Abstract
Background: Decreased insulin clearance could be a relatively upstream abnormality in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Previous studies have shown that sodium-glucose cotransporter 2 inhibitor (SGLT2i) increases insulin–C-peptide ratio, a marker of insulin clearance, and improves metabolic parameters. We evaluated the effects of the SGLT2i tofogliflozin on metabolic clearance rate of insulin (MCRI) with a hyperinsulinemic euglycemic clamp study, the gold standard for measuring systemic insulin clearance. Methods: Study participants were 12 Japanese men with type 2 diabetes. We evaluated MCRI and tissue-specific insulin sensitivity with a hyperinsulinemic euglycemic clamp (insulin infusion rate, 40 mU/m2·min) before and immediately after a single dose (n = 12) and 8 weeks (n = 9) of tofogliflozin. We also measured ectopic fat in muscle and liver and the abdominal fat area using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively, before and after 8 weeks of tofogliflozin. Results: MCRI did not change after a single dose of tofogliflozin (594.7 ± 67.7 mL/min·m2 and 608.3 ± 90.9 mL/min·m2, p = 0.61) or after 8 weeks (582.5 ± 67.3 mL/min·m2 and 602.3 ± 67.0 mL/min·m2, p = 0.41). The 8-week treatment significantly improved glycated hemoglobin and decreased body weight (1.7%) and the subcutaneous fat area (6.4%), whereas insulin sensitivity and ectopic fat in muscle and liver did not change significantly. Conclusions: MCRI did not change after a single dose or 8 weeks of tofogliflozin. Increased MCRI does not precede a decrease in body fat or improved glycemic control.
Highlights
Hyperinsulinemia is observed after weight gain and is considered as an important pathophysiological feature of type 2 diabetes mellitus and other metabolic diseases [1].hyperinsulinemia is associated with hypertension, as well as cardiovascular, renal, and liver diseases [1,2,3,4]
Previous reports have demonstrated that a surrogate marker of insulin clearance during a meal load test is higher after a single dose of an sodium-glucose cotransporter 2 inhibitor (SGLT2i) or chronic treatment [34,35]
It remains unclear whether SGLT2i treatment alters systemic insulin clearance as measured by a hyperinsulinemic euglycemic clamp study
Summary
Hyperinsulinemia is observed after weight gain and is considered as an important pathophysiological feature of type 2 diabetes mellitus and other metabolic diseases [1].hyperinsulinemia is associated with hypertension, as well as cardiovascular, renal, and liver diseases [1,2,3,4]. Previous human studies have demonstrated that low insulin clearance may be the primary mechanism of hyperinsulinemia in black African compared with white European [12,13] and decreased insulin clearance is a risk factor for obesity [14,15], metabolic syndrome [16], and nonalcoholic fatty liver disease (NAFLD) [17,18,19]. Decreased insulin clearance could be a relatively upstream abnormality in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Previous studies have shown that sodium-glucose cotransporter 2 inhibitor (SGLT2i) increases insulin–C-peptide ratio, a marker of insulin clearance, and improves metabolic parameters. We evaluated the effects of the SGLT2i tofogliflozin on metabolic clearance rate of insulin (MCRI) with a hyperinsulinemic euglycemic clamp study, the gold standard for measuring systemic insulin clearance.
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