The Role of Glucagon in the Pathophysiology and Treatment of Type 2 Diabetes

Abstract

Of particular interest are the abilities of glucose-lowering drugs to preserve a normal counterregulatory glucagon response in hypoglycemic conditions and, thus, avoid hypoglycemic adverse events. [...]as will be discussed, potential benefits can be gained from emerging glucagon-modulating therapeutic strategies. The insulin:glucagon ratio determined by measurement of plasma glucagon levels may vary from the portal insulin:glucagon ratio, and conclusions on peripheral measures should always be approached with caution because of higher insulin and glucagon concentrations in portal circulation compared with peripheral.3 Modest changes in insulin and/or glucagon secretion lead to amplified responses on glucose metabolism, in part because of the portal insulin:glucagon ratio. [...]this provides a strong physiological argument for the rationale of targeting glucagon secretion. [...]among older agents, pioglitazone, the only thiazolidinedione widely marketed globally, did not have an effect on either fasting or postprandial glucagon concentrations in 2 studies that measured glucagon.89,90 Amylin Mimetics Pramlintide, the only amylin mimetic marketed in the United States, decreases postprandial glucagon responses.91,92,175 This is not unexpected because the hormone amylin inhibits glucagon secretion.10,175 DPP-4is The DPP-4i and GLP-1RA (discussed later) drug classes have been studied to a greater extent regarding their effects on glucagon than the older drug classes because their effects in this regard are widely recognized.12,51,171 The DPP-4is are "incretin enhancers" that prevent the degradation of endogenously produced glucose-dependent insulinotropic polypeptide and GLP-1, thus extending their action. Glucagon is a key regulator of normal fuel metabolism, and both fasting and postprandial hyperglucagonemia make substantial contributions to the fasting hyperglycemia and postprandial glucose excursions that characterize T2D. Because patients with T2D have defects in glucagon control, improved restoration of metabolic control by therapies that also suppress glucagon, including DPP-4is and GLP-1RAs, would be beneficial.