Dapagliflozin stimulates glucagon secretion at high glucose: experiments and mathematical simulations of human A-cells

Abstract

Glucagon is one of the main regulators of blood glucose levels and dysfunctional stimulus secretion coupling in pancreatic A-cells is believed to be an important factor during development of diabetes. However, regulation of glucagon secretion is poorly understood. Recently it has been shown that Na+/glucose co-transporter (SGLT) inhibitors used for the treatment of diabetes increase glucagon levels in man. Here, we show experimentally that the SGLT2 inhibitor dapagliflozin increases glucagon secretion at high glucose levels both in human and mouse islets, but has little effect at low glucose concentrations. Because glucagon secretion is regulated by electrical activity we developed a mathematical model of A-cell electrical activity based on published data from human A-cells. With operating SGLT2, simulated glucose application leads to cell depolarization and inactivation of the voltage-gated ion channels carrying the action potential, and hence to reduce action potential height. According to our model, inhibition of SGLT2 reduces glucose-induced depolarization via electrical mechanisms. We suggest that blocking SGLTs partly relieves glucose suppression of glucagon secretion by allowing full-scale action potentials to develop. Based on our simulations we propose that SGLT2 is a glucose sensor and actively contributes to regulation of glucagon levels in humans which has clinical implications.

No direct effect of SGLT2 activity on glucagon secretion

“…***p < 0.001 (one-way ANOVA followed by Bonferroni post hoc test). ND, non-diabetic; T2D, type 2 diabetic; NC, no sample control continuation hereof, attenuation of SGLT2 activity by SGLT2 inhibitors was predicted to partly relieve the suppressive actions of glucose on glucagon secretion [23]. However, this model assumes that SGLT2 is expressed by the alpha cell and contrasts to the findings in our study.…”

“…Based on studies performed on human islets or the glucagon-secreting cell line α-TC1, it was suggested that the hyperglucagonaemia might be a direct effect of the inhibitors on the pancreatic alpha cell [5,22], leading to reduced glucose uptake by the alpha cell. Indeed, a mathematical model based on the study by Bonner et al [5] supported the notion that SGLT2 activity in the alpha cell leads to small depolarisations and subsequent inactivation of voltage-gated ion channels, resulting in reduced glucagon secretion [23]. In Expression of glucose transporters in human alpha, beta and delta cells and SGLT2 protein in rat and human islets.…”

Efficacy and safety of sodium–glucose cotransporter 2 inhibitor ipragliflozin on glycemic control and cardiovascular parameters in Japanese patients with type 2 diabetes mellitus; Fukuoka Study of Ipragliflozin (FUSION)

“…Reduction of S-CPR and serum insulin concentration could be beneficial not only for pancreatic β cell protection but also for preventing cardiovascular events and cancer. Recently, SGLT2I have been reported to increase serum glucagon level [16], but this increase did not occur in the present study, probably because of combination therapy with other anti-diabetic agents. As shown in Table 1, 79.1% of the patients in the present study were being treated with DPP-4I at the baseline and 63.4% with biguanides (metformin).…”

Different glucagon effects during DPP‐4 inhibition versus SGLT‐2 inhibition in metformin‐treated type 2 diabetes patients

“…26 Accordingly, glucagon-producing alpha cells express SGLT-2 receptors, and dapagliflozin has been shown to increase glucagon secretion when added to isolated human islets. [26][27][28] The present study also shows that there are differences in action between DPP-4 inhibition and SGLT-2 inhibition on beta-cell function, as the prandial AUC for C-peptide was approximately 50% higher after vildagliptin than after dapagliflozin treatment. As glucose levels did not differ between the groups, and as C-peptide kinetics have been shown not to be affected by DPP-4 inhibition 29 or SGLT-2 inhibition, 30 the different actions of the 2 treatments on the Cpeptide response to meal ingestion is compatible with a hypothesis that insulin secretion is augmented more efficiently by DPP-4 Plasma levels of intact and total GIP and GLP-1 before and after ingestion of a mixed meal after 2-week treatment with vildagliptin or dapagliflozin in 28 patients with metformin-treated type 2 diabetes.…”

“…The mechanism behind the higher glucagon levels during SGLT‐2 inhibition is less clear, but may be the result of a direct stimulation of glucagon secretion from alpha‐cells, which was first demonstrated in experimental animals in 2002, and is executed by inhibition of cellular glucose entry . Accordingly, glucagon‐producing alpha cells express SGLT‐2 receptors, and dapagliflozin has been shown to increase glucagon secretion when added to isolated human islets …”