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A hyperglycemic clamp is an established method to assess insulin secretion and is generally used only for this purpose. To determine whether it could also be used to assess insulin sensitivity, we compared insulin sensitivity indices (ISI) obtained during euglycemic and hyperglycemic clamp experiments in 22 nonobese volunteers (body mass index, 23.9 +/- 0.6 kg/m2) and in 20 obese individuals (body mass index, 30.8 +/- 1.3 kg/m2) matched for age and gender. The ISI values (micromoles per kg.min/pmol) of the obese group assessed during hyperglycemic (0.088 +/- 0.011) and euglycemic (0.050 +/- 0.005) clamp experiments were both significantly lower than the ISI of the nonobese group assessed in hyperglycemic and euglycemic clamp experiments (0.179 +/- 0.024 and 0.096 +/- 0.009, respectively; both P less than 0.01). Although the ISI values obtained with hyperglycemic clamps were consistently greater than those obtained with euglycemic clamp (0.137 +/- 0.016 vs. 0.075 +/- 0.007; P less than 0.001), they were highly correlated (r = 0.84; P less than 0.0001). Moreover, when these indices were converted to clearance rates, thereby correcting for the mass action effects of glucose on glucose disposal, the values obtained with the hyperglycemic clamp (0.0137 +/- 0.0016 mL/kg.min/pmol) were statistically identical to those obtained with the euglycemic clamp (0.0142 +/- 0.0013 mL/kg.min/pmol), as indicated by a regression equation having an intercept of 0 and a slope (1.03) not different from 1. We, therefore, conclude that the hyperglycemic clamp and the euglycemic clamp yield comparable estimates of insulin sensitivity and that, under appropriate conditions, the hyperglycemic clamp technique may be used to assess both insulin sensitivity and insulin secretion in the same individual in a single experiment.

Made available in DSpace on 2022-04-28T18:56:02Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-05-01 To assess whether an increased genetic predisposition for type 2 diabetes mellitus (T2DM) influences the contributions of insulin resistance and impaired insulin secretion to impaired glucose tolerance (IGT), 437 subjects not known to have T2DM underwent an oral glucose tolerance test and a 3-hour hyperglycemic clamp. Plasma insulin responses and insulin sensitivity were compared between all subjects (unselected for demographic or anthropometric characteristics) who had normal glucose homeostasis and no first-degree T2DM relative (n = 133), IGT with a first-degree T2DM relative (IGT/FH+, n = 74), or IGT without a first-degree T2DM relative (IGT/FH-, n = 50). Compared with those with normal glucose homeostasis, first- and second-phase plasma insulin responses were reduced approximately 45% and 30%, respectively (both P < .001), in IGT/FH+, whereas insulin sensitivity was only approximately 20% reduced (P = .011). In contrast, in IGT/FH-, first-phase plasma insulin responses were only approximately 20% reduced (P = .016), second-phase plasma insulin responses were not reduced, but insulin sensitivity was approximately 40% reduced (P < .001). The IGT/FH+ group differed significantly from the IGT/FH- group by having 25% to 30% lower first-phase plasma insulin responses (P = .026) and 25% to 30% greater insulin sensitivity (P = .027). Adjustment for obesity abolished the differences in insulin resistance but not plasma insulin responses. However, when the IGT groups were stratified into subgroups based on body mass index (BMI), first-phase plasma insulin responses were approximately 30% lower in IGT/FH+ with a BMI of at least 27 kg/m2 (P = .018) but similar in IGT/FH+ with a BMI less than 27 kg/m2 compared with the corresponding IGT/FH- subgroups. We conclude that, in IGT, an increased genetic predisposition for T2DM increases the contribution of impaired insulin secretion to its pathophysiology. This effect is enhanced by obesity. Department of Endocrinology Carl T Hayden VA Medical Center, Phoenix, AZ 85012 Department of Internal Medicine University Medical Center Utrecht, Utrecht Department of Clinical Medicine Faculdade de Medicina Botucatu University of Sao Paulo State, Sao Paulo Department of Internal Medicine II Ludwig-Maximilians University, Munich Diabetes/Metabolism Unit Henry Dunant Foundation, Athens Department of Medicine University of Rochester School of Medicine, Rochester, NY 14642

