The microsomal glucose-6-phosphatase enzyme of pancreatic islets

Waddell, Ian D.; Burchell, Ann

doi:10.1042/bj2550471

Cited by 64 publications

(42 citation statements)

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“…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].…”

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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: 53%

“…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].…”

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confidence: 99%

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

et al. 1998

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“…Immunoblot analysis of microsomal samples was carried out exactly as described in [16] using sheep antiserum previously shown to be monospecific for the rat hepatic microsomal glucose-6-phosphatase enzyme [6,17].…”

Section: Sds-page Autoradiography and Immunoblot Analysismentioning

confidence: 99%

Identification of the human hepatic microsomal glucose‐6‐phosphatase enzyme

et al. 1988

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“…Luminal H6PHD has dual catalytic activity including G6P dehydrogenase and 6-phosphogluconolactonase activities. Its K m for G6P is low (≈1.5 μM), far less than the corresponding value of 0.5-5.0 mM for G6Pase (Waddell & Burchell 1988, Waddell et al 1990, Foster et al 1991, Minassian et al 1995, Kelmer-Bracht et al 2003.…”

Section: Kinetic Considerationsmentioning

confidence: 99%

“…. (Waddell & Burchell 1988, Waddell et al 1990, Foster et al 1991, Minassian et al 1995, Kelmer-Bracht et al 2003, When the temporal production of CO 2 production is linear, the reactions are at steady state. Under our experimental conditions, using high concentrations of NADP, the two-substrate enzyme reactions (namely vH and vPG) reduce to single-substrate MM kinetics.…”

Section: Kinetic Considerationsmentioning

confidence: 99%

Cortisol promotes endoplasmic glucose production via pyridine nucleotide redox

Wang

Mick

Xie

et al. 2016

Journal of Endocrinology

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Both increased adrenal and peripheral cortisol production, the latter governed by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), contribute to the maintenance of fasting blood glucose. In the endoplasmic reticulum (ER), the pyridine nucleotide redox state (NADP/NADPH) is dictated by the concentration of glucose-6-phosphate (G6P) and the coordinated activities of two enzymes, hexose-6-phosphate dehydrogenase (H6PDH) and 11β-HSD1. However, luminal G6P may similarly serve as a substrate for hepatic glucose-6-phophatase (G6Pase). A tacit belief is that the G6P pool in the ER is equally accessible to both H6PDH and G6Pase. Based on our inhibition studies and kinetic analysis in isolated rat liver microsomes, these two aforesaid luminal enzymes do share the G6P pool in the ER, but not equally. Based on the kinetic modeling of G6P flux, the ER transporter for G6P (T 1 ) preferentially delivers this substrate to G6Pase; hence, the luminal enzymes do not share G6P equally. Moreover, cortisol, acting through 11β-HSD1, begets a more reduced pyridine redox ratio. By altering this luminal redox ratio, G6P flux through H6PDH is restrained, allowing more G6P for the competing enzyme G6Pase. And, at low G6P concentrations in the ER lumen, which occur during fasting, this acute cortisol-induced redox adjustment promotes glucose production. This reproducible cortisol-driven mechanism has been heretofore unrecognized. Microsomal cortisol and glucosez wang and others

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The microsomal glucose-6-phosphatase enzyme of pancreatic islets

Cited by 64 publications

References 53 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

Identification of the human hepatic microsomal glucose‐6‐phosphatase enzyme

Cortisol promotes endoplasmic glucose production via pyridine nucleotide redox

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