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Methazolamide Is a New Hepatic Insulin Sensitizer That Lowers Blood Glucose In Vivo
- Source :
- Diabetes
- Publication Year :
- 2012
- Publisher :
- American Diabetes Association, 2012.
-
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.
- Subjects :
- Blood Glucose
Male
medicine.medical_specialty
medicine.drug_class
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
Methazolamide
Mice, Obese
Type 2 diabetes
Biology
Diabetes Mellitus, Experimental
Rats, Sprague-Dawley
Mice
Oxygen Consumption
Internal medicine
Diabetes mellitus
Pyruvic Acid
Internal Medicine
medicine
Animals
Homeostasis
Hypoglycemic Agents
Insulin
Carbonic anhydrase inhibitor
Carbonic Anhydrase Inhibitors
nutritional and metabolic diseases
Glucose clamp technique
Streptozotocin
medicine.disease
Pharmacology and Therapeutics
Metformin
Rats
Mice, Inbred C57BL
Endocrinology
Liver
Glucose Clamp Technique
Glucose-6-Phosphatase
Insulin Resistance
Glycolysis
Phosphoenolpyruvate Carboxykinase (ATP)
medicine.drug
Subjects
Details
- ISSN :
- 1939327X and 00121797
- Volume :
- 61
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....bf3c99a4b41759527d27bfa64be54e0b