Dose‐ranging study with the glucokinase activator <scp>AZD1656</scp> in patients with type 2 diabetes mellitus on metformin

Wilding, John; Leonsson-Zachrisson, Maria; Wessman, Catrin; Johnsson, Eva

doi:10.1111/dom.12088

Cited by 84 publications

(117 citation statements)

References 25 publications

(42 reference statements)

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“…However, given the metabolic heterogeneity of ␤-cells in rodent islets (37), the present study suggests that GKAs may be beneficial in poorly responsive ␤-cells while being simultaneously toxic to middle-and highly-responsive ␤-cells through a variety of mechanisms proposed to contribute to glucotoxicity (1). If such "glucotoxic-like" effects of long-term GKA treatment at intermediate glucose concentration were confirmed in human islets, it could contribute to the secondary failure of GKAs in T2D (22,31,47).…”

Section: E636mentioning

confidence: 68%

“…If GKAs undoubtedly trigger liver steatosis (4,6,34), their potential toxicity to ␤-cells remains unclear (4,35,38,43,44,46). Thus, although some GKAs proved beneficial to ␤-cell survival and GSIS under glucotoxic conditions and in islets from T2D patients (8,35,46), their secondary failure during long-term treatment (22,31,47) reopened the question of their toxicity to ␤-cells. This possible caveat of GKAs has been previously considered nonrelevant on the ground that ␤-cell stimulation is reduced following the GKA-mediated reduction in glycemia (12).…”

Section: E636mentioning

confidence: 99%

“…Given the pivotal role of GK in glucose homeostasis, small-molecule GK activators (GKAs) were developed that augment GSIS and hepatic glucose utilization (17), thereby improving glucose homeostasis in rodent and human type 2 diabetes (T2D) (3,7,11,13,29,31,33,48). However, although some GKAs may improve ␤-cell survival and GSIS under glucotoxic conditions, the loss of GKA effectiveness during long-term treatment of T2D (22,47) raises questions about their possible toxicity, e.g., through sustained ␤-cell stimulation.…”

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confidence: 99%

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Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration

Roma

Duprez

Jonas³

2015

American Journal of Physiology-Endocrinology and Metabolism

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Roma LP, Duprez J, Jonas JC. Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration. Am J Physiol Endocrinol Metab 309: E632-E639, 2015. First published August 11, 2015; doi:10.1152/ajpendo.00154.2015.-In rat pancreatic islets, ␤-cell gene expression, survival, and subsequent acute glucose stimulation of insulin secretion (GSIS) are optimally preserved by prolonged culture at 10 mM glucose (G10) and markedly altered by culture at G5 or G30. Here, we tested whether pharmacological glucokinase (GK) activation prevents these alterations during culture or improves GSIS after culture. Rat pancreatic islets were cultured 1-7 days at G5, G10, or G30 with or without 3 M of the GK activator Ro 28-0450 (Ro). After culture, ␤-cell apoptosis and islet gene mRNA levels were measured, and the acute glucose-induced increase in NAD(P)H autofluorescence, intracellular calcium concentration, and insulin secretion were tested in the absence or presence of Ro. Prolonged culture of rat islets at G5 or G30 instead of G10 triggered ␤-cell apoptosis and reduced their glucose responsiveness. Addition of Ro during culture differently affected ␤-cell survival and glucose responsiveness depending on the glucose concentration during culture: it was beneficial to ␤-cell survival and function at G5, detrimental at G10, and ineffective at G30. In contrast, acute GK activation with Ro increased the glucose sensitivity of islets cultured at G10 but failed at restoring ␤-cell glucose responsiveness after culture at G5 or G30. We conclude that pharmacological GK activation prevents the alteration of ␤-cell survival and function by long-term culture at G5 but mimics glucotoxicity when added to G10. The complex effects of glucose on the ␤-cell phenotype result from changes in glucose metabolism and not from an effect of glucose per se. apoptosis; glucotoxicity; insulin secretion; pancreatic ␤-cell GLUCOSE STIMULATION OF INSULIN SECRETION (GSIS) by endocrine pancreatic ␤-cells depends on the acceleration of glucose metabolism through glycolysis and the TCA cycle, with enhanced production of metabolic coupling factors (25,39,41). Besides these rapid effects, glucose exerts complex long-term effects on the ␤-cell phenotype (2,10,16,18,27,45). During long-term culture of rodent islets, ␤-cell gene expression, survival, and glucose responsiveness are optimally preserved in the presence of 10 mM glucose (G10), whereas they are markedly altered by culture at either nonstimulating (G5) or very high (G30) glucose concentrations. In other words, culture at G10 vs. G5 is beneficial, whereas culture at G30 vs. G10 is detrimental to ␤-cell gene expression, survival, and glucose responsiveness. The beneficial effect of culture at G10 vs. G5 is usually attributed to the stimulation of energetic metabolism. In contrast, the deleterious effects of culture at G30 vs. G10, which we later refer to as glucotoxicity, could result from the further increase in metabolism with increased production o...

