KATP-channels and glucose-regulated glucagon secretion

doi:10.1016/j.tem.2008.07.003

Trends in Endocrinology & Metabolism

Volume 19, Issue 8, October 2008, Pages 277-284

https://doi.org/10.1016/j.tem.2008.07.003 Get rights and content

Glucagon, secreted by the α-cells of the pancreatic islets, is the most important glucose-increasing hormone of the body. The precise regulation of glucagon release remains incompletely defined but has been proposed to involve release of inhibitory factors from neighbouring β-cells (paracrine control). However, the observation that glucose can regulate glucagon secretion under conditions when insulin secretion does not occur argues that the α-cell is also equipped with its own intrinsic (exerted within the α-cell itself) glucose sensing. Here we consider the possible mechanisms involved with a focus on ATP-regulated K⁺-channels and changes in α-cell membrane potential.

Introduction

Glucagon is the principal hormone responsible for maintaining plasma glucose at appropriate levels during periods of increased functional demand 1, 2. Glucagon is released by α-cells of the pancreatic islets in response to a fall in plasma glucose levels (hypoglycaemia), β-adrenergic stimulation, lipids (such as oleate and palmitate) and amino acids (like arginine) 3, 4, 5. Control of glucagon secretion from α-cells involves paracrine [3], neuronal (mediated by the autonomic nervous system [6]) and intrinsic mechanisms [7]. All of these mechanisms potentially contribute to the physiological regulation of glucagon secretion. However, the observation that glucose remains capable of regulating glucagon release in isolated pancreatic islets, where the nerves have been severed, demonstrates the existence of nonneuronal regulatory mechanisms exerted within the islet itself; however, the nature of this intrinsic regulation remains debated.

The α-cells comprise a small fraction (15–20%) of the pancreatic islet cells; therefore, much effort has been invested into isolating pure fractions of α-cells by fluorescence-activated cell sorting (FACS) [8]. Biochemical characterization of α-cells obtained from FACS analysis has revealed that they express glucokinase and ATP-regulated K⁺-channels (K_ATP-channels) 9, 10, 11, two proteins regarded as hallmarks of β-cell glucose sensing [12]. In fact, increasing glucose concentrations results in a concentration-dependent acceleration of glucose metabolism in both α- and β-cells [13]. Measurements of α-cell cytoplasmic ATP ([ATP]_i) using targeted expression of the ATP-sensor luciferase reveal that α-cell [ATP]_i is high at low glucose levels and, as in β-cells, increases even further in response to glucose 14, 15. In the α-cell, glucagon is stored in dense core secretory granules. Glucagon is released from the α-cell by Ca²⁺-dependent exocytosis of these secretory granules [5]. The α-cell is electrically excitable, and the ion channels involved in action potential firing and exocytosis of glucagon have been characterized in some detail 5, 10, 16, 17.

Despite the recent increase in our knowledge of α-cell physiology and biochemistry, we still lack a coherent model of metabolic regulation of the α-cell. Indeed, given the many similarities between α- and β-cells, one might wonder why glucose inhibits secretion from one (glucagon, from α-cells) while stimulating secretion from the other (insulin, from β-cells). The answer to this question is clinically significant because diabetes is often associated with aberrant hypersecretion of glucagon at high plasma glucose levels (normally inhibited at such levels), which contributes to the hyperglycaemia that is a hallmark of diabetes and that is believed to underlie the secondary complications associated with the disease [18]. Conversely, during hypoglycaemia (i.e. low plasma glucose, for example, induced by injection of too much insulin), diabetic patients frequently exhibit impaired counter-regulation and fail to increase glucagon release 1, 19, 20, 21. Hypoglycaemia is a clinically significant problem and is believed to cause 2–4% of deaths in insulin-treated diabetic patients [1]. Understanding the cellular and molecular regulation of glucagon secretion may lead to refinement of current therapies and to the discovery of new targets that would reduce the risk of this life-threatening condition.

Section snippets

Paracrine regulation of glucagon secretion

Glucagon secretion from the α-cell involves both intrinsic (i.e. within the α-cell itself) and paracrine mechanisms (mediated by factors released by the neighbouring β- and δ-cells). Paracrine regulation of α-cells by β-cells is facilitated by the architecture of the islet. In the human islets an extensive lattice of α-cells extends throughout the islet and into regions rich in β-cells, and the two cell types are often situated in immediate proximity of each other. The significance of paracrine

Intrinsic α-cell regulation of glucagon secretion: role of K_ATP-channels

In addition to paracrine control of glucagon release, which has recently been extensively reviewed elsewhere [3], α-cells clearly also possess an intrinsic glucose-sensing mechanism that accounts for their ability to respond to glucose at concentrations too low to elicit insulin or somatostatin secretion (Figure 1a). It has been proposed that this intrinsic regulation involves a store-operated depolarizing current. At low glucose, conductance is active because intracellular Ca²⁺ stores are

Pancreatic α-cells are electrically active in the absence of glucose

Pancreatic α-cells are electrically excitable and use electrical signals to couple variations of plasma glucose to changes in glucagon release. Unlike β-cells, α-cells fire action potentials in the absence of glucose 5, 17, 38, 39. Electrophysiological recordings from mouse α-cells suggest that action potentials (Figure 2a) depend on a low-threshold T-type Ca²⁺-channel (involved in the pacemaking of the α-cell), voltage-gated tetrodotoxin-sensitive Na⁺-channels (mediating the upstroke of the

