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.
Highlights
The regulation of glucagon secretion is subject of intense debate and several mechanisms have been proposed
We confirm clinical findings showing that SGLT2 inhibitors increase glucagon secretion at elevated glucose levels, and based on our theoretical investigations we propose that dapagliflozin activate pancreatic A-cells mainly via effects on electrical activity
We show that inhibition of SGLT2 with dapagliflozin doubles glucagon secretion at high glucose concentrations (Fig. 1)
Summary
The regulation of glucagon secretion is subject of intense debate and several mechanisms have been proposed. In mouse A-cells Na+- and Ca2+-current dependent electrical activity is directly regulated by KATP-channel activity[19,20], and we proposed that increasing the glucose concentration leads to closure of KATP-channels, A-cell plasma membrane depolarization and subsequent inactivation of the voltage-dependent Na+ and Ca2+-channels, reducing the amplitude of A-cell action potentials[21]. The inhibitory effect of KATP-channel closure on electrical activity and glucagon secretion was later confirmed in human A-cells[22]. We confirm that dapagliflozin directly affects glucagon secretion and investigate the cellular mechanisms underlying these findings with a mathematical model of A-cell electrical activity developed from human data, potentially explaining the clinical observations in diabetic patients
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