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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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“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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1 retracted
Insulin Sensitivity and Insulin Binding to Monocytes in Maturity-Onset Diabetes
Defronzo, R., Deibert, D., Hendler, R., Felig, P., & Soman, V. (1979) · Journal of Clinical Investigation · doi:10.1172/jci109394 · Cited by 188
Retracted(1975) · Journal of AOAC INTERNATIONAL · doi:10.1093/jaoac/58.5.1085 · Cited by 20,078
Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance.
National Diabetes Data Group (1979) · Diabetes · doi:10.2337/diab.28.12.1039 · Cited by 4,909
(1966) · Food and Cosmetics Toxicology · doi:10.1016/s0015-6264(66)80573-4 · Cited by 4,296
Coated Charcoal Immunoassay of Insulin
Herbert, V. D., Lau, K., Gottlieb, C. W., & Bleicher, S. J. (1965) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-25-10-1375 · Cited by 2,969
Calculation of substrate oxidation rates in vivo from gaseous exchange.
Frayn, K. N. (1983) · Journal of Applied Physiology · doi:10.1152/jappl.1983.55.2.628 · Cited by 2,365
DeFronzo, R. A., Jacot, E., Jequier, E., Maeder, E., Wahren, J., & Felber, J. P. (1981) · Diabetes · doi:10.2337/diab.30.12.1000 · Cited by 1,770
Shulman, G. I., Rothman, D. L., Jue, T., Stein, P., DeFronzo, R. A., & Shulman, R. G. (1990) · New England Journal of Medicine · doi:10.1056/nejm199001253220403 · Cited by 1,248
Effect of fatty acids on glucose production and utilization in man.
Ferrannini, E., Barrett, E. J., Bevilacqua, S., & DeFronzo, R. A. (1983) · Journal of Clinical Investigation · doi:10.1172/jci111133 · Cited by 1,050
Kolterman, O., Gray, R. S., Griffin, J., BURSTEIN, P. J., Insel, J. R., Scarlett, J. A., & Olefsky, J. M. (1981) · Journal of Clinical Investigation · doi:10.1172/jci110350 · Cited by 628
Cited by
Sorted by citations
Mechanisms of fatty acid-induced inhibition of glucose uptake.
Boden, G., Chen, X., Ruiz, J., White, J. V., & Rossetti, L. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117252 · Cited by 3,720
Fuel selection in human skeletal muscle in insulin resistance: a reexamination.
Kelley, D. E., & Mandarino, L. J. (2000) · Diabetes · doi:10.2337/diabetes.49.5.677 · Cited by 1,017
“Adapted from Kelley and Mandarino (21) and Kelley et al.”
BackgroundMethodInfluentialSelf-citationMetabolic Flexibility in Health and Disease
Goodpaster, B. H., & Sparks, L. M. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.015 · Cited by 995
Comprehensive review on lactate metabolism in human health
Adeva‐Andany, M. M., López-Ojén, M., Funcasta-Calderón, R., Ameneiros-Rodríguez, E., Donapetry, C., Vila-Altesor, M., & Rodríguez-Seijas, J. (2014) · Mitochondrion · doi:10.1016/j.mito.2014.05.007 · Cited by 636
“In response to insulin infusion, lactate output from the skeletal muscle has been reported similar in diabetic patients and in healthy subjects in some studies (Juel et al., 2004; Kelley and Mandarino, 1990) while others find that the interstitialmuscle lactate concentration does not increase significantly during the…”
BackgroundResultInfluentialExercise and Insulin Sensitivity: A Review
Borghouts, L. B., & KEIZER, H. A. (2000) · International Journal of Sports Medicine · doi:10.1055/s-2000-8847 · Cited by 617
Metabolic flexibility and insulin resistance
Galgani, J. E., Moro, C., & Ravussin, E. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90558.2008 · Cited by 532
“Further support for these findings comes from studies in which glucose disposal rates were matched by increasing the glucose or insulin infusion rates (27, 66).”
BackgroundImpaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus.
Kelley, D. E., & Simoneau, J. A. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117600 · Cited by 487
Self-citationThe Role of Skeletal Muscle Glycogen Breakdown for Regulation of Insulin Sensitivity by Exercise
Jensen, J., Rustad, P. I., Kolnes, A. J., & Lai, Y.-C. (2011) · Frontiers in Physiology · doi:10.3389/fphys.2011.00112 · Cited by 412
“…that hyperglycemia compensate for impaired insulin-mediated activation of glycogen synthase and glycogen storage in type 2 diabetic subjects (Kelley and Mandarino, 1990; Vaag et al., 1992; Mevorach et al., 1998), but these data also show a defect in regulation of glycogen storage as a…”
BackgroundKelley, D. E., & Goodpaster, B. H. (2001) · Diabetes Care · doi:10.2337/diacare.24.5.933 · Cited by 411
“Evidence supporting this notion has arisen from studies by Kelley and Mandarino (53) of patients with type 2 diabetes under conditions of fasting hyperglycemia.”
