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Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus.
Open accessAbstract
Seven non-insulin-dependent diabetes mellitus (NIDDM) patients participated in three clamp studies performed with [3-3H]- and [U-14C]glucose and indirect calorimetry: study I, euglycemic (5.2 +/- 0.1 mM) insulin (269 +/- 39 pM) clamp; study II, hyperglycemic (14.9 +/- 1.2 mM) insulin (259 +/- 19 pM) clamp; study III, euglycemic (5.5 +/- 0.3 mM) hyperinsulinemic (1650 +/- 529 pM) clamp. Seven control subjects received a euglycemic (5.1 +/- 0.2 mM) insulin (258 +/- 24 pM) clamp. Glycolysis and glucose oxidation were quantitated from the rate of appearance of 3H2O and 14CO2; glycogen synthesis was calculated as the difference between body glucose disposal and glycolysis. In study I, glucose uptake was decreased by 54% in NIDDM vs. controls. Glycolysis, glycogen synthesis, and glucose oxidation were reduced in NIDDM patients (P < 0.05-0.001). Nonoxidative glycolysis and lipid oxidation were higher. In studies II and III, glucose uptake in NIDDM was equal to controls (40.7 +/- 2.1 and 40.7 +/- 1.7 mumol/min.kg fat-free mass, respectively). In study II, glycolysis, but not glucose oxidation, was normal (P < 0.01 vs. controls). Nonoxidative glycolysis remained higher (P < 0.05). Glycogen deposition increased (P < 0.05 vs. study I), and lipid oxidation remained higher (P < 0.01). In study III, hyperinsulinemia normalized glycogen formation, glycolysis, and lipid oxidation but did not normalize the elevated nonoxidative glycolysis or the decreased glucose oxidation. Lipid oxidation and glycolysis (r = -0.65; P < 0.01), and glucose oxidation (r = -0.75; P < 0.01) were inversely correlated. In conclusion, in NIDDM: (a) insulin resistance involves glycolysis, glycogen synthesis, and glucose oxidation; (b) hyperglycemia and hyperinsulinemia can normalize total body glucose uptake; (c) marked hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and nonoxidative glycolysis; (d) hyperglycemia cannot overcome the defects in glucose oxidation and nonoxidative glycolysis; (e) lipid oxidation is elevated and is suppressed only with hyperinsulinemia.
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“In type 2 diabetic individuals, the glycolytic/glucose oxidative pathway has been shown to be impaired [229].”
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Metadata
- Authors
- Del Prato, S., Bonadonna, R. C., Bonora, E., Gulli, G., Solini, A., Shank, M., & DeFronzo, R. A.
- Affiliations
- University of Padua (IT)
- Venue
- Journal of Clinical Investigation
- Published
- 1993-02-01
- Volume
- 91
- Issue
- 2
- Pages
- 484-494
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC287962
- OpenAlex
- W2158104654
- Cited by
- 170
- References
- 51
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 6 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 2 · 2018: 11 · 2017: 4 · 2016: 3 · 2015: 7 · 2014: 7 · 2013: 6 · 2012: 2
- FWCI
- 6.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Funders
- American Diabetes Association
- Università degli Studi di Padova
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 24092)
- National Center for Research Resources (M01-RR-013436)
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- type 2 diabetes, insulin resistance, insulin action, glucose uptake, glycolysis, glucose oxidation, glycogen synthesis, lipid oxidation, hyperinsulinemic-euglycemic clamp, hyperglycemic clamp, glucose disposal, skeletal muscle metabolism, glycogen accumulation, nonoxidative glucose metabolism
- MeSH terms
- Adult, Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Female, Glucose, Glycogen, Glycolysis, Humans, Insulin, Lactates, Liver, Male, Middle Aged, Oxidation-Reduction, Lactic Acid, Lipid Metabolism
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