phosphocreatine and Insulin-Resistance

Low birth weight (LBW) is associated with an increased risk of insulin resistance and downregulation of oxidative phosphorylation (OXPHOS) genes when exposed to a metabolic challenge of high-fat overfeeding (HFO). To elaborate further on the differential effects of HFO in LBW subjects, we measured in vivo mitochondrial function, insulin secretion, hepatic glucose production, and plasma levels of key regulatory hormones before and after 5 days of HFO in 20 young LBW and 26 normal-birth-weight (NBW) men. The LBW subjects developed peripheral insulin resistance after HFO due to impaired endogenous glucose storage (9.42 ± 4.19 vs. 5.91 ± 4.42 mg·kg FFM(-1)·min(-1), P = 0.01). Resting muscle phosphorcreatine and total ATP in muscle increased significantly after HFO in LBW subjects only, whereas additional measurements of mitochondrial function remained unaffected. Despite similar plasma FFA levels, LBW subjects displayed increased fat oxidation during insulin infusion compared with normal-birth-weight (NBW) subjects after HFO (0.37 ± 0.35 vs. 0.17 ± 0.33 mg·kg FFM(-1)·min(-1), P = 0.02). In contrast to NBW subjects, the plasma leptin levels of LBW subjects did not increase, and the plasma gastric inhibitory polypeptide (GIP) as well as pancreatic polypeptide (PP) levels increased less in LBW compared with NBW subjects during HFO. In conclusion, HFO unmasks dissociation between insulin resistance and mitochondrial dysfunction in LBW subjects, suggesting that insulin resistance may be a cause, rather than an effect, of impaired muscle OXPHOS gene expression and mitochondrial dysfunction. Reduced increments in response to HFO of fasting plasma leptin, PP, and GIP levels may contribute to insulin resistance, lower satiety, and impaired insulin secretion in LBW subjects.

Topics: Adenosine Triphosphate; Adipokines; Adult; Cross-Over Studies; Denmark; Diabetes Mellitus, Type 2; Dietary Fats; Gastric Inhibitory Polypeptide; Glucose; Humans; Infant, Low Birth Weight; Infant, Newborn; Insulin Resistance; Leptin; Lipid Metabolism; Male; Mitochondria, Muscle; Muscle, Skeletal; Pancreatic Polypeptide; Phosphocreatine; Protein Precursors; Registries; Young Adult

Recent studies identified the rs9939609 A-allele of the FTO (fat mass and obesity associated) gene as being associated with obesity and type 2 diabetes. We studied the role of the A-allele in the regulation of peripheral organ functions involved in the pathogenesis of obesity and type 2 diabetes.. Forty-six young men underwent a hyperinsulinemic euglycemic clamp with excision of skeletal muscle biopsies, an iv glucose tolerance test, 31phosphorous magnetic resonance spectroscopy, and 24-h whole body metabolism was measured in a respiratory chamber.. The FTO rs9939609 A-allele was associated with elevated fasting blood glucose and plasma insulin, hepatic insulin resistance, and shorter recovery half-times of phosphocreatine and inorganic phosphate after exercise in a primarily type I muscle. These relationships--except for fasting insulin--remained significant after correction for body fat percentage. The risk allele was not associated with fat distribution, peripheral insulin sensitivity, insulin secretion, 24-h energy expenditure, or glucose and fat oxidation. The FTO genotype did not influence the mRNA expression of FTO or a set of key nuclear or mitochondrially encoded genes in skeletal muscle during rest.. Increased energy efficiency--and potentially increased mitochondrial coupling--as suggested by faster recovery rates of phosphocreatine and inorganic phosphate in oxidative muscle fibers may contribute to the increased risk of obesity and type 2 diabetes in homozygous carriers of the FTO A-risk allele. Hepatic insulin resistance may represent the key metabolic defect responsible for mild elevations of fasting blood glucose associated with the FTO phenotype.

Topics: Adult; Alleles; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Blood Glucose; Energy Metabolism; Homozygote; Humans; Insulin; Insulin Resistance; Isometric Contraction; Liver; Male; Mitochondria, Muscle; Muscle, Skeletal; Oxidative Phosphorylation; Phosphates; Phosphocreatine; Polymorphism, Single Nucleotide; Proteins; Up-Regulation; Young Adult

A high-fat, high-calorie diet is associated with obesity and type 2 diabetes. However, the relative contribution of metabolic defects to the development of hyperglycaemia and type 2 diabetes is controversial. Accumulation of excess fat in muscle and adipose tissue in insulin resistance and type 2 diabetes may be linked with defective mitochondrial oxidative phosphorylation. The aim of the current study was to investigate acute effects of short-term fat overfeeding on glucose and insulin metabolism in young men. We studied the effects of 5 days' high-fat (60% energy) overfeeding (+50%) versus a control diet on hepatic and peripheral insulin action by a hyperinsulinaemic euglycaemic clamp, muscle mitochondrial function by (31)P magnetic resonance spectroscopy, and gene expression by qrt-PCR and microarray in 26 young men. Hepatic glucose production and fasting glucose levels increased significantly in response to overfeeding. However, peripheral insulin action, muscle mitochondrial function, and general and specific oxidative phosphorylation gene expression were unaffected by high-fat feeding. Insulin secretion increased appropriately to compensate for hepatic, and not for peripheral, insulin resistance. High-fat feeding increased fasting levels of plasma adiponectin, leptin and gastric inhibitory peptide (GIP). High-fat overfeeding increases fasting glucose levels due to increased hepatic glucose production. The increased insulin secretion may compensate for hepatic insulin resistance possibly mediated by elevated GIP secretion. Increased insulin secretion precedes the development of peripheral insulin resistance, mitochondrial dysfunction and obesity in response to overfeeding, suggesting a role for insulin per se as well GIP, in the development of peripheral insulin resistance and obesity.

