Modulation of adipoinsular axis in prediabetic Zucker diabetic fatty rats by diazoxide

Ramin Alemzadeh, Kathryn M. Tushaus

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Abstract

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 β-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 β3-adrenoreceptor mRNA (P < 0.005) and adenylate cyclase activity (P < 0.01) in adipose tissue from ZDF rats only, whereas it enhanced islet β3-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 co-enzyme 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-incIuced β-cell rest improved the lipid profile, enhanced the metabolic efficiency off insulin, and prevented β-cell dysfunction and diabetes in diabetes-prone animals. This therapeutic strategy may be beneficial in preventing β-cell failure and progression to diabetes in humans.

Original languageEnglish (US)
Pages (from-to)5476-5484
Number of pages9
JournalEndocrinology
Volume145
Issue number12
DOIs
StatePublished - Dec 1 2004

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Diazoxide
Insulin
Messenger RNA
Adenylyl Cyclases
Glucose
Triglycerides
Zucker Rats
Fatty Acid Synthases
Lipogenesis
Metabolome
Adiponectin
Hyperinsulinism
Leptin
Nonesterified Fatty Acids
Adrenergic Receptors
Type 2 Diabetes Mellitus
Weight Gain
Adipose Tissue
Hemoglobins
Eating

All Science Journal Classification (ASJC) codes

  • Endocrinology

Cite this

Modulation of adipoinsular axis in prediabetic Zucker diabetic fatty rats by diazoxide. / Alemzadeh, Ramin; Tushaus, Kathryn M.

In: Endocrinology, Vol. 145, No. 12, 01.12.2004, p. 5476-5484.

Research output: Contribution to journalArticle

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