Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes

Abstract

BACKGROUND. Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose-lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes. METHODS. Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity. RESULTS. Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity. CONCLUSIONS. Metformin has a direct and AMPK-dependent effect on GLP-1-secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin's glucose-lowering effect and mode of action. TRIAL REGISTRATION. NCT02050074 (https://clinicaltrials.gov/ct2/show/NCT02050074).

Metformin upregulates mitophagy in patients with T2DM: A randomized placebo‐controlled study

“…However, the similar findings were noted in the voglibose and the placebo group, which can be attributed to the comparable magnitude of weight reduction in these participants, hence negating the insulin‐sensitizing effect of metformin. Intriguingly, the HOMA‐β indices were found to be modestly higher in the metformin‐treated group, which could be ascribed to the reduction in glucotoxicity, and glucagon‐like peptide 1 (GLP‐1)‐mediated improvement in β‐cell function, as metformin also stimulates GLP‐1 secretion . Further, upregulated mitophagy could have also contributed to the improved β‐cell function, as strengthened by regression analysis, which revealed a positive association of HOMA‐β indices with a key mitophagy player PINK1.…”

Mechanism of glucose‐lowering by metformin in type 2 diabetes: Role of bile acids

“…Studies using the GLP‐1 receptor antagonist, exendin (9‐39), in animals and humans have shown that blocking GLP‐1 receptor signalling reduces glucose‐lowering by metformin substantially, indicating that GLP‐1 has a major role in mediating this effect of metformin. For example, in insulin‐resistant rats, during a euglycaemic clamp, intraduodenal metformin failed to increase the glucose infusion rate in the presence of exendin (9‐39) and in patients with T2DM, oral metformin stimulated GLP‐1 secretion and the associated glucose‐lowering was attenuated by exendin (9‐39) …”

“…The effect of metformin to increase GLP‐1 secretion has been observed in health and T2DM, albeit inconsistently. In acute experimental settings, a single dose of metformin (between 850 mg and 1500 mg) was reported to increase fasting and postprandial GLP‐1 concentrations in some, but not all, studies. However, studies relating to administration of metformin for between 4 weeks and 18 months have more consistently shown elevations in GLP‐1, although one study failed to observe an effect .…”

“…There are inconsistent reports from in vitro studies; one, using a rat enteroendocrine cell line, observed that metformin did not stimulate GLP‐1 secretion, while another, using human cells, suggested the opposite . A recent study reported that metformin induced GLP‐1 secretion ex vivo in human gut mucosa, suggesting the potential for metformin to stimulate GLP‐1 secretion directly . If this were the case, infusing metformin into the distal small intestine, where GLP‐1‐releasing L‐cells are abundant, would be anticipated to enhance GLP‐1 secretion (as is evident with other GLP‐1 stimuli, such as glucose); however, there was no difference in the effects of metformin (1 g) administered into the ileum compared to metformin administered into the duodenum on GLP‐1 secretion, gastric emptying or the glycaemic response to oral glucose in patients with T2DM (Figure ) .…”

“…For example, in insulin-resistant rats, during a euglycaemic clamp, intraduodenal metformin failed to increase the glucose infusion rate in the presence of exendin 25 and in patients with T2DM, oral metformin stimulated GLP-1 secretion and the associated glucoselowering was attenuated by exendin (9-39). 26…”