Topics: Adipokines; Administration, Oral; Adult; Blood Glucose; Body Composition; Body Weight; C-Peptide; Cross-Over Studies; Dietary Fats; Gastric Inhibitory Polypeptide; Gene Expression; Glucose; Glucose Clamp Technique; Glycolysis; Heat-Shock Proteins; Humans; Insulin; Insulin Resistance; Lipids; Liver; Male; Muscle, Skeletal; Oxidative Phosphorylation; Pancreatic Polypeptide; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphates; Phosphocreatine; Transcription Factors

Cardiac disease is the leading cause of mortality in type 2 diabetes mellitus (T2DM). Pioglitazone has been associated with improved cardiac outcome but also with an elevated risk of heart failure. We determined the effects of pioglitazone on myocardial function in relation to cardiac high-energy phosphate, glucose, and fatty acid metabolism and triglyceride content in T2DM patients.. Seventy-eight T2DM men without structural heart disease or inducible ischemia as assessed by dobutamine stress echocardiography were assigned to pioglitazone (30 mg/d) or metformin (2000 mg/d) and matching placebo for 24 weeks. The primary end point was change in cardiac diastolic function from baseline relative to myocardial metabolic changes, measured by magnetic resonance imaging, proton and phosphorus magnetic resonance spectroscopy, and [(18)F]-2-fluoro-2-deoxy-D-glucose and [(11)C]palmitate positron emission tomography. No patient developed heart failure. Both therapies similarly improved glycemic control, whole-body insulin sensitivity, and blood pressure. Pioglitazone versus metformin improved the early peak flow rate (P=0.047) and left ventricular compliance. Pioglitazone versus metformin increased myocardial glucose uptake (P<0.001), but pioglitazone-related diastolic improvement was not associated with changes in myocardial substrate metabolism. Metformin did not affect myocardial function but decreased cardiac work relative to pioglitazone (P=0.006), a change that was paralleled by a reduced myocardial glucose uptake and fatty acid oxidation. Neither treatment affected cardiac high-energy phosphate metabolism or triglyceride content. Only pioglitazone reduced hepatic triglyceride content (P<0.001).. In T2DM patients, pioglitazone was associated with improvement in some measures of left ventricular diastolic function, myocardial glucose uptake, and whole-body insulin sensitivity. The functional changes, however, were not associated with myocardial substrate and high-energy phosphate metabolism.

Topics: Adenosine Triphosphate; Aged; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fatty Acids; Glycated Hemoglobin; Heart; Humans; Hypoglycemic Agents; Insulin Resistance; Liver; Male; Metabolic Syndrome; Metformin; Middle Aged; Myocardium; Phosphocreatine; Pioglitazone; PPAR alpha; Radionuclide Imaging; Stroke Volume; Sulfonylurea Compounds; Thiazolidinediones; Triglycerides; Ventricular Dysfunction, Left; Ventricular Remodeling

Mitochondrial dysfunction may contribute to the development of insulin resistance and type 2 diabetes. Nucleoside reverse transcriptase inhibitors (NRTIs), specifically stavudine, are known to alter mitochondrial function in human immunodeficiency virus (HIV)-infected individuals, but the effects of stavudine on glucose disposal and mitochondrial function in muscle have not been prospectively evaluated. In this study, we investigated short-term stavudine administration among healthy control subjects to determine effects on insulin sensitivity. A secondary aim was to determine the effects of stavudine on mitochondrial DNA (mtDNA) and function. Sixteen participants without personal or family history of diabetes were enrolled. Subjects were randomized to receive stavudine, 30-40 mg, twice a day, or placebo for 1 mo. Insulin sensitivity determined by glucose infusion rate during the hyperinsulinemic euglycemic clamp was significantly reduced after 1-mo exposure in the stavudine-treated subjects compared with placebo (-0.8 +/- 0.5 vs. +0.7 +/- 0.3 mg.kg(-1).min(-1), P = 0.04, stavudine vs. placebo). In addition, muscle biopsy specimens in the stavudine-treated group showed significant reduction in mtDNA/nuclear DNA (-52%, P = 0.005), with no change in placebo-treated subjects (+8%, P = 0.9). (31)P magnetic resonance spectroscopy (MRS) studies of mitochondrial function correlated with insulin sensitivity measures (r2 = 0.5, P = 0.008). These findings demonstrate that stavudine administration has potent effects on insulin sensitivity among healthy subjects. Further studies are necessary to determine whether changes in mtDNA resulting from stavudine contribute to effects on insulin sensitivity.

Topics: Adult; Body Composition; DNA, Mitochondrial; Female; Glucose; Glucose Clamp Technique; Humans; Insulin Resistance; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria, Muscle; Muscle, Skeletal; Phosphocreatine; Phosphorus; Protons; Reverse Transcriptase Inhibitors; Stavudine

Plasma concentrations of amino acids are frequently elevated in insulin-resistant states, and a protein-enriched diet can impair glucose metabolism. This study examined effects of short-term plasma amino acid (AA) elevation on whole-body glucose disposal and cellular insulin action in skeletal muscle. Seven healthy men were studied for 5.5 h during euglycemic (5.5 mmol/l), hyperinsulinemic (430 pmol/l), fasting glucagon (65 ng/l), and growth hormone (0.4 microg/l) somatostatin clamp tests in the presence of low (approximately 1.6 mmol/l) and increased (approximately 4.6 mmol/l) plasma AA concentrations. Glucose turnover was measured with D-[6,6-(2)H(2)]glucose. Intramuscular concentrations of glycogen and glucose-6-phosphate (G6P) were monitored using (13)C and (31)P nuclear magnetic resonance spectroscopy, respectively. A approximately 2.1-fold elevation of plasma AAs reduced whole-body glucose disposal by 25% (P < 0.01). Rates of muscle glycogen synthesis decreased by 64% (180--315 min, 24 plus minus 3; control, 67 plus minus 10 micromol center dot l(-1) center dot min(-1); P < 0.01), which was accompanied by a reduction in G6P starting at 130 min (DeltaG6P(260--300 min), 18 plus minus 19; control, 103 plus minus 33 micromol/l; P < 0.05). In conclusion, plasma amino acid elevation induces skeletal muscle insulin resistance in humans by inhibition of glucose transport/phosphorylation, resulting in marked reduction of glycogen synthesis.

