Pathogenesis of Insulin Resistance in Skeletal Muscle

In the paper

“Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis.”

• Also stated in: § 1. Introduction · plain

  “The decreased insulin-stimulated glucose uptake is due to impaired insulin signaling and multiple postreceptor intracellular defects including impaired glucose transport and glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis [7–10] (Table 1).”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [7] Cusi K Maezono K Osman A Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle The Journal of Clinical Investigation 2000 105 3 311 320 10675357 PMC377440 source
• Not checked yetcites [8] Bajaj M DeFronzo RA Metabolic and molecular basis of insulin resistance Journal of Nuclear Cardiology 2003 10 3 311 323 12794631 source
• Not checked yetcites [9] Bouzakri K Koistinen HA Zierath JR Molecular mechanisms of skeletal muscle insulin resistance in type 2 diabetes Current Diabetes Reviews 2005 1 2 167 174 18220592 source
• Not checked yetcites [10] Karlsson HKR Zierath JR Insulin signaling and glucose transport in insulin resistant human skeletal muscle Cell Biochemistry and Biophysics 2007 48 2-3 103 113 17709880 source

In the paper

“A common mutation in the IRS-1 gene (Gly-972-Arg) has been associated with type 2 diabetes, insulin resistance, and obesity, but the physiologic significance of this mutation remains to be established [170].”

What the sources say

• Partly supported

  The Abstract and Discussion report an association between Gly-972-Arg and NIDDM (type 2 diabetes), and the Discussion says its physiological significance remains unproven. The claimed associations with insulin resistance and obesity are not supported: the Finnish-subjects results found no differences in insulin-sensitivity measures or BMI between carriers and noncarriers. (LLM, conf=0.90)

  cites [170] Hitman GA Hawrami K McCarthy MI Insulin receptor substrate-1 gene mutations in NIDDM; implications for the study of polygenic disease Diabetologia 1995 38 4 481 486 7796990 sourceExperimental — accuracy not yet measured

In the paper

“These studies indicate that insulin resistance in skeletal muscle in subjects with T2DM is manefisted, not only by a reduction in the magnitude of insulin action, but also by s delayed onset of insulin action to”

In the paper

“During the postabsorptive state, the plasma insulin concentration is low. Since the plasma insulin concentration is the principal factor that restrains lipolysis in adipocytes [21] and stimulates glucose uptake in skeletal muscle [21], during the fasting state, muscle glucose uptake is low and the plasma FFA concentration is elevated.”

What the sources say

• Not checked yetcites [21] Groop LC Bonadonna RC DelPrato S Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance The Journal of Clinical Investigation 1989 84 1 205 213 2661589 PMC303971 source

In the paper

“Thus, under fasting conditions, FFA serves as the principal fuel source for energy production in skeletal muscle, while the brain exclusively utilizes glucose.”

What the sources say

• Not checked yetcites [21] Groop LC Bonadonna RC DelPrato S Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance The Journal of Clinical Investigation 1989 84 1 205 213 2661589 PMC303971 source

In the paper

“Thus, the dose response curve relating insulin-stimulated glucose uptake and the plasma insulin concentration shifts to the right with an increase in EC50 (to ~120–140 μU/mL) in subjects with T2DM (Figure 1).”

In the paper

“The postprandial hyperglycemia stimulates insulin secretion from the pancreas and the rise in plasma insulin concentration stimulates glucose uptake in skeletal muscle leading to the disposal of ingested glucose [1–4].”

What the sources say

• Not checked yetcites [1] DeFronzo RA Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes Diabetes Reviews 1997 5 3 177 269
• Not checked yetcites [2] DeFronzo RA The triumvirate: β-cell, muscle, liver. A collusion responsible for NIDDM Diabetes 1988 37 6 667 687 3289989 source
• Not checked yetcites [3] DeFronzo RA Pathogenesis of type 2 diabetes mellitus Medical Clinics of North America 2004 88 4 787 835 15308380 source
• Not checked yetcites [4] Defronzo RA From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus Diabetes 2009 58 4 773 795 19336687 PMC2661582 source

In the paper

“Following glucose ingestion, the increase in plasma glucose concentration stimulates insulin secretion from the beta cell and the resultant hyperinsulinemia suppresses lipolysis, leading to decline in plasma FFA concentration and subsequent decrease in the rate of lipid oxidation.”

What the sources say

• Not checked yetcites [1] DeFronzo RA Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes Diabetes Reviews 1997 5 3 177 269

In the paper

“However, with increasing plasma insulin concentration, glycogen synthase is activitaed by insulin and glycogen synthesise predominate (~70% of glucose disposal) [24].”

What the sources say

• Not checked yetcites [24] Thiebaud D Jacot E DeFronzo RA Maeder E Jequier E Felber JP The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man Diabetes 1982 31 11 957 963 6757014 source

In the paper

“Muscle insulin resistance strongly correlates with IMCL, independent of total body fat mass and diabetes status [56], while the correlation between EMCL and insulin ressitance is not significant.”

What the sources say

• Not checked yetcites [56] Krssak M Falk Petersen K Dresner A Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study Diabetologia 1999 42 1 113 116 10027589 source

In the paper

“More recent studies [55, 56] using magnetic resonance spectroscopy have demonstrated that although IMCL fat content contributes only a small fraction (~1%) to the total muscle fat content, it plays a key role in the development of insulin resistance in skeletal muscle compared to EMCL.”

What the sources say

• Not checked yetcites [55] Perseghin G Scifo P De Cobelli F Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents Diabetes 1999 48 8 1600 1606 10426379 source
• Not checked yetcites [56] Krssak M Falk Petersen K Dresner A Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study Diabetologia 1999 42 1 113 116 10027589 source

In the paper

“Insulin resistance in skeletal muscle also has been reported in association with the normal ageing process [37], dyslipidemia (increased plasma triglyceride/decreased HDL cholesterol) [4, 26], and in association with many disease states including polycystic ovary syndrome (PCOs) [38], chronic kidney failure [39], heart failure [40], myotonic dystrophy [41], and lipodystrophy [42].”

