Pancreatic α-Cells and Insulin-Deficient Diabetes

Abstract

Glucagon plays a major role in glucose homeostasis. This pancreatic hormone acts primarily on the liver activating gluconeogenesis and glycogenolysis, which promote hepatic glucose output, and increases plasma glucose levels (1, 2). Although glucagon secretion by pancreatic -cells is inhibited at high glucose concentrations, this process is augmented at low glucose levels (3). In this manner, glucagon release is one of the main lines of defense against hypoglycemia (4, 5). The complementary function of glucagon and insulin and their different regulation by nutrients and other control signals allow for the maintenance of plasma glucose levels within physiological ranges. Furthermore, glucagon stimulates hepatic fatty acid oxidation and ketogenesis, regulates food intake by central actions, increases adipose tissue thermogenesis and opposes to several insulin actions (2, 6). In addition to its role in glucose homeostasis, a growing body of evidence indicates that glucagon is also involved in the pathophysiology of diabetes and some of its complications. Hyperglucagonemia, either absolute or relative to plasma insulin levels, has been related with increased hepatic glucose output in type 1 diabetes (T1D), which aggravates hyperglycemia. Despite the high plasma glucose levels present in diabetic individuals, glucagon secretion is not suppressed (4). In this regard, several therapeutic designs involve the decrease of glucagon secretion from pancreatic -cells and/or the attenuation of glucagon actions on peripheral tissues (7). With the progression of T1D, the ability of pancreatic -cells to respond to hypoglycemia becomes impaired, leading to defective counterregulation to falling plasma glucose levels (4, 5). This is a life-threatening situation, particularly in those diabetic patients subjected to insulin treatment (iatrogenic hypoglycemia) (8). All these functional defects in glucagon secretion in T1D have been related with the lack of intraislet insulin signaling in pancreatic -cells, intrinsic -cell glucose-sensing defects, and/or altered neural regulation of glucagon release (2, 8). However, the specific nature of these functional defects is still not well defined. The dynamics of the pancreatic -cell mass also seems to play an important role to maintain absolute or relative hyperglucagonemia in diabetes. Although T1D leads to specific immunological attack and destruction of pancreatic -cells, which results in decreased -cell mass, -cell mass has been reported to be invariable or slightly increased in different models of autoimmune and insulin-deficient diabetes (9–11). This survival ability of pancreatic -cells in a T1D environment may be probably related with their better autonomous immune responses (12) and survival gene networks (13) compared with -cells. Despite the importance of pancreatic -cells and glucagon secretion in glucose homeostasis and diabetes, the research about the physiology of this islet population has been neglected for a long time. In part, this minor attention has been due to the central role of pancreatic -cells in the pathogenesis of diabetes, which has been the focus of most islet biology research. The study on -cells was also hampered because of the lack of physiological identification patterns to recognize this islet cell type. Additionally, the number of pancreatic -cells within the islet are scarce in rodents (15%–20% of total cells), the main animal models used in diabetology (14). All these factors, together with the difficulties to separate from non-cells in enriched samples as well as limitations of conventional techniques, have been a further restriction for a deeper exploration of this islet cell type. However, since the nineties, numerous technical advances have allowed to overcome these problems and to undertake in depth studies on the regulation