Reversal of diet-induced glucose intolerance by hepatic expression of a variant glycogen-targeting subunit of protein phosphatase-1

Rosa Gasa, Catherine Clark, Ruojing Yang, Anna A. Depaoli-Roach, Christopher B. Newgard

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Glycogen-targeting subunits of protein phosphatase-1 facilitate interaction of the phosphatase with enzymes of glycogen metabolism. Expression of one family member, PTG, in the liver of normal rats improves glucose tolerance without affecting other plasma variables but leaves animals unable to reduce hepatic glycogen stores in response to fasting. In the current study, we have tested whether expression of other targeting subunit isoforms, such as the liver isoform GL, the muscle isoform GM/RGl, or a truncated version of GM/RGl termed GMΔC in liver ameliorates glucose intolerance in rats fed on a high fat diet (HF). HF animals overexpressing GMΔC, but not GL or GM/RGl, exhibited a decline in blood glucose of 35-44 mg/dl relative to control HF animals during an oral glucose tolerance test (OGTT) such that levels were indistinguishable from those of normal rats fed on standard chow at all but one time point. Hepatic glycogen levels were 2.1-2.4-fold greater in GL- and GMΔC-overexpressing HF rats compared with control HF animals following OGTT. In a second set of studies on fed and 20-h fasted HF animals, GMΔC-overexpressing rats lowered their liver glycogen levels by 57% (from 402 ± 54 to 173 ± 27 μg of glycogen/mg of protein) in the fasted versus fed states compared with only 44% in GL-overexpressing animals (from 740 ± 35 to 413 ± 141 μg of glycogen/mg of protein). Since the OGTT studies were performed on 20-h fasted rats, this meant that GMΔC-overexpressing rats synthesized much more glycogen than GL-overexpressing HF rats during the OGTT (419 versus 117 μg of glycogen/mg of protein, respectively), helping to explain why GMΔC preferentially enhanced glucose clearance. We conclude that GMΔC has a unique combination of glycogenic potency and responsiveness to glycogenolytic signals that allows it to be used to lower blood glucose levels in diabetes.

Original languageEnglish (US)
Pages (from-to)1524-1530
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number2
DOIs
StatePublished - Jan 11 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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