Effects of Dapagliflozin as an Adjunct Therapy to Insulin in Streptozotocin-induced Diabetic Rats

Abstract

<b>Abstract ID 17705</b> <b>Poster Board 505</b> Type 1 diabetes mellitus (T1DM) is a chronic metabolic disorder caused by the autoimmune destruction of insulin-producing beta-cells of the pancreas. Insulin, the mainstay of treatment for T1DM, is often inadequate for optimal blood glucose (BG) control with dangerous side effects such as hypoglycemia. Adjunct therapies have been proposed to provide better BG control and reduce hypoglycemic episodes. Dapagliflozin, a potent sodium-glucose co-transporter 2 (SGLT2) inhibitor, is a new class of hypoglycemic agents for type 2 diabetes, and its potential as an adjunct therapy to insulin in T1DM has been confirmed in clinical studies. However, the increased risk of diabetic ketoacidosis associated with dapagliflozin is a major concern preventing its clinical usage as an adjunct therapy for T1DM. To this end, the efficacy and safety of dapagliflozin in streptozotocin (60 mg/kg)-induced diabetic rats were evaluated using in&nbsp;vivo (3 weeks of baseline after diabetes induction and 8 weeks of treatment) and ex vivo studies. Male Sprague Dawley rats (300-400 g) were divided into 5 groups (n=4-6): healthy, diabetic control, diabetic treated with insulin, diabetic treated with insulin+dapagliflozin (1 mg/kg PO daily), and diabetic treated with dapagliflozin alone. Treatment with insulin or insulin+dapagliflozin caused diabetic rats to maintain body weight with reduced urination and water intake compared to diabetic control. Insulin+dapagliflozin provided better BG control with reduced total insulin injection as compared to insulin alone. Dapagliflozin, as expected, increased urine output and water intake. Lipid panel including total cholesterol, TAG, and HDL was not significantly different in rats treated with insulin+dapagliflozin vs insulin alone. Ex vivo studies indicated a trend of higher kidney weight/body weight and increased sizes of glomeruli in rats treated with insulin+dapagliflozin as compared to diabetic control or healthy rats. Moreover, a significant increase in beta-cell regeneration was observed in the rats treated with insulin alone or insulin+dapagliflozin as compared to diabetic control rats. The plasma concentration of ketones under various experimental conditions will be determined using a beta-hydroxybutyrate assay kit to assess diabetic ketoacidosis. The significance of this study is investigating the effects of dapagliflozin in a type 1 diabetic animal model, which allows ex vivo studies to assess its effects on multiple individual organs and tissues. <b>Support/Funding Information:</b> Southern Illinois University Edwardsville internal research grant Southern Illinois University Edwardsville research grants for graduate students