title: Mutational analysis of the coding regions of the genes encoding protein kinase B-alpha and -beta, phosphoinositide-dependent protein kinase-1, phosphatase targeting to glycogen, protein phosphatase inhibitor-1, and glycogenin: lessons from a search for genetic variability of the insulin-stimulated glycogen synthesis pathway of skeletal muscle in NIDDM patients.
abstract: The finding of a reduced insulin-stimulated glucose uptake and glycogen synthesis in the skeletal muscle of glucose-tolerant first-degree relatives of patients with NIDDM, as well as in cultured fibroblasts and skeletal muscle cells isolated from NIDDM patients, has been interpreted as evidence for a genetic involvement in the disease. The mode of inheritance of the common forms of NIDDM is as yet unclear, but the prevailing hypothesis supports a polygenic model. In the present study, we tested the hypothesis that the putative inheritable defects of insulin-stimulated muscle glycogen synthesis might be caused by genetic variability in the genes encoding proteins shown by biochemical evidence to be involved in insulin-stimulated glycogen synthesis in skeletal muscle. In 70 insulin-resistant Danish NIDDM patients, mutational analysis by reverse transcription-polymerase chain reaction-single strand conformation polymorphism-heteroduplex analysis was performed on genomic DNA or skeletal muscle-derived cDNAs encoding glycogenin, protein phosphatase inhibitor-1, phophatase targeting to glycogen, protein kinase B-alpha and -beta, and the phosphoinositide-dependent protein kinase-1. Although a number of silent variants were identified in some of the examined genes, we found no evidence for the hypothesis that the defective insulin-stimulated glycogen synthesis in skeletal muscle in NIDDM is caused by structural changes in the genes encoding the known components of the insulin-sensitive glycogen synthesis pathway of skeletal muscle.
authors.affiliation: Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Denmark. larh@hagedorn.dk
authors.forename: L
authors.initials: L
authors.lastname: Hansen
authors.forename: H
authors.initials: H
authors.lastname: Fjordvang
authors.forename: S K
authors.initials: SK
authors.lastname: Rasmussen
authors.forename: H
authors.initials: H
authors.lastname: Vestergaard
authors.forename: S M
authors.initials: SM
authors.lastname: Echwald
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: D
authors.initials: D
authors.lastname: Alessi
authors.forename: S
authors.initials: S
authors.lastname: Shenolikar
authors.forename: A R
authors.initials: AR
authors.lastname: Saltiel
authors.forename: F
authors.initials: F
authors.lastname: Barbetti
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D002352:Carrier Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D004722:Endoribonucleases; D005260:Female; D014644:Genetic Variation / Q000502:physiology; D005964:Glucosyltransferases; D006003:Glycogen / Q000096:biosynthesis; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D007536:Isomerism; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D010641:Phenotype; D010749:Phosphoprotein Phosphatases; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt; D016601:RNA-Binding Proteins / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C491294:PPP1R3C protein, human; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; C051887:glycogenin; C021042:protein phosphatase inhibitor-1; D006003:Glycogen; D005964:Glucosyltransferases; D064413:3-Phosphoinositide-Dependent Protein Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D004722:Endoribonucleases; D010749:Phosphoprotein Phosphatases; C097081:PPP1R8 protein, human