A widespread amino acid polymorphism at codon 905 of the glycogen-associated regulatory subunit of protein phosphatase-1 is associated with insulin resistance and hypersecretion of insulin
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A widespread amino acid polymorphism at codon 905 of the glycogen-associated regulatory subunit of protein phosphatase-1 is associated with insulin resistance and hypersecretion of insulin. / Hansen, Lars; Hansen, Torben; Vestergaard, Henrik; Bjørbæk, Christian; Echwald, Søren M.; Clausen, Jesper O.; Chen, Yu Hua; Chen, Mao Xiang; Cohen, Patricia T. W.; Pedersen, Oluf.
I: Human Molecular Genetics, Bind 4, Nr. 8, 1995, s. 1313-20.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - A widespread amino acid polymorphism at codon 905 of the glycogen-associated regulatory subunit of protein phosphatase-1 is associated with insulin resistance and hypersecretion of insulin
AU - Hansen, Lars
AU - Hansen, Torben
AU - Vestergaard, Henrik
AU - Bjørbæk, Christian
AU - Echwald, Søren M.
AU - Clausen, Jesper O.
AU - Chen, Yu Hua
AU - Chen, Mao Xiang
AU - Cohen, Patricia T. W.
AU - Pedersen, Oluf
PY - 1995
Y1 - 1995
N2 - The regulatory G-subunit of the glycogen-associated form of protein phosphatase 1 (PP1) plays a crucial part in muscle tissue glycogen synthesis and breakdown. As impaired insulin stimulated glycogen synthesis in peripheral tissues is considered to be a pathogenic factor in subsets of non-insulin-dependent diabetes mellitus (NIDDM) and obesity, the G-subunit of PP1 should be viewed as a candidate gene for inherited insulin resistance. When applying heteroduplex formation analysis and nucleotide sequencing of PP1G-subunit cDNA from 30 insulin resistant white NIDDM patients two cases were identified as heterozygous carriers of an Asp905 --> Tyr substitution. The carrier prevalence of the PP1G-subunit variant was 18% in 150 healthy subjects and 13% in 313 NIDDM subjects (chi 2 = 1.94, p = 0.16). Twenty-seven healthy subjects volunteered for a 4 h euglycaemic, hyperinsulinaemic clamp in combination with indirect calorimetry in order to elucidate the potential impact of the Tyr905 substitution on the whole body glucose metabolism. Interestingly, the Tyr905 variant was associated with altered routing of glucose: a decreased insulin stimulated non-oxidative glucose metabolism of peripheral tissues (glycogen synthesis) (p < 0.04) and an increased basal glucose oxidation rate (p < 0.04) when compared with wild type carriers. A population-based sample of 380 unrelated young healthy Caucasians was examined during a combined intravenous glucose and tolbutamide test to address whether the Asp905/Tyr905 polymorphism was associated with alterations in insulin secretion which might be secondary to the insulin resistance of skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
AB - The regulatory G-subunit of the glycogen-associated form of protein phosphatase 1 (PP1) plays a crucial part in muscle tissue glycogen synthesis and breakdown. As impaired insulin stimulated glycogen synthesis in peripheral tissues is considered to be a pathogenic factor in subsets of non-insulin-dependent diabetes mellitus (NIDDM) and obesity, the G-subunit of PP1 should be viewed as a candidate gene for inherited insulin resistance. When applying heteroduplex formation analysis and nucleotide sequencing of PP1G-subunit cDNA from 30 insulin resistant white NIDDM patients two cases were identified as heterozygous carriers of an Asp905 --> Tyr substitution. The carrier prevalence of the PP1G-subunit variant was 18% in 150 healthy subjects and 13% in 313 NIDDM subjects (chi 2 = 1.94, p = 0.16). Twenty-seven healthy subjects volunteered for a 4 h euglycaemic, hyperinsulinaemic clamp in combination with indirect calorimetry in order to elucidate the potential impact of the Tyr905 substitution on the whole body glucose metabolism. Interestingly, the Tyr905 variant was associated with altered routing of glucose: a decreased insulin stimulated non-oxidative glucose metabolism of peripheral tissues (glycogen synthesis) (p < 0.04) and an increased basal glucose oxidation rate (p < 0.04) when compared with wild type carriers. A population-based sample of 380 unrelated young healthy Caucasians was examined during a combined intravenous glucose and tolbutamide test to address whether the Asp905/Tyr905 polymorphism was associated with alterations in insulin secretion which might be secondary to the insulin resistance of skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
KW - Base Sequence
KW - Case-Control Studies
KW - DNA
KW - DNA Primers
KW - Diabetes Mellitus, Type 2
KW - Female
KW - Gene Frequency
KW - Genetic Variation
KW - Glucose
KW - Glycogen
KW - Humans
KW - Insulin
KW - Insulin Resistance
KW - Male
KW - Middle Aged
KW - Molecular Sequence Data
KW - Nucleic Acid Heteroduplexes
KW - Phosphoprotein Phosphatases
KW - Polymorphism, Genetic
KW - Protein Phosphatase 1
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1093/hmg/4.8.1313
DO - 10.1093/hmg/4.8.1313
M3 - Journal article
C2 - 7581368
VL - 4
SP - 1313
EP - 1320
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 8
ER -
ID: 174866753