BackgroundResultSelf-citationZierath, J. R., He, L., Gumà, A., Wahlström, E. O., Klip, A., & Wallberg-Henriksson, H. (1996) · Diabetologia · doi:10.1007/bf02658504 · Cited by 402
“Hyperglycaemia per se has been shown to compensate for the defect in insulin action on glucose utilization in patients with NIDDM [13-16] or insulin-dependent diabetes mellitus [17], and in rodents with experimentally induced NIDDM [18].”
BackgroundM USCLE T RIGLYCERIDE AND I NSULIN R ESISTANCE
Kelley, D. E., Goodpaster, B. H., & Storlien, L. (2002) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.22.010402.102912 · Cited by 364
Self-citationThe Cellular Fate of Glucose and Its Relevance in Type 2 Diabetes
Bouché, C., Serdy, S., Kahn, C. R., & Goldfine, A. B. (2004) · Endocrine Reviews · doi:10.1210/er.2003-0026 · Cited by 361
Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes.
Boden, G., & Chen, X. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118160 · Cited by 344
Rothman, D. L., Magnusson, I., Cline, G., Gerard, D., Kahn, C. R., Shulman, R. G., & Shulman, G. I. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.4.983 · Cited by 325
Rothman, D. L., Shulman, R. G., & Shulman, G. I. (1992) · Journal of Clinical Investigation · doi:10.1172/jci115686 · Cited by 327
Vaag, A., Henriksen, J. E., & Beck-Nielsen, H. (1992) · Journal of Clinical Investigation · doi:10.1172/jci115656 · Cited by 299
Insulin-induced vasodilatation: physiology or pharmacology?
Yki‐Järvinen, H., & Utriainen, T. (1998) · Diabetologia · doi:10.1007/s001250050919 · Cited by 261
“NIDDM. As in patients with IDDM, studies in which insulin stimulation of glucose extraction and blood flow have been measured under physiological insulin concentrations using either venous occlusion plethysmography [71, 72], impedance plethysmography [73], indicator dilution [7, 74, 75] or PET and [ 15 O]H 2 O [76] ac…”
MethodDela, F., Larsen, J. J., Mikines, K. J., Ploug, T., Petersen, L. N., & Galbo, H. (1995) · Diabetes · doi:10.2337/diab.44.9.1010 · Cited by 286
“However, the decreased insulin-mediated glucose uptake, oxidation, and storage are compensated for by the prevailing hyperglycemia (11,12), which tends to normalize these metabolic processes.”
BackgroundRichardson, D. K., Kashyap, S., Bajaj, M., Cusi, K., Mandarino, S. J., Finlayson, J., DeFronzo, R. A., Jenkinson, C. P., & Mandarino, L. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m408985200 · Cited by 259
Self-citationKelley, D. E., Mintun, M. A., Watkins, S. C., Simoneau, J. A., Jadali, F., Fredrickson, A., Beattie, J., & Thériault, R. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118724 · Cited by 228
“Insulin-stimulated FDG uptake in skeletal muscle was equivalent in hyperglycemic NIDDM and euglycemic nondiabetic subjects (43), findings consistent with hyperglycemic compensation of insulin resistance in NIDDM (44).”
ResultSelf-citationInsulin action at a molecular level – 100 years of progress
White, M. F., & Kahn, C. R. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101304 · Cited by 221
Skeletal muscle lipid accumulation in obesity, insulin resistance, and type 2 diabetes
Goodpaster, B. H., & Wolf, D. L. (2004) · Pediatric Diabetes · doi:10.1111/j.1399-543x.2004.00071.x · Cited by 214
“ever, have reduced efficiency in the uptake of plasma fatty acid by skeletal muscle (60, 61), indicating that plasma FFA availability is not the sole factor determining muscle FFA uptake.”
BackgroundRasmussen, B. B., Holmbäck, U. C., Volpi, E., Morio, B., Paddon‐Jones, D., & Wolfe, R. R. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15715 · Cited by 229
Insulin differentially regulates systemic and skeletal muscle vascular resistance
Baron, A., & Brechtel, G. (1993) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1993.265.1.e61 · Cited by 179
Glucose transport in human skeletal muscle cells in culture. Stimulation by insulin and metformin.
