Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus.
Open accessAbstract
The diminished ability of insulin to promote glucose disposal and storage in muscle has been ascribed to impaired activation of glycogen synthase (GS). It is possible that decreased glucose storage could occur as a consequence of decreased glucose uptake, and that GS is impaired secondarily. Muscle glucose uptake in 15 diabetic subjects was matched to 15 nondiabetic subjects by maintaining fasting hyperglycemia during infusion of insulin. Leg muscle glucose uptake, glucose oxidation (local indirect calorimetry), release of glycolytic products, and muscle glucose storage, as well as muscle GS and pyruvate dehydrogenase (PDH) were determined before and during insulin infusion. Basal leg glucose oxidation and PDH were increased in the diabetics. Insulin-stimulated leg glucose uptake in the diabetics (8.05 +/- 1.41 mumol/[min.100 ml leg tissue]) did not differ from controls (5.64 +/- 0.37). Insulin-stimulated leg glucose oxidation, nonoxidized glycolysis, and glucose storage (2.48 +/- 0.27, 0.68 +/- 0.15, and 5.04 +/- 1.34 mumol/[min.100 ml], respectively) were not different from controls (2.18 +/- 0.12, 0.62 +/- 0.16, and 2.83 +/- 0.31). PDH and GS in noninsulin-dependent diabetes mellitus (NIDDM) were also normal during insulin infusion. When diabetics were restudied after being rendered euglycemic by overnight insulin infusion, GS and PDH were reduced compared with hyperglycemia. Thus, fasting hyperglycemia is sufficient to normalize insulin-stimulated muscle glucose uptake in NIDDM, and glucose is distributed normally to glycogenesis and glucose oxidation, possibly by normalization of GS and PDH.
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Studies in which glucose disposal rates were matched by increasing the glucose or insulin infusion rates provide further support for these findings.
“Further support for these findings comes from studies in which glucose disposal rates were matched by increasing the glucose or insulin infusion rates ([27](#r27), [66](#r66)).”
From Metabolic flexibility and insulin resistance (2008) · cites this paper as [27]
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“Kelley and Mandarino (9) reported that, in contrast to the predictions of the original glucose–fatty acid cycle, during conditions of hyperglycemia and high glucose oxidation, fat oxidation was concomitantly lower in muscle of individuals with type 2 diabetes, and this effect was exacerbated by obesity (10,11).”
ResultHøjlund, K., Stæhr, P., Hansen, B. F., Green, K. A., Hardie, D. G., Richter, E. A., Beck‐Nielsen, H., & Wojtaszewski, J. F. P. (2003) · Diabetes · doi:10.2337/diabetes.52.6.1393 · Cited by 122 · see citing works
Mechanisms for abnormal postprandial glucose metabolism in type 2 diabetes
Woerle, H. J., Szoke, E., Meyer, C., Dostou, J. M., Wittlin, S. D., Gosmanov, N. R., Welle, S. L., & Gerich, J. E. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00529.2004 · Cited by 109 · see citing works
“We presume that this was because of the ability of hyperglycemia to compensate for decreased insulin release and insulin sensitivity, as has been demonstrated in glucose clamp experiments (35).”
BackgroundZierath, J. R., Galuska, D., Nolte, L. A., Th�rne, A., Kristensen, J. S., & Wallberg‐Henriksson, H. (1994) · Diabetologia · doi:10.1007/bf00398054 · Cited by 106 · see citing works
“cose uptake observed under euglycaemic conditions in vivo [31, 32 ].”