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Section: E636mentioning

confidence: 68%

Section: E636mentioning

confidence: 99%

mentioning

confidence: 99%

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Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration

Roma

Duprez

Jonas³

2015

American Journal of Physiology-Endocrinology and Metabolism

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“…Although many classes of drugs are currently available for glycemic control in T2DM, there remains a great need for drugs with new mechanisms of action that can be added to or replace currently available drugs (Mittermayer et al, 2015). reduction in hemoglobin A1c (HbA1c) in T2DM patients (Meininger et al, 2011;Wilding et al, 2013;Kiyosue et al, 2013;Kazierad et al, 2013). However, clinical trials of several GK activators also revealed a loss of efficacy over time with sustained treatment and an increase in plasma triglyceride (TG) levels.…”

Section: Introductionmentioning

confidence: 99%

Increased hepatic triglyceride level induced by a glucokinase activator in mice

Namekawa

Yasui

Katayanagi

et al. 2018

Fundam. Toxicol. Sci.

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“…Given its major role in glucose metabolism, efforts have been undertaken to develop glucokinase activators as a potential new class of glucose-lowering drugs (4). Clinical studies have demonstrated that these systemic activators are capable of lowering plasma glucose levels, albeit at the expense of hypoglycemia (5,6). This undesired side effect could be circumvented by organ-specific glucokinase activators, which only act in the liver, not in the pancreas (7).…”

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confidence: 99%

A Common Gene Variant in Glucokinase Regulatory Protein Interacts With Glucose Metabolism on Diabetic Dyslipidemia: the Combined CODAM and Hoorn Studies

et al. 2016

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OBJECTIVESmall molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP) are potential new glucose-lowering targets. They stimulate hepatic glucose disposal by increasing glucokinase activity in the liver. It can, however, be anticipated that increased hepatic glucokinase activity might be accompanied by the development of hypertriglyceridemia, particularly in type 2 diabetes. We examined whether the strength of association between rs1260326, a common, functional gene variant in GKRP, and plasma lipids is affected by glucose metabolism. RESEARCH DESIGN AND METHODSrs1260326 was genotyped in subjects with normal glucose metabolism (n = 497), subjects with impaired glucose metabolism (n = 256), and patients with type 2 diabetes (n = 351) in the combined Hoorn and Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) studies. RESULTSThe strength of association between the rs1260326 minor T allele and plasma triglycerides increased from normal glucose metabolism to impaired glucose metabolism to type 2 diabetes (P for interaction = 0.002). The inverse relation between rs1260326 and plasma HDL cholesterol was again most prominent in type 2 diabetes (P for interaction = 0.004). Similar trends were observed when the Hoorn and CODAM cohorts were analyzed separately. Comparable results were obtained when glucose metabolism strata were replaced by continuous indices of glucose metabolism, i.e., HbA 1c and fasting plasma glucose. CONCLUSIONSThese findings illustrate that common gene variants, such as rs1260326, can have substantial effect sizes when they are studied in specific populations, such as type 2 diabetes. Moreover, our results shed light on potential side effects of small molecule disruptors of the GKRP-glucokinase complex, especially when glucose control is suboptimal.

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Dose‐ranging study with the glucokinase activator AZD1656 in patients with type 2 diabetes mellitus on metformin

Abstract: Addition of AZD1656 (individually titrated) to metformin gave significant improvements in glycaemic control up to 4 months, although efficacy diminished over time.

Cited by 84 publications

References 25 publications

Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration

Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration

Increased hepatic triglyceride level induced by a glucokinase activator in mice

A Common Gene Variant in Glucokinase Regulatory Protein Interacts With Glucose Metabolism on Diabetic Dyslipidemia: the Combined CODAM and Hoorn Studies

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