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Sodium–glucose cotransporter 2 inhibitor (SGLT2i) treatment is a therapeutic approach for type 2 diabetes mellitus (T2DM). Some reports have shown that SGLT2i treatment improves insulin resistance; however, few studies have evaluated insulin resistance by the glucose clamp method. Hepatic insulin clearance (HIC) is a new pathophysiological mechanism of T2DM. The effect of SGLT2i treatment on hepatic insulin clearance and insulin resistance is not well known. We investigated the effect of SGLT2i treatment on insulin resistance, insulin secretion, incretin levels, body composition, and hepatic insulin clearance. We conducted a meal tolerance test (MTT) and a hyperinsulinemic-euglycemic clamp test in 9 T2DM patients. Ipragliflozin (50 mg/day) was administered, and the MTT and clamp test were performed after 4 months. We calculated HIC as the postprandial C-peptide AUC-to-insulin AUC ratio. We also measured GLP-1, GIP, and glucagon levels during the MTT. Body weight and HbA1c were decreased, although not significantly, after 4 months of treatment. Postprandial glucose, fasting insulin and postprandial insulin were significantly decreased. Insulin resistance with the glucose clamp was not changed, but the HOMA-IR and insulin sensitivity indices were significantly improved. Incretin and glucagon levels were not changed. Hepatic insulin clearance was significantly increased, but whole-body insulin clearance was not changed. The FIB-4 index and fatty liver index were significantly reduced. The HOMA-beta and insulinogenic indices were not changed, but the C-peptide index was significantly increased. Although the number of patients was small, these results suggested that SGLT2i treatment improved liver function, decreased hepatic insulin resistance, and increased hepatic insulin clearance, despite the small weight reduction.

Introduction: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a medication for type 2 diabetes mellitus (T2DM). Some reports showed SGLT2i improved insulin resistance, however, the effect on insulin resistance is not well established. Hepatic insulin clearance (HIC) is new pathophysiology of T2DM. The effect of SGLT2i on hepatic insulin clearance and insulin resistance is not well known. We investigated the effect of SGLT2i on insulin resistance, insulin secretion, incretins, body composition, and hepatic insulin clearance. Materials and Methods: We conducted a meal tolerance test (MTT), and the hyperinsulinemic-euglycemic clamp in 9 T2DM patients. 50 mg/day ipragliflozin was admitted, MTT and clamp were performed after 4 months. We calculated the postprandial C-peptide AUC to insulin AUC ratio as the HIC. We also measured GLP1, GIP, and glucagon levels during MTT. Results: Body weight, HbA1c, and body composition were not significantly changed after 4 months of treatment. Postprandial glucose, fasting, and postprandial insulin were significantly decreased. The insulin resistance of the glucose clamp was not changed, but HOMA-IR and insulin sensitivity index (ISI) were significantly improved. Incretins and glucagon were not changed. Hepatic insulin clearance was significantly increased, but whole-body insulin clearance was not changed. Fib 4 index and fatty liver index were significantly reduced. HOMA-beta and insulinogenic index was not changed but the C-peptide index was significantly increased. Conclusions: Although patients’ number was small, these results suggest that SGLT2i treatment decreased hepatic insulin resistance, increased hepatic insulin clearance, and decreased hyperinsulinemia, it might protect beta-cell function.

IntroductionHepatic insulin clearance (HIC) is an important pathophysiology of type 2 diabetes. HIC was reported to decrease in patients with type 2 diabetes and metabolic syndrome. However, hyperglycemia was suggested to enhance HIC, and it is not known whether poorly controlled diabetes increases HIC in patients with type 2 diabetes. We investigated whether HIC was increased in patients with poorly controlled diabetes, and whether HIC was associated with insulin resistance and incretins.Research design and methodsWe performed a meal tolerance test and the hyperinsulinemic–euglycemic clamp in 21 patients with type 2 diabetes. We calculated the postprandial C-peptide area under the curve (AUC)-to-insulin AUC ratio as the HIC; measured fasting and postprandial glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon levels and analyzed serum adiponectin and zinc transporter-8 (ZnT8) gene polymorphism.ResultsThe HIC significantly correlated with glycated hemoglobin (HbA1c) (r_S=0.58, pr_S=−0.77, pr_S=−0.66, pConclusionsThese results suggest that HIC was increased in patients with high HbA1c type 2 diabetes, low insulin secretion, low insulin resistance and high adiponectin conditions.