Topics: Adenosine Diphosphate; Adult; Amino Acids; Blood Glucose; Deuterium; Epinephrine; Fasting; Glucagon; Glucose Clamp Technique; Glucose-6-Phosphate; Glycogen; Human Growth Hormone; Humans; Hydrocortisone; Hydrogen-Ion Concentration; Insulin; Insulin Resistance; Kinetics; Magnetic Resonance Spectroscopy; Male; Muscle, Skeletal; Phosphates; Phosphocreatine; Phosphorylation; Somatostatin

Klinefelter syndrome (XXY) occurs in 1 in 600 males, resulting in testosterone deficiency and a high prevalence of insulin resistance. Testosterone deficiency in men is a known cause of insulin resistance, and mitochondrial dysfunction is hypothesized to mediate this relationship. The aim of this cross-sectional study was to evaluate muscle mitochondrial function in XXY compared with male controls. Twenty-seven boys with XXY (age 14.7±1.8 years) were compared with 87 controls (age 16.9±0.9). In-vivo calf muscle mitochondrial function was assessed via phosphorus magnetic resonance spectroscopy (

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Adolescent; Case-Control Studies; Child; Cross-Sectional Studies; Humans; Insulin Resistance; Klinefelter Syndrome; Magnetic Resonance Spectroscopy; Male; Mitochondria; Mitochondria, Muscle; Muscle, Skeletal; Phosphocreatine; Testosterone

Whilst several studies have explored adolescent metabolic and cognitive function after preterm birth, few have explored muscle function and physical activity. We set out to examine the relationship between gestational age and muscle metabolism in a cohort of adolescents who were born preterm. Participants were recruited from the Newcastle preterm birth growth study cohort. They did not have severe neurological disease and were not on daily medication. Participants underwent an assessment of oxidative muscle function using phosphorus magnetic resonance spectroscopy that included the half-time for recovery of equilibrium of phosphocreatine, τ½PCr. In addition, we measured key variables that might affect muscle function including physical activity levels determined by 3-day accelerometry, body composition using air displacement plethysmography, insulin sensitivity using the homeostatic model assessment/Matsuda index and serum vitamin D concentrations. 60 adolescents (35F) median age 15.6 years (range 12.1−18.8) with a median gestation of 31 weeks (range 24 to 34 weeks) underwent a single assessment. Males were more active and spent less time in sedentary mode. Time spent in light activity was associated with insulin sensitivity (IS) (Matsuda Index; p < 0.05) but there were no strong correlations between activity levels and gestational age. Greater fat mass, waist circumference and body mass index were all associated with lower IS. Gestational age was negatively associated with adjusted measures of oxidative muscle function (τ½PCr). In a stepwise multivariate linear regression model, gestational age at birth was the most significant predictor of oxidative muscle function (p = 0.005). Higher serum vitamin D levels were also associated with faster phosphocreatine recovery time (p = 0.045). Oxidative function in the skeletal muscle of adolescents born preterm is associated with gestational age and vitamin D concentrations. Our study suggests that being born preterm may have a long-term impact on muscle metabolism.

Topics: Adolescent; Body Composition; Exercise; Female; Humans; Infant; Infant, Newborn; Insulin Resistance; Male; Muscles; Phosphocreatine; Premature Birth; Vitamin D; Vitamins

In older adults, type-2 diabetes mellitus (T2DM) impacts cognition and increases dementia risk. Prior studies suggest that impaired neuroplasticity may contribute to the cognitive decline in T2DM, but the underlying mechanisms of altered neuroplasticity are unclear. We investigated the relationship of the concentration of glutamatergic metabolites with measures of cortical plasticity in older adults across the spectrum of glucose intolerance/insulin resistance.. Forty adults (50-87 years: 17-T2DM, 14-pre-diabetes, 9-controls) underwent magnetic resonance spectroscopy to quantify glutamate and other key metabolites within a 2 cm. Group differences were observed in relative concentrations of glutamine (p = .028), glucose (p = .008), total cholines (p = .048), and the glutamine/glutamate ratio (p = .024). Cortical plasticity was reduced in both T2DM and pre-diabetes groups relative to controls (p-values < .05). Only the T2DM group showed a significant positive association between glutamate concentration and plasticity (r = .56, p = .030).. Neuroplastic mechanisms are already impaired in pre-diabetes. In T2DM, reduced cortico-motor plasticity is associated with lower cortical glutamate concentration.. Impaired plasticity in T2DM is associated with low glutamatergic metabolite levels. The glutamatergic neurotransmission system constitutes a potential therapeutic target for cognitive problems linked to plasticity-related deficiencies in T2DM.

Topics: Aged; Aged, 80 and over; Aging; Aspartic Acid; Creatine; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Intolerance; Glutamic Acid; Glutamine; Glutathione; Glycerylphosphorylcholine; Humans; Inositol; Insulin Resistance; Magnetic Resonance Spectroscopy; Male; Middle Aged; Motor Cortex; Neuronal Plasticity; Phosphocreatine; Phosphorylcholine; Prediabetic State; Theta Rhythm; Transcranial Magnetic Stimulation

Some individuals with type 2 diabetes do not reap metabolic benefits from exercise training, yet the underlying mechanisms of training response variation are largely unexplored. We classified individuals with type 2 diabetes (. PCr recovery rate as an indicator of in vivo muscle mitochondrial function in vastus lateralis (. By design, nonresponders decreased and responders increased PCr recovery rate with training. In nonresponders, insulin sensitivity did not improve and glycemic control (HbA. A training response variation for clinical risk factors in individuals with type 2 diabetes is reflected by distinct basal myocellular epigenomic profiles in muscle tissue, some of which are maintained in HSkMCs, suggesting a cell-autonomous underpinning. Our data provide new evidence to potentially shift the diabetes treatment paradigm for individuals who do not benefit from training, such that supplemental treatment can be designed.