BACKGROUND The mechanisms by which menopause may influence the systemic subclinical atherosclerosis are unexplained. The aim of this cross-sectional study was to evaluate the associations between early menopause, established cardiovascular (c-v) risk factors, metabolic parameters (insulin secretion and sensitivity, plasma adiponectin), and carotid intima-media thickness (IMT) in healthy women. METHODS In 74 menopausal women (mean age = 51 +/- 3 years, mean duration of menopause = 2.9 +/- 1.2 years) and in 74 nonmenopausal women comparable for age and body mass index (BMI), common carotid artery (CCA) luminal diameter, and IMT in different carotid segments were measured in digitized ultrasound images. Insulin sensitivity and secretion were assessed using the euglycemic hyperinsulinemic clamp technique and oral glucose tolerance test (OGTT). Insulin secretion was reconstructed by mathematical modeling. RESULTS CCA diameter (5.55 +/- 0.46 vs. 5.21 +/- 0.51 mm, P less than 0.001), CCA IMT (608 +/- 78 vs. 576 +/- 74 mu m, P less than 0.01) and systolic blood pressure (BP) 0 17 +/- 12 vs. 113 +/- 11 mm Hg, P less than 0.05) were higher in menopausal women, whereas CCA IMT/diameter ratio and IMT in other carotid segments did not differ between the groups. By multivariate models, independent predictors of CCA diameter were menopause and body weight (cumulative R-2 = 0.37) and independent correlates of CCA IMT were luminal diameter, systolic BP and low-density lipoprotein (LDL) cholesterol (cumulative R-2 = 0.48). Fasting insulin, insulin secretion, and sensitivity and plasma adiponectin were similar in the two groups and were not related to carotid IMT. CONCLUSIONS Early menopause is associated with CCA remodeling, characterized by a proportional increase in luminal diameter and wall thickness, independent of atherosclerotic risk factors and metabolic variables.

OBJECTIVE - To evaluate the time course of leptin, adiponectin, and resting energy expenditure (REE) responses in overweight elderly males after acute resistance exercise protocols of various intensity configurations. RESEARCH DESIGN AND METHODS - Forty inactive men (65-82 years) were randomly assigned to one of four groups (n = 10/group): control, low-intensity resistance exercise, moderate-intensity resistance exercise, and high-intensity resistance exercise. Exercise energy cost, REE, leptin, adiponectin, cortisol, insulin, lactate, glucose, nonesterified fatty acids (NEFAs), and glycerol were determined at baseline, immediately after exercise, and during a 72-h recovery period. RESULTS- Exercise energy cost was lower in high-intensity than in low-intensity and moderate-intensity groups (221.6 ± 8.8 vs. 295.6 ± 10.7 and 281.6 ± 9.8 kcal, P < 0.001). Lactate, glucose, NEFAs, and glycerol concentrations increased (P < 0.001) after exercise and returned to baseline thereafter in all groups. REE increased (P < 0.001) in all groups at 12 h in an intensity-dependent manner (P < 0.05). REE reached baseline after 48 h in the low- and moderate-intensity groups and after 72 h in the high-intensity group. Cortisol peaked in all active groups after exercise (P < 0.001) and remained elevated (P < 0.001) for 12 h. After adjustment for plasma volume shifts, leptin remained unaltered. Adiponectin concentration increased after 12 h and remained elevated for 24 h only in the high-intensity group (P < 0.001). CONCLUSIONS - Resistance exercise does not alter circulating leptin concentration but does increase REE and adiponectin in an intensity-dependent manner for as long as 48 and 24 h, respectively, in overweight elderly individuals. It appears that resistance exercise may represent an effective approach for weight management and metabolic control in overweight elderly individuals. © 2009 by the American Diabetes Association.

