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Decreased insulin activation of glycogen synthase in skeletal muscles in young nonobese Caucasian first-degree relatives of patients with non-insulin-dependent diabetes mellitus
Open accessAbstract
Insulin resistance in non-insulin-dependent diabetes is associated with a defective insulin activation of the enzyme glycogen synthase in skeletal muscles. To investigate whether this may be a primary defect, we studied 20 young (25 +/- 1 yr) Caucasian first-degree relatives (children) of patients with non-insulin-dependent diabetes, and 20 matched controls without a family history of diabetes. Relatives and controls had a normal oral glucose tolerance, and were studied by means of the euglycemic hyperinsulinemic clamp technique, which included performance of indirect calorimetry and muscle biopsies. Insulin-stimulated glucose disposal was decreased in the relatives (9.2 +/- 0.6 vs 11.5 +/- 0.5 mg/kg fat-free mass per (FFM) min, P less than 0.02), and was due to a decreased rate of insulin-stimulated nonoxidative glucose metabolism (5.0 +/- 0.5 vs 7.5 +/- 0.4 mg/kg fat-free mass per min, P less than 0.001). The insulin-stimulated, fractional glycogen synthase activity (0.1/10 mmol liter glucose-6-phosphate) was decreased in the relatives (46.9 +/- 2.3 vs 56.4 +/- 3.2%, P less than 0.01), and there was a significant correlation between insulin-stimulated, fractional glycogen synthase activity and nonoxidative glucose metabolism in relatives (r = 0.76, P less than 0.001) and controls (r = 0.63, P less than 0.01). Furthermore, the insulin-stimulated increase in muscle glycogen content over basal values was lower in the relatives (13 +/- 25 vs 46 +/- 9 mmol/kg dry wt, P = 0.05). We conclude that the defect in insulin activation of muscle glycogen synthase may be a primary, possibly genetically determined, defect that contributes to the development of non-insulin-dependent diabetes.
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“Multiple investigators unequivocally have demonstrated that lean NGT offspring of two parents with type 2 diabetes exhibit moderate to severe skeletal muscle insulin resistance ( 28 – 33 ).”
From Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes (2009) · cites this paper as [31]
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“The ability of insulin to stimulate glycogen synthase also is diminished in the normal glucose-tolerant, insulin-resistant relatives of type 2 diabetic individuals [218].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [218]
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“Data have been presented arguing both for (41, 42) and against (43) transport/phosphorylation as the rate-limiting step for glucose uptake in NIDDM during insulin infusion.”
BackgroundInsulin-stimulated glucose uptake in healthy and insulin-resistant skeletal muscle
Deshmukh, A. S. (2015) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2015-0041 · Cited by 84
Beck‐Nielsen, H., Vaag, A. A., Poulsen, P., & Gaster, M. (2003) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/s1521-690x(03)00041-1 · Cited by 77
Self-citationGenetic determinants and molecular pathways in the pathogenesis of Type 2 diabetes
Jin, W., & Patti, M. (2008) · Clinical Science · doi:10.1042/cs20080090 · Cited by 78
Dual Regulation of Muscle Glycogen Synthase during Exercise by Activation and Compartmentalization
Prats, C., Helge, J. W., Nordby, P., Qvortrup, K., Ploug, T., Dela, F., & Wojtaszewski, J. F. P. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m900845200 · Cited by 79
General Characteristics of the Insulin Resistance Syndrome
Beck‐Nielsen, H. (1999) · Drugs · doi:10.2165/00003495-199958001-00003 · Cited by 77
“In the Joslin Diabetes Center study, outcomes in the offspring of parents with type 2 diabetes indicated that insulin resistance may precede diabetes;[6] results of investigations in first-degree relatives of patients with type 2 diabetes were in agreement with this observation, since they appeared to show development…”
ResultSelf-citationDysregulation of Lipid and Glucose Metabolism in Nonalcoholic Fatty Liver Disease
Bhat, N., & Mani, A. (2023) · Nutrients · doi:10.3390/nu15102323 · Cited by 85
“As a consequence, the glycogen stores of the muscle are depleted, which is one of the first manifestations of insulin resistance [21–23].”
BackgroundThe Intracellular Mechanism of Insulin Resistance in Pancreatic Cancer Patients
Liu, J., Knezetic, J. A., Strömmer, L., Permert, J., Larsson, J., & Adrian, T. E. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.3.6400 · Cited by 81
“(30, 32 ). The present study demonstrated that the insulin resistance seen in pancreatic cancer patients is associated with multiple defects of skeletal muscle glycogen synthase.”
BackgroundDevelopment of insulin resistance and reversal by thiazolidinediones in C2C12 skeletal muscle cells
Kumar, N., & Dey, C. S. (2002) · Biochemical Pharmacology · doi:10.1016/s0006-2952(02)01509-5 · Cited by 75
Urocortin 2 modulates glucose utilization and insulin sensitivity in skeletal muscle
Chen, A., Brar, B. K., Choi, C. S., Rousso, D. L., Vaughan, J. M., Kuperman, Y., Kim, S. N., Donaldson, C., Smith, S. M., Jamieson, P. M., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607337103 · Cited by 75
Nyholm, B., Nielsen, M. F., Kristensen, K., Nielsen, S., Ostergard, T., Pedersen, S. B., Christiansen, T., Richelsen, B., Jensen, M., & Schmitz, O. (2004) · European Journal of Endocrinology · doi:10.1530/eje.0.1500207 · Cited by 72
Skeletal muscle and insulin sensitivity: pathophysiological alterations
Ryder, J. (2001) · Frontiers in bioscience · doi:10.2741/ryder · Cited by 73
“This tissue accounts for ~80% of total glucose disposal under insulin-stimulated conditions (4), and defects in insulin action in skeletal muscle precede the clinical diagnosis of the disease (5).”