Topics: Biopsy; Blood Glucose; Diabetes Mellitus, Type 2; Epigenomics; Exercise; Female; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Mitochondria, Muscle; Muscle, Skeletal; Phosphocreatine; Recovery of Function; Time Factors

Diabetes mellitus (DM) associated liver damage is a major health burden. Hepatocellular-damage in DM characterized with elevated endoplasmic reticulum stress (ER) and may enhanced insulin-resistance. Phosphocreatine (PCr) a rapidly high-energy-reserve molecule of phosphates naturally occurs in liver, brain and skeletal muscle. This study aimed to investigate the protective effect of PCr on the liver-injury-associated with DM and to report the mechanism involved. Wistar rat's diabetes model was induced using streptozotocin (STZ), and the animals were treated with 20 mg/kg, or 50 mg/kg PCr injection. Blood glucose level, and body wt were recorded. Liver tissues homogenate were analyzed for liver damage markers alanine transaminase (ALT), aspartate transaminase (AST). Liver tissues proteins further evaluated for apoptosis, endoplasmic reticulum stress (ER), and insulin resistance biomarkers using western blotting. Our results revealed that PCr reduced blood glucose level, improved body wt, ameliorates liver function enzymes. Furthermore, PCr upregulates anti-apoptotic Bcl2 proteins expression, and down-regulates significantly pro-apoptotic casp3 and Bax proteins expression in vivo and invitro. Moreover, ER stress CHOP, GRP78 and ATF4 biomarkers level were significantly attenuated in PCr treated animals comparing to STZ diabetes associated liver-damage model with significant improving in insulin-resistance Akt and IRS-1. Our results revealed that treating with PCr in diabetes-associated liver injury models decreased blood glucose level and possess protective effect in-vitro and in-vivo, which could be suggested as potential therapeutic strategy for diabetes associated liver injury patients.

Topics: Animals; Apoptosis; Biomarkers, Tumor; Blood Glucose; Body Weight; Carcinoma, Hepatocellular; Cell Shape; Cell Survival; Diabetes Mellitus, Experimental; Disease Models, Animal; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Hep G2 Cells; Humans; Insulin Resistance; Liver; Liver Neoplasms; Metabolome; Oxidative Stress; Phosphocreatine; Protective Agents; Rats, Wistar; Signal Transduction; Streptozocin

Obesity is associated with cardiometabolic disturbances, which may have significant implications for musculoskeletal health and exercise tolerance.. We sought to determine the association between muscle structure, function, and metabolism in adolescents across the weight spectrum.. This cross-sectional case-control study included overweight and obese participants (n = 24) 8-18 years of age with a body mass index (BMI) ≥ 85th percentile for age and gender, and non-obese participants (n = 24) with a BMI < 85. A slower phosphocreatine recovery following aerobic exercise is strongly associated with increasing adiposity. A slower metabolic recovery following aerobic exercise stress suggests that endurance exercise training in obese adolescents may be an optimal strategy to target exercise intolerance in this cohort.

Topics: Adiposity; Adolescent; Body Composition; Case-Control Studies; Child; Cross-Sectional Studies; Exercise; Female; Humans; Insulin Resistance; Magnetic Resonance Spectroscopy; Male; Muscle, Skeletal; Overweight; Pediatric Obesity; Phosphocreatine; Triglycerides

Insulin resistance, altered lipid metabolism and mitochondrial dysfunction in skeletal muscle would play a major role in type 2 diabetes mellitus (T2DM) development, but the causal relationships between these events remain conflicting. To clarify this issue, gastrocnemius muscle function and energetics were investigated throughout a multidisciplinary approach combining in vivo and in vitro measurements in Goto-Kakizaki (GK) rats, a non-obese T2DM model developing peripheral insulin resistant without abnormal level of plasma non-esterified fatty acids (NEFA). Wistar rats were used as controls. Mechanical performance and energy metabolism were assessed strictly non-invasively using magnetic resonance (MR) imaging and 31-phosphorus MR spectroscopy (31P-MRS). Compared with control group, plasma insulin and glucose were respectively lower and higher in GK rats, but plasma NEFA level was normal. In resting GK muscle, phosphocreatine content was reduced whereas glucose content and intracellular pH were both higher. However, there were not differences between both groups for basal oxidative ATP synthesis rate, citrate synthase activity, and intramyocellular contents for lipids, glycogen, ATP and ADP (an important in vivo mitochondrial regulator). During a standardized fatiguing protocol (6 min of maximal repeated isometric contractions electrically induced at a frequency of 1.7 Hz), mechanical performance and glycolytic ATP production rate were reduced in diabetic animals whereas oxidative ATP production rate, maximal mitochondrial capacity and ATP cost of contraction were not changed. These findings provide in vivo evidence that insulin resistance is not caused by an impairment of mitochondrial function in this diabetic model.

Topics: Adenosine Triphosphate; Animals; Diabetes Mellitus, Experimental; Electric Stimulation; Energy Metabolism; Hydrogen-Ion Concentration; Insulin Resistance; Magnetic Resonance Imaging; Male; Mitochondria; Muscle Contraction; Muscle, Skeletal; Phosphocreatine; Rats; Rats, Wistar; Time Factors

Cardiac hypertrophy is accompanied by significant alterations in energy metabolism. Whether these changes in energy metabolism precede and contribute to the development of heart failure in the hypertrophied heart is not clear.. Mice were subjected to cardiac hypertrophy secondary to pressure-overload as a result of an abdominal aortic constriction (AAC). The rates of energy substrate metabolism were assessed in isolated working hearts obtained 1, 2, and 3 weeks after AAC. Mice subjected to AAC demonstrated a progressive development of cardiac hypertrophy. In vivo assessment of cardiac function (via echocardiography) demonstrated diastolic dysfunction by 2 weeks (20% increase in E/E'), and systolic dysfunction by 3 weeks (16% decrease in % ejection fraction). Marked cardiac insulin-resistance by 2 weeks post-AAC was evidenced by a significant decrease in insulin-stimulated rates of glycolysis and glucose oxidation, and plasma membrane translocation of glucose transporter 4. Overall ATP production rates were decreased at 2 and 3 weeks post-AAC (by 37% and 47%, respectively) because of a reduction in mitochondrial oxidation of glucose, lactate, and fatty acids that was not accompanied by an increase in myocardial glycolysis rates. Reduced mitochondrial complex V activity was evident at 3 weeks post-AAC, concomitant with a reduction in the ratio of phosphocreatine to ATP.. The development of cardiac insulin-resistance and decreased mitochondrial oxidative metabolism are early metabolic changes in the development of cardiac hypertrophy, which create an energy deficit that may contribute to the progression from hypertrophy to heart failure.