BackgroundResultLactate, a Neglected Factor for Diabetes and Cancer Interaction
Wu, Y., Dong, Y., Atefi, M. S., Liu, Y., Elshimali, Y., & Vadgama, J. V. (2016) · Mediators of Inflammation · doi:10.1155/2016/6456018 · Cited by 105 · see citing works
Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance
Prato, S. D., Matsuda, M., Simonson, D., Groop, L., Sheehan, P., Leonetti, F., Bonadonna, R., & DeFronzo, R. (1997) · Diabetologia · doi:10.1007/s001250050735 · Cited by 106 · see citing works
Vestergaard, H., Lund, S., Larsen, F. S., Bjerrum, O. J., & Pedersen, O. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116466 · Cited by 98 · see citing works
Effects of Exercise Training on Abdominal Obesity and Related Metabolic Complications
Buemann, B., & Tremblay, A. (1996) · Sports Medicine · doi:10.2165/00007256-199621030-00004 · Cited by 99 · see citing works
Pathophysiological role of metabolic flexibility on metabolic health
Galgani, J. E., & Fernández‐Verdejo, R. (2020) · Obesity Reviews · doi:10.1111/obr.13131 · Cited by 90 · see citing works
“• From a previous study, we compared MetF with glucose measured after 1 h of a 75-g oral glucose load and during a 2-h EHC.59 δRQ in the EHC correlated with GDR; δRQ in the OGTT correlated with the glucose dose (in g/kg of weight). δRQ was therefore adjusted for glucose disposal rate in the EHC and for glucose dose in…”
BackgroundInfluentialColetta, D. K., & Mandarino, L. J. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00363.2011 · Cited by 90 · see citing works
“In vivo, higher free fatty acids and triglycerides induced by an infusion of lipid emulsions, with or without heparin to activate lipase, have been shown to reduce insulin action and insulin signaling, as measured by a decreased ability of insulin to stimulate glucose disposal (8, 9, 12, 15, 27, 28, 48).”
BackgroundSelf-citationContribution of muscle and liver to glucose-fatty acid cycle in humans
Saloranta, C., Koivisto, V. A., Widén, E., Falholt, K., DeFronzo, R. A., Härkönen, M., & Groop, L. (1993) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1993.264.4.e599 · Cited by 90 · see citing works
Carey, P. E., Halliday, J., Snaar, J. E. M., Morris, P. G., & Taylor, R. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00471.2002 · Cited by 88 · see citing works
“Interestingly, close inspection of data on leg glucose balance in normal subjects after a mixed meal shows a biphasic pattern, with the second peak of uptake starting at 120 min, the time at which we observe commencement of net glycogen synthesis (7, 21).”
BackgroundColberg, S. R., Hagberg, J. M., McCole, S. D., Zmuda, J. M., Thompson, P. D., & Kelley, D. E. (1996) · Journal of Applied Physiology · doi:10.1152/jappl.1996.81.5.2027 · Cited by 85 · see citing works
“Abnormalities of glucose and lipid metabolism are present at rest in individuals with NIDDM (17, 18) and could affect substratemetabolism during exercise.”
BackgroundSelf-citationPyridine Nucleotide Redox Abnormalities in Diabetes
Ido, Y. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1630 · Cited by 83 · see citing works
“that plasma concentrations of free fatty acids (FFA) (11), lactate (4, 20, 53, 113), and branched chain amino acids (BCAA, including leucine, isoleucines, and valine) (107, 116) are also elevated in diabetes.”
Role of muscle in triglyceride metabolism
Goodpaster, B. H., & Kelley, D. E. (1998) · Current Opinion in Lipidology · doi:10.1097/00041433-199806000-00008 · Cited by 84 · see citing works
Self-citationInsulin action in skeletal muscle from patients with NIDDM
Zierath, J. R., Krook, A., & Wallberg‐Henriksson, H. (1998) · Springer eBooks · doi:10.1007/978-1-4615-5647-3_16 · Cited by 83 · see citing works
Interaction of carbohydrate and fat fuels in human skeletal muscle: impact of obesity and NIDDM
Mandarino, L. J., Consoli, A., Jain, A., & Kelley, D. E. (1996) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1996.270.3.e463 · Cited by 83 · see citing works
Self-citationHøjlund, K., Birk, J. B., Klein, D. K., Levin, K., Rose, A. J., Hansen, B. F., Nielsen, J. N., Beck‐Nielsen, H., & Wojtaszewski, J. F. P. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0897 · Cited by 77 · see citing works
The NAD ratio redox paradox: why does too much reductive power cause oxidative stress?
Teodoro, J. S., Rolo, A. P., & Palmeira, C. M. (2012) · Toxicology Mechanisms and Methods · doi:10.3109/15376516.2012.759305 · Cited by 75 · see citing works
“In fact, whether it is glucose, free fatty acids (Boden, 2003), triglycerides (TG) (Frohlich & Steiner, 2000), lactate (Kelley & Mandarino, 1990), ketone bodies (Avogaro et al., 1996) or amino acids (Vannini et al., 1982), there is a permanent increase in the availability of metabolic substrates.”
