Pharmacodynamic effects of the oral glucokinase activator <scp>AZD6370</scp> after single doses in healthy volunteers assessed with euglycaemic clamp

Sjöstrand, Mikaela; Ericsson, Henrik; Hartford, Marianne; Norjavaara, Ensio; Eriksson, Jan W.

doi:10.1111/j.1463-1326.2012.01672.x

Cited by 10 publications

(4 citation statements)

References 25 publications

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“…This process can be promoted by glucokinase activators (GKAs). Unfortunately, recent warnings about the side effects (e.g., hypoglycemia) of antidiabetic drugs such as GKAs − highlight the urgent demands for alternative and safer therapies, ideally through dietary polyphenols.…”

Section: Introductionmentioning

confidence: 99%

Multiple Comparisons of Glucokinase Activation Mechanisms of Five Mulberry Bioactive Ingredients in Hepatocyte

Yang

et al. 2015

J. Agric. Food Chem.

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Glucokinase (GK) activity, which is rapidly regulated by glucokinase regulatory protein (GKRP) in the liver, is crucial for blood glucose homeostasis. In this paper, the GK activation mechanisms of 1-deoxynojrimycin (DNJ), resveratrol (RES), oxyresveratrol (OXY), cyanidin-3-glucoside (C3G), and cyanidin-3-rutinoside (C3R) were compared. The results revealed that DNJ, RES, C3G, and C3R could differently improve glucose consumption and enhance intracellular GK activities. DNJ and RES significantly promoted GK translocation at 12.5 μM, whereas other ingredients showed moderate effects. DNJ, C3G, and C3R could rupture intramolecular hydrogen bonds of GK to accelerate its allosteric activation at early stage. RES and OXY could bind to a "hydrophobic pocket" on GK to stabilize the active GK at the final stage. Otherwise, RES, OXY, C3G, and C3R could interact with GKRP at the F1P binding site to promote GK dissociation and translocation. Enzymatic assay showed that RES (15-50 μM) and OXY (25-50 μM) could significantly enhance GK activities, which was caused by their binding properties with GK. Moreover, the most dramatic up-regulation effects on GK expression were observed in C3G and C3R groups. This work expounded the differences between GK activation mechanisms, and the new findings would help to develop new GK activators.

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Section: Introductionmentioning

confidence: 99%

Multiple Comparisons of Glucokinase Activation Mechanisms of Five Mulberry Bioactive Ingredients in Hepatocyte

Yang

et al. 2015

J. Agric. Food Chem.

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“…After 7 days dosing at 30 mg·kg −1 ·day −1 , AZD6370 significantly reduced blood glucose in male gk wt/del mice over the period 0.8–8 h post‐dose, reaching a nadir of 5–6 mM glucose 0.5–1 h post‐dose from a pre‐dose baseline of 11–12 mM. A dose of 30 mg·kg −1 ·day −1 of AZD6370 in mice corresponds to a therapeutically relevant acute dose in man (Table ; Norjavaara et al ., ; Sjöstrand et al ., ). At a much higher dose (400 mg·kg −1 ·day −1 ), glucose levels were lowered for a longer period but importantly, no hypoglycaemia was observed.…”

Section: Discussionmentioning

confidence: 97%

Characterization of the heterozygous glucokinase knockout mouse as a translational disease model for glucose control in type 2 diabetes

Baker

Atkinson

Wilkinson

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEThe global heterozygous glucokinase (GK) knockout (gk wt/del ) male mouse, fed on a high-fat (60% by energy) diet, has provided a robust and reproducible model of hyperglycaemia. This model could be highly relevant to some facets of human type 2 diabetes (T2D). We aimed to investigate the ability of standard therapeutic agents to lower blood glucose at translational doses, and to explore the glucose-lowering potential of novel glucokinase activators (GKAs) in this model. EXPERIMENTAL APPROACHWe measured the ability of insulin, metformin, glipizide, exendin-4 and sitagliptin, after acute or repeat dose administration, to lower free-feeding glucose levels in gk wt/del mice. Further, we measured the ability of novel GKAs, GKA23, GKA71 and AZD6370 to control glucose either alone or in combination with some standard agents. KEY RESULTSA single dose of insulin (1 unit·kg ), AZD6370 also lowered basal levels of glucose without inducing hypoglycaemia. CONCLUSION AND IMPLICATIONSStandard glucose-lowering therapeutic agents demonstrated significant acute glucose lowering in male gk wt/del mice at doses corresponding to therapeutic free drug levels in man, suggesting the potential of these mice as a translatable model of human T2D. Novel GKAs also lowered glucose in this mouse model.

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“…Recent clinical data demonstrate that GKAs can acutely lower glucose levels in non‐diabetic and type 2 diabetic subjects (Bonadonna et al ., ; Ericsson et al ., ; Morrow et al ., ; Norjavaara et al ., ; Sjöstrand et al ., ). Repeat dose studies have shown glucose control can be maintained for 4 weeks (Morrow et al ., ) and up to 14 weeks (Meininger et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Chronic glucokinase activator treatment at clinically translatable exposures gives durable glucose lowering in two animal models of type 2 diabetes

Baker

Wilkinson

Atkinson

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEPharmacological activation of glucokinase (GK) lowers blood glucose in animal models and humans, confirming proof of concept for this mechanism. However, recent clinical evidence from chronic studies suggests that the glucose-lowering effects mediated by glucokinase activators (GKAs) are not maintained in patients with type 2 diabetes (T2D). Existing preclinical data with GKAs do not explain this loss of sustained glucose-lowering efficacy in patients. Here, we have assessed the effects of chronic (up to 11 months) treatment with two different GKAs in two models of T2D. EXPERIMENTAL APPROACHTwo validated animal models of T2D, insulin-resistant obese Zucker rats and hyperglycaemic gk wt/del mice, were treated with two different GKAs for 1 or 11 months respectively at exposures that translate to clinical exposures in humans. Blood glucose, cholesterol, triglycerides and insulin were measured. GKA pharmacokinetics were also determined. KEY RESULTSTreatment with either GKA provided sustained lowering of blood glucose for up to 1 month in the Zucker rat and up to 11 months in hyperglycaemic gk wt/del mice, with maintained compound exposures. This efficacy was achieved without increases in plasma or hepatic triglycerides, accumulation of hepatic glycogen or impairment of glucose-stimulated insulin secretion. CONCLUSIONS AND IMPLICATIONSChronic treatment with two GKAs in two animal models of diabetes provided sustained lowering of blood glucose, in marked contrast to clinical findings. Therefore, either these animal models of T2D are not good predictors of responses in human T2D or we need a better understanding of the consequences of GK activation in humans.

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Pharmacodynamic effects of the oral glucokinase activator AZD6370 after single doses in healthy volunteers assessed with euglycaemic clamp

Cited by 10 publications

References 25 publications

Multiple Comparisons of Glucokinase Activation Mechanisms of Five Mulberry Bioactive Ingredients in Hepatocyte

Multiple Comparisons of Glucokinase Activation Mechanisms of Five Mulberry Bioactive Ingredients in Hepatocyte

Characterization of the heterozygous glucokinase knockout mouse as a translational disease model for glucose control in type 2 diabetes

Chronic glucokinase activator treatment at clinically translatable exposures gives durable glucose lowering in two animal models of type 2 diabetes

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