Topics: Adenosine Triphosphate; Animals; Aorta, Abdominal; Arterial Pressure; Blood Glucose; Cardiomegaly; Disease Models, Animal; Disease Progression; Energy Metabolism; Fatty Acids; Glucose Transporter Type 4; Glycolysis; Heart Failure, Systolic; Insulin; Insulin Resistance; Lactic Acid; Ligation; Male; Mice; Mice, Inbred C57BL; Mitochondria, Heart; Mitochondrial Proton-Translocating ATPases; Myocardium; Oxidation-Reduction; Phosphocreatine; Stroke Volume; Time Factors; Ventricular Function, Left; Ventricular Pressure

Lipid accumulation in skeletal muscle and the liver is strongly implicated in the development of insulin resistance and type 2 diabetes, but the mechanisms underpinning fat accrual in these sites remain incompletely understood. Accumulating evidence of muscle mitochondrial dysfunction in insulin-resistant states has fuelled the notion that primary defects in mitochondrial fat oxidation may be a contributory mechanism. The purpose of our study was to determine whether patients with congenital lipodystrophy, a disorder primarily affecting white adipose tissue, manifest impaired mitochondrial oxidative phosphorylation in skeletal muscle.. Mitochondrial oxidative phosphorylation was assessed in quadriceps muscle using 31P-magnetic resonance spectroscopy measurements of phosphocreatine recovery kinetics after a standardized exercise bout in nondiabetic patients with congenital lipodystrophy and in age-, gender-, body mass index-, and fitness-matched controls.. The phosphocreatine recovery rate constant (k) was significantly lower in patients with congenital lipodystrophy than in healthy controls (P<0.001). This substantial (∼35%) defect in mitochondrial oxidative phosphorylation was not associated with significant changes in basal or sleeping metabolic rates.. Muscle mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy, a paradigmatic example of primary adipose tissue dysfunction. This finding suggests that changes in mitochondrial oxidative phosphorylation in skeletal muscle could, at least in some circumstances, be a secondary consequence of adipose tissue failure. These data corroborate accumulating evidence that mitochondrial dysfunction can be a consequence of insulin-resistant states rather than a primary defect. Nevertheless, impaired mitochondrial fat oxidation is likely to accelerate ectopic fat accumulation and worsen insulin resistance.

Topics: Adult; Blood Glucose; Female; Humans; Insulin Resistance; Lipodystrophy, Congenital Generalized; Male; Mitochondria, Muscle; Oxidative Phosphorylation; Phosphocreatine; Quadriceps Muscle

Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes. It has thus been suggested that primary and/or genetic abnormalities in mitochondrial function may lead to accumulation of toxic lipid species in muscle and elsewhere, impairing insulin action on glucose metabolism. Alternatively, however, defects in insulin signaling may be primary events that result in mitochondrial dysfunction, or there may be a bidirectional relationship between these phenomena. To investigate this, we examined mitochondrial function in patients with genetic defects in insulin receptor (INSR) signaling. We found that phosphocreatine recovery after exercise, a measure of skeletal muscle mitochondrial function in vivo, was significantly slowed in patients with INSR mutations compared with that in healthy age-, fitness-, and BMI-matched controls. These findings suggest that defective insulin signaling may promote mitochondrial dysfunction. Furthermore, consistent with previous studies of mouse models of mitochondrial dysfunction, basal and sleeping metabolic rates were both significantly increased in genetically insulin-resistant patients, perhaps because mitochondrial dysfunction necessitates increased nutrient oxidation in order to maintain cellular energy levels.

Topics: Adiponectin; Adipose Tissue; Adult; Antigens, CD; Basal Metabolism; Case-Control Studies; Exercise Test; Fasting; Female; Glycated Hemoglobin; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Mitochondria, Muscle; Mutation, Missense; Oxygen Consumption; Phosphocreatine; Point Mutation; Protein Structure, Tertiary; Receptor, Insulin; Sedentary Behavior; Sleep

Periods of rapid growth require an increase in energy use and substrate formation. Mitochondrial function contributes to each of these and therefore may play a role in longitudinal growth.. Twenty-nine children and adolescents of ages 8-15 yr were enrolled in a comprehensive longitudinal assessment of glucose homeostasis and mitochondrial function. Fasting laboratory studies and an estimate of mitochondrial function (as assessed by the time to recovery of phosphocreatine (PCr) concentration after submaximal quadriceps extension/flexion exercise using (31)P magnetic resonance spectroscopy) were obtained at baseline and annually for 2 yr.. Data were complete for 23 subjects. Subjects were 11.3 ± 1.9 (sd) yr old at the beginning of the study; 61% were male. Average annualized growth velocity at 1 yr for boys was 7.1 ± 1.5 cm/yr and for girls 6.5 ± 1.7 cm/yr. More rapid recovery of PCr concentration, suggestive of greater skeletal muscle oxidative phosphorylation capacity at baseline, was associated with faster growth velocity in the subsequent year (r(2) = 0.29; P = 0.008). In multivariate modeling, baseline mitochondrial function remained significantly and independently associated with growth (R(2) for model = 0.51; P = 0.05 for effect of phosphocreatine recovery time constant), controlling for age, gender, Tanner stage, body mass index Z-score, and height Z-score.. We report a novel association between time to recovery of PCr concentration after submaximal exercise and faster annual linear growth in healthy children. Future studies are needed to determine the physiological mechanisms and clinical consequences of this observation.

