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 G(L), the muscle isoform G(M)/R(Gl), or a truncated version of G(M)/R(Gl) termed G(M)DeltaC in liver ameliorates glucose intolerance in rats fed on a high fat diet (HF). HF animals overexpressing G(M)DeltaC, but not G(L) or G(M)/R(Gl), 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 G(L)- and G(M)DeltaC-overexpressing HF rats compared with control HF animals following OGTT. In a second set of studies on fed and 20-h fasted HF animals, G(M)DeltaC-overexpressing rats lowered their liver glycogen levels by 57% (from 402 +/- 54 to 173 +/- 27 microg of glycogen/mg of protein) in the fasted versus fed states compared with only 44% in G(L)-overexpressing animals (from 740 +/- 35 to 413 +/- 141 microg of glycogen/mg of protein). Since the OGTT studies were performed on 20-h fasted rats, this meant that G(M)DeltaC-overexpressing rats synthesized much more glycogen than G(L)-overexpressing HF rats during the OGTT (419 versus 117 microg of glycogen/mg of protein, respectively), helping to explain why G(M)DeltaC preferentially enhanced glucose clearance. We conclude that G(M)DeltaC 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.
Highlights
Hepatic glycogen storage is impaired in all major forms of diabetes, contributing to the development of hyperglycemia [1,2,3]
Adenovirus-mediated expression of the various glycogen-targeting subunit isoforms in liver was evaluated by semiquantitative multiplex RT-PCR analysis in animals fed on the high fat diet (HF)
B, quantitative analysis of the ratio of each transgene:TATA-binding protein (TBP) for all animals included in the oral glucose tolerance test (OGTT) protocol
Summary
Hepatic glycogen storage is impaired in all major forms of diabetes, contributing to the development of hyperglycemia [1,2,3]. Recent studies have highlighted an important role for glycogen-targeting subunits of protein phosphatase-1 (PP1) in spatial organization and regulation of glycogen metabolism [9] Prominent members of this gene family include GM or RGl (hereafter referred to as GM/RGl), expressed primarily in striated skeletal muscle [10], GL, expressed primarily in liver [11], and protein targeting to glycogen (PTG) [12, 13] and PPPR6 [14], expressed in a wide range of tissues. We have performed one in vivo study in which hepatic overexpression of PTG in normal rats was shown to improve glucose tolerance without perturbation of lipid homeostasis [17] These animals had markedly elevated liver glycogen levels in the fed state and almost no reduction in hepatic glycogen stores in response to an overnight fast, suggesting that they might be more susceptible to perturbations in glycemic control during prolonged fasting, sustained exercise, or other stressful circumstances. GM/RGl is distinguished from other targeting subunits by virtue of its large
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