Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulin-dependent diabetes mellitus and obesity
Abstract
To assess the role of insulin receptor (IR) tyrosine kinase in human insulin resistance, we examined the kinase activity of IR of skeletal muscle biopsies from eight lean and five obese nondiabetics and six obese subjects with noninsulin-dependent diabetes mellitus (NIDDM). Biopsies were taken during euglycemic clamps at insulin infusion rates of 0, 40, 120, and 1200 mU/m2.min. IRs were immobilized on insulin agarose beads, and autophosphorylation and histone 2B phosphorylation were measured. Phosphatase and protease inhibitors preserved the in vivo phosphorylation state of the IRs. Glucose disposal rates (GDR) were reduced according to insulin dose by 23-30% in the obese (P < 0.05) and 43-64% in the NIDDM subjects (P < 0.0005). IR autophosphorylation was increased up to 9-fold in controls and was reduced (P = 0.04) in NIDDM compared to obese subjects. Histone-2B kinase was increased up to 6-fold in controls and was reduced by 50% in NIDDM. Kinase values by both methods were similar in lean and obese controls. In vivo stimulation of kinase was well correlated to the increase in GDR, as was the decrement in kinase in NIDDM to the decrement in GDR. These results suggest that defects in muscle IR kinase are significant in the in vivo insulin resistance of NIDDM, but not that of obesity.
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Most but not all investigators found reduced insulin receptor tyrosine kinase activity in skeletal muscle from normal-weight and obese diabetic subjects that cannot be explained by receptor number or binding affinity.
“Most [1, 7, 152, 153, 156, 161] but not all [155] investigators have found a reduction in tyrosine kinase activity that cannot be explained by alterations in insulin receptor number or insulin receptor binding affinity.”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [161]
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Pathogenesis of type 2 diabetes mellitus
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- Authors
- Nolan, J. J.
- Affiliations
- University of California San Diego (US)
- ORCID
- Nolan, J. J.
- Venue
- Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1994-02-01
- Volume
- 78
- Issue
- 2
- Pages
- 471-477
- ISSN
- 0021-972X (ISSN-L)
- OpenAlex
- W2092414667
- Cited by
- 108
- References
- 5
- Citations by year
- 2023: 1 · 2021: 2 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 3 · 2015: 4 · 2014: 1 · 2013: 3 · 2012: 2
- FWCI
- 2.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r29dk038949-05)
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK DK 33651, NIDDK DK-38949, NIDDK DK-33649)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- insulin receptor tyrosine kinase, insulin resistance, type 2 diabetes, obesity, skeletal muscle, glucose disposal rate, insulin receptor autophosphorylation, euglycemic clamp, insulin signaling
- MeSH terms
- Adult, Blood Glucose, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Enzyme Activation, Glucose, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Muscles, Obesity, Receptor, Insulin, Time Factors
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