BackgroundPDH-E1α Dephosphorylation and Activation in Human Skeletal Muscle During Exercise
Pilegaard, H., Birk, J. B., Sacchetti, M., Mourtzakis, M., Hardie, D. G., Stewart, G. A., Neufer, P. D., Saltin, B., van Hall, G., & Wojtaszewski, J. F. P. (2006) · Diabetes · doi:10.2337/db06-0152 · Cited by 74 · see citing works
Bak, J. F., Møller, N., Schmitz, O., Saaek, A., & Pedersen, O. B. (1992) · Diabetologia · doi:10.1007/bf00429100 · Cited by 72 · see citing works
“Also in line with previous studies [ 33-35 ] is our finding that the activity indices for GS (A0.5 for G6P) in the basal state were similar in control subjects and diabetic patients (both before and after diet treatment).”
BackgroundResultInfluentialKemp, G. J., & Brindle, K. M. (2012) · Diabetes · doi:10.2337/db11-1725 · Cited by 68 · see citing works
“Also shown, for comparison, are reported effects on the (much lower) estimates of oxidative ATP synthesis from AVD O2 consumption measurements: insulin stimulates this significantly in some (47–49) but not all (50,51) reports.”
Background1 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 · see citing works
Vaag, A. A., Damsbo, P., Nielsen, O. H., & Beck‐Nielsen, H. (1992) · Diabetologia · doi:10.1007/bf00400856 · Cited by 68 · see citing works
Glucose-Fatty Acid Interaction in Skeletal Muscle and Adipose Tissue in Insulin Resistance
Cahová, M., Vavřínková, H., & Kazdová, L. (2007) · Physiological Research · doi:10.33549/physiolres.930882 · Cited by 63 · see citing works
Peripheral glucose metabolism in human hyperprolactinaemia
Foss, M. C., de Paula, F. J. A., Paccola, G. M. G. F., & Piccinato, C. E. (1995) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1995.tb00541.x · Cited by 65 · see citing works
Turpeinen, A., Takala, T., Nuutila, P., Axelin, T., Luotolahti, M., Haaparanta‐Solin, M., Bergman, J. R., Hämäläinen, H., Iida, H., Mäki, M. T., et al. (1999) · Diabetes · doi:10.2337/diabetes.48.6.1245 · Cited by 65 · see citing works
Insulin 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 64 · see citing works
“... are studied by the hyperinsulinemic clamp procedure under fasting ambient blood glucose concentrations (isoglycemic-hyperinsulinemic clamp), similar rates of insulin-mediated glucose utilization are observed [5] (Fig. 1). Under these conditions, hyperglycemia per se can fully compensate for defect(s) in fasting an…”
BackgroundRudwill, F., O’Gorman, D. J., Lefai, É., Chery, I., Zahariev, A., Normand, S., Pagano, A. F., Chopard, A., Damiot, A., Laurens, C., et al. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-02267 · Cited by 61 · see citing works
Rossetti, L., & Hu, M. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116919 · Cited by 60 · see citing works
Boon, H., Blaak, E. E., Saris, W. H. M., KEIZER, H. A., Wagenmakers, A. J. M., & van Loon, L. J. C. (2006) · Diabetologia · doi:10.1007/s00125-006-0482-2 · Cited by 59 · see citing works
“However, data on arteriovenous differences in plasma NEFA concentrations over the leg or arm have more consistently displayed reduced fasting plasma NEFA uptake and/or oxidation in type 2 diabetes patients compared with normoglycaemic controls [11, 14, 20], despite elevated systemic plasma NEFA and glucose levels [14,…”
BackgroundResultNielsen, M. F., Basu, R., Wise, S., Caumo, A., Cobelli, C., & Rizza, R. A. (1998) · Diabetes · doi:10.2337/diabetes.47.11.1735 · Cited by 76 · see citing works
Crook, E. D., Zhou, J., Daniels, M. C., Neidigh, J. L., & McClain, D. A. (1995) · Diabetes · doi:10.2337/diab.44.3.314 · Cited by 57 · see citing works
“Yet, under similar conditions, other studies have shown a normalization of GS activity with hyperglycemia in humans with type II diabetes (32-34) and in diabetic rats (35).”
