Effects of SGLT2 Inhibitors on Insulin Secretion and Insulin Resistance—Results from a Cross-Sectional Study
Authors: WASEDA NAOKO , SATOH HIROAKI , YOSHIDA CHISA , IKEDA FUKI , KANAZAWA AKIO , WATADA HIROTAKA 
Published: June 2018

SGLT2 inhibitors lower blood glucose levels by inhibiting renal glucose reabsorption independently of insulin action. In addition, SGLT2 inhibitors are known to enhance endogenous glucose production by increasing glucagon level, despite lowering fasting glucose. However, the effect of SGLT2 inhibitors on glucose metabolism have not been fully elucidated yet. Therefore, we investigated the effect of SGLT2 inhibitors on insulin secretion and resistance. In this cross-sectional study, we recruited the subjects with type 2 diabetes mellitus who admitted to our hospital for diabetes education from January 2015 to September 2017. A total of 197 patients were enrolled in this study and divided into 26 subjects taken with SGLT2 inhibitor (S) and 171 subjects without SGLT2 inhibitor (NS). β-Cell function were assessed by 24-hour urinary C-peptide immune reactivity (CPR), fasting CPR, HOMA2-%β, δ CPR by glucagon test, and fasting and 2 hours after breakfast CPR index (CPI). Insulin resistance was assessed by HOMA2-IR which was calculated using HOMA2 Computer Model. The visceral and subcutaneous fat areas (VFA and SFA) were measured at the umbilical level using CT scans. Age, BMI, GA, HbA1c were comparable between the two groups. Regarding the β-Cell function, 24-hour urinary CPR, fasting CPI, 2 hours after breakfast CPI, HOMA2-%β showed no significant difference between the two groups, however, 6 minutes CPR and δ CPR in the glucagon test were significantly lowered by 27% (P = 0.0002) and 38% (P = 0.00001) in the S group compared to the NS group, respectively. Regarding the insulin resistance, HOMA2-IR was significantly lowered by 21% (P = 0.0077) in the S group compared to the NS group, although BMI, VFA, and VFA/VSA were not significantly different between the two groups.
In conclusion, this cross-sectional study indicates the possibility that SGLT2 inhibitors blunt the glucagon induced insulin secretion in β-Cell and improve insulin resistance independently of visceral fat mass.

Disclosure
N. Waseda: None. H. Satoh: None. C. Yoshida: None. F. Ikeda: None. A. Kanazawa: Speaker's Bureau; Self; Sanofi K.K., Kissei Pharmaceutical Co., Ltd. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.