title: Methazolamide is a new hepatic insulin sensitizer that lowers blood glucose in vivo.
abstract: 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 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. 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.
authors.affiliation: Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Victoria, Australia. nicky.konstantopoulos@deakin.edu.au
authors.forename: Nicky
authors.initials: N
authors.lastname: Konstantopoulos
authors.forename: Juan C
authors.initials: JC
authors.lastname: Molero
authors.forename: Sean L
authors.initials: SL
authors.lastname: McGee
authors.forename: Briana
authors.initials: B
authors.lastname: Spolding
authors.forename: Tim
authors.initials: T
authors.lastname: Connor
authors.forename: Melissa
authors.initials: M
authors.lastname: de Vries
authors.forename: Stephen
authors.initials: S
authors.lastname: Wanyonyi
authors.forename: Richard
authors.initials: R
authors.lastname: Fahey
authors.forename: Shona
authors.initials: S
authors.lastname: Morrison
authors.forename: Courtney
authors.initials: C
authors.lastname: Swinton
authors.forename: Sharon
authors.initials: S
authors.lastname: Jones
authors.forename: Adrian
authors.initials: A
authors.lastname: Cooper
authors.forename: Lucia
authors.initials: L
authors.lastname: Garcia-Guerra
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Foletta
authors.forename: Guy
authors.initials: G
authors.lastname: Krippner
authors.forename: Sofianos
authors.initials: S
authors.lastname: Andrikopoulos
authors.forename: Ken R
authors.initials: KR
authors.lastname: Walder
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D015309:Glucose Clamp Technique; D005952:Glucose-6-Phosphatase / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008704:Methazolamide / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010101:Oxygen Consumption / Q000187:drug effects; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000187:drug effects; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D002257:Carbonic Anhydrase Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D019289:Pyruvic Acid; D008687:Metformin; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D008704:Methazolamide