BackgroundFriedman, J. E., Caro, J., Pories, W. J., Azevedo, J. L., & Dohm, G. L. (1994) · Metabolism · doi:10.1016/0026-0495(94)90188-0 · Cited by 52 · see citing works
Nellemann, B., Vendelbo, M. H., Nielsen, T. S., Bak, A. M., Høgild, M. L., Pedersen, S. B., Biensø, R. S., Pilegaard, H., Møller, N., Jessen, N., et al. (2013) · Acta Physiologica · doi:10.1111/apha.12183 · Cited by 51 · see citing works
“Our observation that PDHa activity did not increase during insulin stimulation was not expected and disagrees with some (Mandarino et al. 1987, Tsintzas et al. 2007) but not all (Kelley & Mandarino 1990) existing human data.”
ResultVind, B. F., Birk, J. B., Vienberg, S. G., Andersen, B., Beck‐Nielsen, H., Wojtaszewski, J. F. P., & Højlund, K. (2012) · Diabetologia · doi:10.1007/s00125-012-2482-8 · Cited by 51 · see citing works
“In three studies using physiological levels of insulin [17, 18, 21], it was observed that hyperglycaemia normalised insulin-stimulated GS fractional”
BackgroundResultInfluentialNolan, J. J. (1994) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.78.2.471 · Cited by 108 · see citing works
López-Palau, N. E., & Olais-Govea, J. M. (2020) · Scientific Reports · doi:10.1038/s41598-020-69629-0 · Cited by 53 · see citing works
Macauley, M., Smith, F. E., Thelwall, P. E., Hollingsworth, K. G., & Taylor, R. (2015) · Clinical Science · doi:10.1042/cs20140681 · Cited by 49 · see citing works
Role of impaired intracellular glucose metabolism in the insulin resistance of aging
Gumbiner, B. M., Thorburn, A. W., Ditzler, T. M., Bulacan, F., & Henry, R. R. (1992) · Metabolism · doi:10.1016/0026-0495(92)90296-m · Cited by 49 · see citing works
Barrett, E. J., & Rattigan, S. (2012) · Diabetes · doi:10.2337/db12-0271 · Cited by 47 · see citing works
“The combined measurements of bulk blood flow together with the A-V substrate concentration differences proved to be a powerful tool for quantifying the metabolism of carbohydrates (21), fats (22), amino acids (23), and oxygen (24) by the limb tissues.”
MethodPolonsky, K. S., & Burant, C. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-29738-7.00031-9 · Cited by 50 · see citing works
Lipoprotein lipase mediated fatty acid delivery and its impact in diabetic cardiomyopathy
Kim, M. S., Wang, Y., & Rodrigues, B. B. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2011.10.001 · Cited by 46 · see citing works
Franch, J., Knudsen, J., Ellis, B. A., Pedersen, P. K., Cooney, G. J., & Jensen, J. (2002) · Diabetes · doi:10.2337/diabetes.51.2.449 · Cited by 45 · see citing works
“Despite higher concentrations of triglycerides and enzymes metabolizing FFA, glucose oxidation is increased in muscles with reduced insulin sensitivity (23,24,43,49,50).”
BackgroundSkeletal muscle lipid metabolism: A frontier for new insights into fuel homeostasis
Cortright, R. N., Muoio, D. M., & Dohm, G. L. (1997) · The Journal of Nutritional Biochemistry · doi:10.1016/s0955-2863(97)89660-x · Cited by 44 · see citing works
High-fat and obesogenic diets: current and future strategies to fight obesity and diabetes
Teodoro, J. S., Varela, A. T. I. F., Rolo, A. P., & Palmeira, C. M. (2014) · Genes & Nutrition · doi:10.1007/s12263-014-0406-6 · Cited by 42 · see citing works
Kiilerich, K., Gudmundsson, M., Birk, J. B., Lundby, C., Taudorf, S., Plomgaard, P., Saltin, B., Pedersen, P. A., Wojtaszewski, J. F. P., & Pilegaard, H. (2009) · Diabetes · doi:10.2337/db09-1032 · Cited by 42 · see citing works
“The impact of exercise on PDH regulation in skeletal muscle unrelated to the metabolic status of the cell and body may reflect that exercise can overcome potential inhibition of carbohydrate utilization present in resting skeletal muscle when circulating FFA levels are increased (2).”
