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Restoration of hepatic glucokinase expression corrects hepatic glucose flux and normalizes plasma glucose in zucker diabetic fatty rats.
- Source :
-
Diabetes [Diabetes] 2009 Jan; Vol. 58 (1), pp. 78-86. Date of Electronic Publication: 2008 Oct 24. - Publication Year :
- 2009
-
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.<br />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.<br />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.<br />Conclusions: Alteration of hepatic GK activity in ZDF rats has profound effects on plasma glucose and hepatic glucose flux.
- Subjects :
- Adenoviridae genetics
Aging
Animals
Blotting, Western
Body Weight
Carrier Proteins genetics
Carrier Proteins metabolism
Diabetes Mellitus, Experimental blood
Diabetes Mellitus, Experimental genetics
Glucagon blood
Glucokinase genetics
Hyperglycemia blood
Hyperglycemia genetics
Hyperglycemia metabolism
Insulin blood
Liver metabolism
Male
Rats
Rats, Zucker
Blood Glucose metabolism
Diabetes Mellitus, Experimental metabolism
Glucokinase metabolism
Glucose metabolism
Liver enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1939-327X
- Volume :
- 58
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 18952838
- Full Text :
- https://doi.org/10.2337/db08-1119