Dapagliflozin restores insulin and growth hormone secretion in obese mice

Abstract

The well-documented hormonal disturbance in a general obese population is characterised by an increase in insulin secretion and a decrease in growth hormone (GH) secretion. Such hormonal disturbance promotes an increase in fat mass, which deteriorates obesity and accelerates the development of insulin resistance and type 2 diabetes. While the pathological consequence is alarming, the pharmaceutical approach attempting to correct such hormonal disturbance remains limited. By applying an emerging anti-diabetic drug, the sodium-glucose cotransporter 2 inhibitor, dapagliflozin (1 mg/kg/day for 10 weeks), to a hyperphagic obese mouse model, we observed a significant improvement in insulin and GH secretion as early as 4 weeks after the initiation of the treatment. Restoration of pathological disturbance of insulin and GH secretion reduced fat accumulation and preserved lean body mass in the obese animal model. Such phenotypic improvement followed with concurrent improvements in glucose and lipid metabolism, insulin sensitivity, as well as the expression of metabolic genes that were regulated by insulin and GH. In conclusion, 10 weeks of treatment with dapagliflozin effectively reduces hyperinsulinemia and restores pulsatile GH secretion in the hyperphagic obese mice with considerable improvement in lipid and glucose metabolism. Promising outcomes from this study may provide insights into drug intervention to correct hormonal disturbance in obesity to delay the diabetes progression.

SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans

“…SGLT2 inhibitors (SGLT2i), called gliflozins, decrease glycemia by blocking glucose reabsorption by the kidney, thus promoting glucosuria. They are extensively used to treat diabetes and exert other beneficial effects such as improvement of insulin sensitivity and β-cell function, cardiorenal protection, and weight loss [ [1] , [2] , [3] , [4] , [5] , [6] , [7] ]. SGLT2i-induced glucosuria is associated with metabolic responses, including an increase in lipolysis, endogenous glucose, and ketone body production [ 3 , 8 , 9 ].…”

Stimulation of endogenous pulsatile growth hormone secretion by activation of growth hormone secretagogue receptor reduces the fat accumulation and improves the insulin sensitivity in obese mice

“…Plasma‐free fatty acids (FFA) and insulin levels were measured by the NEFA C kit (Wako, Japan) and a Rat/Mouse Insulin ELISA Kit (Millipore, USA), respectively. Liver triglyceride content was measured as previously described 7 . Briefly, triglyceride from liver was extracted and converted into glycerol by saponification at 55°C overnight in ethanolic potassium hydroxide solution (2 parts ethanol: 1 part 30% potassium hydroxide).…”

“…Liver triglyceride content was measured as previously described. 7 Briefly, triglyceride from liver was extracted and converted into glycerol by saponification at 55°C overnight in ethanolic potassium hydroxide solution (2 parts ethanol: 1 part 30% potassium hydroxide). The reaction was terminated by 1M MgCl 2 , and the glycerol concentration was measured by Triglyceride Reagent (F6428; Sigma-Aldrich, Australia) according to the manufacturer's instruction.…”

“…1 In adults, GH promotes lipolysis and lipid oxidation during the postabsorptive period and thus plays an essential role in regulating the substrate metabolism and body composition. 2 In obese humans [3][4][5] and rodents, 6,7 the GH secretion, particularly pulsatile secretion, is significantly decreased. The reduced GH secretion in obese individuals, accompanied by hyperinsulinemia, leads to further lipid accumulation in tissues and other metabolic complications, such as insulin resistance.…”

Comparison of the Effect of Dapagliflozin on Contrast to Standard Therapy of the Patients With Type 2 Diabetes Mellitus and Concomitant Obesity, Their Effect on Laboratory and Anthropometric Parameters

“…However, this medicine does not interfere with the normal production of endogenous glucose in response to hypoglycemia and acts independently of insulin secretion and action. Urinary glucose excretion induced by dapagliflozin is associated with calorie loss and weight loss [9]. Suppression of the co-transport of glucose and sodium by dapagliflozin may be accompanied by minor urine output and temporary excretion of sodium by urine [8].…”