The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

SGLT2 inhibitor prevents hyperinsulinemia and restores pulsatile growth hormone secretion in obese pre-diabetic mice (#93)

Zhengxiang Huang 1 , Lili Huang 1 , Chengjian Wang 1 , Shanli Zhu 1 , Michael Cowley 2 , Chen Chen 1
  1. School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
  2. Department of Physiology, Monash University, Melbourne, Australia

The sodium/glucose cotransporter 2 inhibitor (SGLT2i), which promotes urinary glucose excretion, is a novel drug for overt type 2 diabetes (T2D) patients. It has not been used for obese pre-diabetic individuals. Insulin and growth hormone (GH) are both important hormones in regulating glucose and lipid metabolisms but in opposite ways. Insulin promotes fat storage, while GH promotes lipolysis and fat oxidation. Hyperinsulinemia inhibits GH secretion, and physiological GH secretion in pulsatile pattern does not cause insulin resistance. In obese pre-diabetic individuals, hyperinsulinemia and reduced pulsatile GH secretion co-exist. The imbalance of two hormones contributes to fat accumulation and insulin resistance, leading to more severe hyperinsulinemia and hypo-GH, forming a vicious cycle. Whether SGLT2i treatment ameliorates hyperinsulinemia and hypo-GH in obese pre-diabetic individuals remains unknown. In this experiment, 8-week SGLT2i (dapagliflozin, 1mg/kg/d) treatment reduced hyperinsulinemia and partially restored pulsatile GH secretion in hyperphagia obese pre-diabetic melanocortin 4 receptor knockout (MC4RKO) mice (both sex, but GH measurement performed only in male mice, 18 weeks of age at the end of treatment). Lipolysis and lipid oxidation gene expression were increased in treated mice, whereas lipogenesis and inflammation gene expression were reduced, leading to decreased whole body fat mass. Along the amelioration in lipid metabolism, triglyceride content in liver and muscle was decreased and the insulin sensitivity was significantly improved. In addition, the glucose tolerance was improved in treated mice, with the increase in first phase glucose-stimulated insulin secretion from pancreatic beta cells. The treatment did not change food intake, daily activity or energy expenditure, but promoted lipid usage under a negative energy balance through increasing urinary glucose excretion. Therefore, by preventing hyperinsulinemia and restoring pulsatile GH secretion, SGLT2i improved glucose and lipid metabolisms in hyperphagia obese pre-diabetic mice. Our work highlights the potential application of SGLT2i in obese pre-diabetic individuals.