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Diabetes. 2009 Jan;58(1):78-86. doi: 10.2337/db08-1119. Epub 2008 Oct 24.

Restoration of hepatic glucokinase expression corrects hepatic glucose flux and normalizes plasma glucose in zucker diabetic fatty rats.

Author information

1
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Abstract

OBJECTIVE:

We examined in 20-week-old Zucker diabetic fatty (ZDF) rats whether restoration of hepatic glucokinase (GK) expression would alter hepatic glucose flux and improve hyperglycemia.

RESEARCH DESIGN AND METHODS:

ZDF rats were treated at various doses with an adenovirus that directs the expression of rat liver GK (AdvCMV-GKL) dose dependently, and various metabolic parameters were compared with those of nondiabetic lean littermates (ZCL rats) before and during a hyperglycemic clamp. Viral infection per se did not affect hepatic GK activity, since expression of a catalytically inactive form of GK did not alter endogenous hepatic GK activity.

RESULTS:

ZDF rats compared with ZCL rats have lower hepatic GK activity (11.6 +/- 1.9 vs. 32.5 +/- 3.2 mU/mg protein), marked hyperglycemia (23.9 +/- 1.2 vs. 7.4 +/- 0.3 mmol/l), higher endogenous glucose production (80 +/- 3 vs. 38 +/- 3 micromol x kg(-1) x min(-1)), increased glucose-6-phosphatase flux (150 +/- 11 vs. 58 +/- 8 micromol x kg(-1) x min(-1)), and during a hyperglycemic clamp, a failure to suppress endogenous glucose production (80 +/- 7 vs. -7 +/- 4 micromol x kg(-1) x min(-1)) and promote glucose incorporation into glycogen (15 +/- 5 vs. 43 +/- 3 micromol/g liver). Treatment of ZDF rats with different doses of AdvCMV-GKL, which restored hepatic GK activity to one to two times that of ZCL rats, normalized plasma glucose levels and endogenous glucose production. During a hyperglycemic clamp, glucose production was suppressed and glucose incorporation into glycogen was normal.

CONCLUSIONS:

Alteration of hepatic GK activity in ZDF rats has profound effects on plasma glucose and hepatic glucose flux.

PMID:
18952838
PMCID:
PMC2606896
DOI:
10.2337/db08-1119
[Indexed for MEDLINE]
Free PMC Article

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