konstantopoulos-methazolamideis-2012.pdf (1.66 MB)
Methazolamide is a new hepatic insulin sensitizer that lowers blood glucose in vivo
journal contribution
posted on 2012-08-01, 00:00 authored by Nicky Konstantopoulos, Juan Molero Navajas, Sean McgeeSean Mcgee, Briana RandallBriana Randall, Timothy ConnorTimothy Connor, Melissa de Vries, Stephen Wanyonyi, Richard Fahey, Shona MorrisonShona Morrison, Courtney SwintonCourtney Swinton, Sharon Jones, Adrian Cooper, Lucia Garcia-Guerra, Victoria Foletta, G Krippner, S Andrikopoulos, Ken WalderKen WalderWe 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.
History
Journal
DiabetesVolume
61Issue
8Pagination
2146 - 2154Publisher
American Diabetes AssociationLocation
Alexandria, Va.Publisher DOI
ISSN
0012-1797eISSN
1939-327XLanguage
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2012, American Diabetes AssociationUsage metrics
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