What the sources say

• Not checked yetcites [37] DeFronzo RA Glucose intolerance and aging. Evidence for tissue insensitivity to insulin Diabetes 1979 28 12 1095 1101 510806 source
• Not checked yetcites [4] Defronzo RA From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus Diabetes 2009 58 4 773 795 19336687 PMC2661582 source
• Not checked yetcites [26] Ginsberg H Kimmerling G Olefsky JM Reaven GM Demonstration of insulin resistance in untreated adult onset diabetic subjects with fasting hyperglycemia The Journal of Clinical Investigation 1975 55 3 454 461 1117064 PMC301772 source
• Not checked yetcites [38] Lankarani M Valizadeh N Heshmat R Peimani M Sohrabvand F Evaluation of insulin resistance and metabolic syndrome in patients with polycystic ovary syndrome Gynecological Endocrinology 2009 25 8 504 507 19499403 source

In the paper

“Thus, obese NGT subjects without a family history for T2DM [33, 34] and individuals with essential hypertension [35] and ischemic heart disease [36] also have a 35–50% decrease in whole body insulin-mediated glucose disposal (Figure 3).”

What the sources say

• Not checked yetcites [33] Kahn SE Hull RL Utzschneider KM Mechanisms linking obesity to insulin resistance and type 2 diabetes Nature 2006 444 7121 840 846 213 17167471 source
• Not checked yetcites [34] Bogardus C Lillioja S Mott D Reaven GR Kashiwagi A Foley JE Relationship between obesity and maximal insulin-stimulated glucose uptake in vivo and in vitro in Pima Indians The Journal of Clinical Investigation 1984 73 3 800 805 6368588 PMC425083 source
• Not checked yetcites [35] Ferrannini E Buzzigoli G Bonadonna R Insulin resistance in essential hypertension The New England Journal of Medicine 1987 317 6 350 357 3299096 source
• Not checked yetcites [36] Bressler P Bailey SR Matsuda M DeFronzo RA Insulin resistance and coronary artery disease Diabetologia 1996 39 11 1345 1350 8933003 source

In the paper

“Both acute (4 hours) and chronic (4 days) physiologic elevation of plasma FFA concentration in insulin sensitive individuals impairs insulin signaling and causes insulin resistance in skeletal muscle [28, 62–68].”

What the sources say

• Not checked yetcites [28] DeFronzo RA Soman V Sherwin RS Hendler R Felig P Insulin binding to monocytes and insulin action in human obesity, starvation, and refeeding The Journal of Clinical Investigation 1978 62 1 204 213 350903 PMC371755 source
• Not checked yetcites [62] Griffin ME Marcucci MJ Cline GW Free fatty acid-induced insulin resistance is associated with activation of protein kinase C θ and alterations in the insulin signaling cascade Diabetes 2000 48 6 1270 1274 10342815 source
• Not checked yetcites [63] Dresner A Laurent D Marcucci M Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity The Journal of Clinical Investigation 1999 103 2 253 259 9916137 PMC407880 source
• Not checked yetcites [64] Yu C Chen Y Cline GW Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle The Journal of Biological Chemistry 2002 277 52 50230 50236 12006582 source
• Not checked yetcites [65] Belfort R Mandarino L Kashyap S Dose-response effect of elevated plasma free fatty acid on insulin signaling Diabetes 2005 54 6 1640 1648 15919784 source
• Not checked yetcites [66] Itani SI Ruderman NB Schmieder F Boden G Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IκB-α Diabetes 2002 51 7 2005 2011 12086926 source
• Not checked yetcites [67] Richardson DK Kashyap S Bajaj M Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle The Journal of Biological Chemistry 2005 280 11 10290 10297 15598661 source
• Not checked yetcites [68] Boden G Chen X Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes The Journal of Clinical Investigation 1995 96 3 1261 1268 7657800 PMC185747 source

In the paper

“These studies indicate that although insulin resistance in skeletal muscle is a hallmark of T2DM, muscle insulin resistance and the accompanying insulin resistance syndrome are more widely prevalent and the metabolic and clinical consequences of insulin resistance (e.g., increased cardiovascular risk) affect nondiabetic individuals as well.”

In the paper

“Muscle biopsy studies [53, 54] have demonstrated increased triglyceride content in skeletal muscle of obese NGT subjects compared to lean individuals and an inverse relationship between muscle insulin sensitivity and the intramuscular triglyceride content.”

What the sources say

• Not checked yetcites [53] Pan DA Lillioja S Kriketos AD Skeletal muscle triglyceride levels are inversely related to insulin action Diabetes 1997 46 6 983 988 9166669 source
• Not checked yetcites [54] Phillips DIW Caddy S Ilic V Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in nondiabetic subjects Metabolism 1996 45 8 947 950 8769349 source

In the paper

“In addition, insulin resistance develops in acute severe illnesses such as injury and sepsis, perhaps secondary to the acute inflammatory state that prevails [43].”

What the sources say

• Not checked yetcites [43] Van Cromphaut SJ Vanhorebeek I Van den Berghe G Glucose metabolism and insulin resistance in sepsis Current Pharmaceutical Design 2008 14 19 1887 1899 18691100 source

In the paper

“In insulin resistant individuals, for example, nondiabetic obese and lean type 2 diabetic subjects, the ability of insulin to inhibit lipolysis and reduce plasma FFA concentration is markedly impaired [21, 59], leading to an increased rate of lipolysis and chronic elevation in the plasma FFA concentration.”

What the sources say

• Not checked yetcites [21] Groop LC Bonadonna RC DelPrato S Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance The Journal of Clinical Investigation 1989 84 1 205 213 2661589 PMC303971 source
• Not checked yetcites [59] Groop LC Saloranta C Shank M Bonadonna RC Ferrannini E DeFronzo RA The role of free fatty acid metabolism in the pathogenesis of insulin resistance in obesity and noninsulin-dependent diabetes mellitus Journal of Clinical Endocrinology and Metabolism 1991 72 1 96 107 1986032 source

In the paper

“These observations collectively indicate that muscle triglyceride (which is metabolic inert) is not directly involved in determining insulin sensitivity but rather represents a marker of imbalance between lipid supply and lipid oxidation in skeletal muscle, while increases in intramyocellar FACoA and other lipotoxic metabolites (DAG, ceramide) have a more direct role in the development of skeletal”

In the paper

“The mitochondrial defect in ATP synthesis rate documented in vivo with MRS could be due to a reduction in the number of mitochondria in skeletal muscle with normal function of individual mitochondria, an intrinsic defect in a quantitively normal number of mitochondria, or some combination of the two.”

In the paper

“Indeed, early studies demonstrated the rate of lipolysis was a key determinant of FFA uptake and oxidation in skeletal muscle and documented a linear relationship between the plasma LCFA concentration and their rate of uptake and oxidation in the muscle [85–87].”

