Reducing hyperglucagonemia in type 2 diabetes using low dose
Fasting hyperglucagonemia is a key feature of type 2 diabetes (T2D), which leads to increased hepatic glucose production and exacerbates hyperglycemia. Preclinical studies have shown that low concentrations of sulfonylureas can partially restore appropriate glucose-regulated glucagon secretion in islets from donors with T2D. In this pilot clinical trial, sixteen participants with T2D (diet controlled or on metformin alone) underwent a 4-week open-label, non-randomized, dose-titration (0.3–6mg/day) trial of an oral glibenclamide suspension. The dose was increased every 3-4 days and fasting blood samples (for glucagon, glucose, insulin, C-peptide and glibenclamide measurement) were taken prior to each dose change. Masked continuous glucose monitoring (CGM) was used throughout the study. Glibenclamide at 0.3mg/day reduced glucagon by 32% in the four participants with fasting hyperglucagonemia (25.6pmol/L vs 17.4pmol/L; p<0.05) but not in those with normal levels. Fasting insulin and C-peptide were unaffected, and doses 3mg/day significantly increased time spent hypoglycemic. The study results suggest that fasting hyperglucagonemia can be reduced by 1/3 in patients with T2D, using <10% the normal glibenclamide starting dose, without causing hypoglycemia or affecting insulin secretion.