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

Article


Konstantopoulos, Nicky, Molero, Juan C., McGee, Sean L., Spolding, Briana, Connor, Tim, de Vries, Melissa, Wanyonyi, Stephen, Fahey, Richard, Morrison, Shona, Swinton, Courtney, Jones, Sharon, Cooper, Adrian, Garcia-Guerra, Lucia, Foletta, Victoria C., Krippner, Guy, 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. https://doi.org/10.2337/db11-0578
Article Title

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

ERA Journal ID16015
Article CategoryArticle
AuthorsKonstantopoulos, Nicky (Author), Molero, Juan C. (Author), McGee, Sean L. (Author), Spolding, Briana (Author), Connor, Tim (Author), de Vries, Melissa (Author), Wanyonyi, Stephen (Author), Fahey, Richard (Author), Morrison, Shona (Author), Swinton, Courtney (Author), Jones, Sharon (Author), Cooper, Adrian (Author), Garcia-Guerra, Lucia (Author), Foletta, Victoria C. (Author), Krippner, Guy (Author), Andrikopoulos, Sofianos (Author) and Walder, Ken R. (Author)
Journal TitleDiabetes
Journal Citation61 (8), pp. 2146-2154
Number of Pages9
Year2012
Place of PublicationUnited States
ISSN0012-1797
1939-327X
Digital Object Identifier (DOI)https://doi.org/10.2337/db11-0578
Web Address (URL)http://diabetes.diabetesjournals.org/content/diabetes/61/8/2146.full.pdf
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.

Keywordscarbonic-anhydrase inhibition; gene-expression signature; activated protein-kinase; metformin; gluconeogenesis;
ANZSRC Field of Research 2020321406. Pharmacogenomics
321401. Basic pharmacology
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Byline AffiliationsDeakin University
Verva Pharmaceuticals, Australia
University of Melbourne
Institution of OriginUniversity of Southern Queensland
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