Inhibition of SGLT2 in Pancreatic Alpha Cells Drives Glucagon Gene Expression

June 18, 2014
Dennis Bittner, PhD

Researchers have identified a previously unrecognized mechanism for SGLT2 inhibitors in the regulation of glucagon and gluconeogenic gene expression.

Gliflozins, specific and potent inhibitors of the sodium-glucose linked transporter2 (SGLT2) protein, represent a new class of oral anti-diabetic agents used for the treatment of type 2 diabetes. Some SGLT2 inhibitor drugs are already on the market and are playing important roles in improving glycemic control in type 2 diabetes patients. More are in development. Development of gliflozins has focused on their inhibition of SGLT2 protein function in the kidney while their mode of action in other metabolic tissues has not been characterized.

Caroline Bonner, PhD, Postdoctoral Research Fellow in Islet Biology at European Genomic Institute for Diabetes in Lille, France, presented data Tuesday at the American Diabetes Association’s 74th Scientific Sessions during a session on the expression and function of SGLT2 in a different organ, the pancreas.

Bonner introduced the topic by reminding the audience that several metabolic organs are involved in the regulation of glucose production, uptake, reabsorption, and elimination. “The sodium-dependent glucose cotransporter protein SGLT2 dominates glucose reabsorption in the kidney. This is an adaptive mechanism that ensures energy availability during fasting. This mechanism becomes maladaptive in type 2 diabetes, as excess glucose is reabsorbed by the kidneys into the bloodstream, worsening hyperglycemia. Inhibition of SGLT2 prevents renal glucose reabsorption, resulting in glycosuria, but the underlying molecular mechanisms by which SGLT2 acts in the pancreas and liver remains largely unknown,” she said.

Use of gliflozins in clinical settings has offered clues indicating that there is still much to be learned about these useful inhibitors. Canagliflozin improves glycemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Dapagliflozin, a potent and specific SGLT2 inhibitor, improves glycemic control over 2 weeks in patients with type 2 diabetes. However, while blocking reabsorption of glucose into the bloodstream and promoting renal glucose excretions, gliflozins also stimulate plasma glucagon secretion and exogenous glucose production in the liver. The aim of the current study was to determine if the paradoxical increase in plasma glucagon levels and hepatic glucose production was related to the expression and action of SGLT2 in the endocrine pancreas.

Bonner reported on work with FACS-purified human alpha cells and paraffin-embedded human pancreatic tissue that demonstrates for the first time that SGLT2 is specifically enriched in human pancreatic alpha cells. SGLT2 gene expression was seen to be down-regulated while glucagon was up-regulated in both rodent and human islet cell models of insulin resistance designed to simulate the cellular conditions of type 2 diabetes.

The same effect, down-regulation of SLGT2 and up-regulation of glucagon, was seen in human islet cells grafted into insulin-resistant mice. By varying the levels of glucose in their human islet model, Bonner and colleagues were able to demonstrate that the down-regulation of endogenous SGLT2 gene expression and increases in glucagon mRNA observed were a result of glucotoxicity.

In gene knockdown experiments using siRNA against SGLT2, the expected depression in SGLT2 expression was accompanied by an increase in glucagon expression. Expression of SGLT1 (a related gene responsible for only 10% of glucose reabsorption in the kidney) was also seen to be increased in islet cells when SGLT2 was knocked down with siRNA. A similar effect was seen when the islet cells were treated with SGLT2 inhibitor dapagliflozin (ie, both SGLT1 and glucagon increased markedly). Finally, treatment of insulin-resistant mice with dapagliflozin resulted in elevated plasma glucagon levels and increased gluconeogenic gene expression in the liver of the mice under fasted conditions.

Bonner concluded the presentation by saying, “SGLT2 is specifically expressed in pancreatic alpha cells. This expression is down-regulated under the conditions of type 2 diabetes. This down-regulation is associated with an increase in both SGLT1 and glucagon gene expression, and expression in the liver of genes related to gluconeogenesis. Taken together, these results reveal a previously unrecognized mechanism for SGLT2 inhibitors in the regulation of glucagon and gluconeogenic gene expression.”