Background: The mechanisms by which menopause may influence the systemic subclinical atherosclerosis are unexplained. The aim of this cross-sectional study was to evaluate the associations between early menopause, established cardiovascular (c-v) risk factors, metabolic parameters (insulin secretion and sensitivity, plasma adiponectin), and carotid intima-media thickness (IMT) in healthy women. Methods: In 74 menopausal women (mean age = 51 ± 3 years, mean duration of menopause = 2.9 ± 1.2 years) and in 74 nonmenopausal women comparable for age and body mass index (BMI), common carotid artery (CCA) luminal diameter, and IMT in different carotid segments were measured in digitized ultrasound images. Insulin sensitivity and secretion were assessed using the euglycemic hyperinsulinemic clamp technique and oral glucose tolerance test (OGTT). Insulin secretion was reconstructed by mathematical modeling. Results: CCA diameter (5.55 ± 0.46 vs. 5.21± 0.51 mm, P < 0.001), CCA IMT (608 ± 78 vs. 576 ± 74 νm, P < 0.01) and systolic blood pressure (BP) (117 ± 12 vs. 113 ± 11 mm Hg, P < 0.05) were higher in menopausal women, whereas CCA IMT/diameter ratio and IMT in other carotid segments did not differ between the groups. By multivariate models, independent predictors of CCA diameter were menopause and body weight (cumulative R2= 0.37) and independent correlates of CCA IMT were luminal diameter, systolic BP and low-density lipoprotein (LDL) cholesterol (cumulative R2= 0.48). Fasting insulin, insulin secretion, and sensitivity and plasma adiponectin were similar in the two groups and were not related to carotid IMT. Conclusions: Early menopause is associated with CCA remodeling, characterized by a proportional increase in luminal diameter and wall thickness, independent of atherosclerotic risk factors and metabolic variables. © 2009 American Journal of Hypertension, Ltd.

Latencies of the brain-stem auditory evoked potentials were observed to increase in subjects whose plasma glucose levels were reduced. These changes appeared to be attributable to reduced body temperature, rather than direct effects of hypoglycemia on the auditory nerve or the brain-stem. The results suggest the need for caution in interpreting evoked potential measurements under hypoglycemia.

The present studies were undertaken to quantitate the relative contributions of the indirect and direct pathways for hepatic glycogen repletion and to determine the role of splanchnic tissues in provision of C precursors used for the indirect pathway. For this purpose, we administered oral glucose (1.4 g/kg) enriched with [1-14C]glucose to 18-h fasted dogs and measured net hepatic and net gastrointestinal glucose, lactate, and alanine balance, hepatic and gastrointestinal fractional extraction [( 3H]lactate), release and uptake of lactate, as well as the total amount of hepatic glycogen formed from the oral glucose and the 14C labeling pattern of the glycogen-glucose C. Although net hepatic glucose uptake (8.7 +/- 0.6 g, 27% of the oral load) exceeded the amount of glycogen formed from the oral glucose (6.3 +/- 1.1 g), analysis of radioactivity in C-1 of the glycogen glucose indicated that nearly 50% of the glycogen was formed by the indirect pathway. Net hepatic uptake of lactate (1.4 +/- 0.1 g) and alanine (1.5 +/- 0.1 g) could account for greater than 90% of glycogen formed by the indirect pathway if all of the lactate and alanine taken up by the liver had been incorporated into glycogen. Release of lactate and alanine by splanchnic tissues approximated the amount of lactate and alanine taken up by the liver. However, in addition to taking up lactate, the liver also produced nearly as much lactate as the gastrointestinal tract (1.8 +/- 0.2 vs. 2.0 +/- 0.3 g, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE - To investigate the effect of acute resistance exercise on adipose tissue tria- cylglycerol lipase activity (TGLA) in lean and obese men. RESEARCH DESIGN AND METHODS - Nine lean and eight obese men performed 30 min of circuit resistance exercise. Adipose tissue and blood were sampled during exercise for TGLA, metabolite, and hormone determinations. Respiratory exchange ratio (RER) was measured throughout exercise. RESULTS - Energy expenditure of exercise relative to body mass was higher in the lean and RER was higher in the obese men, suggesting lower fat oxidation. TGLA increased 18-fold at 5 min of exercise in the lean men and 16-fold at 10 min of exercise in the obese men. The delayed lipolytic activation in the obese men was reflected in erum nonesterified fatty acid and glycerol concentrations. Plasma insulin increased in the obese but did not change in the lean men. CONCLUSIONS - Resistance exercise upregulated adipose tissue lipolysis and enhanced energy expenditure in lean and obese men, with a delayed lipolytic activation in the obese men. © 2008 by the American Diabetes Association.

