Role of glucagon in treating diabetes: Evidence and concepts (胰高血糖素在糖尿病治疗中的作用：证据与概念)

Understanding of the physiology of glucagon action has undergone major refinement over the decades, from the initial identification of the islet peptide as one responsible for increasing hepatic glucose production, although in a fashion exhibiting tacchyphylaxis, coordinating in an inverse fashion with insulin in states of hyperand hypoglycemia, to the current expanding view of the peptide as evincing a number of additional metabolic roles, involved in satiety and energy expenditure and so with potential effects in obesity and dyslipidemia. With fixed basal insulin levels, over the physiological range of hepatic sinusoidal glucagon from 0 to 200 pg/ mL, hepatic glucose production increases linearly from 0 to 5 mg/kg body weight per min, with a further doubling of hepatic glucose production possible with glucagon levels increasing above the physiological range. This is a highly regulated process, because increases in glucose are associated with lower glucagon levels, whereas decreases in glucose are associated with higher glucagon levels, with reciprocal changes in insulin concentrations, which largely appear to control glucagon secretion by a paracrine effect mediated by the much higher intra-islet insulin concentrations perfusing the glucagon-producing islet α-cells. Indeed, in the insulinopenic state of type 1 diabetes models, glucagon may paradoxically increase with increasing blood glucose levels, and perfusion of islets with anti-insulin serum leads to an immediate increase in glucagon secretion. Thus, the association of type 2 diabetes with elevations in glucagon would be anticipated as a function of disorganization of islet architecture with reduction in β-cell number, and a paradoxical rise in glucagon is seen in the postprandial period in type 2 diabetes, as opposed to the fall in non-diabetic people. Furthermore, in rodent models of type 1 diabetes, deletion of the glucagon receptor markedly ameliorates hyperglycemia, and a similar improvement of glycemia can be seen in type 1 diabetic individuals given low-dose insulin along with somatostatin to suppress glucagon, whereas the additional administration of glucagon causes recurrence of hyperglycemia. Conceptually, then, one can consider glucagon suppression by increased insulin with hyperglycemia, and glucagon stimulation by reduction in insulin with hypoglycemia, as coordinate responses of insulin and glucagon lacking in diabetes, both type 1 and type 2, in a fashion central both to worsening hyperglycemia and, more subtly, to failure of the buffering effect of glucagon against hypoglycemia. There are, however, a number of areas of study suggesting that glucagon action may extend beyond glycemia to include effects on weight and lipid homeostasis. Leptin suppresses glucagon when administered peripherally and, of interest, intracerebroventricularly. Glucagon increases lipolysis, increases resting energy expenditure, and reduces meal size, acting with glucagon-like peptide-1 (GLP-1) in producing a central satiety effect, an observation that has led to the development of a variety of potential therapies acting as co-agonists of both glucagon and GLP-1. These central glucagon and GLP-1 effects are furthermore associated with central control of glucagon stimulation by both sympathetic and parasympathetic fibers of the autonomic nervous system, as well as by the action of GLP-1 in reducing α-cell glucagon secretion, to large extent indirectly via stimulation of insulin and somatostatin secretion, with controversy as to whether GLP-1 does or does not have direct effects on the α-cell, although there is definite evidence that, in the setting of hyperglycemia, GLP-1 reduces glucagon levels substantially in type 1 diabetic patients. Glucagon may increase lipolysis. Another effect of glucagon is in increasing circulating levels of fibroblast growth factor (FGF) 21, an effect seen in both non-diabetic and type 1 diabetic individuals, with FGF21 having potential central as well as peripheral actions in increasing energy expenditure and having insulin sensitizing effects, and with the weight loss seen with glucagon administration not occurring in animals not expressing FGF21. Some of the above considerations offer a mechanism for the reduced glucagon response to hypoglycemia beginning early in the course of type 1 diabetes, and glucagon has long been appreciated to have a potential therapeutic role given the 20–30% annual likelihood of severe hypoglycemia in type 1 diabetes, although this treatment is actually used by relatively few type 1 diabetic patients. New approaches to closed-loop pump treatment have made use of dual infusion of glucagon as well as insulin in reducing the likelihood of hypoglycemia. Some studies of incretin-based treatment of type 1 diabetes have shown glycemic benefit and, although this has not been demonstrated in all trials, a potential bs_bs_banner