weight, oral) and semaglutide (2 nmol / kg body weight, intraperitoneal) were administered once daily for 21 days. Plasma was collected following 21-day study period prior to termination. Values are Mean ± SEM. Changes deemed significant when *p<0.05, **p<0.01 and ***p<0.001 , compared to HFF control,Ap<0.05 andAAp<0.01 , compared to GPR84 compound with semaglutide.

[0035] Figure 9: Effects of embelin, analogues #45, #46 and semaglutide on insulin sensitivity (%basal) with associated area above the curve (AAC) in HFF C57BI / 6 mice. GPR84 compounds (0.1 mol / kg body weight, oral) and semaglutide (2nmol / kg body weight, intraperitoneal) were administered once daily for 21 days. Following this treatment period, an insulin sensitivity test (1.5U / kg bovine insulin, i.p) was conducted. Values are Mean ± SEM (n=6 mice / group). ***p<0.001 , compared to HFF control.

[0036] Figure 10. Effects of embelin, analogues #45, #46 and semaglutide on insulin sensitivity (%basal) with associated AAC in HFF GPR84 knockout C57BI / 6 mice. GPR84 compounds (0.1 mol / kg body weight, oral) and semaglutide (2nmol / kg body weight, intraperitoneal) were administered once daily for 21 days. Following this treatment period, an insulin sensitivity test (1 ,5U / kg bovine insulin, i.p) was conducted. Values are Mean ± SEM (n=6 mice / group). *p<0.05 and **p<0.01 , compared to HFF control.

[0037] Figure 11 . Effects of long term agonism of GPR84 compounds (#45 and #46), embelin and semaglutide on percentage fat content in diet-induced diabetes in HFF wild-type and GPR84 knock-out (KO) C57BI / 6 mice. GPR84 compounds (0.1 mol / kg body weight, oral) and semaglutide (1.5U / kg body weight, intraperitoneal) were administered once daily for 21 days. Values are Mean ± SEM (n=6 mice / group). Changes deemed significant when *p<0.05 and ***p<0.001 , compared to wild-type equivalent.AAAp<0.001 , compared to HFF WT control.555p<0.001 , compared to KO HFF control.

[0038] Figure 12. Effects of GPR84 agonism on plasma IL-6 in lean C57BL / 6J and HFF mice. Treatment with novel agonists #45 and #46 (0.1 pmol / kg bw, oral), and semaglutide (2nmol / kg bw, intraperitoneal) was administered once-daily for 21 days. Values are Mean ± SEM (n=6). *p<0.05, **p<0.01 , ***p<0.001 , compared to HFF control mice.Detailed Description

[0039] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the presently described subject matter pertains. The meaning and scope of these terms should be clear, but in cases of ambiguity, the definitions articulated herein supersede any definitions found in dictionaries or external sources.

[0040] Within the specification and the appended claims, unless explicitly stated otherwise, the ensuing terms are ascribed the meanings outlined: The term “alkyl” refers to a saturated hydrocarbon chain, meaning it contains only single bonds and no double or triple bonds between carbon atoms. As used herein, alkyl groups are denoted C#.# wherein # indicates the number of carbon atoms, for example, C1-6 alkyl. Common alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and so on.

[0041] The term “benzene” refers to a six-carbon hexagonal ring. Each carbon atom has a single hydrogen atom attached to it.

[0042] The term “bromobenzene” refers to a molecule similar to benzene but wherein a hydrogen atom has been replaced with a bromine atom.

[0043] The term “butyl” refers to a C4 alkyl having the structure C4H9. Butyl may be straight or branched. There are four possible butyl groups: n-butyl, isobutyl, sec-butyl or tert-butyl. The groups differ in the way carbon atoms are connected. In n-butyl, all four carbon atoms are in a straight chain. In isobutyl, three carbon atoms are bonded to a central carbon. In sec-butyl, one end of the chain has two methyl groups (CH3) attached to the second carbon. In tert-butyl, all three hydrogens on the second carbon atom are replaced by methyl groups.