BackgroundHigh-intensity exercise and carbohydrate-reduced energy-restricted diet in obese individuals
Sartor, F., de Morree, H. M., MATSCHKE, V., Marcora, S., Milousis, A., Thom, J. M., & Kubis, H. (2010) · European Journal of Applied Physiology · doi:10.1007/s00421-010-1571-y · Cited by 42 · see citing works
“Oxidative capacity is reduced in obese individuals and patients with type 2 diabetes mellitus ( Kelley and Mandarino 1990; Kelley et al. 1999).”
BackgroundInfluence of AMP-activated protein kinase and calcineurin on metabolic networks in skeletal muscle
Long, Y. C., & Zierath, J. R. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90259.2008 · Cited by 42 · see citing works
Beck‐Nielsen, H., Nielsen, O. H., Vaag, A. A., & ALFORD, F. P. (1994) · Diabetologia · doi:10.1007/s001250050097 · Cited by 42 · see citing works
“Glucose uptake in skeletal muscles, as measured by A-V glucose differences in the arm and leg, has usually been found to be close to normal or slightly increased under the prevailing hyperglycaemia [7, 15].”
BackgroundPedraza, N., Solanes, G., Carmona, M. C., Iglesias, R., Viñas, O., Mampel, T., Vázquez‐Carrera, M., Giralt, M., & Villarroya, F. (2000) · Diabetes · doi:10.2337/diabetes.49.7.1224 · Cited by 42 · see citing works
Preclinical developments in type 2 diabetes
Lenhard, J. M., & Gottschalk, W. K. (2002) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(02)00092-3 · Cited by 39 · see citing works
Ghzaiel, I., Zarrouk, A., Nury, T., Libergoli, M., Florio, F., Hammouda, S., Ménétrier, F., Avoscan, L., Yammine, A., Samadi, M. H., et al. (2021) · Antioxidants · doi:10.3390/antiox10111772 · Cited by 36 · see citing works
“In fact, in response to insulin stimulation, mitochondria of elderly subjects are unable to move from lipid oxidation to carbohydrate oxidation as do mitochondria of young subjects, showing a loss of metabolic flexibility during aging [17].”
BackgroundMultiple metabolic effects of CGRP in conscious rats: role of glycogen synthase and phosphorylase
Rossetti, L., Farrace, S., Choi, S. B., Giaccari, A., Sloan, L., Frontoni, S., & Katz, M. S. (1993) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1993.264.1.e1 · Cited by 36 · see citing works
Current understanding of the chronic stress response to burn injury from human studies
Osborne, T. J., Wall, B. A., Edgar, D. W., Fairchild, T. J., & Wood, F. M. (2023) · Burns & Trauma · doi:10.1093/burnst/tkad007 · Cited by 35 · see citing works
Xing, Z., Yang, T., Li, X., Xu, H., Hong, Y., Shao, S., Li, T., Ye, L., Li, Y., Jin, X., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115545 · Cited by 35 · see citing works
- Authors
- Kelley, D. E., & Mandarino, L. J.
- Affiliations
- University of Pittsburgh (US)
- United States Department of Veterans Affairs (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1990-12-01
- Volume
- 86
- Issue
- 6
- Pages
- 1999-2007
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC329837
- OpenAlex
- W2171543951
- Cited by
- 210
- References
- 37
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 4 · 2020: 6 · 2019: 6 · 2018: 4 · 2017: 5 · 2016: 3 · 2015: 5 · 2014: 5 · 2013: 4 · 2012: 8
- FWCI
- 2.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- Research to Prevent Blindness
- Deutsches Krebsforschungszentrum
- National Institutes of Health (5r01dk041075-03)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK41075)
- National Center for Research Resources (M01RR000056)
- 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
- hyperglycemia, type 2 diabetes, muscle glucose uptake, glycogen synthase, pyruvate dehydrogenase, insulin resistance, glycogen synthesis, glycolysis
- MeSH terms
- Alanine, Calorimetry, Diabetes Mellitus, Type 2, Glucose, Glycogen Synthase, Glycolysis, Humans, Hyperglycemia, Insulin, Lactates, Leg, Lipid Mobilization, Muscles, Pyruvate Dehydrogenase Complex
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