Cited by 299Metabolism, Diabetes, and CancerDiabetes, Cardiovascular Risks, and LipoproteinsGlycogen Storage Diseases and Myoclonus

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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

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Vaag, A, Henriksen, J E, Beck-Nielsen, H·1992·Journal of Clinical Investigation

DOI 10.1172/jci115656PMC PMC442922

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Abstract

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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Beck‐Nielsen, H., Henriksen, J. E., Vaag, A. A., & Nielsen, O. H. (1995) · Diabetes Research and Clinical Practice · doi:10.1016/0168-8227(95)01082-o · Cited by 28
Self-citation
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Björntorp, P. A. (1993) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1993.tb38738.x · Cited by 28
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“…of its gene product as a critical regulator of glycogen synthase (Doherty et al. 1995; Munro et al. 2002), and the observation that type 2 diabetic patients are characterized by a decreased rate of glycogen synthesis in skeletal muscle in response to insulin (Shulman et al. 1990; Vaag et al. 1992).”
BackgroundInfluential
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Free Fatty Acids Induce Peripheral Insulin Resistance Without Increasing Muscle Hexosamine Pathway Product Levels in Rats
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“Additionally, prior reports have found an absence of [22] or reduced insulin action on skeletal muscle glycogen synthase from insulin-resistant humans [24, 25] and monkeys [23] and in first degree relatives of Type 2 diabetic patients [26].”
Background
Variation in the AU(AT)-Rich Element within the 3'-Untranslated Region of PPP1R3 Is Associated with Variation in Plasma Glucose in Aboriginal Canadians
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Background
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“Its activity is reduced in NIDDM (1-3) and in nondiabetic subjects with insulin resistance (1,4,5).”
BackgroundSelf-citation
Plasma cytokine levels in young and elderly twins: genes versus environment and relation to in vivo insulin action
Grunnet, L. G., Poulsen, P., Pedersen, B. K., Mandrup-Poulsen, T. R., & Vaag, A. A. (2005) · Diabetologia · doi:10.1007/s00125-005-0080-8 · Cited by 24
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BackgroundSelf-citation
Metabolic Dysfunction-Associated Steatotic Liver Disease Complicated by Diabetes: Pathophysiology and Emerging Therapies
Goto, H., & Takamura, T. (2025) · Journal of Obesity & Metabolic Syndrome · doi:10.7570/jomes25017 · Cited by 28
“50,51 Moreover, observational studies have shown that glycogen synthesis in skeletal muscle is reduced in elderly individuals, compared with younger ones, whereas hepatic de novo lipogenesis is enhanced.”
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“In subjects with a family history of NIDDM, insulin resistance on glycogen synthesis occurs before the development of overt diabetes (Schalin-Jantti et al., 1992; Vaag et al., 1992).”
Background
The pathogenesis of NIDDM: the role of the pancreatic beta cell
Zawalich, W. S., & Kelley, G. G. (1995) · Diabetologia · doi:10.1007/bf00400590 · Cited by 20
“Consistent with the concept that insulin resistance is the primal manifestation of developing diabetes, or the prediabetic state, are several recently published reports [6-8].”
Background
Regulation of Muscle Glucose Uptake In Vivo
Mandarino, L. J., Bonadonna, R. C., McGuinness, O. P., Halseth, A. E., & Wasserman, D. H. (2001) · Comprehensive physiology · doi:10.1002/cphy.cp070227 · Cited by 19
Prandial glucose effectiveness and fasting gluconeogenesis in insulin-resistant first-degree relatives of patients with type 2 diabetes.
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“Glucose and lipid oxidation Indirect calorimetry was performed using a computerized flow-through canopy gas analyzer system (Deltatrac; Datex, Helsinki, Finland), as previously described (4).”
MethodSelf-citation
The Ups and Downs of Insulin Resistance and Type 2 Diabetes: Lessons from Genomic Analyses in Humans
Sales, V., & Patti, M. (2012) · Current Cardiovascular Risk Reports · doi:10.1007/s12170-012-0283-8 · Cited by 17
Male preponderance in early diagnosed type 2 diabetes is associated with the ARE insertion/deletion polymorphism in the PPP1R3A locus
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“Glycogen-synthase (GS) catalyses one of the rate-determining steps in glycogen synthesis in muscle and defective insulin-mediated activation of muscle GS has been found in glucose tolerant, but insulin resistant first-degree relatives of Caucasian type 2 diabetic patients [3].”
Background
Genetic epidemiology of non‐insulin‐dependent diabetes
Valsania, P., & Micossi, P. (1994) · Diabetes/Metabolism Reviews · doi:10.1002/dmr.5610100404 · Cited by 16
Exercise-Induced Improvements in Insulin Sensitivity Are Not Attenuated by a Family History of Type 2 Diabetes
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Impaired endothelial function and insulin action in first-degree relatives of patients with type 2 diabetes mellitus
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Self-citation
Circulating 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) levels are associated with hyperglycemia and β cell dysfunction in a Chinese population
Zhang, S., Chen, P., Jin, H., Yi, J., Xie, X., Yang, M., Gao, T., Yang, L., Hu, C., Zhang, X., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-03271-1 · Cited by 15
Triglycerides, High-Density Lipoprotein Cholesterol, and Risk of Ischemic Heart Disease: A View from the Copenhagen Male Study
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“…syndrome X. 21,65 Several family studies have shown that healthy, non-diabetic, normotensive relatives to patients with one or more of the following diagnoses: type-2 diabetes, 66,76,77 hypertension, 78–80 and IHD, 81 are relatively more insulin resistance and/or hyperinsulinemic and dyslipidemic.”
Physical Activity and Insulin Resistance in Man
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Polymorphism of the Glycogen Synthase Gene in Hypertensive and Normotensive Subjects
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Cyclosorus terminans Extract Ameliorates Insulin Resistance and Non-Alcoholic Fatty Liver Disease (NAFLD) in High-Fat Diet (HFD)-Induced Obese Rats
Songtrai, S., Pratchayasakul, W., Arunsak, B., Chunchai, T., Kongkaew, A., Chattipakorn, N., Chattipakorn, S. C., & Kaewsuwan, S. (2022) · Nutrients · doi:10.3390/nu14224895 · Cited by 14
A Defect in Glycogen Synthesis Characterizes Insulin Resistance in Hypertensive Patients With Type 2 Diabetes
Solini, A., Virgilio, F. D., Chiozzi, P., Fioretto, P., Passaro, A., & Fellin, R. (2001) · Hypertension · doi:10.1161/01.hyp.37.6.1492 · Cited by 14

Authors: Vaag, A., Henriksen, J. E., & Beck-Nielsen, H.
Affiliations: Odense University Hospital (DK)
ORCID: Vaag, A
Henriksen, J E
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1992-03-01
Volume: 89
Issue: 3
Pages: 782-788
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci115656
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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Decreased insulin activation of glycogen synthase in skeletal muscles in young nonobese Caucasian first-degree relatives of patients with non-insulin-dependent diabetes mellitus

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