Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance
Open accessAbstract
Insulin resistance is instrumental in the pathogenesis of type 2 diabetes mellitus and the Insulin Resistance Syndrome. While insulin resistance involves decreased glucose transport activity in skeletal muscle, its molecular basis is unknown. Since muscle GLUT4 glucose transporter levels are normal in type 2 diabetes, we have tested the hypothesis that insulin resistance is due to impaired translocation of intracellular GLUT4 to sarcolemma. Both insulin-sensitive and insulin-resistant nondiabetic subgroups were studied, in addition to type 2 diabetic patients. Biopsies were obtained from basal and insulin-stimulated muscle, and membranes were subfractionated on discontinuous sucrose density gradients to equilibrium or under nonequilibrium conditions after a shortened centrifugation time. In equilibrium fractions from basal muscle, GLUT4 was decreased by 25-29% in both 25 and 28% sucrose density fractions and increased twofold in both the 32% sucrose fraction and bottom pellet in diabetics compared with insulin-sensitive controls, without any differences in membrane markers (phospholemman, phosphalamban, dihydropyridine-binding complex alpha-1 subunit). Thus, insulin resistance was associated with redistribution of GLUT4 to denser membrane vesicles. No effects of insulin stimulation on GLUT4 localization were observed. In non-equilibrium fractions, insulin led to small GLUT4 decrements in the 25 and 28% sucrose fractions and increased GLUT4 in the 32% sucrose fraction by 2.8-fold over basal in insulin-sensitive but only by 1.5-fold in both insulin-resistant and diabetic subgroups. The GLUT4 increments in the 32% sucrose fraction were correlated with maximal in vivo glucose disposal rates (r = +0.51, P = 0.026), and, therefore, represented GLUT4 recruitment to sarcolemma or a quantitative marker for this process. Similar to GLUT4, the insulin-regulated aminopeptidase (vp165) was redistributed to a dense membrane compartment and did not translocate in response to insulin in insulin-resistant subgroups. In conclusion, insulin alters the subcellular localization of GLUT4 vesicles in human muscle, and this effect is impaired equally in insulin-resistant subjects with and without diabetes. This translocation defect is associated with abnormal accumulation of GLUT4 in a dense membrane compartment demonstrable in basal muscle. We have previously observed a similar pattern of defects causing insulin resistance in human adipocytes. Based on these data, we propose that human insulin resistance involves a defect in GLUT4 traffic and targeting leading to accumulation in a dense membrane compartment from which insulin is unable to recruit GLUT4 to the cell surface.
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Insulin-mediated translocation of GLUT4 to the muscle sarcolemmal membrane is impaired in patients with type 2 diabetes mellitus.
“Insulin-mediated translocation of GLUT4 to the muscle sarcolemmal membrane was impaired in patients with type 2 diabetes mellitus.24,25”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [25]
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- Authors
- Garvey, W. T., Maianu, L., Zhu, J. H., Brechtel-Hook, G., Wallace, P., & Baron, A. D.
- Affiliations
- Medical University of South Carolina (US)
- Richard L. Roudebush VA Medical Center (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 1998-06-01
- Volume
- 101
- Issue
- 11
- Pages
- 2377-2386
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508827
- OpenAlex
- W2038081709
- Cited by
- 459
- References
- 64
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- FWCI
- 5.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- Medical University of South Carolina (M01-RR-1070)
- Dartmouth College
- University of South Carolina
- National Institutes of Health (M01-RR-1070)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 38764, P-60DK20542, DK42469, P60DK020542)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- insulin resistance, skeletal muscle, GLUT4 translocation, sarcolemma, type 2 diabetes, insulin-stimulated glucose transport, membrane vesicles, subcellular localization, CD13, glucose disposal, membrane subfractions, metabolic syndrome, insulin-stimulated glucose uptake
- MeSH terms
- Adult, Aminopeptidases, Biological Transport, Centrifugation, Density Gradient, Female, Humans, Insulin Resistance, Male, Middle Aged, Monosaccharide Transport Proteins, Muscle Proteins, Cystinyl Aminopeptidase, Muscle, Skeletal, Glucose Transporter Type 4
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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