BackgroundZierath, J. R., & Wallberg‐Henriksson, H. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb04270.x · Cited by 71
Bak, J. F., Møller, N., Schmitz, O., Saaek, A., & Pedersen, O. B. (1992) · Diabetologia · doi:10.1007/bf00429100 · Cited by 72
“Recent reports from first-degree relatives of patients with Type 2 diabetes suggest that impaired insulin stimulation of glucose storage [43] and reduced insulin stimulation of GS activity in muscle [ 44 ] may be primary defects in this disease.”
BackgroundThe Genetics of Human Noninsulin-Dependent (Type 2) Diabetes Mellitus
Elbein, S. C. (1997) · Journal of Nutrition · doi:10.1093/jn/127.9.1891s · Cited by 69
Jackson, S., Bagstaff, S. M., Lynn, S., Yeaman, S. J., Turnbull, D. M., & Walker, M. (2000) · Diabetes · doi:10.2337/diabetes.49.7.1169 · Cited by 67
1 Cellular insulin action and insulin resistance
Garvey, W. T., & Birnbaum, M. J. (1993) · Baillière s Clinical Endocrinology and Metabolism · doi:10.1016/s0950-351x(05)80237-x · Cited by 67
Glintborg, D., Hermann, A. P., Andersen, M., Hagen, C., Beck‐Nielsen, H., Veldhuis, J. D., & Henriksen, J. E. (2006) · Fertility and Sterility · doi:10.1016/j.fertnstert.2005.12.067 · Cited by 68
Self-citationZawalich, W. S., & Zawalich, K. C. (2000) · Endocrinology · doi:10.1210/endo.141.9.7636 · Cited by 70
Bjørbæk, C., Echwald, S. M., Hubricht, P., Vestergaard, H., Hansen, T., Zierath, J., & Pedersen, O. (1994) · Diabetes · doi:10.2337/diab.43.8.976 · Cited by 61
“Both in patients with NIDDM and in their glucose-tolerant first-degree relatives, reduced insulin-stimulated glycogen synthesis in skeletal muscle has been reported (3,17).”
BackgroundKrützfeldt, J., Kausch, C., Volk, A., Klein, H., Kristian, R. E. T. T., Häring, H., & Stümvoll, M. (2000) · Diabetes · doi:10.2337/diabetes.49.6.992 · Cited by 66
“Moreover, impaired insulin activation of glycogen synthase (15) and IR kinase (16) have been described in muscle biopsies from FDRs.”
BackgroundStorgaard, H., Jensen, C. B., Vaag, A. A., Vølund, A., & Madsbad, S. (2003) · Metabolism · doi:10.1016/s0026-0495(03)00102-1 · Cited by 63
Self-citationMultiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families
Humphriss, D. B., Stewart, M. W., Berrish, T. S., Barriocanal, L. A., Trajano, L. R., Ashworth, L., Brown, M. D., Miller, M., Avery, P. J., Alberti, K. G. M. M., et al. (1997) · Diabetologia · doi:10.1007/s001250050805 · Cited by 64
“Decreased insulinstimulated glycogen deposition in skeletal muscle appears to be a key abnormality [16, 19 ], while physical fitness, an important determinant of insulin sensitivity in normal man [30], has recently been reported to be decreased in a comparable group of normal glucose tolerant relatives [22].”
BackgroundInsulin action in skeletal muscle from patients with NIDDM
Zierath, J. R., Krook, A., & Wallberg‐Henriksson, H. (1998) · Molecular and Cellular Biochemistry · doi:10.1023/a:1006861628496 · Cited by 65
“Despite the decreased insulin-stimulated glycogen synthase activity in skeletal muscle from patients with NIDDM, fasting levels of skeletal muscle glycogen are comparable between lean NIDDM patients and controls [11, 24].”
BackgroundResultElevated plasma glucose 2 h postchallenge predicts defects in beta-cell function
Byrne, M. M., Sturis, J., Sobel, R., & Polonsky, K. S. (1996) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1996.270.4.e572 · Cited by 61
Pratipanawatr, T., Cusi, K., Ngo, P., Pratipanawatr, W., Mandarino, L. J., & DeFronzo, R. A. (2002) · Diabetes · doi:10.2337/diabetes.51.2.462 · Cited by 61
Metadata
- Authors
- Vaag, A., Henriksen, J. E., & Beck-Nielsen, H.
- Affiliations
- Odense University Hospital (DK)
- Venue
- Journal of Clinical Investigation
- Published
- 1992-03-01
- Volume
- 89
- Issue
- 3
- Pages
- 782-788
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC442922
- OpenAlex
- W2041249629
- Cited by
- 299
- References
- 58
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 7 · 2017: 2 · 2016: 5 · 2015: 6 · 2014: 3 · 2013: 5 · 2012: 3
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Diabetesforeningen
- 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 › Biochemistry › Glycogen Storage Diseases and Myoclonus
- Keywords
- insulin resistance, type 2 diabetes, glycogen synthase, skeletal muscle, first-degree relatives, genetic susceptibility, insulin-stimulated glucose disposal, nonoxidative glucose metabolism, muscle glycogen, hyperinsulinemic-euglycemic clamp
- MeSH terms
- Adult, Blood Glucose, Diabetes Mellitus, Type 2, Enzyme Activation, Glycogen Synthase, Humans, Insulin, Insulin Resistance, Muscles, White People
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