What the sources say

• Not checked yetcites [85] Hagenfeldt L Metabolism of free fatty acids and ketone bodies during exercise in normal and diabetic man Diabetes 1979 28 supplement 1 66 70 104895 source
• Not checked yetcites [86] Hagenfeldt L Wahren J Human forearm muscle metabolism during exercise. II. Uptake, release and oxidation of individual FFA and glycerol Scandinavian Journal of Clinical and Laboratory Investigation 1968 21 3 263 276 5708695 source
• Not checked yetcites [87] Havel RJ Ekelund LG Holmgren A Kinetic analysis of the oxidation of palmitate-1-14C in man during prolonged heavy muscular exercise Journal of Lipid Research 1967 8 4 366 373 6033603 source

In the paper

“The accumulation of fat inside the muscle fiber could originate from excess supply of FFA to the muscle, a decreased rate of muscle fat oxidation, or some combination of the two.”

In the paper

“Insulin resistance also is a characteristic feature of the normal aging process and is associated with a decrease in mitochondrial ATP synthesis rate and an increase in intramyocellar fat content [109].”

What the sources say

• Not checked yetcites [109] Petersen KF Befroy D Dufour S Mitochondrial dysfunction in the elderly: possible role in insulin resistance Science 2003 300 5622 1140 1142 12750520 PMC3004429 source

In the paper

“(vii) weight loss, induced by bariatric surgery, results in a complete normalization of insulin sensitivity despite the presence of continued obesity (BMI reduced from 49 to 39 kg/m2) [79]. The normalization of muscle insulin sensitivity is associated with a reduction of muscle fat content to normal despite a persistent increase in total body fat content [79].”

What the sources say

• Not checked yetcites [79] Greco AV Mingrone G Giancaterini A Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion Diabetes 2002 51 1 144 151 11756334 source

In the paper

“Conversely, reduction of plasma FFA concentration in insulin resistant individuals, for example, type 2 diabetic subjects, augments insulin-stimulated glucose disposal in skeletal muscle [69–72], and the improvement in insulin sensitivity is closely associated with a reduction in intramyocellular FACoA concentration [69].”

What the sources say

• Not checked yetcites [69] Bajaj M Suraamornkul S Romanelli A Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long-chain fatty acyl-CoAs and insulin action in type 2 diabetic patients Diabetes 2005 54 11 3148 3153 16249438 source
• Not checked yetcites [70] Bajaj M Suraamornkul S Kashyap S Cusi K Mandarino L DeFronzo RA Sustained reduction in plasma free fatty acid concentration improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes Journal of Clinical Endocrinology and Metabolism 2004 89 9 4649 4655 15356076 source
• Not checked yetcites [71] Vaag A Skott P Damsbo P Gall M-A Richter EA Beck-Nielsen H Effect of the antilipolytic nicotinic acid analogue acipimox on whole-body and skeletal muscle glucose metabolism in patients with non-insulin-dependent diabetes mellitus The Journal of Clinical Investigation 1991 88 4 1282 1290 1918378 PMC295597 source
• Not checked yetcites [72] Santomauro ATMG Boden G Silva MER Overnight lowering of free fatty acids with acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects Diabetes 1999 48 9 1836 1841 10480616 source

In the paper

“An acquired defect potentially could be reversed or prevented, while an inherited defect would be permanent.”

In the paper

“There is abundant evidence which indicates that CD36 plays an important role in LCFA uptake into skeletal muscle in rodents and human and its concentration and activity are increased following exercise [89–96].”

What the sources say

• Not checked yetcites [89] Gargiulo CE Stunlsatz-Krouper SM Schaffer JE Localization of adipocyte long-chain fatty acyl-CoA synthetase at the plasma membrane Journal of Lipid Research 1999 40 5 881 892 10224157 source
• Not checked yetcites [90] Ibrahimi A Bonen A Blinn WD Muscle-specific overexpression of FAT/CD36 enhances fatty acid oxidation by contracting muscle, reduces plasma triglycerides and fatty acids, and increases plasma glucose and insulin The Journal of Biological Chemistry 1999 274 38 26761 26766 10480880 source
• Not checked yetcites [91] Febbraio M Abumrad NA Hajjar DP A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism The Journal of Biological Chemistry 1999 274 27 19055 19062 10383407 source
• Not checked yetcites [92] Luiken JJFP Arumugam Y Dyck DJ Increased rates of fatty acid uptake and plasmalemmal fatty acid transporters in obese Zucker rats The Journal of Biological Chemistry 2001 276 44 40567 40573 11504711 source
• Not checked yetcites [93] Steinberg GR Dyck DJ Calles-Escandon J Chronic leptin administration decreases fatty acid uptake and fatty acid transporters in rat skeletal muscle The Journal of Biological Chemistry 2002 277 11 8854 8860 11729182 source
• Not checked yetcites [94] Cameron-Smith D Burke LM Angus DJ A short-term, high-fat diet up-regulates lipid metabolism and gene expression in human skeletal muscle American Journal of Clinical Nutrition 2003 77 2 313 318 12540388 source
• Not checked yetcites [95] Roepstorff C Helge JW Vistisen B Kiens B Studies of plasma membrane fatty acid-binding protein and other lipid-binding proteins in human skeletal muscle Proceedings of the Nutrition Society 2004 63 2 239 244 15294037 source
• Not checked yetcites [96] Bonen A Parolin ML Steinberg GR Triacylglycerol accumulation in human obesity and type 2 diabetes is associated with increased rates of skeletal muscle fatty acid transport increased sarcolemmal FAT/CD36 FASEB Journal 2004 18 10 1144 1146 15132977 source

In the paper

“Since the majority of fat oxidation take place in the mitochondria, impaired fat oxidation in insulin resistant individuals suggests the presence of a mitochondrial defect that contributes to the impaired muscle fat oxidation and increased IMCL fat content.”

In the paper

“During conditions of decreased fat oxidation and increased CD36 levels, muscle uptake of LCFA increased, resulting in increased muscle triglyceride synthesis and increased IMCL content [97, 98].”