[0044] The term “carbocyclyl” refers to a cyclic ring or system composed entirely of carbon atoms in its backbone. The carbocyclyl may be aromatic or non-aromatic. Multiple rings may be connected in different ways, such as fused, bridged, or spiroconnected. Fused rings share a pair of carbon atoms. Bridged rings are linked by a single carbon atom bridge. And spiro-connected rings are connected by a single atom that is part of both rings. Carbocyclyls can have varying degrees of saturation, containing single, double or triple bonds within the system. Aromatic carbocyclyls have delocalized electrons, providing aromatic character. Benzene is an exemplary aromatic carbocyclyl. Non-aromatic carbocyclyls lack aromaticity and can be categorised depending on degree of saturation: cycloalkyls (all single bonds), cycloalkenyls (at least one double bond), or cycloalkynyls (at least one triple bond). Carbocyclyls may have 3 to 20 carbon atoms. Medium sized carbocyclyls may have 3 to 10 carbon atoms, and smaller carbocyclyls may have 3 to 6 carbon atoms. Some common carbocyclyl rings include cyclopropyl, cyclohexyl, cyclohexenyl, adamantyl, and benzene (aromatic).

[0045] The term “halo” refers to any element in Group 17 of the periodic table. These elements are fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0046] The term “heterocyclyl” means a cyclic ring or ring system containing at least one atom (the heteroatom) other than carbon within its backbone. The rings can be non-aromatic, fused, bridged or spiro-connected. Further, heterocyclyls may have single, double or triple bonds. The heteroatom may either be in an aromatic or non- aromatic ring. Heterocyclyls may have 3 to 20 members. Medium sized heterocyclyls may have 3 to 10 members, and smaller heterocyclyls may have 3 to 6 members. Examples of heterocyclyls include azepines, imidazolines, morpholines, piperidines, and pyridines.

[0047] The term “substituted” in reference to a substituted group refers to a group that is derived from an unsubstituted parent group by replacing one or more hydrogen atoms with another atom or group (substituent). Types of substituents, unless otherwise specifies, include aliphatic groups (alkyl, alkenyl, alkynyl or heteroalkyl groups), carbocyclyl or heterocyclyl groups. Other substituents include: halogens, cyano group, hydroxyl group, alkoxy groups, aryloxy groups, thiol group, haloalkyl group, haloalkoxy group, amino groups, nitro groups, carbamoyl groups, thiocarbamoyl groups, amido groups, sulfonamido groups, carboxy groups, acyl groups, or functional groups like cyanate, isocyanato, thiocyanato, sulfinyl, sulfonyl, sulfino, and oxy. Groups described as “optionally substituted” herein may contain one of the aforementioned substituents.

[0048] The invention will now be described by way of the following non-limiting examples.

[0049] Example 1

[0050] A structure of one exemplary compound according to the invention is provided below.

[0051] The above compound is labelled as 45 or NED-59245 in the Figures.

[0052] Example 2

[0053] A structure of one exemplary compound according to the invention is provided below.

[0054] The above compound is labelled as 46 or NED-49246 in the Figures.

[0055] As shown in Figure 1 , NED-59245 and NED-49246 at a concentration of 10'8M caused a 1.7- and 1.8-fold increase respectively in insulin release in vitro. This is a significantly greater increase when compared to other known anti-diabetic drugs, exendin, when used at the same concentration. Thus, the compounds of the present invention provide an improved insulin release effect when compared to known antidiabetic drugs.

[0056] Referring now to Figure 2, it is shown that beta cell proliferation is significantly increased for both NED-59245 and NED-49246 relative to the control. Figure 3 demonstrates that administration of the novel GPR84 compounds results in no cytotoxicity of pancreatic beta cells. Figure 4 demonstrates that GPR84 agonist-based compounds protects against cytokine-induced pancreatic beta cell apoptosis.

