Metabolic and Hemodynamic Effects of Moxonidine in the Zucker Diabetic Fatty Rat Model of Type 2 Diabetes

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Abstract

We studied the effect of moxonidine, an imidazoline ligand, on metabolic and hemodynamic parameters in Zucker diabetic fatty rats, a model of type 2 diabetes.In one group (metabolic group), 8-week-old rats were started on a diet containing either moxonidine (3 or 10 mg [centered dot] kg (-1) [centered dot] day-1) or vehicle for 4 weeks. Body weight and food intake were monitored daily, plasma insulin and glucose were monitored weekly, and an oral glucose tolerance test (OGTT) was performed at study's end. In another group of rats (hemodynamic group), radio frequency transmitters were implanted 1 week before starting the diet, and mean blood pressure, heart rate, and motor activity were continuously monitored at baseline and for 4 weeks after beginning drug exposure. Moxonidine (10 mg [centered dot] kg-1 [centered dot] day-1) significantly decreased elevated glucose levels and prevented the decrease in plasma insulin noted in vehicle-treated or pair-fed groups. Moxonidine also decreased fasting glucose (3 and 10 mg [centered dot] kg-1 [centered dot] day-1) and prevented the decrease in fasting insulin (10 mg [centered dot] kg-1 [centered dot] day-1) compared with vehicle. Fasting glucose at 10 mg [centered dot] kg-1. day-1 was equivalent to lean littermates. Both doses significantly increased glucose disposal and the insulin secretory response during the OGTT. Moxonidine lowered daily mean arterial pressure compared with both baseline values and vehicle and decreased daily heart rates. Motor activity was unaffected, except for an increase in the 10 mg [centered dot] kg-1 [centered dot] day1 group during low activity periods. Moxonidine did not significantly affect body weight, fluid intake, or urine volume, but the 10 mg [centered dot] kg-1 [centered dot] day (-1) dose reduced urinary protein excretion compared with vehicle-treated animals. These results demonstrate that, in an animal model of type 2 diabetes, the antihypertensive agent moxonidine induces a beneficial effect on abnormal glucose metabolism and renal protein excretion at doses that are effective in lowering arterial blood pressures and heart rate. Diabetes 48:1093-1100, 1999

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