What the sources say

• Not checked yetcites [97] Kiens B Roemen THM Van der Vusse GJ Muscular long-chain fatty acid content during graded exercise in humans American Journal of Physiology 1999 276 2 E352 E357 9950796
• Not checked yetcites [98] Roepstorff C Vistisen B Roepstorff K Kiens B Regulation of plasma long-chain fatty acid oxidation in relation to uptake in human skeletal muscle during exercise American Journal of Physiology 2004 287 4 E696 E705 15186996 source

In the paper

“(ii) the decrease in insulin resistance brought about by reducing the plasma FFA concentration with acipimox in insulin resistant individuals is associated with a reduction in intracellular FACoA content, and the magnitude of decrease in insulin resistance strongly correlates with the decrease in FACoA content [69];”

What the sources say

• Not checked yetcites [69] Bajaj M Suraamornkul S Romanelli A Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long-chain fatty acyl-CoAs and insulin action in type 2 diabetic patients Diabetes 2005 54 11 3148 3153 16249438 source

In the paper

“(v) in rodents, injection of recombinant adiponectin increases fat oxidation, reduces intamyocellular lipid, and improves insulin sensitivity [77];”

What the sources say

• Not checked yetcites [77] Yamauchi T Kamon J Waki H The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity Nature Medicine 2001 7 8 941 946 11479627 source

In the paper

“Subjects with T2DM also have decreased exercise tolerance and impaired recovery of intracellular phosphocreatinine concentration following exercise [107, 108]”

What the sources say

• Not checked yetcites [107] Scheuermann-Freestone M Madsen PL Manners D Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes Circulation 2003 107 24 3040 3046 12810608 source
• Not checked yetcites [108] Schrauwen-Hinderling VB Kooi ME Hesselink MKC Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects Diabetologia 2007 50 1 113 120 17093944 source

In the paper

“More recent studies have reported that under conditions of marked increase in energy demand in the muscle, for example, during exercise, LCFAs uptake initially increases linearly then plateaus [88], suggesting the existence of a facilitated transport mechanism for LCFA into skeletal muscle.”

What the sources say

• Not checked yetcites [88] Kiens B Essen-Gustavsson B Christensen NJ Saltin B Skeletal muscle substrate utilization during submaximal exercise in man: effect of endurance training Journal of Physiology 1993 469 459 478 8271208 PMC1143880 source

In the paper

“The CD36 content and LCFA transport capacity have been reported to be increased in obese and T2DM individuals and correlate with increased muscle triglyceride content, while fat oxidation is decreased.”

In the paper

“Collectively, these studies indicate the existence of an intrensic defect in mitochondrial capacity to oxidize fat in obesity and T2DM.”

In the paper

“(vi) muscle-specific over expression of lipoprotein lipase leads to the accumulation of fat/FACoA in muscle and severe muscle insulin resistance, while the fat content and insulin sensitivity in other tissues, that is, liver, remain unchanged [78];”

What the sources say

• Not checked yetcites [78] Kim JK Fillmore JJ Chen Y Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance Proceedings of the National Academy of Sciences of the United States of America 2001 98 13 7522 7527 11390966 PMC34701 source

In the paper

“The mitochondrial defect in oxidative phosphorylation described in vivo with MRS and ex vivo in muscle fibers and isolated mitochondria could contribute to the increase in intramyocellar FFA metabolite levels observed in obesity and T2DM and contribute to the insulin resistance.”

In the paper

“one cannot completely exclude the possibility that the mitochondrial defect results secondary to insulin resistance.”

What the sources say

• Not checked yetcites [110] Brehm A Krssak M Schmid AI Nowotny P Waldhäusl W Roden M Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle Diabetes 2006 55 1 136 140 16380486 source

In the paper

“Thus, normal mitochondrial function in young, insulin-sensitive subjects suggests that the mitochondrial defect and insulin-resistance are acquired as part of the normal ageing process.”

In the paper

“An inherited defect in mitochondrial oxidative capacity should be present at or shortly after birth and, most importantly, not be reversable.”

In the paper

“Down regulation of electron transport chain activity in mice by knocking down apoptosis inintiating factor (AIF) resulted in enhanced insulin sensitivity and protection the animal from fat-induced insulin resistance [137].”

What the sources say

• Not checked yetcites [137] Pospisilik JA Knauf C Joza N Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes Cell 2007 131 3 476 491 17981116 source

In the paper

“(i) modest weight reduction (~10% of body weight), produced by dieting and increased physical activity, reduces insulin resistance and intramyocellular lipid content and these changes are associated with increased fat oxidation in skeletal muscle [123]. Furthermore, the magnitude of increase in fat oxidation following weight loss correlated strongly with the decrease in insulin resistance [123];”

What the sources say

• Not checked yetcites [123] Goodpaster BH Katsiaras A Kelley DE Enhanced fat oxidation through physical activity is associated with improvements in insulin sensitivity in obesity Diabetes 2003 52 9 2191 2197 12941756 source

In the paper

“Down regulation of mitochondrial function in myotubes with oligomycin, which inhibits mitochondrial ATP synthesis, and with ethidium bromide, which impairs mitochondrial DNA replication, caused an increase in intracellular fat content, impaired insulin signaling, and decreased insulin-stimulated glucose uptake [135].”

What the sources say

• Not checked yetcites [135] Lim JH Lee JI Suh YH Kim W Song JH Jung MH Mitochondrial dysfunction induces aberrant insulin signalling and glucose utilisation in murine C2C12 myotube cells Diabetologia 2006 49 8 1924 1936 16736133 source

In the paper

“Over expression of the PGC-1 alpha gene in skeletal muscle in mice in vivo enhanced mitochondrial activity, augmented the expression of multiple proteins involved in fat oxidation and glucose transport, and increased by ~35% insulin-stimulated glucose uptake [133].”

What the sources say

• Not checked yetcites [133] Benton CR Nickerson JG Lally J Modest PGC-1α overexpression in muscle in vivo is sufficient to increase insulin sensitivity and palmitate oxidation in subsarcolemmal, not intermyofibrillar, mitochondria The Journal of Biological Chemistry 2008 283 7 4228 4240 18079123 source

In the paper

“Biochemical studies have reported a decrease in the activity of a variety of mitochondrial enzymes [122], also supporting an intrinsic functional mitochondrial defect in type 2 diabetic subjects.”

What the sources say

• Not checked yetcites [122] Mogensen M Sahlin K Fernström M Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes Diabetes 2007 56 6 1592 1599 17351150 source

In the paper

“(ii) marked weight reduction following bariatric surgery in morbidly obese, severely insulin-resistant subjects completely normalized insulin sensitivity, and correction of the insulin resistance was accompanied by depletion of intramyocellar fat content [124].”

