Dapagliflozin Improves Muscle Insulin Sensitivity but Enhances Endogenous Glucose Production

Study Questions:

What is the impact of chronic hyperglycemia on insulin sensitivity in individuals with type 2 diabetes mellitus (T2DM)?


This was a trial in which 18 diabetic men were randomized to receive either the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks. Insulin-mediated whole-body glucose uptake and endogenous glucose production (EGP) were measured at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique.


As expected, dapagliflozin induced glucosuria and markedly lowered fasting plasma glucose. Dapagliflozin treatment increased insulin-mediated tissue glucose disposal by approximately 18%, whereas placebo-treated subjects had no change in insulin sensitivity. Paradoxically, treatment with dapagliflozin was associated with an increase in EGP and increase in fasting plasma glucagon concentration.


The authors concluded that insulin-stimulated whole-body glucose disposal significantly improves following treatment of hyperglycemia with 2 weeks of dapagliflozin treatment.


The limitations of this small study performed only in men aside, the authors provide important information on the impact of chronic hyperglycemia on insulin sensitivity in T2DM, corroborating observations in experimental animals. Interestingly, treatment with dapagliflozin was associated with a paradoxical increase in EGP. As an increase in plasma glucagon concentration provides a plausible explanation for the increase in EGP, the authors suggest, ‘It would be of great interest to examine combination therapy with SGLT2 inhibitor plus an incretin mimetic agent that inhibits glucagon and stimulates insulin secretion.’

Keywords: Insulin, Hyperglycemia, Diabetes Mellitus, Type 2

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