The SGLT2 inhibitor empagliflozin improves insulin sensitivity in db/db mice both as monotherapy and in combination with linagliptin

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• 作者：Matthias Kern^a ; Nora Klö ; ting^b ; Michael Mark^c ; Eric Mayoux^c ; Thomas Klein^c ; Matthias Blü ; her^a ; ^{bluma@medizin.uni-leipzig.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：DIO ; diet-induced obese ; DPP ; dipeptidyl peptidase ; FAS ; fatty acid synthase ; FPG ; fasting plasma glucose ; GDR ; glucose disposal rate ; HbA1c ; glycated hemoglobin ; HGP ; hepatic glucose production ; HPRT ; hypoxanthine phosphoribosyltransferase ; OGTT ; oral glucose tolerance test ; PTP ; protein tyrosine phosphatase ; SCD ; stearoyl-CoA desaturase ; SGLT ; sodium glucose co-transporter ; SOCS ; suppressor of cytokine signaling ; T2D ; type 2 diabetes ; ZDF ; Zucker diabetic fatty
• 刊名：Metabolism
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：65
• 期：2
• 页码：114-123
• 全文大小：515 K

文摘

Combining different drug classes to improve glycemic control is one treatment strategy for type 2 diabetes. The effects on insulin sensitivity of long-term treatment with the sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin alone or co-administered with the dipeptidyl peptidase-4 inhibitor linagliptin (both approved antidiabetes drugs) were investigated in mice using euglycemic–hyperinsulinemic clamps.

Materials and Methods

db/db mice (n = 15/group) were treated for 8 weeks with 10 mg/kg/day empagliflozin monotherapy, 10 mg/kg/day empagliflozin plus 3 mg/kg/day linagliptin combination therapy, or 3 mg/kg/day linagliptin monotherapy. At the end of the study, euglycemic–hyperinsulinemic clamp studies were performed 4 days after the last dose of treatment.

Results

HbA1c and 2-hour fasting glucose concentrations were improved with empagliflozin monotherapy and combination therapy compared with vehicle and linagliptin monotherapy. During the clamp, glucose disposal rates increased and hepatic glucose production decreased with empagliflozin monotherapy and combination therapy compared with vehicle and linagliptin monotherapy. Glucose uptake in liver and kidney was higher with empagliflozin monotherapy and combination therapy compared with vehicle; glucose uptake into both muscle and adipose tissue was only affected by linagliptin treatment. Empagliflozin and combination therapy altered the expression of genes involved in the inflammatory response, fatty acid synthesis and oxidation.

Conclusions

These findings suggest that the insulin-sensitizing effects of SGLT2 inhibition contribute to improvements in glycemic control in insulin-resistant states.