Topics: Adenosine Triphosphate; Adolescent; Aging; Blood Glucose; Body Mass Index; Child; Cohort Studies; Energy Intake; Exercise; Female; Glucose Tolerance Test; Gonadal Steroid Hormones; Growth; Homeostasis; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mitochondria, Muscle; Muscle, Skeletal; Phosphocreatine; Puberty; Sex Characteristics

Prolonged elevation of plasma triglycerides and free fatty acids (FFA) reduces insulin-stimulated glucose disposal and myocellular flux through ATP synthase (fATPase). However, the early effects of lipids per se on fATPase are as yet unclear. Thus, this study examined glucose disposal and fATPase during 3 h of FFA elevation in the presence of low plasma insulinemia. Euglycemic pancreatic clamps with low-dose insulin supplementation (6 mU.m body surface area(-2).min(-1)) were performed in eight healthy men with (LIP) or without (CON) lipid infusion to measure whole body glucose disposal. (31)P/(1)H magnetic resonance spectroscopy of calf muscle was applied to quantify fATPase and concentrations of glucose 6-phosphate (G6P), inorganic phosphate (P(i)), phosphocreatine (PCr), ADP, pH, and IMCL before and during the clamps. Lipid infusion increased plasma FFA approximately twofold and decreased glucose disposal by approximately 50% (110-180 min: LIP 0.87 +/- 0.45 vs. CON 1.75 +/- 0.42 mg.kg(-1).min(-1), P = 0.002; means +/- SD). Intramyocellular G6P tended to rise only under control conditions, whereas PCr, ADP, pH, and IMCL remained unchanged from fasting in LIP and CON. Although P(i) concentrations increased by approximately 18%, fATPase remained unchanged from fasting during the clamps (LIP 10.2 +/- 2.2 vs. CON 10.5 +/- 2.6 micromol.g muscle(-1).min(-1), P = not significant). We conclude that 3 h of lipid elevation fail to affect ATP synthesis despite marked reduction of whole body glucose uptake. This suggests that lipid-induced insulin resistance results primarily from mechanisms decreasing glucose uptake rather than from direct interference of fatty acid metabolites with mitochondrial function.

Topics: Adenosine Diphosphate; Adenosine Triphosphatases; Adenosine Triphosphate; Adult; Cross-Over Studies; Fatty Acids, Nonesterified; Glucose; Glucose Clamp Technique; Glucosephosphate Dehydrogenase; Humans; Insulin Resistance; Magnetic Resonance Spectroscopy; Male; Muscle, Skeletal; Phosphates; Phosphocreatine; Random Allocation

Ageing of the human heart is characterised by morphological, functional and metabolic changes. Short-term interventions and cross-sectional studies in older individuals questioned the possibility that physical exercise may reverse these alterations. In this study we aimed to assess whether in middle-aged men involved in regular and long lasting physical activity these alterations were attenuated.. Left ventricular (LV) magnetic resonance imaging (MRI) and three-dimensional image selected in-vivo spectroscopy (3D-ISIS) (31)P magnetic resonance spectroscopy (MRS) were performed using a 1.5T scanner in 20 healthy, young and 25 healthy middle-aged non-obese men with a sedentary lifestyle (11 young and 14 middle-aged) or undergoing regular aerobic oxidative training (9 young and 11 middle-aged). Insulin sensitivity was estimated by the homeostatic model assessment 2 (HOMA-2) model.. Sedentary young and middle-aged men were not different with respect to LV morphological parameters and systolic function. The phosphocreatine/ATP (PCr/ATP) ratio (marker of high energy phosphates metabolism) and the LV E-peak filling rate/A-peak filling rate ratio (E/A ratio) were lower in sedentary middle-aged than physically active subjects. Parameters of LV systolic function and the PCr/ATP ratio were not different in the middle-aged compared with the young trained men; the E/A peak flow ratio was higher in the middle-aged trained men than in the middle-aged sedentary men. Within the entire population, the PCr/ATP ratio and the E/A peak flow ratio were associated with insulin sensitivity.. Trained middle-aged subjects showed a better pattern of LV energy metabolism and of diastolic function than their sedentary counterparts. At this age the exercise-related cardiac benefits were detectable when physical exercise was performed regularly and for a long period of time.

Topics: Adenosine Triphosphate; Adult; Aging; Anthropometry; Energy Metabolism; Exercise; Humans; Insulin Resistance; Life Style; Magnetic Resonance Imaging; Male; Middle Aged; Motor Activity; Myocardial Contraction; Phosphocreatine; Ventricular Function, Left; Young Adult

Obesity has become an epidemic in children, associated with an increase in insulin resistance and metabolic dysfunction. Mitochondrial function is known to be an important determinant of glucose metabolism in adults. However, little is known about the relationship between mitochondrial function and obesity, insulin resistance, energy expenditure, and pubertal development in children.. Seventy-four participants, 37 overweight (> or = 85th percentile body mass index for age and sex) and 37 normal-weight (< 85th percentile) without personal or family history of diabetes mellitus were enrolled. Subjects were evaluated with an oral glucose tolerance test, metabolic markers, resting energy expenditure, Tanner staging, and (31)P magnetic resonance spectroscopy of skeletal muscle for mitochondrial function.. Overweight and normal-weight children showed no difference in muscle ATP synthesis [phosphocreatine (PCr) recovery after exercise] (32.4 +/- 2.3 vs. 34.1 +/- 2.1, P = 0.58). However, insulin-resistant children had significantly prolonged PCr recovery when compared with insulin-sensitive children, by homeostasis model assessment for insulin resistance quartile (ANOVA, P = 0.04). Similarly, insulin-resistant overweight children had PCr recovery that was prolonged compared with insulin-sensitive overweight children (P = 0.01). PCr recovery was negatively correlated with resting energy expenditure in multivariate modeling (P = 0.03). Mitochondrial function worsened during mid-puberty in association with insulin resistance.. Reduced skeletal muscle mitochondrial oxidative phosphorylation, assessed by PCr recovery, is associated with insulin resistance and an altered metabolic phenotype in children. Normal mitochondrial function may be associated with a healthier metabolic phenotype in overweight children. Further studies are needed to investigate the long-term physiological consequences and potential treatment strategies targeting children with reduced mitochondrial function.

