Methazolamide Is a New Hepatic Insulin Sensitizer That Lowers Blood Glucose In Vivo
- Nicky Konstantopoulos1⇓,
- Juan C. Molero1,
- Sean L. McGee1,
- Briana Spolding1,
- Tim Connor1,
- Melissa de Vries1,
- Stephen Wanyonyi1,
- Richard Fahey1,
- Shona Morrison1,
- Courtney Swinton1,
- Sharon Jones1,
- Adrian Cooper1,
- Lucia Garcia-Guerra1,
- Victoria C. Foletta1,
- Guy Krippner2,
- Sofianos Andrikopoulos3 and
- Ken R. Walder1
- 1Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Victoria, Australia
- 2Verva Pharmaceuticals, Melbourne, Victoria, Australia
- 3Department of Medicine (AH), University of Melbourne, Austin Hospital, Melbourne, Victoria, Australia
- Corresponding author: Nicky Konstantopoulos, .
N.K. and J.C.M. contributed equally to this work.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0578/-/DC1.
- Received May 18, 2011.
- Accepted March 10, 2012.
- © 2012 by the American Diabetes Association.
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