Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion

Abstract

Type 2 diabetes (T2D) is characterized by chronic hyperglycemia resulting from a deficiency in insulin signaling, because of insulin resistance and/or defects in insulin secretion; it is also associated with increases in glucagon and endogenous glucose production (EGP). Gliflozins, including dapagliflozin, are a new class of approved oral antidiabetic agents that specifically inhibit sodium-glucose co-transporter 2 (SGLT2) function in the kidney, thus preventing renal glucose reabsorption and increasing glycosuria in diabetic individuals while reducing hyperglycemia. However, gliflozin treatment in subjects with T2D increases both plasma glucagon and EGP by unknown mechanisms. In spite of the rise in EGP, T2D patients treated with gliflozin have lower blood glucose levels than those receiving placebo, possibly because of increased glycosuria; however, the resulting increase in plasma glucagon levels represents a possible concerning side effect, especially in a patient population already affected by hyperglucagonemia. Here we demonstrate that SGLT2 is expressed in glucagon-secreting alpha cells of the pancreatic islets. We further found that expression of SLC5A2 (which encodes SGLT2) was lower and glucagon (GCG) gene expression was higher in islets from T2D individuals and in normal islets exposed to chronic hyperglycemia than in islets from non-diabetics. Moreover, hepatocyte nuclear factor 4-α (HNF4A) is specifically expressed in human alpha cells, in which it controls SLC5A2 expression, and its expression is downregulated by hyperglycemia. In addition, inhibition of either SLC5A2 via siRNA-induced gene silencing or SGLT2 via dapagliflozin treatment in human islets triggered glucagon secretion through KATP channel activation. Finally, we found that dapagliflozin treatment further promotes glucagon secretion and hepatic gluconeogenesis in healthy mice, thereby limiting the decrease of plasma glucose induced by fasting. Collectively, these results identify a heretofore unknown role of SGLT2 and designate dapagliflozin an alpha cell secretagogue.

Efficacy and Safety of Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes

“…Most of the patients with DKA also had DKA-precipitating factors, including 6 with evidence of autoimmune diabetes (i.e., latent autoimmune diabetes of adulthood, type 1 diabetes, or positive for GAD65 antibody). We speculate that patients with type 1 or type 2 diabetes who have no or low b-cell reserve, coupled with a potential SGLT2 inhibitorassociated increase in glucagon (28)(29)(30) and other metabolic factors, such as elevated free fatty acids, may not take or may be unable to produce sufficient insulin to suppress hepatic ketogenesis (28)(29)(30), which can progress to DKA in the setting of an acute illness, inadequate carbohydrate intake, and an associated increase in insulin resistance.…”

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

“…Many of these transcription factors have been shown to be important in kidney development or kidney disease. 42,49,50 An example of a kidney-specific eQTL is shown in Figure 2D, where the rs946213 variant influences the expression of RRP15 (MIM: 611193). The SNP is located at a promoter and the variant interrupted the GATA5 binding motif.…”

Possible risk factors for the development of sodium-glucose co-transporter 2 inhibitor- associated diabetic ketoacidosis in type 2 diabetes

“…15 Glycogen synthesis is further compromised because SGLT-2 inhibitors increase gluconeogenesis and serum glucagon levels. 7,16 The use of these agents leads to a relative hyperglucagonaemia, and it is the glucagon response to frank hypoglycaemia that is diminished. This relative hyperglucagonaemia promotes lipolysis, and if this is of sufficient magnitude and/or sufficiently prolonged (in the presence of insufficient insulin), this will give rise to the excess fatty acid metabolism diverting to ketones.…”