Topics: Adolescent; Body Weight; Calorimetry, Indirect; Child; Dyslipidemias; Energy Metabolism; Feeding Behavior; Female; Glycemic Index; Humans; Insulin; Insulin Resistance; Lipids; Magnetic Resonance Spectroscopy; Male; Mitochondria; Obesity; Overweight; Phenotype; Phosphocreatine; Puberty; Surveys and Questionnaires

Several lines of evidence support a potential role of skeletal muscle mitochondrial dysfunction in the pathogenesis of insulin resistance and/or type 2 diabetes. However, it remains to be established whether mitochondrial dysfunction represents either cause or consequence of the disease. We examined in vivo skeletal muscle mitochondrial function in early and advanced stages of type 2 diabetes, with the aim to gain insight in the proposed role of mitochondrial dysfunction in the aetiology of insulin resistance and/or type 2 diabetes.. Ten long-standing, insulin-treated type 2 diabetes patients, 11 subjects with impaired fasting glucose, impaired glucose tolerance and/or recently diagnosed type 2 diabetes, and 12 healthy, normoglycaemic controls, matched for age and body composition and with low habitual physical activity levels were studied. In vivo mitochondrial function of the vastus lateralis muscle was evaluated from post-exercise phosphocreatine (PCr) recovery kinetics using (31)P magnetic resonance spectroscopy (MRS). Intramyocellular lipid (IMCL) content was assessed in the same muscle using single-voxel (1)H MRS.. IMCL content tended to be higher in the type 2 diabetes patients when compared with normoglycaemic controls (P=0.06). The(31)P MRS parameters for mitochondrial function, i.e. PCr and ADP recovery time constants and maximum aerobic capacity, did not differ between groups.. The finding that in vivo skeletal muscle oxidative capacity does not differ between long-standing, insulin-treated type 2 diabetes patients, subjects with early stage type 2 diabetes and sedentary, normoglycaemic controls suggests that mitochondrial dysfunction does not necessarily represent either cause or consequence of insulin resistance and/or type 2 diabetes.

Topics: Adenosine Diphosphate; Blood Glucose; Diabetes Mellitus, Type 2; Glucose Intolerance; Humans; Insulin Resistance; Magnetic Resonance Spectroscopy; Middle Aged; Mitochondrial Diseases; Models, Biological; Muscle, Skeletal; Phosphocreatine; Phosphorus Isotopes; Prediabetic State; Severity of Illness Index

Mitochondrial dysfunction and increased intramyocellular lipid (IMCL) content have both been implicated in the development of insulin resistance and type 2 diabetes mellitus, but the relative contributions of these two factors in the aetiology of diabetes are unknown. As obesity is an independent determinant of IMCL content, we examined mitochondrial function and IMCL content in overweight type 2 diabetes patients and BMI-matched normoglycaemic controls.. In 12 overweight type 2 diabetes patients and nine controls with similar BMI (29.4 +/- 1 and 29.3 +/- 0.9 kg/m(2) respectively) in vivo mitochondrial function was determined by measuring phosphocreatine recovery half-time (PCr half-time) immediately after exercise, using phosphorus-31 magnetic resonance spectroscopy. IMCL content was determined by proton magnetic resonance spectroscopic imaging and insulin sensitivity was measured with a hyperinsulinaemic-euglycaemic clamp.. The PCr half-time was 45% longer in diabetic patients compared with controls (27.3 +/- 3.5 vs 18.7 +/- 0.9 s, p < 0.05), whereas IMCL content was similar (1.37 +/- 0.30 vs 1.25 +/- 0.22% of the water resonance), and insulin sensitivity was reduced in type 2 diabetes patients (26.0 +/- 2.2 vs 18.9 +/- 2.3 mumol min(-1) kg(-1), p < 0.05 [all mean +/- SEM]). PCr half-time correlated positively with fasting plasma glucose (r (2) = 0.42, p < 0.01) and HbA(1c) (r (2) = 0.48, p < 0.05) in diabetic patients.. The finding that in vivo mitochondrial function is decreased in type 2 diabetes patients compared with controls whereas IMCL content is similar suggests that low mitochondrial function is more strongly associated with insulin resistance and type 2 diabetes than a high IMCL content per se. Whether low mitochondrial function is a cause or consequence of the disease remains to be investigated.

Topics: Aged; Blood Glucose; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria, Muscle; Muscle, Skeletal; Obesity; Phosphocreatine; Phosphorus Isotopes

High prevalence (48%) of insulin resistance (IR) in patients with mild to moderate kidney function reduction, and the potential pathogenetic role of magnesium (Mg) deficiency in IR prompted us to study skeletal muscle free Mg (fMg) concentration in patients with impaired kidney function.. fMg concentration, intracellular pH (pHi) and parameters of energy balance were determined employing 31P NMR spectroscopy in the calf muscle of the dominant leg of 18 healthy controls (C) and 22 patients (P) with decreased kidney function. 10 patients suffered from insulin resistance (IR).. No difference in fMg concentration in skeletal muscle was observed (C: 0.929 +/- 0.075; P: 0.948 +/- 0.062 mmol/l; x +/- SEM). In patients a slight shift of pHi towards acidic values was found (C: 7.036 +/- 0.0.004; P: 7.013 +/- 0.004; p < 0.004), which was even more expressed in IR patients (7.008 +/- 0.005). Serum creatinine levels and creatinine clearance correlated with pHi in the patient's group. Adenosintriphosphate (ATP) to inorganic phosphate (Pi) ratio in skeletal muscle was lower, phosphocreatine (Pcr)/ATP ratio was higher, while that of Pcr/Pi showed only a trend towards an increase in the patient's group.. In patients with reduction of kidney function IR does not associate with a change in skeletal muscle free magnesium concentration, or deficiency in macroergic phosphate levels. Shift in intracellular pH towards acidic values may participate in IR. Decreased activity of Na+/H+ antiporter is suggested. (Fig. 5, Tab. 2, Ref. 22.)