What the sources say

• Not checked yetcites [124] Greco AV Mingrone G Giancaterini A Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion Diabetes 2002 51 1 144 151 11756334 source

In the paper

“An intrinsic mitochondrial defect, with or without a decrease in mitochondrial density, would be expected to result in impaired lipid oxidation, an increase in intramyocellular lipid content, and the development/exacerbation of insulin resistance.”

In the paper

“In summary it can be concluded that both decreased mitochondrial fat oxidation and increased FFA influx into skeletal muscle take place during insulin resistance state.”

In the paper

“Mutagenesis of any of the three major phosphorylation sites (at residues 1158, 1163, and 1162) impairs insulin receptor tyrosine kinase activity, leading to a decrease in the metabolic and growth-promoting effects of insulin [141, 142].”

What the sources say

• Not checked yetcites [141] Ellis L Clauser E Morgan DO Edery M Roth RA Rutter WJ Replacement of insulin receptor tyrosine residues 1162 and 1163 compromises insulin-stimulated kinase activity and uptake of 2-deoxyglucose Cell 1986 45 5 721 732 3518947 source
• Not checked yetcites [142] Chou CK Dull TJ Russell DS Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin The Journal of Biological Chemistry 1987 262 4 1842 1847 3100537 source

In the paper

“Ex vivo measurement of electron transport chain activity (ETC) [112] and mitochondrial ATP synthesis in isolated mitochondria [120, 121] have demonstrated a decrease in ETC activity and ATP synthesis in obese insulin-resistant individuals compared to lean insulin-sensitive subjects.”

What the sources say

• Not checked yetcites [112] Ritov VB Menshikova EV He J Ferrell RE Goodpaster BH Kelley DE Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes Diabetes 2005 54 1 8 14 15616005 source
• Not checked yetcites [120] Abdul-Ghani MA Jani R Molina M Chavez A Tripathy D DeFronzo RA Decreased mitochondrial ATP synthesis in obese non-diabetic subjects Diabetes 2008 56 supplement 1
• Not checked yetcites [121] Phielix E Schrauwen-Hinderling VB Mensink M Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients Diabetes 2008 57 11 2943 2949 18678616 PMC2570390 source

In the paper

“the improvement in insulin sensitivity following exercise is associated with improved muscle oxidative capacity [125, 126] and increases in both mitochondrial density [127] and activity [128–130]”

What the sources say

• Not checked yetcites [125] Jubrias SA Esselman PC Price LB Cress ME Conley KE Large energetic adaptations of elderly muscle to resistance and endurance training Journal of Applied Physiology 2001 90 5 1663 1670 11299253 source
• Not checked yetcites [126] Holloszy JO Coyle EF Adaptations of skeletal muscle to endurance exercise and their metabolic consequences Journal of Applied Physiology Respiratory Environmental and Exercise Physiology 1984 56 4 831 838 6373687
• Not checked yetcites [127] Chilibeck PD Syrotuik DG Bell GJ The effect of concurrent endurance and strength training on quantitative estimates of subsarcolemmal and intermyofibrillar mitochondria International Journal of Sports Medicine 2002 23 1 33 39 11774064 source
• Not checked yetcites [128] Østergård T Andersen JL Nyholm B Impact of exercise training on insulin sensitivity, physical fitness, and muscle oxidative capacity in first-degree relatives of type 2 diabetic patients American Journal of Physiology 2006 290 5 E998 E1005 16352678 source
• Not checked yetcites [129] Menshikova EV Ritov VB Toledo FGS Ferrell RE Goodpaster BH Kelley DE Effects of weight loss and physical activity on skeletal muscle mitochondrial function in obesity American Journal of Physiology 2005 288 4 E818 E825 15585590 source
• Not checked yetcites [130] Short KR Vittone JL Bigelow ML Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity Diabetes 2003 52 8 1888 1896 12882902 source

In the paper

“However, when oxygen consumption was related to mitochondrial copy number, both diabetic and nondiabetic subjects had similar rates of muscle oxygen consumption, implying a decrease in mitochondrial density without an intrinsic mitochondrial defect in T2DM subjects.”

In the paper

“Since, in these studies [112, 120], ETC activity and mitochondrial ATP synthesis rate were related to the amount of mitochondrial protein and/or citrate synthase activity, these observations indicate the existence of a basic functional defect in mitochondrial activity in skeletal muscle of obese insulin-resistant individuals [115].”

What the sources say

• Not checked yetcites [112] Ritov VB Menshikova EV He J Ferrell RE Goodpaster BH Kelley DE Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes Diabetes 2005 54 1 8 14 15616005 source
• Not checked yetcites [120] Abdul-Ghani MA Jani R Molina M Chavez A Tripathy D DeFronzo RA Decreased mitochondrial ATP synthesis in obese non-diabetic subjects Diabetes 2008 56 supplement 1
• Not checked yetcites [115] Boushel R Gnaiger E Schjerling P Skovbro M Kraunsøe R Dela F Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle Diabetologia 2007 50 4 790 796 17334651 PMC1820754 source

In the paper

“activation of SIRT1 with resveratrol in mice resulted in increased mitochondrial activity and protected the animals from diet-induced obesity and insulin resistance [134].”

What the sources say

• Not checked yetcites [134] Lagouge M Argmann C Gerhart-Hines Z Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α Cell 2006 127 6 1109 1122 17112576 source

In the paper

“EM studies have demonstrated a variety of morphological abnormalities in mitochondria in insulin-resistant individuals [118] and these changes were reversable with weight loss and increased physical activity [119].”

What the sources say

• Not checked yetcites [118] Kelley DE He J Menshikova EV Ritov VB Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes Diabetes 2002 51 10 2944 2950 12351431 source
• Not checked yetcites [119] Toledo FGS Watkins S Kelley DE Changes induced by physical activity and weight loss in the morphology of intermyofibrillar mitochondria in obese men and women Journal of Clinical Endocrinology and Metabolism 2006 91 8 3224 3227 16684829 source

In the paper

“treatment of the muscle cells with azide, an inhibitor of mitochondrial complex IV, increased basal glucose uptake without affecting insulin-stimulated glucose uptake in myotubes [136].”

