Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes

Bebernitz, Gregory R.; Beaulieu, Valerie; Dale, B. A. B.; Deacon, Richard; Duttaroy, Alokesh; Gao, Jiaping; Grondine, Melissa; Gupta, Ramesh C.; Kakmak, Mesut; Kavana, Michael; Kirman, Louise; Liang, Jinsheng; Maniara, Wieslawa; Munshi, Siralee; Nadkarni, Sunil S.; Schuster, Herbert F.; Stams, Travis; Denny, Irene St; Taslimi, Paul; Vash, Brian; Caplan, Shari L.

doi:10.1021/jm900839k

Cited by 83 publications

(64 citation statements)

References 25 publications

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“…However, GKAs may cause serious side effects, as they change a sigmoidal activity curve of GK into a hyperbolic one (8,9), and consequently alter the sensing of blood glucose level by GK in pancreatic β-cells, resulting in hyperinsulinemic hypoglycemia. As an approach to avoid the side effect, moderate or hepatocyte-specific GKAs are under development (36)(37)(38). With the same rationale and based on our result, GKRP can be a target for the development of new antidiabetes drugs that activate GK in hepatocytes.…”

Section: Discussionmentioning

confidence: 78%

Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase

Choi¹,

Seo²,

Kyeong³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Glucokinase (GK) is a monomeric allosteric enzyme and plays a pivotal role in blood glucose homeostasis. GK is regulated by GK regulatory protein (GKRP), and indirectly by allosteric effectors of GKRP. Despite the critical roles of GK and GKRP, the molecular basis for the allosteric regulation mechanism of GK by GKRP remains unclear. We determined the crystal structure of Xenopus GK and GKRP complex in the presence of fructose-6-phosphate at 2.9 Å. GKRP binds to a super-open conformation of GK mainly through hydrophobic interaction, inhibiting the GK activity by locking a small domain of GK. We demonstrate the molecular mechanism for the modulation of GK activity by allosteric effectors of GKRP. Importantly, GKRP releases GK in a sigmoidal manner in response to glucose concentration by restricting a structural rearrangement of the GK small domain via a single ion pair. We find that GKRP acts as an allosteric switch for GK in blood glucose control by the liver.hexokinase | sigmoidicity I conformational restriction | type 2 diabetes

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Section: Discussionmentioning

confidence: 78%

Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase

Choi¹,

Seo²,

Kyeong³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The findings from our cell culture experiments strongly suggested that GKA treatment might provide protection for beta cells in vivo, but even so, there were reasons why these in vitro results might turn out to have limited applicability in whole organisms: (1) insulinoma cells in culture are not the same as normal beta cells as they exist in situ; (2) the conditions under which cells are grown in culture are more malleable than is the milieu in which beta cells live in the intact pancreas; and (3) some GKAs may be much more active in the liver than in the pancreas as a result of differential biodistribution [49]. Our experiments in insulinoma lines provided no information regarding potentially important actions in the liver that could indirectly affect beta cell survival.…”

Section: Discussionmentioning

confidence: 99%

Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat

Futamura¹,

Yao

et al. 2012

Diabetologia

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Aims/hypothesis Glucokinase activators (GKAs) are currently being developed as new therapies for type 2 diabetes and have been shown to enhance beta cell survival and proliferation in vitro. Here, we report the effects of chronic GKA treatment on the development of hyperglycaemia and beta cell loss in the male Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes with severe obesity. Methods Cell protection by GKA was studied in MIN6 and INS-1 cells exposed to hydrogen peroxide. Glucose homeostasis and beta cell mass were evaluated in ZDF rats dosed for 41 days with Cpd-C (a GKA) or glipizide (a sulfonylurea) as food admixtures at doses of approximately 3 and 10 mg kg −1 day −1 . Results Incubation of MIN6 and INS-1 832/3 insulinoma cell cultures with GKA significantly reduced cell death and impairment of intracellular NADH production caused by exposure to hydrogen peroxide. Progression from prediabetes (normoglycaemia and hyperinsulinaemia) to overt diabetes (hyperglycaemia and hypoinsulinaemia) was significantly delayed in male ZDF rats by in-feed treatment with Cpd-C, but not glipizide. Glucose tolerance, tested in the fifth week of treatment, was also significantly improved by Cpd-C, as was pancreatic insulin content and beta cell area. In a limited immunohistochemical analysis, Cpd-C modestly and significantly enhanced the rate of beta cell proliferation, but not rates of beta cell apoptosis relative to untreated ZDF rats. Conclusions/interpretation These findings suggest that chronic activation of glucokinase preserves beta cell mass and delays disease in the ZDF rat, a model of insulin resistance and progressive beta cell failure.

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“…In a prior study, evidence was presented for liver-selective GKA action due to hepatic conversion of an experimental compound [3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide] to an active metabolite (Bebernitz et al, 2009). Consistent with the interpretation of liver-selective action, treatment of diet-induced obese mice with this agent Fig.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Properties of the Glucokinase Activator MK-0941 in Rodent Models of Type 2 Diabetes and Healthy Dogs

Eiki¹,

Nagata²,

Futamura³

et al. 2011

Molecular Pharmacology

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Glucokinase activators (GKAs) are small-molecule agents that enhance glucose sensing by pancreatic ␤ cells and glucose metabolism by hepatocytes. There is strong interest in these agents as potential therapies for type 2 diabetes. Here, we report key pharmacokinetic and pharmacodynamic findings from preclinical studies of the GKA 3- [[6-(ethylsulfonyl. Incubated in vitro with recombinant human glucokinase, 1 M MK-0941 lowered the S 0.5 of this enzyme for glucose from 6.9 to 1.4 mM and increased the maximum velocity of glucose phosphorylation by 1.5-fold. In 2.5 and 10 mM glucose, the EC 50 values for activation of GK by MK-0941 were 0.240 and 0.065 M, respectively. Treatment of isolated rat islets of Langerhans and hepatocytes with 10 M MK-0941 increased insulin secretion by 17-fold and glucose uptake up to 18-fold, respectively. MK-0941 exhibited strong glucose-lowering activity in C57BL/6J mice maintained on a high-fat diet (HFD), db/db mice, HFD plus low-dose streptozotocin-treated mice, and nondiabetic dogs. In both mice and dogs, oral doses of MK-0941 were rapidly absorbed and rapidly cleared from the blood; plasma levels reached maximum within 1 h and fell thereafter with a half-life of ϳ2 h. During oral glucose tolerance testing in dogs, MK-0941 reduced total area-under-the-curve postchallenge (0 -2 h) plasma glucose levels by up to 48% compared with vehicletreated controls. When administered twice daily to mice for 16 days, and once daily to the dog for 4 days, MK-0941 remained efficacious on successive days. These findings support further investigation of MK-0941 as a potential therapeutic agent for treatment of type 2 diabetes.

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Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes

Cited by 83 publications

References 25 publications

Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase

Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase

Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat

Pharmacokinetic and Pharmacodynamic Properties of the Glucokinase Activator MK-0941 in Rodent Models of Type 2 Diabetes and Healthy Dogs

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