Topics: Adenosine Triphosphate; Creatinine; Energy Metabolism; Female; Humans; Hydrogen-Ion Concentration; Insulin Resistance; Kidney Diseases; Magnesium; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle, Skeletal; Phosphates; Phosphocreatine

To examine the impact of insulin resistance on the insulin-dependent and insulin-independent portions of muscle glycogen synthesis during recovery from exercise, we studied eight young, lean, normoglycemic insulin-resistant (IR) offspring of individuals with non-insulin-dependent diabetes mellitus and eight age-weight matched control (CON) subjects after plantar flexion exercise that lowered muscle glycogen to approximately 25% of resting concentration. After approximately 20 min of exercise, intramuscular glucose 6-phosphate and glycogen were simultaneously monitored with 31P and 13C NMR spectroscopies. The postexercise rate of glycogen resynthesis was nonlinear. Glycogen synthesis rates during the initial insulin independent portion (0-1 hr of recovery) were similar in the two groups (IR, 15.5 +/- 1.3 mM/hr and CON, 15.8 +/- 1.7 mM/hr); however, over the next 4 hr, insulin-dependent glycogen synthesis was significantly reduced in the IR group [IR, 0.1 +/- 0.5 mM/hr and CON, 2.9 +/- 0.2 mM/hr; (P < or = 0.001)]. After exercise there was an initial rise in glucose 6-phosphate concentrations that returned to baseline after the first hour of recovery in both groups. In summary, we found that following muscle glycogen-depleting exercise, IR offspring of parents with non-insulin-dependent diabetes mellitus had (i) normal rates of muscle glycogen synthesis during the insulin-independent phase of recovery from exercise and (ii) severely diminished rates of muscle glycogen synthesis during the subsequent recovery period (2-5 hr), which has previously been shown to be insulin-dependent in normal CON subjects. These data provide evidence that exercise and insulin stimulate muscle glycogen synthesis in humans by different mechanisms and that in the IR subjects the early response to stimulation by exercise is normal.

Topics: Adult; Analysis of Variance; Blood Glucose; Diabetes Mellitus, Type 2; Epinephrine; Female; Glucagon; Glucose; Glucose-6-Phosphate; Glucosephosphates; Glycogen; Humans; Hydrogen-Ion Concentration; Infusions, Intravenous; Insulin; Insulin Resistance; Lactates; Magnetic Resonance Spectroscopy; Male; Muscle Contraction; Muscle, Skeletal; Nuclear Family; Phosphates; Phosphocreatine; Physical Exertion; Reference Values

Because skeletal muscle plays a major role in glucose disposal, it may be the primary site of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM). Rates of glycogen synthesis (GS), glucose utilization via glycolysis, glycolytic utilization (GU), and glucose transport (GT) were studied in epitrochlearis muscles (EMs) obtained from 10-wk-old nonfasted Sprague-Dawley rats in which NIDDM was neonatally induced with streptozocin. Plasma glucose in NIDDM rats was elevated (P less than 0.001), whereas plasma insulin was similar in NIDDM and control rats. No differences in muscle weight, protein, glycogen, ATP, phosphocreatine, lactate, lactate-pyruvate ratios, or glucose-6-phosphate were noted in EMs of control and NIDDM rats. EMs were incubated in medium containing 5.6 or 11.2 mM glucose with tracer D-[5-3H]glucose and insulin from 0 to 7.18 x 10(-7) M for 1 or 2 h, and GS, GT, and GU were evaluated. Similar rates of basal (non-insulin-mediated) and insulin-stimulated GS, GU, and GT were observed in EMs of NIDDM and control rats incubated in 5.6 mM glucose for 2 h. Insulin dose-response curves revealed similar sensitivities and responsiveness. Increasing glucose concentration (from 5.6 to 11.2 mM) induced significant increases in basal rates of GS, GU, and GT in EMs of control but not NIDDM rats. Insulin dose-response curves for GS and GT revealed decreased sensitivity and no change in responsiveness in EMs of control and NIDDM rats, even though GU of EMs of NIDDM rats was significantly lower at basal and all other insulin concentrations. These data revealed that both insulin resistance and glucose resistance contribute to the impaired glucose metabolism in EMs of the NIDDM rat.

Topics: Adenosine Triphosphate; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose; Glucosephosphates; Glycogen; Humerus; Insulin; Insulin Resistance; Lactates; Lactic Acid; Muscles; Organ Size; Phosphocreatine; Proteins; Pyruvates; Pyruvic Acid; Rats; Rats, Inbred Strains

Denervated (1-10 days) rat epitrochlearis muscles were isolated, and basal and insulin-stimulated protein and glucose metabolism were studied. Although basal rates of glycolysis and glucose transport were increased in 1-10-day-denervated muscles, basal glycogen-synthesis rates were unaltered and glycogen concentrations were decreased. Basal rates of protein degradation and synthesis were increased in 1-10-day-denervated muscles. The increase in degradation was greater than that in synthesis, resulting in muscle atrophy. Increased rates of proteolysis and glycolysis were accompanied by elevated release rates of leucine, alanine, glutamate, pyruvate and lactate from 3-10-day-denervated muscles. ATP and phosphocreatine were decreased in 3-10-day-denervated muscles. Insulin resistance of glycogen synthesis occurred in 1-10-day denervated muscles. Insulin-stimulated glycolysis and glucose transport were inhibited by day 3 of denervation, and recovered by day 10. Inhibition of insulin-stimulated protein synthesis was observed only in 3-day-denervated muscles, whereas regulation by insulin of net proteolysis was unaffected in 1-10-day-denervated muscles. Thus the results demonstrate enhanced glycolysis, proteolysis and protein synthesis, and decreased energy stores, in denervated muscle. They further suggest a defect in insulin's action on protein synthesis in denervated muscles as well as on glucose metabolism. However, the lack of concurrent changes in all insulin-sensitive pathways and the absence of insulin-resistance for proteolysis suggest multiple and specific cellular defects in insulin's action in denervated muscle.

Topics: Adenosine Triphosphate; Amino Acids; Animals; Female; Glucose; Glycogen; Glycolysis; In Vitro Techniques; Insulin Resistance; Muscle Denervation; Muscle Proteins; Muscles; Organ Size; Phosphocreatine; Rats; Rats, Inbred Strains