Sarabia, V., Lam, L., Burdett, E., Leiter, L. A., & Klip, A. (1992) · Journal of Clinical Investigation · doi:10.1172/jci116005 · Cited by 179
The Suprachiasmatic Nucleus Controls Circadian Energy Metabolism and Hepatic Insulin Sensitivity
Coomans, C. P., van den Berg, S. A. A., Lucassen, E. A., Houben, T., Pronk, A. C. M., van der Spek, R. D., Kalsbeek, A., Biermasz, N. R., Willems van Dijk, K., Romijn, J. A., et al. (2013) · Diabetes · doi:10.2337/db12-0507 · Cited by 173
“clamped at their respective basal glucose levels, because it has been shown that alterations in basal fasting glucose levels alone are sufficient to affect insulin sensitivity (21).”
BackgroundHuman resting energy expenditure varies with circadian phase
Zitting, K.-M., Vujovic, N., Yuan, R. K., Isherwood, C. M., Medina, J. E., Wang, W., Buxton, O. M., Williams, J. S., Czeisler, C. A., & Duffy, J. F. (2018) · Current Biology · doi:10.1016/j.cub.2018.10.005 · Cited by 164
Del Prato, S., Bonadonna, R. C., Bonora, E., Gulli, G., Solini, A., Shank, M., & DeFronzo, R. A. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116226 · Cited by 170
“These differences are unlikely to be explained by a shift in the contribution of different tissues to whole-body glucose disposal in response to hyperinsulinemia or hyperglycemia since we (9, 41 ), as well as others (37, 42), have shown that muscle represents the primary tissue responsible for the disposal of the majo…”
BackgroundResultInfluentialGoodpaster, B. H., & Kelley, D. E. (2002) · Current Diabetes Reports · doi:10.1007/s11892-002-0086-2 · Cited by 155
“Patients with type 2 diabetes, however, have reduced efficiency in the uptake of plasma fatty acid by skeletal muscle [18,25, 30 ], indicating that plasma FFA availability is not the sole factor determining muscle FFA uptake.”
BackgroundSelf-citationKowalski, G. M., & Bruce, C. R. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00165.2014 · Cited by 154
“However, when the T2D patients were rendered euglycemic by prior insulin infusion, defects in muscle glucose disposal became evident (55, 99, 172).”
MethodResultPerdomo, G., Commerford, S. R., Richard, A.-M. T., Adams, S. H., Corkey, B. E., O'Doherty, R. M., & Brown, N. F. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403566200 · Cited by 158
Nuutila, P., Raitakari, M., Laine, H. K., Kirvelä, O., Takala, T., Utriainen, T., Mäkimattila, S., Pitkänen, O., Ruotsalainen, U., Iida, H., et al. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118601 · Cited by 156
Cellular and Molecular Mechanisms of Non-Insulin Dependent Diabetes Mellitus
Kruszynska, Y. T., & Olefsky, J. M. (1996) · Journal of Investigative Medicine · doi:10.1177/108155899604400806 · Cited by 157
Transmembrane glucose transport in skeletal muscle of patients with non-insulin-dependent diabetes.
Bonadonna, R. C., Del Prato, S., Saccomani, M. P., Bonora, E., Gulli, G., Ferrannini, E., Bier, D., Cobelli, C., & DeFronzo, R. A. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116592 · Cited by 149
Paternostro, G., Camici, P. G., Lammertsma, A. A., Marinho, N. V. S., Baliga, R. R., Kooner, J. S., Radda, G. K., & Ferrannini, E. (1996) · Journal of Clinical Investigation · doi:10.1172/jci119015 · Cited by 150
“Thus, the arm skeletal muscle blood flow rates measured by PET in the present study are in the range of those measured in the forearm of healthy subjects during a euglycemic clamp with the use of an indicator dilution method (30) or by venous occlusion plethysmography (31).”
MethodBock, G., Chittilapilly, E. G., Basu, R., TOFFOLO, G. M., Cobelli, C., Chandramouli, V., Landau, B. R., & Rizza, R. A. (2007) · Diabetes · doi:10.2337/db06-1776 · Cited by 148
“Since glucose was clamped in the euglycemic range, the lower rates of disposal presumably reflected decreased muscle glucose uptake (46,47).”
BackgroundMevorach, M., Giacca, A., Aharon, Y., Hawkins, M. A., Shamoon, H., & Rossetti, L. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2720 · Cited by 143
“The biochemical mechanism responsible for this action is likely to involve a selective activation of the skeletal muscle glycogen synthase by glucose (21, 22, 44).”
BackgroundSedentary behaviour is a key determinant of metabolic inflexibility
Rynders, C. A., Blanc, S., DeJong, N., Bessesen, D. H., & Bergouignan, A. (2018) · The Journal of Physiology · doi:10.1113/jp273282 · Cited by 137
Targeting glycogen synthase kinase-3 (GSK-3) in the treatment of Type 2 diabetes
MacAulay, K., & Woodgett, J. R. (2008) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.12.10.1265 · Cited by 140
“Some studies have suggested that activation of glycogen synthase may not be impaired in T2DM, rather that the decreased glycogen storage is due to reduced transport [28] .”
