Back to Search Start Over

Methazolamide Is a New Hepatic Insulin Sensitizer That Lowers Blood Glucose In Vivo

Authors :
Juan Carlos Molero
Victoria C. Foletta
Nicky Konstantopoulos
Stephen Wanyonyi
Adrian Cooper
Guy Y. Krippner
Timothy Connor
Briana Spolding
Courtney Swinton
Ken Walder
Sean L. McGee
Sofianos Andrikopoulos
Sharon Jones
R. Fahey
Shona Morrison
Melissa de Vries
Lucía García-Guerra
Source :
Diabetes
Publication Year :
2012
Publisher :
American Diabetes Association, 2012.

Abstract

We previously used Gene Expression Signature technology to identify methazolamide (MTZ) and related compounds with insulin sensitizing activity in vitro. The effects of these compounds were investigated in diabetic db/db mice, insulin-resistant diet-induced obese (DIO) mice, and rats with streptozotocin (STZ)-induced diabetes. MTZ reduced fasting blood glucose and HbA1c levels in db/db mice, improved glucose tolerance in DIO mice, and enhanced the glucose-lowering effects of exogenous insulin administration in rats with STZ-induced diabetes. Hyperinsulinemic-euglycemic clamps in DIO mice revealed that MTZ increased glucose infusion rate and suppressed endogenous glucose production. Whole-body or cellular oxygen consumption rate was not altered, suggesting MTZ may inhibit glucose production by different mechanism(s) to metformin. In support of this, MTZ enhanced the glucose-lowering effects of metformin in db/db mice. MTZ is known to be a carbonic anhydrase inhibitor (CAI); however, CAIs acetazolamide, ethoxyzolamide, dichlorphenamide, chlorthalidone, and furosemide were not effective in vivo. Our results demonstrate that MTZ acts as an insulin sensitizer that suppresses hepatic glucose production in vivo. The antidiabetic effect of MTZ does not appear to be a function of its known activity as a CAI. The additive glucose-lowering effect of MTZ together with metformin highlights the potential utility for the management of type 2 diabetes.

Details

ISSN :
1939327X and 00121797
Volume :
61
Database :
OpenAIRE
Journal :
Diabetes
Accession number :
edsair.doi.dedup.....bf3c99a4b41759527d27bfa64be54e0b