Skeletal Muscle Insulin Resistance in Normoglycemic Subjects with a Strong Family History of Type 2 Diabetes is Associated with Decreased Insulin-Stimulated Insulin Receptor Substrate-1 Tyrosine Phosphorylation

Wilailak Pratipanawatr, Thongchai Pratipanawatr, Kenneth Cusi, Rachele Berria, John M. Adams, Christopher P. Jenkinson, Katsumi Maezono, Ralph A Defronzo, Lawrence J. Mandarino

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Abstract

Normoglycemic subjects with a strong family history of type 2 diabetes are insulin resistant, but the mechanism of insulin resistance in skeletal muscle of such individuals is unknown. The present study was undertaken to determine whether abnormalities in insulin-signaling events are present in normoglycemic, nonobese subjects with a strong family history of type 2 diabetes. Hyperinsulinemic-euglycemic clamps with percutaneous muscle biopsies were performed in eight normoglycemic relatives of type 2 diabetic patients (FH+) and eight control subjects who had no family history of diabetes (FH-), with each group matched for age, sex, body composition, and ethnicity. The FH+ group had decreased insulin-stimulated glucose disposal (6.64 ± 0.52 vs. 8.45 ± 0.54 mg · kg-1 fat-free mass · min-1; P < 0.05 vs. FH-). In skeletal muscle, the FH+ and FH- groups had equivalent insulin stimulation of insulin receptor tyrosine phosphorylation. In contrast, the FH+ group had decreased insulin stimulation of insulin receptor substrate (IRS)-1 tyrosine phosphorylation (0.522 ± 0.077 vs. 1.328 ± 0.115 density units; P < 0.01) and association of PI 3-kinase activity with IRS-1 (0.299 ± 0.053 vs. 0.466 ± 0.098 activity units; P < 0.05). PI 3-kinase activity was correlated with the glucose disposal rate (r = 0.567, P = 0.02). In five subjects with sufficient biopsy material for further study, phosphorylation of Akt was 0.266 ± 0.061 vs. 0.404 ± 0.078 density units (P < 0.10) and glycogen synthase activity was 0.31 ± 0.06 vs. 0.50 ± 0.12 ng · min-1 · mg-1 (P < 0.10) for FH+ and FH- subjects, respectively. Therefore, despite normal insulin receptor phosphorylation, post-receptor signaling was reduced and was correlated with glucose disposal in muscle of individuals with a strong genetic background for type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)2572-2578
Number of pages7
JournalDiabetes
Volume50
Issue number7-12
StatePublished - Nov 2001

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Insulin Receptor Substrate Proteins
Type 2 Diabetes Mellitus
Tyrosine
Insulin Resistance
Skeletal Muscle
Phosphorylation
Insulin
Insulin Receptor
Phosphatidylinositol 3-Kinases
Glucose
Biopsy
Muscles
Glycogen Synthase
Glucose Clamp Technique
Body Composition
Research Design
Age Groups
Fats

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine

Cite this

Pratipanawatr, W., Pratipanawatr, T., Cusi, K., Berria, R., Adams, J. M., Jenkinson, C. P., ... Mandarino, L. J. (2001). Skeletal Muscle Insulin Resistance in Normoglycemic Subjects with a Strong Family History of Type 2 Diabetes is Associated with Decreased Insulin-Stimulated Insulin Receptor Substrate-1 Tyrosine Phosphorylation. Diabetes, 50(7-12), 2572-2578.

Skeletal Muscle Insulin Resistance in Normoglycemic Subjects with a Strong Family History of Type 2 Diabetes is Associated with Decreased Insulin-Stimulated Insulin Receptor Substrate-1 Tyrosine Phosphorylation. / Pratipanawatr, Wilailak; Pratipanawatr, Thongchai; Cusi, Kenneth; Berria, Rachele; Adams, John M.; Jenkinson, Christopher P.; Maezono, Katsumi; Defronzo, Ralph A; Mandarino, Lawrence J.

In: Diabetes, Vol. 50, No. 7-12, 11.2001, p. 2572-2578.

