Metabolic and Hormonal Effects of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibition

Presentation Number: SAT 579
Date of Presentation: April 1st, 2017

Reilly Coch*1, Jonathan Campbell2 and David A D'Alessio1
1Duke University Medical Center, Durham, NC, 2Duke University School of Medicine, Durham, NC

Abstract

Agents that inhibit sodium-glucose cotransporter-2 (SGLT2) prevent reabsorption of filtered glucose in the proximal tubule of the kidney and permit non-metabolic glucose disposal for patients with type 2 diabetes mellitus. Clinical and pre-clinical studies have found that glucagon secretion is stimulated after ingestion of oral SGLT2 inhibitors, an off-target effect that has been attributed to direct inhibition of SGLT2 in the pancreatic alpha-cell. Clinical studies have documented an increased risk of ketoacidosis in both type 1 and type 2 diabetes. We hypothesized that stimulation of glucagon independently of insulin or glucose concentrations may predispose subjects to ketone-related adverse outcomes.

Using a 2x2 factorial design, we studied the effect of dapagliflozin on pancreatic hormone secretion and ketogenesis in diabetic and non-diabetic C57BL/6J mice. Diabetes was induced with high-dose streptozotocin 180mg/kg given twice over 48 hours. Mice were then treated with dapagliflozin 5mg/kg or vehicle via oral gavage once (acute dosing) or twice daily for 4 days (chronic dosing), followed by a 6 hour fast. Hourly glucose and pancreatic hormone levels were measured in both acute and chronic studies, followed by euthanasia and terminal blood collection (chronic study only). High-sensitivity ELISAs were used to measure insulin and glucagon. Gluconeogenic genes of interest were measured via qPCR from liver and kidney specimens.

Relative to vehicle controls, treatment with dapagliflozin caused dose-responsive hypoglycemia, hyperketonemia and a reduction in serum insulin in fasted, non-diabetic mice. Dapagliflozin improved hyperglycemia in diabetic mice, but caused clinical illness compatible with ketoacidosis. We found no evidence of elevated glucagon after treatment with dapagliflozin. Finally, our gene expression analysis suggests that SGLT2 inhibition may impair renal acid handling by impairing glucose and bicarbonate handling in the kidney. We conclude that the reduction in serum glucose caused by SGLT2 inhibition causes compensatory hypoinsulinemia and can lead to ketosis in both fasting and diabetic animals.

 

Nothing to Disclose: RC, JC, DAD