What the sources say

• Not checked yetcites [136] Brown AE Elstner M Yeaman SJ Turnbull DM Walker M Does impaired mitochondrial function affect insulin signaling and action in cultured human skeletal muscle cells? American Journal of Physiology 2008 294 1 E97 E102 17957036 source

In the paper

“Studies [138, 150] have demonstrated convincingly that inhibitors of PI3K inhibit glycogen synthase activity and abolish glycogen synthesis.”

What the sources say

• Not checked yetcites [138] Saltiel AR Kahn CR Insulin signalling and the regulation of glucose and lipid metabolism Nature 2001 414 6865 799 806 11742412 source
• Not checked yetcites [150] Shepherd PR Nave BT Siddle K Insulin stimulation of glycogen synthesis and glycogen synthase activity is blocked by wortmannin and rapamycin in 3T3-L1 adipocytes: evidence for the involvement of phosphoinositide 3-kinase and p70 ribosomal protein-56 kinase Biochemical Journal 1995 305 1 25 28 7826337 PMC1136424 source

In the paper

“Thus, conditions that increase serine phosphorylation of IRS-1 impair tyrosine phosphorylation by the insulin receptor and its activation, thus, leading to an impartment in the insulin signaling cascade.”

In the paper

“Association of the p85 subunit of PI3K with IRS-1 and activation of PI3K also are greatly attenuated in obese nondiabetic and type 2 diabetic subjects compared with lean healthy controls [7, 165, 166].”

What the sources say

• Not checked yetcites [7] Cusi K Maezono K Osman A Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle The Journal of Clinical Investigation 2000 105 3 311 320 10675357 PMC377440 source
• Not checked yetcites [165] Krook A Björnholm M Galuska D Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients Diabetes 2000 49 2 284 292 10868945 source
• Not checked yetcites [166] Kim Y-B Nikoulina SE Ciaraldi TP Henry RR Kahn BB Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes The Journal of Clinical Investigation 1999 104 6 733 741 10491408 PMC408433 source

In the paper

“Increased activity of protein kinase C (PKC-β and δ has been reported in insulin resistant states and can be induced during lipid infusion [174, 175].”

What the sources say

• Not checked yetcites [174] Schmitz-Peiffer C Browne CL Oakes ND Alterations in the expression and cellular localization of protein kinase C isozymes ε and θ are associated with insulin resistance in skeletal muscle of the high-fat-fed rat Diabetes 1997 46 2 169 178 9000691 source
• Not checked yetcites [175] Schmitz-Peiffer C Oakes ND Browne CL Kraegen EW Biden TJ Reversal of chronic alterations of skeletal muscle protein kinase C from fat-fed rats by BRL-49653 American Journal of Physiology 1997 273 5 E915 E921 9374677

In the paper

“In summary, impaired association of PI3K with IRS-1 and its subsequent activation are characteristic abnormalities in type 2 diabetics, and these defects are correlated closely with in vivo muscle insulin resistance.”

In the paper

“The ability of insulin to activate insulin receptor and IRS-1 tyrosine phosphorylation in muscle in obese nondiabetic subjects is modestly reduced; whereas in type 2 diabetics insulin-stimulated insulin receptor and IRS-1 tyrosine phosphorylation are severely impaired [7].”

What the sources say

• Not checked yetcites [7] Cusi K Maezono K Osman A Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle The Journal of Clinical Investigation 2000 105 3 311 320 10675357 PMC377440 source

In the paper

“Because nitric oxide synthase also is activated by the IRS-1/PIS-K pathway, impaired insulin signaling leads to reduced nitric oxide generation and endothelial dysfunction, which have implicated in the development of accelerated atherosclerosis in T2DM individuals.”

In the paper

“a decrease in insulin receptor number cannot be demonstrated in over half of type 2 diabetic subjects, and it has been difficult to demonstrate a correlation between reduced insulin binding and the severity of insulin resistance [156–158].”

What the sources say

• Not checked yetcites [156] Kashiwagi A Verso MA Andrews J In vitro insulin resistance of human adipocytes isolated from subjects with noninsulin-dependent diabetes mellitus The Journal of Clinical Investigation 1983 72 4 1246 1254 6355180 PMC370408 source
• Not checked yetcites [157] Lonnroth P Digirolamo M Krotkiewski M Smith U Insulin binding and responsiveness in fat cells from patients with reduced glucose tolerance and type II diabetes Diabetes 1983 32 8 748 754 6347772 source
• Not checked yetcites [158] Olefsky JM Reaven GM Insulin binding in diabetes. Relationships with plasma insulin levels and insulin sensitivity Diabetes 1977 26 7 680 688 873075 source

In the paper

“Inhibition of the MAPK kinase pathway prevents the stimulation of cell growth by insulin but has no effect on the metabolic actions of the hormone [147].”

What the sources say

• Not checked yetcites [147] Lazar DF Wiese RJ Brady MJ Mitogen-activated protein kinase kinase inhibition does not block the stimulation of glucose utilization by insulin The Journal of Biological Chemistry 1995 270 35 20801 20807 7657664 source

In the paper

“Inhibitors of PI3K impair glucose transport and block the activation of glycogen synthase and hexokinase- (HK-) II expression [138–146]”

What the sources say

• Not checked yetcites [138] Saltiel AR Kahn CR Insulin signalling and the regulation of glucose and lipid metabolism Nature 2001 414 6865 799 806 11742412 source
• Not checked yetcites [139] Pessin JE Saltiel AR Signaling pathways in insulin action: molecular targets of insulin resistance The Journal of Clinical Investigation 2000 106 2 165 169 10903329 PMC314316 source
• Not checked yetcites [140] Whitehead JP Clark SF Ursø B James DE Signalling through the insulin receptor Current Opinion in Cell Biology 2000 12 2 222 228 10712920 source
• Not checked yetcites [141] Ellis L Clauser E Morgan DO Edery M Roth RA Rutter WJ Replacement of insulin receptor tyrosine residues 1162 and 1163 compromises insulin-stimulated kinase activity and uptake of 2-deoxyglucose Cell 1986 45 5 721 732 3518947 source
• Not checked yetcites [142] Chou CK Dull TJ Russell DS Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin The Journal of Biological Chemistry 1987 262 4 1842 1847 3100537 source
• Not checked yetcites [143] Virkamäki A Ueki K Kahn CR Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance The Journal of Clinical Investigation 1999 103 7 931 943 10194465 PMC408269 source
• Not checked yetcites [144] Sun XJ Miralpeix M Myers MG Jr. Expression and function of IRS-1 in insulin signal transmission Journal of Biological Chemistry 1992 267 31 22662 22672 1385403 source
• Not checked yetcites [145] Cross D Alessi D Vandenheed J McDowell H Hundal H Cohen P The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin but not rapamycin Biochemical Journal 1994 267 303 321 PMC1137550 7945242
• Not checked yetcites [146] Osawa H Sutherland C Robey RB Printz RL Granner DK Analysis of the signaling pathway involved in the regulation of hexokinase II gene transcription by insulin The Journal of Biological Chemistry 1996 271 28 16690 16694 8663315 source

In the paper

“Early studies have demonstrated a modest 20–30% reduction in insulin binding to monocytes and adipocytes from type 2 diabetic patients, but this has not been a consistent finding [1, 151–154].”