BackgroundGalgani, J. E., Heilbronn, L. K., Azuma, K., Kelley, D. E., Albu, J. B., Pi-Sunyer, X., Smith, S. R., Ravussin, E., & and the Look AHEAD Adipose Research Group (2008) · Diabetes · doi:10.2337/db08-0043 · Cited by 133
“Few studies have compared in vivo fuel oxidation under similar glucose disposal rates in diabetic and nondiabetic subjects (5,17,18).”
BackgroundMethodResultInfluentialSelf-citationReversibility of insulin resistance in obese diabetic patients: role of plasma lipids
Mingrone, G., Gaetano, A. D., Greco, A. V., Capristo, E., Benedetti, G., Castagneto, M., & Gasbarrini, A. (1997) · Diabetologia · doi:10.1007/s001250050721 · Cited by 132
“This indirectly suggests a reversibility of enzyme glycogen synthase inhibition found in obese subjects [36, 37], and increased pyruvate dehydrogenase complex activity, which is known to be reduced in obese individuals [38, 39].”
BackgroundMechanism by Which Caloric Restriction Improves Insulin Sensitivity in Sedentary Obese Adults
Johnson, M. L., Distelmaier, K., Lanza, I. R., Irving, B. A., Robinson, M. M., Konopka, A. R., Shulman, G. I., & Nair, K. S. (2016) · Diabetes · doi:10.2337/db15-0675 · Cited by 129
“Altered glucose (10), fatty acid (11), and amino acid metabolism (12) are reported in obese people, including an inability to adjust to fuel availability (13,14).”
BackgroundMetabolic Adaptations to Dexamethasone‐Induced Insulin Resistance in Healthy Volunteers
Nicod, N., Giusti, V., Besse, C., & Tappy, L. (2003) · Obesity Research · doi:10.1038/oby.2003.90 · Cited by 125
Vaag, A., Skött, P., Damsbo, P., Gall, M. A., Richter, E. A., & Beck-Nielsen, H. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115432 · Cited by 123
Mitochondrial Deficiency Is Associated With Insulin Resistance
Goodpaster, B. H. (2013) · Diabetes · doi:10.2337/db12-1612 · Cited by 124
“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 123
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
“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., Galuska, D., Nolte, L., Thörne, A., Kristensen, J., & Wallberg-Henriksson, H. (1994) · Diabetologia · doi:10.1007/bf00398054 · Cited by 67
“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 107
Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance
Prato, S. D., Matsuda, M., Simonson, D. C., Groop, L., Sheehan, P., Leonetti, F., Bonadonna, R. C., & DeFronzo, R. A. (1997) · Diabetologia · doi:10.1007/s001250050735 · Cited by 100
Vestergaard, H., Lund, S., Larsen, F. S., Bjerrum, O. J., & Pedersen, O. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116466 · Cited by 98
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 98
Pathophysiological role of metabolic flexibility on metabolic health
Galgani, J. E., & Fernández‐Verdejo, R. (2020) · Obesity Reviews · doi:10.1111/obr.13131 · Cited by 97
“• 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
“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
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 89
“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
“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 84
“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
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 82
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 82
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
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 74
“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
Bak, J. F., Møller, N., Schmitz, O., Saaek, A., & Pedersen, O. B. (1992) · Diabetologia · doi:10.1007/bf00429100 · Cited by 72
“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 71
“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
Vaag, A. A., Damsbo, P., Nielsen, O. H., & Beck‐Nielsen, H. (1992) · Diabetologia · doi:10.1007/bf00400856 · Cited by 67
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 64
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
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
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 65
“... 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
Rossetti, L., & Hu, M. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116919 · Cited by 60
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 60
“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
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
“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 51
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 53
“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 52
“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
López-Palau, N. E., & Olais-Govea, J. M. (2020) · Scientific Reports · doi:10.1038/s41598-020-69629-0 · Cited by 53
Macauley, M., Smith, F. E., Thelwall, P. E., Hollingsworth, K. G., & Taylor, R. (2015) · Clinical Science · doi:10.1042/cs20140681 · Cited by 50
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
Barrett, E. J., & Rattigan, S. (2012) · Diabetes · doi:10.2337/db12-0271 · Cited by 48
“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 53
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 48
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
“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
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 45
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
“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
“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 41
Beck‐Nielsen, H., Nielsen, O. H., Vaag, A. A., & ALFORD, F. P. (1994) · Diabetologia · doi:10.1007/s001250050097 · Cited by 42
“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
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 40
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 37
“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
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
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
Metadata
- 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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