There are two principal topics and questions surrounding GLP-1 and the islet a-cell. These are a) how GLP-1 inhibits glucagon secretion from a-cells and b) How and under what circumstances do islet a-cells start to produce authentic bioactive GLP-1?

Under normal physiological circumstances, classical concepts suggest that 'normal' uninjured α cells within a normal disease-free pancreas do not produce GLP-1 or an intestinal PGDP profile. under physiological circumstances. In contrast, however multiple reports indicate that islet injury (streptozotocin or related toxins) metabolic stress, exposure to cytokines, or pancreatic and/or islet injury or inflammation can lead to induction of PC1/3 gene expression and GLP-1 production in α cells.

This was first described in rodents with experimental diabetes arising from chemical ablation of rat β cells with streptozotocin. Analysis of STZ-induced islets revealed induction of a cell expression of PC1/3 and increased levels of bioactive GLP-1(7-36amide) in pancreatic extracts.

Multiple studies have subsequently shown that pro-inflammatory cytokines such as interleukin-6 (IL-6) directly increased α cell expression of PC1/3 and GLP-1 in mouse and human islets and in isolated islet cell lines. Acute administration of IL-6 improved glucose tolerance and insulin secretion in wildtype, but not in Glp1r-/- mice. Evidence for GLP-1 production and PC1/3 expression in human islet a-cells ex vivo was obtained using a combination of immunohistochemistry, western blotting, and mass spectrometry. Cultured human islets released bioactive GLP-1 in response to high glucose and arginine, and islets from human donors with a known history of T2D exhibited higher basal GLP-1 secretion. Reconciling these findings made using isolated islets or inflamed and injured pancreata, generally ex vivo, is challenging to reconcile with the existing human data. Notably, circulating levels of GLP-1 are generally normal or modestly reduced in most subjects with various forms of T2D. It is always possible that modest amounts of GLP-1 are made and secreted from human a-cells and act locally on b-cells, but the concentrations are not sufficient to spill over into the peripheral circulation. Whether normal uninjured or diabetic human a cells in their normal intraislet location produce significant amounts of bioactive GLP-1 in the normal or diabetic human pancreas is remains uncertain. Indeed there is little data demonstrating that perfusion of a normal rodent or human pancreas would yield significant amounts of bioactive GLP-1 in the perfusate.

How does GLP-1 inhibit glucagon secretion?Although one obvious mechanism might be throught direct inhibition of GLP-1Rs expressed and functional in individual a-cells, it has been very difficult to obtain convincing data, either using antibodies, reporter mice, or isolated a-cell transcriptomics, that would support meaningful expression of the GLP-1R in a substantial number of rodent or human a-cells. Hence the available data suggests that the effects of GLP-1 to inhibit glucagon secretion are indirect, either via the CNS, the b-cell, the d-cell, or additional indirect mechanisms.

Following engagement of GLP-1Rs on the b-cell, GLP-1 may inhibit glucagon secretion through one or more'inhibitory' b-cell-derived products, such as insulin, GABA, ephrin ligands, or zinc. The b-cell is unlikely to be the sole target for the inhibitory effects of GLP-1 on a-cells, as GLP-1R agonists inhibit glucagon secretion in C-peptide-negative subjects with T1DM.  Studies employing somatostatin receptor 2 (SSRT2) antagonists and Ssrt2-/- mice strongly suggests that the inhibitory actions of GLP-1 on a-cells are indirect and mediated through somatostatin-dependent mechanisms.