Paracrine inhibition via G protein inwardly rectifying potassium channels regulates glucagon secretion from human pancreatic alpha cells

Impaired glucagon secretion from pancreatic alpha cells is a cause of life-threatening hypoglycemia in individuals with type 1 diabetes (T1D). The mechanisms that lead to defective glucagon secretion remain unclear. Here, we show that the human alpha cell's competence to secrete glucagon depends on paracrine inhibitory input from beta (serotonin [5-HT], γ-aminobutyric acid [GABA]) and delta (somatostatin [SST]) cells. These paracrine signals activate G protein-coupled receptors (GPCRs) that open G protein-gated inwardly rectifying potassium (GIRK) channels, which have a major impact on glucagon secretion. In the absence of this paracrine input, glucagon secretion progressively diminishes until it habituates completely. Strikingly, 5-HT, GABA, and SST restored impaired glucagon secretion in islets from donors with long-duration T1D. These findings indicate that paracrine inhibition is needed to prevent habituation of glucagon secretion. As beta cells are destroyed in T1D, alpha cells lose this inhibition, and consequently, their capacity to adequately secrete glucagon to counter hypoglycemia.