What the sources say

• Not checked yetcites [1] DeFronzo RA Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes Diabetes Reviews 1997 5 3 177 269
• Not checked yetcites [151] Freidenberg GR Henry RR Klein HH Reichart DR Olefsky JM Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic subjects Journal of Clinical Investigation 1987 79 1 240 250 3540010 PMC424032 source
• Not checked yetcites [152] Caro JF Sinha MK Raju SM Insulin receptor kinase in human skeletal muscle from obese subjects with and without noninsulin dependent diabetes The Journal of Clinical Investigation 1987 79 5 1330 1337 3033021 PMC424378 source
• Not checked yetcites [153] Caro JF Ittoop O Pories WJ Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity The Journal of Clinical Investigation 1986 78 1 249 258 3522628 PMC329556 source
• Not checked yetcites [154] Trischitta V Brunetti A Chiavetta A Benzi L Papa V Vigneri R Defects in insulin-receptor internalization and processing in monocytes of obese subjects and obese NIDDM patients Diabetes 1989 38 12 1579 1584 2684714 source

In the paper

“Hexokinase isoenzymes (HK-I–IV) catalyze the first committed step of glucose metabolism, the intracellular conversion of free glucose to glucose-6-phosphate (Glu-6-P) [183, 184, 186, 198].”

What the sources say

• Not checked yetcites [183] Bell GI Kayano T Buse JB Molecular biology of mammalian glucose transporters Diabetes Care 1990 13 3 198 208 2407475 source
• Not checked yetcites [184] Joost H-G Bell GI Best JD Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators American Journal of Physiology 2002 282 4 E974 E976 11882521
• Not checked yetcites [186] Rogers PA Fisher RA Harris H An electrophoretic study of the distribution and properties of human hexokinases Biochemical Genetics 1975 13 11-12 857 866 1239274 source
• Not checked yetcites [198] Printz RL Ardehali H Koch S Granner DK Human hexokinase II mRNA and gene structure Diabetes 1995 44 3 290 294 7883116 source

In the paper

“Muscle tissue from lean and obese type 2 diabetic subjects exhibits normal or increased levels of GLUT4 mRNA expression and normal levels of GLUT4 protein, thus demonstrating that transcriptional and translational regulation of GLUT4 is not impaired [190, 191].”

What the sources say

• Not checked yetcites [190] Pedersen O Bak JF Andersen PH Evidence against altered expression of GLUT1 or GLUT4 in skeletal muscle of patients with obesity for NIDDM Diabetes 1990 39 7 865 870 2354749 source
• Not checked yetcites [191] Eriksson J Koranyi L Bourey R Insulin resistance in type 2 (non-insulin-dependent) diabetic patients and their relatives is not associated with a defect in the expression of the insulin-responsive glucose transporter (GLUT-4) gene in human skeletal muscle Diabetologia 1992 35 2 143 147 1547918 source

In the paper

“Several groups have looked for point mutations in the HK-II gene in individuals with type 2 diabetes, and, although several nucleotide substitutions have been found, none are close to the glucose and ATP binding sites and none have been associated with insulin resistance [203–205].”

What the sources say

• Not checked yetcites [203] Lehto M Huang X Davis EM Human hexokinase II gene: exon-intron organization, mutation screening in NIDDM, and its relationship to muscle hexokinase activity Diabetologia 1995 38 12 1466 1474 8786021 source
• Not checked yetcites [204] Laakso M Malkki M Kekalainen P Kuusisto J Deeb SS Polymorphisms of the human hexokinase II gene: lack of association with NIDDM and insulin resistance Diabetologia 1995 38 5 617 622 7489847 source
• Not checked yetcites [205] Echwald SM Bjorbaek C Hansen T Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity Diabetes 1995 44 3 347 353 7883123 source

In the paper

“Large populations of type 2 diabetics have been screened for mutations in the GLUT4 gene [196]. Such mutations are very uncommon and, when detected, have been of questionable physiologic significance.”

What the sources say

• Not checked yetcites [196] Choi W-H O’Rahilly S Buse JB Molecular scanning of insulin-responsive glucose transporter (GLUT4) gene in NIDDM subjects Diabetes 1991 40 12 1712 1718 1756912 source

In the paper

“Impaired glycogen synthesis also has been documented in the normal-glucose tolerant offspring of two diabetic parents, in the first-degree relatives of type 2 diabetic individuals, and in the normoglycemic twin of a monozygotic twin pair in which the other twin has type 2 diabetes [206, 210, 211].”

What the sources say

• Not checked yetcites [206] Gulli G Ferrannini E Stern M Haffner S DeFronzo RA The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents Diabetes 1992 41 12 1575 1586 1446799 source
• Not checked yetcites [210] Rothman DL Magnusson I Cline G Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus Proceedings of the National Academy of Sciences of the United States of America 1995 92 4 983 987 7862678 PMC42621 source
• Not checked yetcites [211] Vaag A Henriksen JE Madsbad S Holm N Beck-Nielsen H Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus The Journal of Clinical Investigation 1995 95 2 690 698 7860750 PMC295536 source

In the paper

“These observations indicate that in type 2 diabetic individuals, although both glucose transport and glucose phosphorylation are severely resistant to the action of insulin, impaired glucose phosphorylation (HK-II) appears to be the rate-limiting step for insulin action.”

In the paper

“In response to physiologic euglycemic hyperinsulinemia of 2 to 4 hours' duration, HK-II cytosolic activity, protein content, and mRNA levels increase by 50% to 200% in healthy nondiabetic subjects, and this is associated with the translocation of hexokinase II from the cytosol to the mitochondria.”

