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.
Chambers et al reintroduced expression of the glucagon gene into the gut (using Vil-Cre) or the pancreas (Pdx1-Cre) of Gcg-/- mice and interrogated the glucoregulatory consequences using exendin(9-39) to block GLP-1 action in the context of an oral glucose challenge. Remarkably, exendin(9-39) did not impair glycemic excursions when Gcg expression was re-established in the gut, but did impair glucose tolerance when Gcg expression was reintroduced under the control of Pdx1-Cre. These findings led to the conclusions that pancreatic PGDPs, notably GLP-1, may be more important than gut PGDPs, for control of glucose homeosatsis. The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice Cell Metab. 2017 Apr 4;25(4):927-934
An Editorial from Joel Habener highlighted these findings in the same issue. Pancreas and Not Gut Mediates the GLP-1-Induced Glucoincretin Effect Cell Metab. 2017 Apr 4;25(4):757-758.
More recent studies from multiple groups have once again highlighted that pancreatic glucagon, acting via the GLP-1 receptor, through mechanisms sensitive to exendin(9-39)is an important stimulator of glucose-dependent insulin secretion Insulin Secretion Depends on Intra-islet Glucagon Signaling Cell Rep. 2018 Oct 30;25(5):1127-1134.e2 and β Cell tone is defined by proglucagon peptides through cAMP signaling JCI Insight. 2019 Mar 7;4(5). pii: 126742. and Glucagon lowers glycemia when β-cells are active JCI Insight. 2019 Jul 23;5. pii: 129954. and Intra-islet glucagon signaling is critical for maintaining glucose homeostasis JCI Insight. 2019 Apr 23;5. pii: 127994.
Song and colleagues re-examined the importance of pancreatic vs. intestinal PGDPs using a complementary strategy focused on deletion of the Gcg gene from the entire gut, or the distal GI tract while leaving Gcg expression intact in the pancreas and brain. ELISAs detected active GLP-1, albeit at extremely low levels relative to glucagon, in the mouse and human pancreas. Substantial reduction of gut Gcg expression markedly reduced circulating levels of GLP-1, and impaired glucose homeostasis, associated with increased levels of GIP, and accelerated gastric emptying. GcgDistalGut-/- mice similarly exhibited lower circulating GLP-1 and impaired oral glucose tolerance. Nevertheless, plasma levels of insulin remained normal following glucose administration in the absence of gut-derived GLP-1. Thesefindings highlighted the importance of gut PGDPs for maintaining levels of circulating GLP-1, control of gastric emptying and glucose homeostasis. Gut-Proglucagon-Derived Peptides Are Essential for Regulating Glucose Homeostasis in Mice Cell Metab. 2019 Aug 30. pii: S1550-4131(19)30438-3