Effects of the SGLT2 inhibitor ipragliflozin on food intake, appetite-regulating hormones, and arteriovenous differences in postprandial glucose levels in type 2 diabetic rats

Abstract Aims The sodium-glucose cotransporter (SGLT) 2 inhibitor, ipragliflozin, improves not only hyperglycemia but also obesity in type 2 diabetic animals and patients; however, there have been concerns that it may also cause an increase in compensatory food intake. Appetite is regulated by complex mechanisms involving the central nervous system, part of which involves appetite-related hormones and arteriovenous differences in postprandial glucose levels. We evaluated the effect of ipragliflozin in type 2 diabetic rats on food intake, appetite-related hormones and arteriovenous differences in postprandial glucose levels, and their correlation with food intake. Main methods Ipragliflozin and several antidiabetic drugs were administered to type 2 diabetic rats and various parameters concerning food intake were measured. Key findings Ipragliflozin significantly increased urinary glucose excretion and reduced postprandial hyperglycemia. Compared to normal rats, diabetic rats exhibited hyperphagia and elevated plasma levels of the appetite-stimulating hormones neuropeptide Y and ghrelin. Ipragliflozin induced significant weight loss and reduced plasma levels of appetite-stimulating hormones without affecting food intake. Diabetic rats exhibited a significantly reduced arteriovenous difference in postprandial glucose levels due to insulin insufficiency; this was improved by ipragliflozin, which increased renal arteriovenous differences in glucose levels by increasing urinary glucose excretion. Significance: These results indicate that the SGLT2 inhibitor, ipragliflozin, exerts antihyperglycemic actions by increasing urinary glucose excretion, and induces weight loss without a compensatory increase in food intake in type 2 diabetic mice. The mechanisms underlying these effects can be attributed, in part, to an increased arteriovenous difference in postprandial glucose levels and improved regulation of appetite-related hormones in the diabetic animal model. While this study was conducted in rodents and the results may be distinct from those in humans, it is possible that some of the pharmacological mechanisms, including the regulation of appetite-related hormones, can be extrapolated to clinical settings and may be valuable for further studies including clinical investigations.