Research output: Contribution to journalArticle

Pratipanawatr, Wilailak ; Pratipanawatr, Thongchai ; Cusi, Kenneth ; Berria, Rachele ; Adams, John M. ; Jenkinson, Christopher P. ; Maezono, Katsumi ; Defronzo, Ralph A ; Mandarino, Lawrence J. / Skeletal Muscle Insulin Resistance in Normoglycemic Subjects with a Strong Family History of Type 2 Diabetes is Associated with Decreased Insulin-Stimulated Insulin Receptor Substrate-1 Tyrosine Phosphorylation. In: Diabetes. 2001 ; Vol. 50, No. 7-12. pp. 2572-2578.
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abstract = "Normoglycemic subjects with a strong family history of type 2 diabetes are insulin resistant, but the mechanism of insulin resistance in skeletal muscle of such individuals is unknown. The present study was undertaken to determine whether abnormalities in insulin-signaling events are present in normoglycemic, nonobese subjects with a strong family history of type 2 diabetes. Hyperinsulinemic-euglycemic clamps with percutaneous muscle biopsies were performed in eight normoglycemic relatives of type 2 diabetic patients (FH+) and eight control subjects who had no family history of diabetes (FH-), with each group matched for age, sex, body composition, and ethnicity. The FH+ group had decreased insulin-stimulated glucose disposal (6.64 ± 0.52 vs. 8.45 ± 0.54 mg · kg-1 fat-free mass · min-1; P < 0.05 vs. FH-). In skeletal muscle, the FH+ and FH- groups had equivalent insulin stimulation of insulin receptor tyrosine phosphorylation. In contrast, the FH+ group had decreased insulin stimulation of insulin receptor substrate (IRS)-1 tyrosine phosphorylation (0.522 ± 0.077 vs. 1.328 ± 0.115 density units; P < 0.01) and association of PI 3-kinase activity with IRS-1 (0.299 ± 0.053 vs. 0.466 ± 0.098 activity units; P < 0.05). PI 3-kinase activity was correlated with the glucose disposal rate (r = 0.567, P = 0.02). In five subjects with sufficient biopsy material for further study, phosphorylation of Akt was 0.266 ± 0.061 vs. 0.404 ± 0.078 density units (P < 0.10) and glycogen synthase activity was 0.31 ± 0.06 vs. 0.50 ± 0.12 ng · min-1 · mg-1 (P < 0.10) for FH+ and FH- subjects, respectively. Therefore, despite normal insulin receptor phosphorylation, post-receptor signaling was reduced and was correlated with glucose disposal in muscle of individuals with a strong genetic background for type 2 diabetes.",
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AU - Pratipanawatr, Thongchai

AU - Cusi, Kenneth

AU - Berria, Rachele

AU - Adams, John M.

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AB - Normoglycemic subjects with a strong family history of type 2 diabetes are insulin resistant, but the mechanism of insulin resistance in skeletal muscle of such individuals is unknown. The present study was undertaken to determine whether abnormalities in insulin-signaling events are present in normoglycemic, nonobese subjects with a strong family history of type 2 diabetes. Hyperinsulinemic-euglycemic clamps with percutaneous muscle biopsies were performed in eight normoglycemic relatives of type 2 diabetic patients (FH+) and eight control subjects who had no family history of diabetes (FH-), with each group matched for age, sex, body composition, and ethnicity. The FH+ group had decreased insulin-stimulated glucose disposal (6.64 ± 0.52 vs. 8.45 ± 0.54 mg · kg-1 fat-free mass · min-1; P < 0.05 vs. FH-). In skeletal muscle, the FH+ and FH- groups had equivalent insulin stimulation of insulin receptor tyrosine phosphorylation. In contrast, the FH+ group had decreased insulin stimulation of insulin receptor substrate (IRS)-1 tyrosine phosphorylation (0.522 ± 0.077 vs. 1.328 ± 0.115 density units; P < 0.01) and association of PI 3-kinase activity with IRS-1 (0.299 ± 0.053 vs. 0.466 ± 0.098 activity units; P < 0.05). PI 3-kinase activity was correlated with the glucose disposal rate (r = 0.567, P = 0.02). In five subjects with sufficient biopsy material for further study, phosphorylation of Akt was 0.266 ± 0.061 vs. 0.404 ± 0.078 density units (P < 0.10) and glycogen synthase activity was 0.31 ± 0.06 vs. 0.50 ± 0.12 ng · min-1 · mg-1 (P < 0.10) for FH+ and FH- subjects, respectively. Therefore, despite normal insulin receptor phosphorylation, post-receptor signaling was reduced and was correlated with glucose disposal in muscle of individuals with a strong genetic background for type 2 diabetes.

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