GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation

Abstract

Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic β-cells in a glucose dependent manner. Several pathways mediate this action by rapid, kinase phosphorylation-dependent, but gene expression-independent mechanisms. Since GLP-1-induced insulin secretion requires glucose metabolism, we aimed to address the hypothesis that GLP-1 receptor (GLP-1R) signalling can modulate glucose uptake and utilization in β-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 β-cells and rodent islets to the GLP-1R agonist Exendin-4 (50 nM). Here we report for the first time that prolonged stimulation of the GLP-1R for 18 hours promotes metabolic reprogramming of β-cells. This is evidenced by up-regulation of glycolytic enzyme expression, increased rates of glucose uptake and consumption, as well as augmented ATP content, insulin secretion and glycolytic flux after removal of Exendin-4. In our model, depletion of Hypoxia-Inducible Factor 1 alpha (HIF-1α) impaired the effects of Exendin-4 on glucose metabolism, while pharmacological inhibition of Phosphoinositide 3-kinase (PI3K) or mTOR completely abolished such effects. Considering the central role of glucose catabolism for stimulus-secretion coupling in β-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated β-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression.

Neuroprotection of rhGLP‐1 in diabetic rats with cerebral ischemia/reperfusion injury via regulation of oxidative stress, EAAT2, and apoptosis

“…However, pretreatment with rhGLP‐1 obviously resulted in the upregulation of EAAT2 expression, indicating that rhGLP‐1 might play a key role in protecting neuronal cell from ischemia‐induced death by resistance to glutamate excitotoxicity. Recent a research confirmed that GLP‐1R signaling promotes β‐cell glucose metabolism via mTOR‐dependent hypoxia‐inducible factor 1 alpha activation (Carlessi et al, ), we will confirm the relationship between oxidative stress, m‐TOR signaling, and EAAT2 in future studies.…”

Oleate disrupts cAMP signaling, contributing to potent stimulation of pancreatic β-cell autophagy

“…Our findings are not necessarily in dispute with the recent demonstration that GLP1 augments LC3II accumulation due to glucolipotoxicity (25), because the mechanism of action was not addressed in that study, and so might be independent of cAMP. Other data showing that GLP1 activates both mTORC1 (66) and AMPK (67) would also seem to exclude these protein kinases, suggesting that the mechanism linking GLP1 with autophagy in ␤-cells is likely to be unusual. It is probably also context dependent, because GLP1 inhibits LC3II accumulation due to tacrolimus dosing (68) in contrast to the situation with glucolipotoxicity (25).…”

The regulatory G protein signaling complex, Gβ5–R7, promotes glucose- and extracellular signal–stimulated insulin secretion

“…Many of GSISmodulating inputs are mediated by G proteincoupled receptors (GPCRs). For example, receptors of glucagon-like peptide GLP-1 promote GSIS via activation of Gs and the corresponding rise in cAMP (6,7). Receptors of vasopressin and adenosine promote GSIS via activation of Gq (8)(9)(10).…”