In the paper

“Because the number of GLUT4 transporters in the muscle of diabetic subjects is normal, impaired GLUT4 translocation and decreased intrinsic activity of the glucose transporter must be responsible for the defect in muscle glucose transport.”

In the paper

“Nonetheless, these studies are consistent in demonstrating that abnormalities in both muscle glucose phosphorylation and glucose transport are well established early in the natural history of type 2 diabetes and cannot be explained by glucose toxicity.”

In the paper

“In human skeletal muscle, HK-II transcription is regulated by insulin, whereas HK-I mRNA and protein levels are not affected by insulin [199, 200].”

What the sources say

• Not checked yetcites [199] Vogt C Ardehali H Iozzo P Regulation of hexokinase II expression in human skeletal muscle in vivo Metabolism 2000 49 6 814 818 10877213 source
• Not checked yetcites [200] Pendergrass M Koval J Vogt C Insulin-induced hexokinase II expression is reduced in obesity and NIDDM Diabetes 1998 47 3 387 394 9519744 source

In the paper

“Studies using 31P nuclear magnetic resonance in combination with [1-14C] glucose also have demonstrated that both insulin-stimulated muscle glucose transport and glucose phosphorylation are impaired in type 2 diabetic subjects, but the defect in transport exceeds the defect in phosphorylation [194].”

What the sources say

• Not checked yetcites [194] Cline GW Petersen KF Krssak M Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes The New England Journal of Medicine 1999 341 4 240 246 10413736 source

In the paper

“The regulatory subunit of PP1 has two serine phosphorylation sites, called site 1 and site 2. Phosphorylation of site 2 by cAMP-dependent protein kinase inactivates PP1; whereas phosphorylation of site 1 by insulin activates PP1, leading to the stimulation of glycogen synthase.”

In the paper

“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.”

What the sources say

• Not checked yetcites [192] Bonadonna RC Del Prato S Saccomani MP Transmembrane glucose transport in skeletal muscle of patients with non-insulin-dependent diabetes The Journal of Clinical Investigation 1993 92 1 486 494 8326013 PMC293636 source
• Not checked yetcites [193] Bonadonna RC Del Prato S Bonora E Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM Diabetes 1996 45 supplement 3 915 925 8666143 source

In the paper

“GLUT4, the insulin regulatable transporter, is found in skeletal muscle, has a Km of approximately 5 mmol/L, which is close to that of the plasma glucose concentration, and is associated with HK-II [173, 174].”

What the sources say

• Not checked yetcites [173] Yu C Chen Y Cline GW Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle The Journal of Biological Chemistry 2002 277 52 50230 50236 12006582 source
• Not checked yetcites [174] Schmitz-Peiffer C Browne CL Oakes ND Alterations in the expression and cellular localization of protein kinase C isozymes ε and θ are associated with insulin resistance in skeletal muscle of the high-fat-fed rat Diabetes 1997 46 2 169 178 9000691 source

In the paper

“The impairment in glycogen synthase activation is likely due to a defect in the ability of insulin to phosphorylate IRS-1, causing a reduced association of the p85 subunit of PI 3-kinase with IRS-1 and decreased activation of the enzyme PI3K.”

In the paper

“Glycogen synthase mRNA and protein levels, however, are decreased in muscle of type 2 diabetic patients, partly explaining the decreased glycogen synthase activity [221, 222].”

What the sources say

• Not checked yetcites [221] Vestergaard H Lund S Larsen FS Bjerrum OJ Pedersen O Glycogen synthase and phosphofructokinase protein and mRNA levels in skeletal muscle from insulin-resistant patients with non-insulin-dependent diabetes mellitus The Journal of Clinical Investigation 1993 91 6 2342 2350 8514849 PMC443291 source
• Not checked yetcites [222] Vestergaard H Bjorbaek C Andersen PH Bak JF Pedersen O Impaired expression of glycogen synthase mRNA in skeletal muscle of NIDDM patients Diabetes 1991 40 12 1740 1745 1756915 source

In the paper

“Several silent nucleotide substitutions were found in the PP1 and ISPK-1 genes in the Danish population”

What the sources say

• Not checked yetcites [226] Bjørbæk C Vik TA Echwald SM Cloning of a human insulin-stimulated protein kinase (ISPK-1) gene and analysis of coding regions and mRNA levels of the ISPK-1 and the protein phosphatase-1 genes in muscle from NIDDM patients Diabetes 1995 44 1 90 97 7813820 source
• Not checked yetcites [227] Prochazka M Mochizuki H Baier LJ Cohen PTW Bogardus C Molecular and linkage analysis of type-1 protein phosphatase catalytic beta-subunit gene: lack of evidence for its major role in insulin a resistance in Pima Indians Diabetologia 1995 38 4 461 466 7796987 source

In the paper

“Insulin has no effect on muscle PFK activity, mRNA levels, or protein content in either nondiabetic or diabetic individuals [221].”

What the sources say

• Not checked yetcites [221] Vestergaard H Lund S Larsen FS Bjerrum OJ Pedersen O Glycogen synthase and phosphofructokinase protein and mRNA levels in skeletal muscle from insulin-resistant patients with non-insulin-dependent diabetes mellitus The Journal of Clinical Investigation 1993 91 6 2342 2350 8514849 PMC443291 source

In the paper

“Under basal conditions, total glycogen synthase activity in type 2 diabetic subjects is reduced, and the ability of insulin to activate glycogen synthase is severely impaired [7, 215–217].”

What the sources say

• Not checked yetcites [7] Cusi K Maezono K Osman A Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle The Journal of Clinical Investigation 2000 105 3 311 320 10675357 PMC377440 source
• Not checked yetcites [215] Damsbo P Vaag A Hother-Nielsen O Beck-Nielsen H Reduced glycogen synthase activity in skeletal muscle from obese patients with and without type 2 (non-insulin-dependent) diabetes mellitus Diabetologia 1991 34 4 239 245 1906024 source
• Not checked yetcites [216] Mandarino LJ Wright KS Verity LS Effects of insulin infusion on human skeletal muscle pyruvate dehydrogenase, phosphofructokinase, and glycogen synthase: evidence for their role in oxidative and nonoxidative glucose metabolism The Journal of Clinical Investigation 1987 80 3 655 663 2957389 PMC442287 source
• Not checked yetcites [217] Thorburn AW Gumbiner B Bulacan F Wallace P Henry RR Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake The Journal of Clinical Investigation 1990 85 2 522 529 2105341 PMC296454 source