Dapagliflozin Improves Insulin Sensitivity in the Obese Prediabetic Canine

Abstract

SGLT2 inhibition has positive effects on glucose balance, reducing fasting and postprandial glucose levels, however little is known about the effects of SGLT2 inhibitors on lipid levels. PKPD simulation for this canine model was applied for dose selection of dapagliflozin (dapa). Seven dogs were fed a high fat diet for 6 weeks, then received a single low dose of streptozotocin (18.5mg/kg) to induce mild type 2 diabetes. Animals were exposed to dapa (n=4, 1.25mg/kg) or placebo (n=3) once per day for 6 weeks, while remaining on the high fat diet. Animals were then subjected to the intravenous glucose tolerance test (IVGTT) to assess glucose tolerance and insulin response to glucose, and the euglycemic hyperinsulinemic clamp protocol in conjunction with tracer infusions to evaluate adipose tissue, skeletal muscle and hepatic insulin sensitivity. In the IVGTT, modeling techniques are used to estimate the acute insulin response to a glucose bolus, which was not altered with dapa treatment, but insulin sensitivity was significantly improved compared to placebo-treated animals (dapa 0.54±0.22, control -0.95±0.51mU/l-1.minute-1, p=0.05). The glucose infusion required for euglycemia during steady state in the clamp was decreased with dapa (dapa -3.0±1.05, control 1.53±1.28 mg/minute/kg, change from pre-drug timepoint, P=0.038), supporting the IVGTT results. Urinary glucose disposal rate during the clamp was inconsistent. There is a trend towards higher FFA levels in dapa-treated animals under noninsulin stimulated conditions (P=0.054). These may be a regulator of hepatic glucose production, or reflect a switch towards lipid utilization. We conclude that 6 weeks of dapa treatment improves insulin sensitivity in a canine model of mild type 2 diabetes. Further studies on lipid metabolism, body fat deposition and insulin clearance are on-going. Disclosure R.L. Paszkiewicz: None. R.N. Bergman: Advisory Panel; Self; Ingredion, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; GI Dynamics Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Self; Novo Nordisk A/S. I. Asare Bediako: None. H.J. Mkrtchyan: None. V. Gopaul: Employee; Self; AstraZeneca. H. Yang: Employee; Self; AstraZeneca. E. Lundborg: Employee; Self; AstraZeneca. S. Kim: None. I. Formentini: Employee; Self; AstraZeneca. C.M. Kolka: Research Support; Self; AstraZeneca.