Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production

Abstract

Chronic hyperglycemia impairs insulin action, resulting in glucotoxicity, which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors. Here, we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 (SGLT2) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes. Eighteen diabetic men were randomized to receive either dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks. We measured insulin-mediated whole body glucose uptake and endogenous glucose production (EGP) at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique. Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose. Insulin-mediated tissue glucose disposal increased by approximately 18% after 2 weeks of dapagliflozin treatment, while placebo-treated subjects had no change in insulin sensitivity. Surprisingly, following dapagliflozin treatment, EGP increased substantially and was accompanied by an increase in fasting plasma glucagon concentration. Together, our data indicate that reduction of plasma glucose with an agent that works specifically on the kidney to induce glucosuria improves muscle insulin sensitivity. However, glucosuria induction following SGLT2 inhibition is associated with a paradoxical increase in EGP. These results provide support for the glucotoxicity hypothesis, which suggests that chronic hyperglycemia impairs insulin action in individuals with type 2 diabetes.

Figure 1. Whole body and tissue glucose disposal during the euglycemic insulin clamp studies performed in subjects with type 2 diabetes before (Baseline) and after 14 days of treatment with dapagliflozin (Dapa) or placebo (Plac). *P < 0.05.

Figure 2. Basal EGP before and after ingestion of dapagliflozin or placebo EGP was measured on day 0 with the euglycemic clamp, on days 1 and 2 before subjects ingested dapagliflozin or placebo, and on days 2, 3, and 14 during dapagliflozin treatment.

Note the break in the time scale (x axis) between days 2 and 3 and between days 3 and 14.

Figure 3. Plasma glucose, insulin, and glucagon concentrations and EGP in the study.

On day 2, the ³H-glucose infusion was started 3 hours before drug ingestion (time 0) and continued for 4 hours after drug ingestion (see Methods for more details).

Figure 4. Change in the fasting plasma insulin and fasting plasma glucagon concentrations and the ratio between the fasting plasma glucagon to insulin concentrations after dapagliflozin and placebo administration relative to baseline.

The baseline plasma insulin and glucagon concentrations represent the mean on the day of the baseline insulin clamp and on days 1 and 2 when HGP was measured. FPI, fasting plasma insulin; EOS, end of study. *P < 0.05, **P < 0.01.