Diazoxide attenuates insulin secretion and hepatic lipogenesis in zucker diabetic fatty rats.
BACKGROUND
Attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, in Zucker diabetic fatty (ZDF) rats, an animal model of type 2 diabetes and leptin resistance, decreased weight gain, improved lipid profile and prevented diabetes. Since the opposing effects of insulin and leptin regulate hepatic lipogenesis, we studied effects of insulin suppression on key insulin-sensitive genes regulating hepatic lipogenesis.


METHODS
DZ (150 mg/kg/day) or vehicle [pair-fed (PF) and control (C)] was administered to pre-diabetic obese ZDF and ZDF lean (ZL) rats for 8 weeks.


RESULTS
Hepatic glucose transporter-2 protein expression decreased only in DZ-ZDF rats (p<0.001). However, insulin receptor substrate-1/2 protein expressions were enhanced in DZ-ZDF (p<0.02) and DZ-ZL (p<0.03) rats corresponding to increased phosphorylated protein kinase B levels in both strains (p<0.03). DZ increased glycogen synthase expression in ZDF (p<0.005) and ZL (p<0.002) rats. DZ reduced expression of sterol regulatory element-binding protein-1c, (p<0.0001), fatty acid synthase (p<0.002), acetyl CoA carboxylase (p<0.001), hormone-sensitive lipase (p<0.005), and peroxisome proliferator agonist receptor-gamma (p<0.02) in ZDF rats, without altering expressions of acyl CoA oxidase, peroxisome proliferator receptor-alpha, and carnitine palmitoyl transferase-1. DZ decreased hepatic triglycerides (p<0.001), long chain acyl-CoA (p<0.001) and cholesterol (p<0.01) contents only in ZDF rats, but increased glycogen content in both strains (p<0.02).


CONCLUSIONS
Suppression of hyperinsulinemia by DZ enhanced hepatic insulin sensitivity and decreased expression of key genes regulating hepatic lipogenesis without altering genes regulating lipid oxidation; implying that attenuation of hyperinsulinemic state by DZ enhances metabolic efficiency of insulin and is therapeutically beneficial.
Alemzadeh
Ramin
R
Pediatric Endocrinology & Metabolism, Medical College of Wisconsin, Milwaukee, WI 53226, USA. ralemzad@mcw.edu
Tushaus
Kathryn
K
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D003981:Diazoxide / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D000078790:Insulin Secretion; D047908:Intracellular Signaling Peptides and Proteins; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D047493:PPAR alpha / Q000235:genetics; D048068:PPAR-beta / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011236:Prediabetic State / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics
D051273:Glucose Transporter Type 2; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D008112:Liver Glycogen; D047493:PPAR alpha; D048068:PPAR-beta; D010750:Phosphoproteins; D012333:RNA, Messenger; C495683:Slc2a2 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D006006:Glycogen Synthase; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D003981:Diazoxide