Methazolamide is a new hepatic insulin sensitizer that lowers blood glucose in vivo

Konstantopoulos, Nicky and Molero, Juan C. and McGee, Sean L. and Spolding, Briana and Connor, Tim and de Vries, Melissa and Wanyonyi, Stephen and Fahey, Richard and Morrison, Shona and Swinton, Courtney and Jones, Sharon and Cooper, Adrian and Garcia-Guerra, Lucia and Foletta, Victoria C. and Krippner, Guy and Andrikopoulos, Sofianos and Walder, Ken R. (2012) Methazolamide is a new hepatic insulin sensitizer that lowers blood glucose in vivo. Diabetes, 61 (8). pp. 2146-2154. ISSN 0012-1797

Abstract

We previously used Gene Expression Signature technology to identify methazolarnide (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 HbA(1c) 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. Hyperinsulinentic-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 (CM); however, CAIs acetazolamide, ethoxyzolamide, dichlorphenamide, chlorthalidone, and fmosemide 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 CM. The additive glucose-lowering effect of MTZ together with metformin highlights the potential utility for the management of type 2 diabetes.


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Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Additional Information: Files associated with this item cannot be displayed due to copyright restrictions.
Faculty / Department / School: No Faculty
Date Deposited: 24 Feb 2017 06:27
Last Modified: 22 Mar 2017 01:04
Uncontrolled Keywords: carbonic-anhydrase inhibition; gene-expression signature; activated protein-kinase; metformin; gluconeogenesis;
Fields of Research : 11 Medical and Health Sciences > 1115 Pharmacology and Pharmaceutical Sciences > 111505 Pharmacogenomics
11 Medical and Health Sciences > 1115 Pharmacology and Pharmaceutical Sciences > 111501 Basic Pharmacology
Socio-Economic Objective: C Society > 92 Health > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920104 Diabetes
Identification Number or DOI: 10.2337/db11-0578
URI: http://eprints.usq.edu.au/id/eprint/30598

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