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Cited by 191Metabolism, Diabetes, and CancerDiabetes, Cardiovascular Risks, and LipoproteinsDiabetes Management and Research

Roles of Glucose Transport and Glucose Phosphorylation in Muscle Insulin Resistance of NIDDM

Bonadonna, Riccardo C, Bonora, Enzo, Prato, Stefano Del, Saccomani, Maria Pia, Cobelli, Claudio, Natali, Andrea, Frascerra, Silvia, Pecori, Neda +4 more·1996·Diabetes
DOI 10.2337/diab.45.7.915
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Abstract

Insulin resistance for glucose metabolism in skeletal muscle is a key feature in NIDDM. The quantitative role of the cellular effectors of glucose metabolism in determining this insulin resistance is still imperfectly known. We assessed transmembrane glucose transport and intraceUular glucose phosphorylation in vivo in skeletal muscle in nonobese NIDDM patients. We performed euglycemic insulin clamp studies in combination with the forearm balance technique (brachial artery and deep forearm vein catheterization) in five nonobese NIDDM patients and seven age- and weight-matched control subjects (study 1). d-Mannitol (a nontransportable molecule), 3-O-[14C]methyl-d-glucose (transportable, but not metabolizable) and d[3–3H]glucose (transportable and metabolizable) were simultaneously injected into the brachial artery, and the washout curves were measured in the deep venous effluent blood. In vivo rates of transmembrane transport and intracellular phosphorylation of d-glucose in forearm muscle were determined by analyzing the washout curves with the aid of a multicompartmental model of glucose kinetics in forearm tissues. At similar steady-state concentrations of plasma insulin (∼500 pmol/l) and glucose (∼5.0 mmol/l), the rates of transmembrane influx (34.3 ± 9.1 vs. 58.5 ± 6.5 μmol · min-1 μ kg-1 P < 0.05) and intracellular phosphorylation (5.4 ± 1.6 vs. 38.8 ± 5.1 μmol μ min-1 · kg-1 P < 0.01) in skeletal muscle were markedly lower in the NIDDM patients than in the control subjects. In the NIDDM patients (study 2), the insulin clamp was repeated at hyperglycemia (∼13 mmol/l) trying to match the rates of transmembrane glucose influx measured during the clamp in the controls. The rate of transmembrane glucose influx (62 ± 15 μmol · min-1 · kg-1) in the NIDDM patients was similar to the control subjects, but the rate of intracellular glucose phosphorylation (16.6 ± 7.5 μmol · min-1 · kg-1), although threefold higher than in the patients during study 1 (P < 0.05), was still ∼60% lower than in the control subjects (P < 0.05). These data suggest that when assessed in vivo, both transmembrane transport and intracellular phosphorylation of glucose are refractory to insulin action and add to each other in determining insulin resistance in skeletal muscle of NIDDM patients. It will be of interest to compare the present results with the in vivo quantitation of the initial rate of muscle glucose transport when methodology to perform this measurement becomes available.

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  • In forearm muscle of lean type 2 diabetics, insulin-stimulated glucose transport is markedly impaired, but intracellular glucose phosphorylation is impaired even more, increasing free intracellular glucose.

    “In forearm muscle, insulin-stimulated glucose transport (measured with the triple-tracer technique) is markedly impaired in lean type 2 diabetics [192, 193], but the rate of intracellular glucose phosphorylation is impaired to an even greater extent, resulting in an increase in the free glucose concentration within the intracellular space that is accessible to glucose.”

    From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [193]

  • Because of methodologic differences, the results of the triple-tracer technique and MRI studies cannot be reconciled at present.

    “Because of methodologic differences, the results of the triple-tracer technique [192, 193] and magnetic resonance imaging [194] studies cannot be reconciled at present.”

    From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [193]

  • Using a triple-tracer technique, insulin-stimulated inward muscle glucose transport in forearm skeletal muscle is severely impaired in type 2 diabetic subjects.

    “Using a novel triple-tracer technique, the in vivo dose-response curve for the action of insulin on glucose transport in forearm skeletal muscle has been examined in type 2 diabetic subjects, and insulin-stimulated inward muscle glucose transport has been shown to be severely impaired [192, 193].”

    From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [193]

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Authors
Bonadonna, R. C., Bonora, E., Prato, S. D., Saccomani, M. P., Cobelli, C., Natali, A., Frascerra, S., Pecori, N., Ferrannini, E., Bier, D., DeFronzo, R. A., & Gulli, G.
Affiliations
  • University of Verona (IT)
  • University of Padua (IT)
  • Azienda Ospedaliera Universitaria Integrata Verona (IT)
  • Baylor College of Medicine (US)
  • The University of Texas at San Antonio Health Science Center (US)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
1996-07-01
Volume
45
Issue
7
Pages
915-925
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diab.45.7.915
OpenAlex
W1999857843
Cited by
191
References
0
Citations by year
2025: 4 · 2024: 2 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 5 · 2018: 9 · 2017: 6 · 2016: 6 · 2015: 6 · 2014: 5 · 2013: 5 · 2012: 3
FWCI
3.51
Type
journal article
Language
en
Open access
closed
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • National Institutes of Health (5k04dk000954-05)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK20579, DK 24092, DK-00954)
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 › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
insulin resistance, type 2 diabetes, skeletal muscle glucose transport, glucose phosphorylation, hyperglycemia, forearm muscles, glucose kinetics, hyperinsulinemic-euglycemic clamp
MeSH terms
Adult, Biological Transport, Blood Glucose, Blood Pressure, Diabetes Mellitus, Type 2, Female, Forearm, Glucose, Humans, Hyperinsulinism, Infusions, Intravenous, Insulin, Insulin Resistance, Kinetics, Male, Mannitol, Methylglucosides, Middle Aged, Phosphorylation, Reference Values, Muscle, Skeletal, 3-O-Methylglucose

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