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 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.

AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism

“…Importantly, these data support the AEC-independent activation of AMPK by ETC-1002, which was associated with multiple markers of AMPK activation at the levels of signal transduction, transcription factors, hepatic lipid mass, and lipid biomarkers. An excess of visceral adipose tissue coupled with hyperglycemia and hyperinsulinemia makes the mouse model of DIO an attractive in vivo tool for studying mechanisms of impaired glycemic control and for the characterization of novel therapeutic agents (33)(34)(35)(36)(37)(38). To determine whether ETC-1002 improves glucose homeostasis in vivo, mice were kept on HFD for 12 weeks prior to ETC-1002 treatment.…”

Metformin Supports the Antidiabetic Effect of a Sodium Glucose Cotransporter 2 Inhibitor by Suppressing Endogenous Glucose Production in Diabetic Mice

“…We conducted studies in two obese type 2 diabetes models: the BKS.Cg-Dock7 m+/+ Lepr db /J (db/db), presenting a common murine model used for antidiabetes drug testing (14,15), and the Tallyho/JngJ, recapitulating broader aspects of human "diabesity" (16 At the age of 3 weeks, mice were started on a high-fat diet (Ssniff Spezialdiäten, Soest, Germany) containing palm fat (13.5% of fat), sunflower oil (13.5%), starch (30%), saccharose (10%), casein (20%), lignocellulose (5%), mineral plus vitamin mix (5 and 2%, respectively), safflower oil (0.5%), and linseed oil (0.5). Pharmacological studies were started in 8-week-old db/db and wild-type (wt) references, diabetic 9-week-old Tallyho/JngJ males, or, in the case of one study, chronically diabetic 22-week-old Tallyho/JngJ males.…”

Efficacy and Safety of Oral Methazolamide in Patients With Type 2 Diabetes: A 24-Week, Placebo-Controlled, Double-Blind Study

“…insulin administered to these animals (3). These data suggest that methazolamide is a novel insulin sensitizer that is complementary to metformin.…”