To assess the role of muscle and liver in the pathogenesis of postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM), we administered an oral glucose load enriched with [14C]glucose to 10 NIDDM subjects and 10 age- and weight-matched nondiabetic volunteers and compared muscle glucose disposal by measuring forearm balance of glucose, lactate, alanine, O2, and CO2 (with forearm calorimetry). In addition, we used the dual-lable isotope method to compare overall rates of glucose appearance (Ra) and disappearance (Rd), suppression of endogenous glucose output, and splanchnic glucose sequestration. During the initial 1-1.5 h after glucose ingestion, plasma glucose increased by approximately 8 mM in NIDDM vs. approximately 3 mM in nondiabetic subjects (P less than 0.01); overall glucose Ra was nearly 11 g greater in NIDDM than nondiabetic subjects (45.1 +/- 2.3 vs. 34.4 +/- 1.5 g, P less than 0.01), but glucose Rd was not significantly different in NIDDM (35.1 +/- 2.4 g) and nondiabetic (33.3 +/- 2.7 g) subjects. The greater overall glucose Ra of NIDDM subjects was due to 6.8 g greater endogenous glucose output (13.7 +/- 1.1 vs. 6.8 +/- 1.0 g, P less than 0.01) and 3.8 g less oral glucose splanchnic sequestration of the oral load (31.4 +/- 1.5 vs. 27.5 +/- 0.9 g, P less than 0.05). Although glucose taken up by muscle was not significantly different in NIDDM and nondiabetic subjects (39.3 +/- 3.5 vs. 41.0 +/- 2.5 g/5 h), a greater amount of the glucose taken up by muscle in NIDDM was released as lactate and alanine (11.7 +/- 1.0 vs. 5.2 +/- 0.3 g in nondiabetic subjects, P less than 0.01), and less was stored (11.7 +/- 1.3 vs. 16.9 +/- 1.5 g, P less than 0.05). We conclude that increased systemic glucose delivery, due primarily to reduced suppression of endogenous hepatic glucose output and, to a lesser extent, reduced splanchnic glucose sequestration, is the predominant factor responsible for postprandial hyperglycemia in NIDDM.

The reduced postabsorptive rates of systemic glucose clearance in non-insulin-dependent diabetes mellitus (NIDDM) are thought to be the consequence of insulin resistance in peripheral tissues. Although the peripheral tissues involved have not been identified, it is generally assumed to be primarily muscle, the major site of insulin-mediated glucose disposal. To test this hypothesis, we measured postabsorptive systemic and forearm glucose utilization and clearance in 15 volunteers with NIDDM and 15 age- and weightmatched nondiabetic volunteers. Although systemic glucose utilization was increased in NIDDM subjects (14.5 ± 0.5 vs. 11.2 ± 0.2 μmol · kg−1 · min−1, P < 0.001), systemic glucose clearance was reduced 1.40 ± 0.06 vs. 2.13 ± 0.05 ml · kg−1 · min−1, P < 0.01). Although forearm glucose utilization was increased in NIDDM subjects (0.663 ± 0.058 vs. 0.411 ± 0.019 μmol · dl−1 · min−1, P < 0.001), forearm glucose dl−1 clearance was reduced (0.628 ± 0.044 vs. 0.774 ± 0.037 ml · L−1 · min−1, P < 0.01). However, extrapolation of forearm data to total-body muscle indicated that impaired clearance reduced muscle glucose disposal by only 61 ± 21 μmol

