Metabolic and hemodynamic effects of moxonidine in the Zucker diabetic fatty rat model of type 2 diabetes.
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 x kg(-1) x 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 x kg(-1) x 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 x kg(-1) x day(-1)) and prevented the decrease in fasting insulin (10 mg x kg(-1) x day(-1)) compared with vehicle. Fasting glucose at 10 mg x kg(-1) x 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 x kg(-1) x day(-1) group during low activity periods. Moxonidine did not significantly affect body weight, fluid intake, or urine volume, but the 10 mg x kg(-1) x 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.
Yakubu-Madus
F E
FE
Endocrine Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Johnson
W T
WT
Zimmerman
K M
KM
Dananberg
J
J
Steinberg
M I
MI
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism*; D001794:Blood Pressure; D002940:Circadian Rhythm; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology*; D004435:Eating; D005951:Glucose Tolerance Test; D006339:Heart Rate; D006439:Hemodynamics / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D008297:Male; D009043:Motor Activity; D011507:Proteinuria; D051381:Rats; D011924:Rats, Zucker; D014882:Water-Electrolyte Balance
D000959:Antihypertensive Agents; D001786:Blood Glucose; D007093:Imidazoles; D007328:Insulin; C043482:moxonidine