Glucagon and hyperglycaemia in diabetes

Cryer, Philip E.

doi:10.1042/cs20070434

Cited by 16 publications

(15 citation statements)

References 11 publications

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“…This is manifested as insufficient release of insulin combined with impaired regulation of glucagon secretion [3]. The abnormalities of glucagon secretion are twofold: too much glucagon is secreted during hyperglycaemia and too little is released during hypoglycaemia [4].…”

Section: Introductionmentioning

confidence: 99%

Regulation of glucagon secretion by glucose: paracrine, intrinsic or both?

Walker

Ramracheya

Zhang

et al. 2011

Diabetes Obesity Metabolism

153

187

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Glucagon secretion is regulated by glucose but the mechanisms involved remain hotly debated. Both intrinsic (within the α-cell itself) and paracrine (mediated by factors released β- and/or δ-cells) have been postulated. Glucagon secretion is maximally suppressed by glucose concentrations that do not affect insulin and somatostatin secretion, a finding that highlights the significance of intrinsic regulation of glucagon secretion. Experiments on islets from mice lacking functional ATP-sensitive potassium channels (K(ATP)-channels) indicate that these channels are critical to the α-cell's capacity to sense changes in extracellular glucose. Here, we review recent data on the intrinsic and paracrine regulation of glucagon secretion in human pancreatic islets. We propose that glucose-induced closure of the K(ATP)-channels, via membrane depolarization, culminates in reduced electrical activity and glucagon secretion by voltage-dependent inactivation of the ion channels involved in action potential firing. We further demonstrate that glucagon secretion measured in islets isolated from donors with type-2 diabetes is reduced at low glucose and that glucose stimulates rather than inhibits secretion in these islets. We finally discuss the relative significance of paracrine and intrinsic regulation in the fed and fasted states and propose a unifying model for the regulation of glucagon secretion that incorporates both modes of control.

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Section: Introductionmentioning

confidence: 99%

Regulation of glucagon secretion by glucose: paracrine, intrinsic or both?

Walker

Ramracheya

Zhang

et al. 2011

Diabetes Obesity Metabolism

153

187

View full text Add to dashboard Cite

show abstract

“…Diabetes involves both impaired insulin and glucagon secretion (8). Thus, hyperglucagonemia is thought to contribute to elevated blood glucose levels, and the impaired glucagon response to hypoglycemia represents a limiting factor for insulin treatment in both type 1 and type 2 diabetes (9,10). …”

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confidence: 99%

Membrane Potential-Dependent Inactivation of Voltage-Gated Ion Channels in α-Cells Inhibits Glucagon Secretion From Human Islets

et al. 2010

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OBJECTIVETo document the properties of the voltage-gated ion channels in human pancreatic α-cells and their role in glucagon release.RESEARCH DESIGN AND METHODSGlucagon release was measured from intact islets. [Ca2+]i was recorded in cells showing spontaneous activity at 1 mmol/l glucose. Membrane currents and potential were measured by whole-cell patch-clamping in isolated α-cells identified by immunocytochemistry.RESULTSGlucose inhibited glucagon secretion from human islets; maximal inhibition was observed at 6 mmol/l glucose. Glucagon secretion at 1 mmol/l glucose was inhibited by insulin but not by ZnCl2. Glucose remained inhibitory in the presence of ZnCl2 and after blockade of type-2 somatostatin receptors. Human α-cells are electrically active at 1 mmol/l glucose. Inhibition of KATP-channels with tolbutamide depolarized α-cells by 10 mV and reduced the action potential amplitude. Human α-cells contain heteropodatoxin-sensitive A-type K+-channels, stromatoxin-sensitive delayed rectifying K+-channels, tetrodotoxin-sensitive Na+-currents, and low-threshold T-type, isradipine-sensitive L-type, and ω-agatoxin-sensitive P/Q-type Ca2+-channels. Glucagon secretion at 1 mmol/l glucose was inhibited by 40–70% by tetrodotoxin, heteropodatoxin-2, stromatoxin, ω-agatoxin, and isradipine. The [Ca2+]i oscillations depend principally on Ca2+-influx via L-type Ca2+-channels. Capacitance measurements revealed a rapid (<50 ms) component of exocytosis. Exocytosis was negligible at voltages below −20 mV and peaked at 0 mV. Blocking P/Q-type Ca2+-currents abolished depolarization-evoked exocytosis.CONCLUSIONSHuman α-cells are electrically excitable, and blockade of any ion channel involved in action potential depolarization or repolarization results in inhibition of glucagon secretion. We propose that voltage-dependent inactivation of these channels underlies the inhibition of glucagon secretion by tolbutamide and glucose.

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“…At the peripheral level, sympathetic nerves which innervate alpha cells, but not beta cells, excite additional release of glucagon into the plasma. Finally, the A5 and the adrenal nuclei interchange inhibitory axons and, thus, predominance of A5 is responsible for neural sympathetic activity, hyperinsulinism, hypoglycemia, and bulimia, whereas overactivity of the other neuroendocrine circuitry results in adrenal sympathetic hyperactivity, hyperglucagonism, hyperglycemia, and anorexia 29,30…”

Section: Discussionmentioning

confidence: 99%

Anorexia nervosa depends on adrenal sympathetic hyperactivity: opposite neuroautonomic profile of hyperinsulinism syndrome

Lechín

Dijs²,

Pardey-Maldonado³

et al. 2010

DMSOTT

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ObjectiveThe aim of our study was to determine the central and peripheral autonomic nervous system profiles underlying anorexia nervosa (AN) syndrome, given that affected patients present with the opposite clinical profile to that seen in the hyperinsulinism syndrome.DesignWe measured blood pressure and heart rate, as well as circulating neurotransmitters (noradrenaline, adrenaline, dopamine, plasma serotonin, and platelet serotonin), using high-performance liquid chromatography with electrochemical detection, during supine resting, one minute of orthostasis, and after five minutes of exercise. In total, 22 AN patients (12 binge-eating/purging type and 10 restricting type) and age-, gender-, and race-matched controls (70 ± 10.1% versus 98 ± 3.0% of ideal body weight) were recruited.ResultsWe found that patients with AN had adrenal sympathetic overactivity and neural sympathetic underactivity, demonstrated by a predominance of circulating adrenaline over noradrenaline levels, not only during the supine resting state (52 ± 2 versus 29 ± 1 pg/mL) but also during orthostasis (67 ± 3 versus 32 ± 2 pg/mL, P < 0.05) and after exercise challenge (84 ± 4 versus 30 ± 3 pg/mL, P < 0.01).ConclusionConsidering that this peripheral autonomic nervous system disorder depends on the absolute predominance of adrenomedullary C1 adrenergic nuclei over A5 noradrenergic pontine nucleus, let us ratify the abovementioned findings. The AN syndrome depends on the predominance of overwhelming adrenal sympathetic activity over neural sympathetic activity. This combined central and autonomic nervous system profile contrasts with that registered in patients affected by hyperinsulinism, hypoglycemia, and bulimia syndrome which depends on the absolute predominance of neural sympathetic activity.

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Glucagon and hyperglycaemia in diabetes

Cited by 16 publications

References 11 publications

Regulation of glucagon secretion by glucose: paracrine, intrinsic or both?

Regulation of glucagon secretion by glucose: paracrine, intrinsic or both?

Membrane Potential-Dependent Inactivation of Voltage-Gated Ion Channels in α-Cells Inhibits Glucagon Secretion From Human Islets

Anorexia nervosa depends on adrenal sympathetic hyperactivity: opposite neuroautonomic profile of hyperinsulinism syndrome

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