To examine the effect of aging on insulin secretion (first- and second-phase insulin release) and insulin sensitivity in people with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT).First- and second-phase insulin secretion and insulin sensitivity were assessed in hyperglycemic clamp experiments in 266 individuals with NGT and 130 individuals with IGT, ranging in age from approximately 20 to approximately 70 years. Changes in beta-cell function were compared using the disposition index to adjust for differences in insulin sensitivity.As expected, both phases of insulin release and insulin sensitivity were reduced in individuals with IGT (all P0.01). Insulin sensitivity was not independently correlated with age in either group. In people with NGT, the disposition index for first- and second-phase insulin release decreased similarly at a rate of approximately 0.7% per year. In people with IGT, the disposition indexes for first- and second-phase insulin release decreased at greater rates ( approximately 2.2 and 1.4% per year, P = 0.002 and 0.009, respectively, vs. NGT), with the decrease in first phase being greater than that of second phase (P = 0.025).Insulin secretion (both first and second phase) normally decreases at a rate of approximately 0.7% per year with aging; this decrease in beta-cell function is accelerated about two-fold in people with impaired glucose tolerance-first phase to a greater extent than second phase. Finally, aging per se has no effect on insulin sensitivity independent of changes in body composition.

The metabolic syndrome is a cluster of cardiovascular risk factors that identifies individuals at a relatively high, long-term risk for atherosclerosis, cardiovascular disease, and type 2 diabetes. Insulin resistance and central obesity are the main risk conditions underlying the metabolic syndrome. As obesity rates increase worldwide especially in women, accompanying rising frequency of insulin resistance, dyslipidemia, diabetes, and hypertension contribute to increasing rates of cardiovascular morbidity and mortality. According to the latest NCEP/ATPIII definition of the metabolic syndrome almost 25% (from 6.7 up to 43.5% according to age) of the United States and European adult population appear to have the syndrome and in the recent years it has been more prevalent in men than in women. Prevalence is increasing and the increase seems to be steeper in women. The contribution of the different components of the syndrome differs between genders. Age, endocrine dysfunction (especially loss of ovarian estrogens) as well as genetic factors modify the response to underlying factors. Physical inactivity, which diminishes by age, is more prevalent in women than in men. Treatment goals are to prevent cardiovascular disease by both altering the risk factors that are components of the syndrome and more importantly applying lifestyle modifications with caloric restriction and exercise.

Overtraining syndrome is characterized by declining performance and transient inflammation following periods of severe training with major health implications for the athletes. Currently, there is no single diagnostic marker for overtraining. The present investigation examined the responses of oxidative stress biomarkers to a resistance training protocol of progressively increased and decreased volume/intensity. Twelve males (21.3+/-2.3 years) participated in a 12-week resistance training consisting of five 3-week periods (T1, 2 tones/week; T2, 8 tones/week; T3, 14 tones/week; T4, 2 tones/week), followed by a 3-week period of complete rest. Blood/urine samples were collected at baseline and 96 h following the last training session of each period. Performance (strength, power, jumping ability) increased after T2 and declined thereafter, indicating an overtraining response. Overtraining (T3) induced sustained leukocytosis, an increase of urinary isoprostanes (7-fold), TBARS (56%), protein carbonyls (73%), catalase (96%), glutathione peroxidase, and oxidized glutathione (GSSG) (25%) and a decline of reduced glutathione (GSH) (31%), GSH/GSSG (56%), and total antioxidant capacity. Isoprostanes and GSH/GSSG were highly (r=0.764-0.911) correlated with performance drop and training volume increase. In conclusion, overtraining induces a marked response of oxidative stress biomarkers which, in some cases, was proportional to training load, suggesting that they may serve as a tool for overtraining diagnosis.

