Chronic suppression of insulin by diazoxide alters the activities of key enzymes regulating hepatic gluconeogenesis in Zucker rats.
OBJECTIVE
Chronic attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, improved insulin sensitivity and glucose tolerance and caused down-regulation of lipid metabolizing enzymes in adipose tissue and decreased the rate of weight gain in mildly hyperglycemic obese Zucker rats. Since the liver plays a central role in glucose homeostasis, we studied the effect of chronic insulin suppression on key insulin-sensitive enzymes regulating hepatic gluconeogenesis.


METHODS
DZ (150 mg/kg per day) or vehicle (control) was administered to 7-week-old female obese and lean Zucker rats for a period of 4 weeks.


RESULTS
DZ-treated animals showed lower fasting plasma insulin levels (P<0.001) than their controls. Plasma glucose levels were lower in DZ obese rats than in controls (P<0.001), without a significant change in DZ lean animals. DZ had no effect on glucose transporter 2 protein expression in either strain. DZ treatment resulted in lower hepatic glucokinase (P<0.001) and glucose-6-phosphatase (P<0.0001) and phosphoenolpyruvate carboxykinase (PEPCK) activities only in obese rats compared with controls (P<0.001). However, DZ-treated lean rats demonstrated higher PEPCK activity than controls (P<0.002). DZ-treated animals demonstrated enhanced hepatic glucose-6-phosphate content (P<0.01), glycogen synthase activity (P<0.0001) and glycogen content (P<0.02) compared with their controls despite increased hepatic glycogen phosphorylase a activity in these animals (P<0.02).


CONCLUSIONS
Chronic suppression of hyperinsulinemia in obese Zucker rats by DZ decreased the activities of key enzymes regulating hepatic gluconeogenesis, implying that attenuation of the hyperinsulinemic state by DZ may be therapeutically beneficial.
Alemzadeh
Ramin
R
Department of Pediatrics, University of Tennessee, Graduate School of Medicine, Knoxville, USA. ralemzad@mcw.edu
Holshouser
Sidney
S
Massey
Pam
P
Koontz
John
J
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003981:Diazoxide / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D005260:Female; D005941:Glucokinase / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D051273:Glucose Transporter Type 2; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D006946:Hyperinsulinism / Q000188:drug therapy*; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D013851:Thinness
D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D007328:Insulin; D008055:Lipids; D009004:Monosaccharide Transport Proteins; D006003:Glycogen; D024981:Glycogen Phosphorylase; D006006:Glycogen Synthase; C069767:phosphoenolpyruvate carboxylase kinase; D005941:Glucokinase; D017346:Protein Serine-Threonine Kinases; D005952:Glucose-6-Phosphatase; D003981:Diazoxide