[0057] Figure 5 shows the effects of saline, sitagliptin, embelin, and NED-59245 and NED-49246 on food intake in C57BI / 6 mice. Food intake over time was significantly lower in mice treated with NED-59245 and NED-49246 compared with the control group (saline). Further, from 30 minutes onwards, food intake was significantly lower in mice treated with NED-59245 and NED-49246 when compared to mice treated with known drugs, either sitagliptin or embelin. Thus, the compounds of the present invention provide a marked improvement on known anti-diabetic drugs for appetite suppression.

[0058] Figure 6 shows the effect of embelin, two compounds according to the present invention (labelled 45 and 46 respectively) and semaglutide on (A) blood glucose with (B) associated AUC in HFF male wild-type C57BI / 6 mice. As shown, both compoundssignificantly reduced circulating glucose when compared with the insulin resistant obese mice.

[0059] Figure 7 shows the effects of embelin, two compounds according to the present invention (labelled 45 and 46 respectively) and semaglutide on (C) plasma insulin with (D) associated AUC in HFF male wild-type C57BI / 6 mice. Both compounds and semaglutide significantly lowered the hyperinsulinaemic status of the HFF mice.

[0060] Figure 8 illustrates the effects of embelin, two compounds according to the present invention (labelled 45 and 46 respectively) and semaglutide on (A) plasma GLP-1 and (B) cell proliferation in HFF male wild-type C57BI / 6 mice. A combination of each compound with semaglutide yielded the greatest increase in GLP-1 , indicating a synergistic effect for these compounds with semaglutide. Further, the compounds were also found to have a positive effect on beta cell proliferation. Treatment with these GPR84-based therapies restores pancreatic islet architecture in high fat fed- induced diabetic mice by enhancing beta cell proliferation (NED-59246: 60% increase).

[0061] Figures 6 and 7 demonstrate that NED-59246 (22%) and NED-59245 (15%) significantly reduce plasma glucose and increase insulin secretion in diabetic HFF mice, similar to semaglutide.

[0062] Figure 9 shows that GPR84 compounds NED-59245 and NED-49246 improve insulin sensitivity by 39% (p<0.001) and 27% (p<0.001) respectively in diabetic mice.

[0063] Figure 10 demonstrates the specificity and the significance of the new GPR84 compounds (NED-59245 and NED-49246). The effects of GPR84 compounds (NED- 59245, NED-49246 and embelin) were abolished in the absence of the GPR84 receptor. Only Semaglutide improves insulin sensitivity in GPR84 KO mice.

[0064] Figure 11 further demonstrates the specificity of the NED-59245 and NED- 49246 compounds for the GPR84 receptor and shows that in the absence of the GPR84 receptor, GPR84 compounds (NED-59245 and NED-49246) exhibit higher percentage fat compared to their diabetic wild-type counterparts, only semaglutide improves percentage fat content in the absence of the GPR84 receptor, demonstrating the importance of the GPR84 receptor. Administration of the GPR84 compounds(NED-59245 and NED-49246) also results in a significant percentage reduction in body weight in diabetic mice.

[0065] Figure 12 shows anti-inflammatory actions of agonism of this receptor by NED- 59245 and NED-49246, supported by the decreases in IL-6 observed in treatment groups, showing a direct anti-inflammatory effect, and a protective effect of the receptor against inflammation.

[0066] Where a range of values is provided, for example, concentration ranges, percentage ranges, or ratio ranges, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the described subject matter. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and such embodiments are also encompassed within the described subject matter, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the described subject matter.

[0067] It should be understood that the terms "a" and "an" as used above and elsewhere herein refer to "one or more" of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise. Therefore, the terms “a,” “an” and “at least one” are used interchangeably in this application.