Overtraining syndrome is characterized by declining performance and transient inflammation following periods of severe training with major health implications for the athletes. Currently, there is no single diagnostic marker for overtraining. The present investigation examined the responses of oxidative stress biomarkers to a resistance training protocol of progressively increased and decreased volume/intensity. Twelve males (21.3 +/- 2.3 years) participated in a 12-week resistance training consisting of five 3-week periods (T1, 2 tones/week; T2, 8 tones/week; T3, 14 tonesAveek: T4, 2 tonesAveek), followed by a 3-week period of complete rest. Blood/urine samples were collected at baseline and 96 h following the last training session of each period. Performance (strength, power, jumping ability) increased after T2 and declined thereafter, indicating an overtraining response. Overtraining (T3) induced sustained leukocytosis, an increase of urinary isoprostanes (7-fold), TBARS (56%), protein carbonyls (73%), catalase (96%), glutathione peroxidase, and oxidized glutathione (GSSG) (25%) and a decline of reduced glutathione (GSH) (31%), GSH/GSSG (56%), and total antioxidant capacity. lsoprostanes and GSH/GSSG were highly (r=0.764-0.911) correlated with performance drop and training Volume increase. In conclusion, overtraining induces a marked response of oxidative stress biomarkers, which, in some cases, was proportional to training load, Suggesting that they may serve as a tool for overtraining diagnosis. (c) 2007 Elsevier Inc. All rights reserved.

Aims/hypothesis: Hyperproinsulinaemia and relative hyperglucagonaemia are features of type 2 diabetes. We hypothesised that raised fasting glucagon and proinsulin concentrations may be associated with insulin resistance (IR) in non-diabetic individuals. Methods: We measured IR [by a euglycaemic- hyperinsulinaemic (240 pmol min-1 m-2) clamp technique] in 1,296 non-diabetic (on a 75 g OGTT) individuals [716 women and 579 men, mean age 44 years, BMI 26 kg/m2 (range 18-44 kg/m2)] recruited at 19 centres in 14 European countries. IR was related to fasting proinsulin or pancreatic glucagon concentrations in univariate and multivariate analyses. Given its known relationship to IR, serum adiponectin was used as a positive control. Results: In either sex, both glucagon and proinsulin were directly related to IR, while adiponectin was negatively associated with it (all p < 0.0001). In multivariate models, controlling for known determinants of insulin sensitivity (i.e. sex, age, BMI and glucose tolerance) as well as factors potentially affecting glucagon and proinsulin (i.e. fasting plasma glucose and C-peptide concentrations), glucagon and proinsulin were still positively associated, and adiponectin was negatively associated, with IR. Finally, when these associations were tested as the probability that individuals in the top IR quartile would have hormone levels in the top quartile of their distribution independently of covariates, the odds ratio was ∼2 for both glucagon (p = 0.05) and proinsulin (p = 0.02) and 0.36 for adiponectin (p < 0.0001). Conclusions/interpretation: Whole-body IR is independently associated with raised fasting plasma glucagon and proinsulin concentrations, possibly as a result of IR at the level of alpha cells and beta cells in pancreatic islets. © 2007 Springer-Verlag.

Background: Cell adhesion molecules are proteins expressed on the surface of a variety of cells and mediate the leucocyte response to inflammation. Some of these molecules are released to the plasma as soluble forms, whose presence indicates the degree of vascular endothelial activation or dysfunction. Increased concentrations of soluble adhesion molecules are thought to hamper the immune response and mediate the atherosclerotic inflammatory process. Studies on the effect of exercise on the concentrations of soluble adhesion molecules have almost exclusively used aerobic exercise. Aim: To assess the effect of resistance exercise on the serum concentrations of five cell adhesion molecules during and immediately after 30 min of exercise in lean and obese participants. Methods: Fourteen healthy young men (eight lean and six obese) performed 3 sets of 10 resistance exercises with 10-12 repetitions at 70-75% of one repetition maximum in a circuit training fashion. Venous blood samples were drawn at baseline and at the end of the first, second and third sets. The serum concentrations of vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, E-selectin, P-selectin and L-selectin were measured in a biochip array analyser. Results: No significant changes were observed in the concentrations of these cell adhesion molecules during exercise, or between lean and obese participants. Conclusion: Our data indicate that resistance exercise of moderate to high intensity does not affect the serum concentrations of cell adhesion molecules in healthy young lean or obese men, suggesting no considerable negative effect on immune function.

