Evidence That Extrapancreatic GLUT2-Dependent Glucose Sensors Control Glucagon Secretion

Burcelin, Rémy; Thorens, Bernard

doi:10.2337/diabetes.50.6.1282

Cited by 69 publications

(58 citation statements)

References 55 publications

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“…Whereas the ␤-cell model of glucose sensing would apply to the sensors controlled by high glucose, it is not clear how glucoprivation could stimulate feeding in a GLUT2-dependent manner. We previously reported that in ripglut1;glut2 Ϫ/Ϫ mice (in a mixed genetic background), the glucagon response to both hypoglycemic and hyperglycemic clamps was lost (46). We proposed that these results could be explained by the presence of two sets of glucose sensors, both GLUT2-dependent, one which stimulates glucagon production and which is progressively inhibited when glucose concentrations are increased and the other that generates an inhibitory signal for glucagon secretion, which increases when glucose concentrations rise.…”

Section: Discussionmentioning

confidence: 99%

Evidence From Glut2-Null Mice That Glucose Is a Critical Physiological Regulator of Feeding

et al. 2006

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A role for glucose in the control of feeding has been proposed, but its precise physiological importance is unknown. Here, we evaluated feeding behavior in glut2-null mice, which express a transgenic glucose transporter in their ␤-cells to rescue insulin secretion (ripglut1;glut2 Ϫ/Ϫ mice). We showed that in the absence of GLUT2, daily food intake was increased and feeding initiation and termination following a fasting period were abnormal. This was accompanied by suppressed regulation of hypothalamic orexigenic and anorexigenic neuropeptides expression during the fast-to-refed transition. In these conditions, however, there was normal regulation of the circulating levels of insulin, leptin, or glucose but a loss of regulation of plasma ghrelin concentrations. To evaluate whether the abnormal feeding behavior was due to suppressed glucose sensing, we evaluated feeding in response to intraperitoneal or intracerebroventricular glucose or 2-deoxy-D-glucose injections. We showed that in GLUT2-null mice, feeding was no longer inhibited by glucose or activated by 2-deoxy-D-glucose injections and the regulation of hypothalamic neuropeptide expression by intracerebroventricular glucose administration was lost. Together, these data demonstrate that absence of GLUT2 suppresssed the function of central glucose sensors, which control feeding probably by regulating the hypothalamic melanocortin pathway. Futhermore, inactivation of these glucose sensors causes overeating. Diabetes 55: 988 -995, 2006 T he control of body weight depends on the balance between food intake and energy expenditure. The current epidemic of obesity, which represents a major risk factor for the development of type 2 diabetes and cardiovascular diseases, is caused by a dysregulation of this homeostatic process (1). Both internal and environmental signals cooperate to trigger or terminate food intake and to stimulate anabolic or catabolic pathways. The internal signals are hormones derived from the gut, such as ghrelin, cholecystokinin, glucagon-like peptide-1, or peptide YY 3-36 , from adipocytes (leptin), and pancreatic ␤ cells (insulin) but also nutrients such as glucose and lipids. These signals are integrated by the central nervous system to control feeding and energy expenditure (2,3). In this integrative function, the melanocortin pathway of the hypothalamus plays a critical role, as it is directly regulated by hormones and nutrients (4 -9). This pathway consists of neurons of the arcuate nucleus, which synthesize either orexigenic (neuropeptide Y [NPY] and agouti-related peptide [AgRP]) or anorexigenic (proopiomelanocortin [POMC] and cocaine-and amphetaminerelated transcript [CART]) neuropeptides. These then regulate second-order neurons, in particular those located in the paraventricular hypothalamic nucleus (PVN) or the lateral hypothalamus (LH). Whereas the PVN neurons express anorexigenic peptides such as thyrotropin-releasing hormone (TRH) and corticotropin-releasing hormone (CRH), LH neurons express the orexigenic peptides orexins and...

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Section: Discussionmentioning

confidence: 99%

Evidence From Glut2-Null Mice That Glucose Is a Critical Physiological Regulator of Feeding

et al. 2006

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“…They concluded that insulin maintains an ongoing restraint on ␣-cell secretion and that loss of this inhibition by insulin may account for the hyperglucagonemia observed in insulin-deficient states. These initial observations were followed by a series of in vivo and in vitro experiments (23)(24)(25)(26)(27)(28)(29)(30) [AICAR]) and phlorizin. This combination induced moderate and equivalent hypoglycemia in both diabetic and nondiabetic animals in the absence of marked hyperinsulinemia.…”