Link between K_ATP-channel closure and inhibition of glucagon secretion

How can tolbutamide-induced inhibition of K_ATP-channels inhibit glucagon secretion? Many voltage-gated ion channels exhibit a dual dependence on membrane potential (Figure 2c). Whereas depolarization is required to activate channels, sustained depolarization renders the channels inactivated (nonconducting). The channels inactivate (completely or partially) during the action potential (shown schematically in Figure 2d). Once a channel has undergone inactivation, reactivation can only occur if

Comparison of the effects of glucose and tolbutamide

Figure 4a summarizes the sequence of events leading to inhibition of glucagon secretion initiated by the selective K_ATP-channel blocker tolbutamide or moderate elevation of extracellular [K⁺]. By closing K_ATP-channels, tolbutamide depolarizes the α-cell and potentially leads to inactivation of the ion channels involved in action potential firing and glucagon release. Elevation of extracellular K⁺ has a similar effect. Glucose may exert a tolbutamide-like effect on K_ATP-channel activity and

Significance to the understanding and treatment of diabetes

The concept that glucagon secretion only occurs in a narrow window of K_ATP-channel activity and that an optimum of channel activity exists for maximal glucagon secretion in human and rodent α-cells [7] could have implications for understanding defects of glucagon secretion that are associated with diabetes. In a healthy α-cell exposed to normal plasma glucose concentrations (4–5 mM), K_ATP-channel activity is slightly below that associated with maximal glucagon secretion (Figure 4b, vertical

Concluding remarks and future directions

Here we have reviewed the evidence that α-cells possess an intrinsic glucose-sensing mechanism that controls glucagon secretion and described the role played by K_ATP-channels and changes in membrane potential in this context. Clearly, it is essential to establish precisely how glucose regulates the α-cell membrane potential, especially in human islets. Both functional [7] and immunocytochemical [55] data indicate that human α-cells, like their rodent counterparts, are equipped with K_ATP

Acknowledgements

Supported by the Wellcome Trust and the Swedish Diabetes Association. F.A. is a recipient of a postdoctoral fellowship from Conselho Nacional de Desenvolvimento Cientifico e Tecnológico, Brazil. P.E.M. is a CDA and AHFMR Scholar and holds the Canada Research Chair in Islet Biology.

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Trends in Endocrinology & Metabolism

ReviewKATP-channels and glucose-regulated glucagon secretion

Introduction

Section snippets

Paracrine regulation of glucagon secretion

Intrinsic α-cell regulation of glucagon secretion: role of KATP-channels

Pancreatic α-cells are electrically active in the absence of glucose

Link between KATP-channel closure and inhibition of glucagon secretion

Comparison of the effects of glucose and tolbutamide

Significance to the understanding and treatment of diabetes

Concluding remarks and future directions

Acknowledgements

J. Biol. Chem.

Cell Calcium

FEBS Lett.

FEBS Lett.

FEBS Lett.

Biochem. Biophys. Res. Commun.

Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes

Diabetologia

Glucagon and diabetes

Handb. Exp. Pharmacol.

Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains

Endocr. Rev.

Palmitate stimulation of glucagon secretion in mouse pancreatic alpha-cells results from activation of L-type calcium channels and elevation of cytoplasmic calcium

Diabetes

Adrenaline stimulates glucagon secretion in pancreatic A-cells by increasing the Ca2+ current and the number of granules close to the L-type Ca2+ channels

J. Gen. Physiol.

ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis

Nat. Neurosci.

A KATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans

PLoS Biol.

Interplay of nutrients and hormones in the regulation of glucagon release

Endocrinology

Sulfonylurea-binding sites and ATP-sensitive K+ channels in alpha-TC glucagonoma and beta-TC insulinoma cells

Diabetes

Characterisation of sulphonylurea and ATP-regulated K+ channels in rat pancreatic A-cells

Pflugers Arch.

Immuno-localization of sulphonylurea receptor 1 in rat pancreas

Diabetologia

Insulin granule dynamics in pancreatic beta cells

Diabetologia

Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic alpha-cells

Diabetes

Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells

Nat. Cell Biol.

Regulation of glucagon release in mouse -cells by KATP channels and inactivation of TTX-sensitive Na+ channels

J. Physiol.

Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells

Diabetes

The Banting Memorial Lecture 1975. Diabetes and the alpha cell

Diabetes

Impaired glucose tolerance (IGT) is associated with reduced insulin-induced suppression of glucagon concentrations

Diabetologia

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Diabetologia

Glucose stimulates glucagon release in single rat alpha-cells by mechanisms that mirror the stimulus-secretion coupling in beta-cells

Endocrinology

Beta-cell secretory products activate alpha-cell ATP-dependent potassium channels to inhibit glucagon release

Diabetes

Review
K_ATP-channels and glucose-regulated glucagon secretion

Intrinsic α-cell regulation of glucagon secretion: role of K_ATP-channels

Link between K_ATP-channel closure and inhibition of glucagon secretion