Glucagon secretion and signaling in the development of diabetes

Abstract

Normal release of glucagon from pancreatic islet α-cells promotes glucose mobilization, which counteracts the hypoglycemic actions of insulin, thereby ensuring glucose homeostasis. In treatment of diabetes aimed at rigorously reducing hyperglycemia to avoid chronic complications, the resulting hypoglycemia triggering glucagon release from α-cells is frequently impaired, with ensuing hypoglycemic complications. This review integrates the physiology of glucagon secretion regulating glucose homeostasis in vivo to single α-cell signaling, and how both become perturbed in diabetes. α-cells within the social milieu of the islet micro-organ are regulated not only by intrinsic signaling events but also by paracrine regulation, particularly by adjacent insulin-secreting β-cells and somatostatin-secreting δ-cells. We discuss the intrinsic α-cell signaling events, including glucose sensing and ion channel regulation leading to glucagon secretion. We then discuss the complex crosstalk between the islet cells and the breakdown of this crosstalk in diabetes contributing to the dysregulated glucagon secretion. Whereas, there are many secretory products released by β- and δ-cells that become deficient or excess in diabetes, we discuss the major ones, including the better known insulin and lesser known somatostatin, which act as putative paracrine on/off switches that very finely regulate α-cell secretory responses in health and diabetes. Of note in several type 1 diabetes (T1D) rodent models, blockade of excess somatostatin actions on α-cell could normalize glucagon secretion sufficient to attain normoglycemia in response to hypoglycemic assaults. There has been slow progress in fully elucidating the pathophysiology of the α-cell in diabetes because of the small number of α-cells within an islet and the islet mass becomes severely reduced and inflamed in diabetes. These limitations are just now being surmounted by new approaches.

Keywords: diabetes; glucagon secretion; hypoglycemia; islet α-cell; somatostatin.

Figure 1

Pancreatic endocrine cells are regulated by intrinsic and paracrine signals in response to glucose. At basal glucose levels pancreatic β-cells (A, left) are electrically inactive, owing to their open ATP-sensitive K⁺ (K_ATP) channels and resultant hyperpolarized membrane potential, and thus do not secrete insulin. In contrast, α-cells in the presence of low glucose (A, right) are electrically active, due to a relatively elevated ATP/ADP ratio (even at low glucose). This results in closure of most, but perhaps not all, K_ATP channels and a depolarized membrane potential that allows action potential firing mediated by a combination of voltage-dependent Na⁺, Ca²⁺ (VDCC), and K⁺ (Kv) channels. Entry of Ca²⁺ through VDCCs triggers the exocytosis of glucagon-containing secretory granules. When plasma glucose is increased (B), glucose enters pancreatic islet cells through plasma membrane glucose transporters (GLUT) where it is metabolized through glycolysis and mitochondrial oxidative metabolism. This results in increase in the intracellular ATP/ADP ratio (in the case of α-cells, a further increase) and closure of K_ATP channels. In the β-cell (B, top left) this results in membrane depolarization and firing of action potentials that, in combination with additional mitochondrial signals, results in the exocytosis of insulin-containing granules. In α-cells, further closure of K_ATP channels may further depolarize the membrane and lead to the depolarization-dependent inactivation of Na⁺ channels and VDCCs. Glucagon secretion is also inhibited by paracrine factors secreted from β-cells and pancreatic δ-cells. These signals may interact with putative α-cell metabolic sensors (i.e., PASK and AMPK) to produce the physiological suppression of glucagon secretion.

Figure 2

In the normal physiology, the α-cell is under the tonic inhibitory influence of insulin and therefore somatostatin inhibition of α-cell may be of minor or no importance (Singh et al., 2007). This is in contrast to diabetic islets in diabetes, where α-cell may be more sensitive to insulin and in addition, both circulating and pancreatic somatostatin, are increased. It is generally believed that hypoglycemia is a strong stimulator of glucagon release from the α-cell. However, in islets in-vitro the effect of hypoglycemia is not consistent. This difference may reflect the fact that between in-vitro and in-vivo systems, in-vivo the islets have abundant blood flow, which brings to the islet other factors such as amino acids (i.e., arginine) that can stimulate glucagon release. We hypothesize therefore, that hypoglycemia has an effect only when amino acids or other substances found in blood, are present. In absence of the tonic effect of insulin, somatostatin is the only endogenous inhibitor of glucagon release and insulin exerts a strong inhibitory effect on the α-cell. Therefore, when an antagonist blocks the α-cell receptors, despite the inhibitory effect of injected insulin, the α-cell can release normal amounts of glucagon (Vranic, 2010). The figure is modified from that we previously reported (Vranic, 2010).

Figure 3

In diabetic (D) rats, plasma glucagon increases only marginally during a glucose clamp at 2.5 mmol/L. (A) Hypoglycemia was induced with 10 units/kg of regular insulin was injected subcutaneously. 3000 nmol/kg/h of somatostatin receptor type 2 antagonist (SSTR2a) was infused intravenously starting 30 min before insulin injection (D + SSTR2a). (B) The response of glucagon to hypoglycemia was the same as in normal (N) rats. (C) The data is also shown as area under the curve (AUC) analysis. The data is modified from that we reported in ref. Yue et al. (2011). The SSTR2a is highly specific for glucagon and only marginally for insulin, and it's structure is H-Fpa-cyclo[DCys-PAL-DTrp-Lys-Tle-Cys]-Nal-NH2 (Yue et al., 2011). ^*P < 0.002 D vs. N; ^†P < 0.05 D vs. D+SSTR2a.