Section: Discussionmentioning

confidence: 99%

Regulation of α-Cell Function by the β-Cell in Isolated Human and Rat Islets Deprived of Glucose: the “Switch-off” Hypothesis

et al. 2004

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The "switch-off" hypothesis to explain ␤-cell regulation of ␣-cell function during hypoglycemia has not been assessed previously in isolated islets, largely because they characteristically do not respond to glucose deprivation by secreting glucagon. We examined this hypothesis using normal human and Wistar rat islets, as well as islets from streptozotocin (STZ)-administered ␤-celldeficient Wistar rats. As expected, islets perifused with glucose and 3-isobutryl-1-methylxanthine did not respond to glucose deprivation by increasing glucagon secretion. However, if normal rat islets were first perifused with 16.7 mmol/l glucose to increase endogenous insulin secretion, followed by discontinuation of the glucose perifusate, a glucagon response to glucose deprivation was observed (peak change within 10 min after switch off ‫؍‬ 61 ؎ 15 pg/ml [mean ؎ SE], n ‫؍‬ 6, P < 0.01). A glucagon response from normal human islets using the same experimental design was also observed. A glucagon response (peak change within 7 min after switch off ‫؍‬ 31 ؎ 1 pg/ml, n ‫؍‬ 3, P < 0.01) was observed from ␤-cell-depleted, STZ-induced diabetic rats whose islets still secreted small amounts of insulin. However, when these islets were first perifused with both exogenous insulin and 16.7 mmol/l glucose, followed by switching off both the insulin and glucose perifusate, a significantly larger (P < 0.05) glucagon response was observed (peak change within 7 min after switch off ‫؍‬ 71 ؎ 11 pg/ml, n ‫؍‬ 4, P < 0.01). This response was not observed if the insulin perifusion was not switched off when the islets were deprived of glucose or when insulin was switched off without glucose deprivation. These data uniquely demonstrate that both normal, isolated islets and islets from STZ-administered rats can respond to glucose deprivation by releasing glucagon if they are first provided with increased endogenous or exogenous insulin. These results fully support the ␤-cell switch-off hypothesis as a key mechanism for the ␣-cell response to hypoglycemia.

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“…Mice with inactivation of the Glut2 gene, and that express a transgenic glucose transporter in their pancreatic beta-cells to preserve normal glucose-stimulated insulin secretion (ripglut1;glut2 À/À mice), 61 display plasma glucagon levels in the fed state that are abnormally high. As glucagonemia can be rapidly normalized by ganglionic blockade, 62 this indicates that Glut2 (which is not expressed in alpha-cells) is required for the control of glucagon secretion. This was further shown by the lack of stimulation or decrease in plasma glucagon during, respectively, hypoglycemic or hyperinsulinemic clamp experiments.…”

Section: S64mentioning

confidence: 99%

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Thorens

2008

Int J Obes

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The control of body weight and of blood glucose concentrations depends on the exquisite coordination of the function of several organs and tissues, in particular the liver, muscle and fat. These organs and tissues have major roles in the use and storage of nutrients in the form of glycogen or triglycerides and in the release of glucose or free fatty acids into the blood, in periods of metabolic needs. These mechanisms are tightly regulated by hormonal and nervous signals, which are generated by specialized cells that detect variations in blood glucose or lipid concentrations. The hormones insulin and glucagon not only regulate glycemic levels through their action on these organs and the sympathetic and parasympathetic branches of the autonomic nervous system, which are activated by glucose or lipid sensors, but also modulate pancreatic hormone secretion and liver, muscle and fat glucose and lipid metabolism. Other signaling molecules, such as the adipocyte hormones leptin and adiponectin, have circulating plasma concentrations that reflect the level of fat stored in adipocytes. These signals are integrated at the level of the hypothalamus by the melanocortin pathway, which produces orexigenic and anorexigenic neuropeptides to control feeding behavior, energy expenditure and glucose homeostasis. Work from several laboratories, including ours, has explored the physiological role of glucose as a signal that regulates these homeostatic processes and has tested the hypothesis that the mechanism of glucose sensing that controls insulin secretion by the pancreatic beta-cells is also used by other cell types. I discuss here evidence for these mechanisms, how they integrate signals from other nutrients such as lipids and how their deregulation may initiate metabolic diseases.

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Evidence That Extrapancreatic GLUT2-Dependent Glucose Sensors Control Glucagon Secretion

Cited by 69 publications

References 55 publications

Evidence From Glut2-Null Mice That Glucose Is a Critical Physiological Regulator of Feeding

Evidence From Glut2-Null Mice That Glucose Is a Critical Physiological Regulator of Feeding

Regulation of α-Cell Function by the β-Cell in Isolated Human and Rat Islets Deprived of Glucose: the “Switch-off” Hypothesis

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

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