Glucose Cycling in Islets From Healthy and Diabetic Rats

Khan, Abdul Waheed; Chandramouli, Visvanathan; Östenson, Claes‐Göran; Löw, H.; Landau, Bernard R.; Efendić, Suad

doi:10.2337/diab.39.4.456

Cited by 46 publications

(34 citation statements)

References 23 publications

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“…However, in islets from ob/ob mice, 30±40 % of phosphorylated glucose was dephosphorylated [10]. Glucose cycling was also increased in islets from other animal models of Type II diabetes [11,12]. In accordance with these results, G6Pase activity was several fold higher in islets from diabetic than normal animals [7,13] and islet G6Pase gene expression was increased during the development of diabetes in Zucker rats [14].…”

supporting

confidence: 75%

Increased glucocorticoid sensitivity in islet beta-cells: effects on glucose 6-phosphatase, glucose cycling and insulin release

et al. 1998

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Glucose-6-phosphatase (G6Pase) and glucokinase activities can be demonstrated in pancreatic islets from mammalian species [1±4]. Glucokinase appears to be the rate limiting enzyme of glycolysis in the beta-cell, regulating the dose-response relationship between glucose utilization and insulin release [4]. Since G6Pase opposes the action of glucokinase, a possible role for G6Pase in the metabolic regulation of insulin release was postulated [2,3]. There are several reports of relatively low G6Pase activity in homogenates of normal mammalian islets [1±4], one of activity exceeding that in liver [5] and one of no activity [6]. We found low activity in permeabilized and sonicated islets from normal rats and mice [7]. Sweet et al. [8] also found low G6Pase activity in intact islets from normal rats.Glucose cycling is the simultaneous phosphorylation of glucose to glucose-6-P and dephosphorylation of glucose-6-P to glucose with the resulting consumption of ATP [9]. In accordance with reports of low G6Pase activity, we demonstrated a low rate of glucose cycling in intact islets from normal mice, dephosphorylation occurring at only 3 % of the rate of phosphorylation [10]. However, in islets from ob/ob mice, 30±40 % of phosphorylated glucose was dephosphorylated [10]. Glucose cycling was also increased in islets from other animal models of Type II diabetes [11,12]. In accordance with these results, G6Pase activity was several fold higher in islets from diabetic than normal animals [7,13] and islet G6Pase gene expression was increased during the development of diabetes in Zucker rats [14]. Diabetologia (1998) Summary Glucose-6-phosphatase (G6Pase) activity and the rate of glucose cycling are increased in islets from animal models of Type II (non-insulin-dependent) diabetes mellitus. Glucocorticoid treatment further stimulates these processes and inhibits glucose-induced insulin release. To determine whether these effects result from a direct action of glucocorticoids on the beta-cells, we used isolated islets. The islets were from transgenic mice overexpressing the glucocorticoid receptor in their beta-cells to increase the cells' sensitivity to glucocorticoid. Islets from transgenic and non-transgenic control mice utilized and oxidized the same amount of glucose. In contrast, islet G6Pase activity was 70 % higher, glucose cycling was increased threefold and insulin release was 30 % lower in islets from transgenic mice. Hepatic G6Pase activity was the same in transgenic and control mice. Dexamethasone administration increased G6Pase activity and glucose cycling and decreased insulin release in both transgenic and control mouse islets. We conclude that glucocorticoids stimulate islet G6Pase activity and glucose cycling by acting directly on the beta-cell. That activity may be linked to the inhibition of insulin release. [Diabetologia (1998) 41: 634±639]

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confidence: 75%

Increased glucocorticoid sensitivity in islet beta-cells: effects on glucose 6-phosphatase, glucose cycling and insulin release

et al. 1998

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“…Overexpression of full-length G6PC2 could increase glucose-6-phosphatase activity [14]; thus, it may functionally antagonise glucokinase activity, which is critical for glucose utilisation and glucose-stimulated insulin secretion. Moreover, increased G6PC2 activity has been observed in islets from several animal models of diabetes, including the streptozotocin-induced diabetic rat, Goto-Kakizaki rat and ob/ob mice [15][16][17].…”

Section: Discussionmentioning

confidence: 99%

A genetic variant of G6PC2 is associated with type 2 diabetes and fasting plasma glucose level in the Chinese population

