Diet intake control is indispensable for the gluconeogenic response to sodium–glucose cotransporter 2 inhibition in male mice

Abstract

Aims/Introduction: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) lowers blood glucose and causes a whole-body energy deficit by boosting renal glucose excretion, thus affecting glucose and energy metabolism. This energy deficit not only decreases bodyweight, but also increases food intake. This food intake increase offsets the SGLT2i-induced bodyweight decrease, but the effect of the food intake increase on the SGLT2i regulation of glucose metabolism remains unclear. Materials and Methods: We administered SGLT2i (luseogliflozin) for 4 weeks to hepatic gluconeogenic enzyme gene G6pc reporter mice with/without obesity, which were either fed freely or under a 3-hourly dietary regimen. The effect of feeding condition on the gluconeogenic response to SGLT2i was evaluated by plasma Gaussia luciferase activity, an index of the hepatic gluconeogenic response, in G6pc reporter mice. Energy expenditure was measured by indirect calorimetry. Results: In the lean mice under controlled feeding, SGLT2i decreased bodyweight and plasma glucose, and increased the hepatic gluconeogenic response while decreasing blood insulin. SGLT2i also increased oxygen consumption under controlled feeding. However, free feeding negated all of these effects of SGLT2i. In the obese mice, SGLT2i decreased bodyweight, blood glucose and plasma insulin, ameliorated the upregulated hepatic gluconeogenic response, and increased oxygen consumption under controlled feeding. Under free feeding, although blood glucose was decreased and plasma insulin tended to decrease, the effects of SGLT2idecreased bodyweight, alleviation of the hepatic gluconeogenic response and increased oxygen consumptionwere absent. Conclusions: Food intake management is crucial for SGLT2i to affect glucose and energy metabolism during type 2 diabetes treatment.

The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice

“…Plasma alanine aminotransferase (ALT) levels were measured using the Transaminase CII-Test-Wako kit (Fujifilm Wako Pure Chemical Corp.). Hepatic triglyceride contents were measured using the triglyceride E-Test-Wako kit (Fujifilm Wako Pure Chemical Corp.) 47 . Hepatic MDA levels were measured using the Lipid Peroxidation (MDA) Assay Kit (Colorimetric/Fluorometric) (ab118970, Abcam, Cambridge, UK).…”

Luseogliflozin and caloric intake restriction increase superoxide dismutase 2 expression, promote antioxidative effects, and attenuate aortic endothelial dysfunction in diet‐induced obese mice

“…In the present study, luseogliflozin affected body weight and metabolic disorders under paired feeding but not under free feeding. Several studies have shown that SGLT2 inhibitors increase food intake 25 , and this attenuates body weight reduction and hypoglycemic effects 26 , 27 . It has been also reported that the respiratory exchange ratio (RER) did not change with SGLT2 inhibitor treatment without food intake restriction, on the other hand, SGLT2 inhibitor treatment with food intake restriction decreased the RER, suggesting that sources of energy shifted from glucose to fat.…”

“…It has been also reported that the respiratory exchange ratio (RER) did not change with SGLT2 inhibitor treatment without food intake restriction, on the other hand, SGLT2 inhibitor treatment with food intake restriction decreased the RER, suggesting that sources of energy shifted from glucose to fat. Furthermore, it has been reported that SGLT2 inhibitor treatment decreased body weight and the hepatic gluconeogenic response, and increased energy consumption under controlled feeding in obese mice but free feeding diminished these effects of the SGLT2 inhibitor 26 . Consequently, caloric intake restriction is important for the effects of SGLT2 inhibitors.…”

Diet and exercise are a fundamental part of comprehensive care for type 2 diabetes

“…In an animal study involving mice, it was observed that the use of sodium–glucose cotransporter 2 inhibitors (SGLT‐2i) in conjunction with controlled feeding led to weight loss and a decrease in hepatic gluconeogenic response. However, these effects were diminished in a group of mice with unrestricted access to food 2 . This suggests that dietary control remains essential when combined with glucose‐lowering medications such as SGLT‐2i for optimal glycemic control.…”