Sodium appetite in adult rats following ω-3 polyunsaturated fatty acid deficiency in early development

We examined the effect of ω-3 polyunsaturated fatty acid (PUFA) deficiency during development on sodium appetite. Being raised on an ω-3 PUFA deficient diet increased the intake of 0.5 M NaCl following furosemide-induced sodium depletion by 40%. This occurred regardless of the diet they were maintained on later in life, and the increased consumption persisted for 3 days. In a second study, animals were administered furosemide and low-dose captopril. Sodium consumption of deficient raised animals was again higher than that of the control raised. Fos immunoreactivity in brain areas associated with sodium appetite and excretion were not influenced by diet. Our findings indicate that inadequate dietary ω-3 PUFA during development results in an exaggerated sodium appetite later in life.

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

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.