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

Konstantopoulos, Nicky, Molero, Juan C., McGee, Sean L., Spolding, Briana, Connor, Tim, de Vries, Melissa, Wanyonyi, Stephen, Fahey, Richard, Morrison, Shona, Swinton, Coutney, 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, vol. 61, no. 8, pp. 2146-2154.

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Title Methazolamide is a new hepatic insulin sensitizer that lowers blood glucose in vivo
Author(s) Konstantopoulos, Nicky
Molero, Juan C.
McGee, Sean L.
Spolding, Briana
Connor, Tim
de Vries, Melissa
Wanyonyi, Stephen
Fahey, Richard
Morrison, Shona
Swinton, Coutney
Jones, Sharon
Cooper, Adrian
Garcia-Guerra, Lucia
Foletta, Victoria C.
Krippner, Guy
Andrikopoulos, Sofianos
Walder, Ken R.
Journal name Diabetes
Volume number 61
Issue number 8
Start page 2146
End page 2154
Total pages 9
Publisher American Diabetes Association
Place of publication Alexandria, Va.
Publication date 2012-08
ISSN 0012-1797
1939-327X
Summary 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.
Language eng
Field of Research 110103 Medical Biochemistry: Inorganic Elements and Compounds
Socio Economic Objective 920104 Diabetes
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2012, American Diabetes Association
Persistent URL http://hdl.handle.net/10536/DRO/DU:30047265

Document type: Journal Article
Collection: School of Medicine
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Created: Tue, 21 Aug 2012, 10:45:06 EST by Jane Moschetti

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