Sodium-glucose cotransporter-specific substrate αMG stimulates endogenous glucagon secretion and ameliorates obesity-associated metabolic disorders in mice

OBJECTIVES: While glucagon raises blood glucose levels, it also promotes lipolysis and energy expenditure, and suppresses food intake and gastrointestinal motility, thereby resulting in weight loss. We previously reported that sodium-glucose cotransporter 1 (SGLT1) is highly expressed in pancreatic α cells. The present study aimed to investigate the effects of α-methyl d-glucopyranoside (αMG), an SGLT-specific substrate, on endogenous glucagon secretion and metabolic parameters in obese diabetic mice. METHODS: We injected αMG intraperitoneally daily into high fat, high sucrose diet (HFHSD)-fed mice and db/db mice, and measured metabolic parameters including plasma glucagon concentration. During the treatment with αMG, we evaluated various metabolic conditions, such as body weight, glucose tolerance and hepatic steatosis, in these mice. We also used SGLT1-specific inhibitor and liver-specific glucagon receptor knockout mice to elucidate the underlying mechanism. RESULTS: We showed that αMG stimulates endogenous glucagon secretion, and that chronic injection of αMG led to dramatic weight loss, improved glucose intolerance, and ameliorated hepatic steatosis, by reducing food intake and increasing energy expenditure and fat utilization, among obese diabetic mice. Interestingly amelioration of hepatic steatosis was abolished in liver-specific glucagon receptor knockout mice, but body weight reduction was not abolished. In addition, αMG, although to a modest extent, distinctly enhanced urinary glucose excretion. CONCLUSIONS: These results in this study suggest that αMG stimulates endogenous glucagon secretion and may lead to a therapeutic strategy for obesity-associated metabolic diseases.