Glucose Control of Glucagon Secretion: There Is More to It Than KATP Channels

Diabetes is generally attributed to insulin de-ficiency, but it has become increasingly evidentthat glucagon excess accounts for many dia-betic manifestations (1). In contrast to the con-sensus mechanisms by which hyperglycemia initiates insulin secretion, there are fundamentally different ideas regarding how glucagon release is stimulated by hypogly-cemia. Current hypotheses fall into three categories. First, it is possible that glucose concentration is measured by extrapancreatic sensors that feed back information to glucagon-releasing a-cells via neurons (2,3). Second, since glucagon release is also regulated independently of neural coupling, glucose sensing may be accomplished within the pancreatic islets by b- and d-cells that control the a-cells via paracrine release of inhibitory insulin (4), Zn2+ (5), g-aminobutyric acid (6), or somatostatin (7). Third, there is evidence supporting intrinsic glucose sensing by a-cells. In this category, two hypotheses imply that glucose de