Mathematical Models of the Effect of Glucagon on Glycemia in Individuals With Type 2 Diabetes Treated With Dapagliflozin

Context Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels by promoting urinary glucose excretion, but their overall effects on hormonal and metabolic status remain unclear.Objective We here investigated the roles of insulin and glucagon in the regulation of glycemia in individuals treated with an SGLT2 inhibitor using mathematical model analysis.Methods Hyperinsulinemic-euglycemic clamp and oral glucose tolerance tests were performed in 68 individuals with type 2 diabetes treated with the SGLT2 inhibitor dapagliflozin. Data previously obtained from such tests in 120 subjects with various levels of glucose tolerance and not treated with an SGLT2 inhibitor were examined as a control. Mathematical models of the feedback loops connecting glucose and insulin (GI model) or glucose, insulin, and glucagon (GIG model) were generated.Results Analysis with the GI model revealed that the disposition index/clearance, which is defined as the product of insulin sensitivity and insulin secretion divided by the square of insulin clearance and represents the glucose-handling ability of insulin, was significantly correlated with glycemia in subjects not taking an SGLT2 inhibitor but not in those taking dapagliflozin. Analysis with the GIG model revealed that a metric defined as the product of glucagon sensitivity and glucagon secretion divided by glucagon clearance (designated production index/clearance) was significantly correlated with blood glucose level in subjects treated with dapagliflozin.Conclusion Treatment with an SGLT2 inhibitor alters the relation between insulin effect and blood glucose concentration, and glucagon effect may account for variation in glycemia among individuals treated with such drugs.