Improvement in Insulin Secretion in Diabetes After Diazoxide

Greenwood, R.; Mahler, Robert; Hales, C. N.

doi:10.1016/s0140-6736(76)91473-2

Cited by 107 publications

(85 citation statements)

References 24 publications

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“…We and others have suggested that a depletion of beta cell insulin stores is a cause of the lowered insulin secretion in type 2 diabetes, these proposals being based on studies of animal models of diabetes and of human patients showing a paradoxical rise in stimulated insulin output after pharmacological [12][13][14] and fasting-induced inhibition of insulin secretion [32,33]. The current study supports this view in part, as the lowered insulin response to arginine at high glucose in the ZF-Px rats equalled or exceeded that in other groups after correcting for their relative pancreas insulin contents.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in humans and animals have suggested the concept of hyperglycaemia-induced depletion of the releasable stores of insulin (also called beta cell exhaustion) based on augmented insulin responses following inhibition of insulin secretion by diazoxide or somatostatin [12][13][14]. On the other hand, in vitro and whole-animal studies have reported a direct inhibitory effect of excess NEFA, such as occurs with insulin resistance, on glucose-mediated insulin secretion [15], proinsulin biosynthesis [15,16] and beta cell survival [17,18].…”

Section: Introductionmentioning

confidence: 99%

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Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

Delghingaro-Augusto¹,

Nolan

Gupta

et al. 2009

Diabetologia

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Aims/hypothesis The Zucker fatty (ZF) rat subjected to 60% pancreatectomy (Px) develops moderate diabetes by 3 weeks. We determined whether a progressive fall in beta cell mass and/or beta cell dysfunction contribute to beta cell failure in this type 2 diabetes model. Methods Partial (60%) or sham Px was performed in ZF and Zucker lean (ZL) rats. At 3 weeks post-surgery, beta cell mass and proliferation, proinsulin biosynthesis, pancreatic insulin content, insulin secretion, and islet glucose and lipid metabolism were measured. Results ZL-Px rats maintained normal glycaemia and glucose-stimulated insulin secretion (GSIS) despite incomplete recovery of beta cell mass possibly due to compensatory enhanced islet glucose metabolism and lipolysis. ZF-Px rats developed moderate hyperglycaemia (14 mmol/l), hypertriacylglycerolaemia and relative hypoinsulinaemia. Despite beta cell mass recovery and normal arginine-induced insulin secretion, GSIS and pancreatic insulin content were profoundly lowered in ZF-Px rats. Proinsulin biosynthesis was not reduced. Compensatory increases in islet glucose metabolism above those observed in ZF-Sham rats were not seen in ZF-Px rats. Triacylglycerol content was not increased in ZF-Px islets, possibly due to lipodetoxification by enhanced lipolysis and fatty acid oxidation. Fatty acid accumulation into monoacylglycerol and diacylglycerol was increased in ZF-Px islets together with a 4.5-fold elevation in stearoyl-CoA desaturase mRNA expression. Conclusions/interpretation Falling beta cell mass, reduced proinsulin biosynthesis and islet steatosis are not implicated in early beta cell failure and glucolipotoxicity in ZF-Px rats. Rather, severe beta cell dysfunction with a specific reduction in GSIS and marked depletion of beta cell insulin stores with altered lipid partitioning underlie beta cell failure in this animal model of type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

Delghingaro-Augusto¹,

Nolan

Gupta

et al. 2009

Diabetologia

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“…Treatment with the insulin secretion inhibitor diazoxide prevents impairment of beta cell function in rats administered a 48 h glucose infusion [22], in 90% pancreatectomised diabetic rats [23] and in streptozotocintreated rats [24]. Furthermore, treatment of patients with type 2 diabetes with diazoxide or somatostatin resulted in improved glucagon-and tolbutamide-induced insulin secretion [25] and restored insulin pulsatility and the insulin/ proinsulin ratio in vitro [26]. Recently, Accili and colleagues suggested that protection against hyperglycaemia and oxidative stress could be afforded to beta cells as a result of increased levels of the forkhead protein Foxo1, which can lead to a concerted repression of genes involved in glycolysis, nitric oxide synthesis, G-protein-coupled receptor signalling and ion transport [27].…”

Section: Ermentioning

confidence: 99%

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

et al. 2008

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“…Indeed, sustained increase in circulating free fatty acid levels has been connected with impaired insulin secretion in individuals predisposed to develop T2DM (Kashyap et al 2003), where the altered insulin release kinetics (Lang et al 1981, O'Rahilly et al 1988 plays an important role by decreasing the ability of the hormone to exert its glucose and fatty acid-lowering effects (Paolisso et al 1988). In an attempt to ameliorate the secretory defects, diazoxide was administered to individuals with T2DM for 5 days (Greenwood et al 1976). The drug hyperpolarizes the plasma membrane via opening of the ATP-sensitive K C channels leading to cessation of Ca 2C influx and insulin granular exocytosis leading to b-cell rest (Petit & Loubatieres-Mariani 1992, Seino et al 1997.…”

Section: Introductionmentioning

confidence: 99%

Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

Sargsyan¹,

Ortsäter

Thörn³

et al. 2008

Journal of Endocrinology

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Elevated levels of glucose and lipids are characteristics of individuals with type 2 diabetes mellitus (T2DM). The enhanced nutrient levels have been connected with deterioration of b-cell function and impaired insulin secretion observed in these individuals. A strategy to improve b-cell function in individuals with T2DM has been intermittent administration of K ATP channel openers. After such treatment, both the magnitude and kinetics of insulin secretion are markedly improved. In an attempt to further delineate mechanisms of how openers of K ATP channels improve b-cell function, the effects of diazoxide on markers of endoplasmic reticulum (ER) stress was determined in b-cells exposed to the fatty acid palmitate. The eukaryotic translation factor 2-alpha kinase 3 (EIF2AK3; also known as PERK) and endoplasmic reticulum to nucleus signaling 1 (ERN1; also known as IRE1) pathways, but not the activating transcription factor (ATF6) pathway of the unfolded protein response, are activated in such lipotoxic b-cells. Inclusion of diazoxide during culture attenuated activation of the EIF2AK3 pathway but not the ERN1 pathway. This attenuation was associated with reduced levels of DNA-damage inducible transcript 3 (DDIT3; also known as CHOP) and b-cell apoptosis was decreased. It is concluded that reduction of ER stress may be a mechanism by which diazoxide improves b-cell function.

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Improvement in Insulin Secretion in Diabetes After Diazoxide

Cited by 107 publications

References 24 publications

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

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