Postprandial Suppression of Glucagon Secretion: A Puzzlement.

Pancreatic glucagon is a 29–amino acid hormone processed from proglucagon by prohormone convertase 2 in the pancreatic a-cells (1). Glucagon’s best-established function is to defend against decreases in glucose availability during fasting, stress, and exercise by stimulating hepatic glycogenolysis phasically and hepatic gluconeogenesis tonically (1–5). Glucagon also increases phasically during mixed-nutrient meals (6,7). Although many individual controls of glucagon secretion have been identified (Fig. 1), their interaction under physiological conditions is poorly understood. Glucagon secretion is disturbed in diabetes (1,3–5,8,9). In patients with type 2 diabetes (T2D), fasting plasma glucagon levels are typically increased ;25%, leading to increases in hepatic glucose production and plasma glucose. Furthermore, glucagon levels do not decrease as much following mixed-nutrient or glucose ingestion as they do in healthy individuals (“glucagon nonsuppression”). Fasting plasma glucagon is also increased in type 1 diabetes (T1D) and in the streptozotocin mouse model of T1D, prevention of glucagon action by knockdown of the glucagon receptor prevented diabetes from developing (10). These and other data support the “bihormonal hypothesis of diabetes” that a relative lack of insulin secretion coupled to a relative surfeit of glucagon secretion leads to excessive hepatic glucose production and diabetes (5,9). The role of postprandial glucagon nonsuppression in the progression to T2D is unclear. If glucagon nonsuppression appears early in the progression, it may provide useful insights as to specific pathophysiological changes that increase diabetes risk. Furthermore, understanding its mechanism may provide novel targets for antidiabetes therapy. For these reasons, two groups recently investigated glucagon nonsuppression during oral glucose tolerance tests (OGTT) and reported their findings in Diabetes (11,12). Both were cross-sectional studies involving considerably larger numbers of individuals (1,437 and 4,194, respectively) than studied heretofore (13–19) and including individuals with prediabetes. Nevertheless, the outcomes of the two studies were surprisingly different. In the first study, Færch et al. (11) found that fasting glucagon levels were increased and postprandial glucagon suppression was reduced 30 min after glucose ingestion in individuals with T2D or prediabetes compared with healthy individuals. The data were similar when stratified by insulin sensitivity; i.e., better insulin sensitivity was associated with lower fasting glucagon levels and better 30-min postglucose glucagon suppression. By 120 min, however, glucagon levels were similar in all three groups. Overall, these findings suggest that defective 30-min postprandial glucagon suppression is a relatively early aspect of diabetes risk that is related to insulin insensitivity. In the second new study, presented in this issue of Diabetes, Wagner et al. (12) studied individuals with normal glucose tolerance or prediabetes. Their data appear quite different from the data from Færch et al. (11). First, Wagner et al. found that that many individuals had higher plasma glucagon levels 120 min after ingesting glucose, whereas Færch et al. found that by 120 min, essentially all participants had lower glucagon levels. Second, Wagner et al. found that individuals with 120-min nonsuppression had lower fasting glucagon levels rather than the association between higher fasting glucagon levels and 30-min glucagon nonsuppression reported by Færch et al. Third, again in contrast to the 30-min data from Færch et al., Wagner et al. found that individuals in whom glucagon was not reduced at 120 min were more insulin sensitive and had a lower risk of impaired glucose tolerance compared with individuals in whom glucagon was reduced. Wagner et al. fail to bring these apparent discrepancies between their data and those from Færch et al. into sharp focus but do provide an interesting discussion of how glucagon nonsuppression might be related mechanistically to improved glucose metabolism. How might this controversy be resolved? Subject variables may have some influence on the data but seem unlikely to account fully for the differences. For example, patients with prediabetes in the study by Færch et al. (11)