Zhang

Wang

et al. 2008

Diabetologia

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Aims/hypothesis Single nucleotide polymorphisms (SNPs) in G6PC2 have been reported to be associated with fasting plasma glucose level in several populations of European descent. However, whether G6PC2 variants have a similar effect in other ethnic groups is unknown. The aim of this study was to investigate the effect of common variants of G6PC2 on type 2 diabetes and related clinical features in a Chinese population. Methods We selected four SNPs, rs13387347, rs2232316, rs492594 and rs16856187, tagging all the common variants spanning the G6PC2 gene (r 2 ≥0.8) based on HapMap Chinese data, and genotyped them in a group of 3,676 Shanghai Chinese individuals, comprising 1,876 cases and 1,800 controls. Results Three SNPs were nominally associated with type 2 diabetes, with rs16856187 showing the strongest evidence for association (p=0.0009, empirical p=0.0047). Further conditional analysis revealed that the association signal arose from an individual SNP, rs16856187. This SNP was also associated with fasting plasma glucose level in participants with normal glucose regulation (p=0.0002), with the fasting plasma glucose level observed to increase by 0.067 mmol/l with each copy of the rare C allele. Conclusions/interpretation In this study we identified a novel risk-conferring G6PC2 SNP for type 2 diabetes in a Chinese population and confirmed the previous finding that G6PC2 variants are associated with fasting plasma glucose concentration.

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“…Jego wzmożenie w wątrobie opisywano in vivo u pacjentów z zespołem Cushinga [24]. Prawidłowe wyspy trzustkowe prezentują nieistotne nasilenie tego nieefektywnego procesu, ponieważ tempo defosforylacji glukozy jest bardzo małe [66,67]. Glucose cycling okazuje się natomiast istotnie zwiększony w wyspach gryzoni z otyłością i z cukrzycą, a proces ten jest nasilany pod wpływem GKS poprzez wzrost aktywności wyspowej glukozo-6-fosfatazy [53,66,68].…”

Section: Prace Poglądoweunclassified

“…Enhanced hepatic glucose cycling was demonstrated in vivo in patients with Cushing's syndrome [24]. Normal pancreatic islets display a negligible rate of this futile process because the glucose dephosphorylation rate is very low [66,67]. However, glucose cycling was considerably elevated in islets from diabetic and obese rodents, and this process was enhanced under the GC influence, through an increase in islet glucose-6-phosphatase activity [53,66,68].…”

Section: Inhibitory Glucocorticoid Effect On Insulin Secretion In Vitromentioning

confidence: 99%

Glikokortykosteroidy a czynność komórek beta

Fichna

2017

Endokrynologia Polska

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Glucocorticoids (GCs) play a pivotal role in carbohydrate metabolism. They counteract insulin by decreasing peripheral glucose uptake and stimulating hepatic gluconeogenesis, although they are best known for inducing insulin resistance (IR). Moreover, GCs may attenuate the incretin effect. Nevertheless, their direct impact on beta cells is not fully defined. This review aims to present the current understanding of this subject. Humans exposed to GC excess display IR, impaired glucose tolerance, and eventually develop diabetes. Although their insulin levels are elevated, they present lower insulin output in response to glucose than obese individuals. Rodent models demonstrate that GC-induced IR is accompanied by compensatory beta-cell hyperplasia. GC excess with high-fat diet leads to fasting hyperglycaemia and suppressed glucose-stimulated insulin secretion (GSIS) despite increased beta cell mass. The majority of in vitro studies confirm an inhibitory GC effect on insulin secretion. The mechanism remains ambiguous but might involve its direct influence upon expression of molecules essential for glucose sensing and metabolism, enhanced glucose cycling, down-regulated insulin gene transcription, hampered insulin exocytosis, amplified alpha-adrenergic signalling, and/or increased beta-cell apoptosis. There are also reports that suggest increased GSIS after beta cell exposure to GCs in vitro. Transgenic mice with enhanced corticosterone regeneration within their beta cells present augmented secretory capacity of their islets. To summarise, GCs exert a significant role in carbohydrate balance through various mechanisms, including direct impact on beta cell function. Observed discrepancies may arise from differences in study design. A thorough understanding of GC action will provide important clinical clues for disorders of glucose homeostasis. (Endokrynol Pol 2017; 68 (5): 568-573)

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Glucose Cycling in Islets From Healthy and Diabetic Rats

Cited by 46 publications

References 23 publications

Increased glucocorticoid sensitivity in islet beta-cells: effects on glucose 6-phosphatase, glucose cycling and insulin release

Increased glucocorticoid sensitivity in islet beta-cells: effects on glucose 6-phosphatase, glucose cycling and insulin release

A genetic variant of G6PC2 is associated with type 2 diabetes and fasting plasma glucose level in the Chinese population

Glikokortykosteroidy a czynność komórek beta

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