[0068] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as size, weight, reaction conditions and so forth used in the specification and claims are to the understood as being modified in all instances by the term “about”. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present subject matter. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0069] Throughout the application, descriptions of various embodiments use "comprising" language; however, it will be understood by one of skill in the art, that in some instances, an embodiment can alternatively be described using the language "consisting essentially of or "consisting of."

Claims

CLAIMS1 . A composition, the composition comprising a compound having the formula:wherein:Ri and R2 are each individually H or OH;R3 is optionally substituted C1-6 alkyl, optionally substituted carbocyclyl, or C1-6 alkyl carbocyclyl.

2. The composition of claim 1 wherein R1 is OH and R2 is H.

3. The composition of any preceding claim wherein R3 is butyl, and optionally n- butyl.

4. The composition of claim 3 wherein R3 is optionally substituted benzene.

5. The composition of claim 4 wherein R3 is benzene substituted with halo.

6. The composition of claim 5 wherein R3 is bromobenzene.

7. The composition of claim 1 or claim 2 wherein the compound has the formula:

8. The composition of claim 1 or claim 2 wherein the compound has the formula:

9. The composition of any preceding claim wherein the concentration of the compound in the composition is between 10'10to 10'4M.

10. The composition of claim 10 wherein the concentration of the compound in the composition is between 10'9to 10'5M.

11. The composition of claim 11 wherein the concentration of the compound in the composition 10'8to 10'6M.

12. The composition of any preceding claim further comprising a GLP-1 R agonist.

13. The composition of claim 12 wherein the GLP-1 R agonist is semaglutide.

14. The composition of claim 13 wherein the molar concentration the compound to semaglutide is in the range of 25-75: 1 , 40-60: 1 , or 50: 1 .

15. The composition of claim 13 wherein the concentration of semaglutide in the composition is between 2 x 10'12to 2 x 10'6M.

16. The composition of claim 15 wherein the concentration of semaglutide in the composition is between 2 x 10'11to 2 x 10'7M.

17. The composition of claim 16 wherein the concentration of semaglutide in the composition is 2 x 10'10to 2 x 10'8M.

18. The composition of any preceding claim for use in increasing insulin secretion, increasing circulating glucagon-like peptide 1 (GLP-1), reducing plasma glucose, promoting weight loss, increasing pancreatic islet growth and proliferation, or treating diabetes.

19. Use of the composition of any one of claims 1-17 for the treatment of diabetes.

20. Use of the composition of any one of claims 1-17 for the promotion of weight loss.

21. Use of the composition of any one of claims 1-17 for increasing circulating glucagon-like peptide 1 (GLP-1).

22. Use of the composition of any one of claims 1-17 for reducing plasma glucose.

23. Use of the composition of any one of claims 1-17 for increasing pancreatic islet growth and proliferation24. A method of increasing insulin secretion, appetite suppression, increasing circulating glucagon-like peptide 1 (GLP-1), reducing plasma glucose levels, or treating diabetes, the method involving the steps of administering a composition comprising a compound having the formula:wherein:Ri and R2 are each individually H or OH;R3 is optionally substituted C1-6 alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.

25. The method of claim 24 involving the step of administering a pharmaceutically acceptable amount of the composition.

26. The method of claim 25 involving administering a composition wherein the concentration of the compound in the composition is 0.005 - 0.3 pmol I kg body weight.

27. The method of claim 26 involving administering a composition wherein the concentration of the compound in the composition is 0.01 - 0.2 pmol I kg body weight.

28. The method of claim 27 involving administering a composition wherein the concentration of the compound in the composition is 0.05 - 0.15 pmol I kg body weight.

29. The method of any one of claims 24 to 28, involving administering a composition wherein the concentration of semaglutide in the composition is 0.5 - 4 nmol I kg body weight.

30. The method of claim 29 involving administering a composition wherein the concentration of semaglutide in the composition is 1 - 3 nmol I kg body weight.

31. The method of claim 30 involving administering a composition wherein the concentration of semaglutide in the composition is 1.5 - 2.5 nmol I kg body weight.

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