Modulation of adipoinsular axis in prediabetic zucker diabetic fatty rats by diazoxide.
Dysregulation of the adipoinsular axis in male obese Zucker diabetic fatty (ZDF; fa/fa) rats, a model of type 2 diabetes, results in chronic hyperinsulinemia and increased de novo lipogenesis in islets, leading to beta-cell failure and diabetes. Diazoxide (DZ; 150 mg/kg.d), an inhibitor of insulin secretion, was administered to prediabetic ZDF animals for 8 wk as a strategy for prevention of diabetes. DZ reduced food intake (P < 0.02) and rate of weight gain only in ZDF rats (P < 0.01). Plasma insulin response to glucose load was attenuated in DZ-Zucker lean rats (ZL; P < 0.01), whereas DZ-ZDF had higher insulin response to glucose than controls (P < 0.001). DZ improved hemoglobin A1c (P < 0.001) and glucose tolerance in ZDF (P < 0.001), but deteriorated hemoglobin A1c in ZL rats (P < 0.02) despite normal tolerance in the fasted state. DZ lowered plasma leptin (P < 0.001), free fatty acid, and triglyceride (P < 0.001) levels, but increased adiponectin levels (P < 0.02) only in ZDF rats. DZ enhanced beta3-adrenoreceptor mRNA (P < 0.005) and adenylate cyclase activity (P < 0.01) in adipose tissue from ZDF rats only, whereas it enhanced islet beta3- adrenergic receptor mRNA (P < 0.005) but paradoxically decreased islet adenylate cyclase activity (P < 0.005) in these animals. Islet fatty acid synthase mRNA (P < 0.03), acyl coenzyme A carboxylase mRNA (P < 0.01), uncoupling protein-2 mRNA (P < 0.01), and triglyceride content (P < 0.005) were only decreased in DZ-ZDF rats, whereas islet insulin mRNA and insulin content were increased in DZ-ZDF (P < 0.01) and DZ-ZL rats (P < 0.03). DZ-induced beta-cell rest improved the lipid profile, enhanced the metabolic efficiency of insulin, and prevented beta-cell dysfunction and diabetes in diabetes-prone animals. This therapeutic strategy may be beneficial in preventing beta-cell failure and progression to diabetes in humans.
Department of Pediatrics, Section of Endocrinology and Metabolism, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. ralemzad@mcw.edu
Ramin
R
Alemzadeh
Kathryn M
KM
Tushaus
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D052242:Adiponectin; D000273:Adipose Tissue / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology* / Q000517:prevention & control; D003981:Diazoxide / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D005215:Fasting; D018149:Glucose Intolerance / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D006442:Glycated Hemoglobin / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology; D020738:Leptin / Q000097:blood; D008297:Male; D009765:Obesity / Q000503:physiopathology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011924:Rats, Zucker; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D000262:Adenylyl Cyclases; D052242:Adiponectin; D001786:Blood Glucose; D003981:Diazoxide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D012333:RNA, Messenger; D022702:Receptors, Adrenergic, beta-3; D014280:Triglycerides