Cell adhesion molecules are proteins expressed on the surface of a variety of cells and mediate the leucocyte response to inflammation. Some of these molecules are released to the plasma as soluble forms, whose presence indicates the degree of vascular endothelial activation or dysfunction. Increased concentrations of soluble adhesion molecules are thought to hamper the immune response and mediate the atherosclerotic inflammatory process. Studies on the effect of exercise on the concentrations of soluble adhesion molecules have almost exclusively used aerobic exercise.To assess the effect of resistance exercise on the serum concentrations of five cell adhesion molecules during and immediately after 30 min of exercise in lean and obese participants.Fourteen healthy young men (eight lean and six obese) performed 3 sets of 10 resistance exercises with 10-12 repetitions at 70-75% of one repetition maximum in a circuit training fashion. Venous blood samples were drawn at baseline and at the end of the first, second and third sets. The serum concentrations of vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, E-selectin, P-selectin and L-selectin were measured in a biochip array analyser.No significant changes were observed in the concentrations of these cell adhesion molecules during exercise, or between lean and obese participants.Our data indicate that resistance exercise of moderate to high intensity does not affect the serum concentrations of cell adhesion molecules in healthy young lean or obese men, suggesting no considerable negative effect on immune function.

Made available in DSpace on 2022-04-28T18:55:17Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-08-07 OBJECTIVE - To compare the pathophysiology of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in a more comprehensive and standardized fashion than has hitherto been done. RESEARCH DESIGN AND METHODS - We studied 21 individuals with isolated IFG (IFG/normal glucose tolerance [NGT]), 61 individuals with isolated IGT (normal fasting glucose [NFG]/IGT), and 240 healthy control subjects (NFG/NGT) by hyperglycemic clamps to determine first- and second-phase insulin release and insulin sensitivity. Homeostasis model assessment (HOMA) indexes of β-cell function (HOMA-%B) and insulin resistance (HOMA-IR) were calculated from fasting plasma insulin and glucose concentrations. RESULTS - Compared with NFG/NGT, IFG/NGT had similar fasting insulin concentrations despite hyperglycemia; therefore, HOMA-IR was increased ∼30% (P < 0.05), but clampdetermined insulin sensitivity was normal (P > 0.8). HOMA-%B and first-phase insulin responses were reduced ∼35% (P < 0.002) and ∼30% (P < 0.02), respectively, but second-phase insulin responses were normal (P > 0.5). NFG/IGT had normal HOMA-IR but ∼15% decreased clamp-determined insulin sensitivity (P < 0.03). Furthermore, HOMA-%B was normal but both first-phase (P < 0.0003) and second-phase (P < 0.0001) insulin responses were reduced ∼30%. IFG/NGT differed from NFG/IGT by having ∼40% lower HOMA-%B (P < 0.012) and ∼50% greater second-phase insulin responses (P < 0.005). CONCLUSIONS - Since first-phase insulin responses were similarly reduced in IFG/NGT and NFG/IGT, we conclude that IFG is due to impaired basal insulin secretion and preferential resistance of glucose production to suppression by insulin, as reflected by fasting hyperglycemia despite normal plasma insulin concentrations and increased HOMA-IR, whereas IGT mainly results from reduced second-phase insulin release and peripheral insulin resistance, as reflected by reduced clamp-determined insulin sensitivity. © 2006 by the American Diabetes Association. Department of Endocrinology Carl T. Hayden VA Medical Center, Phoenix, AZ Department of Clinical Medicine Faculdade de Medicina Botucatu University of Sao Paulo State, Sao Paulo Department of Internal Medicine II Ludwig-Maximilians University of Munich, Munich Department of Internal Medicine University Medical Center Utrecht, Utrecht Department of Medicine University of Rochester School of Medicine, Rochester, NY Diabetes/Metabolism Unit Henry Dunant Foundation, Athens Carl T. Hayden VA Medical Center, 650 East Indian School Rd., Phoenix, AZ 85012

Background: Circulating free plasma DNA is implicated in conditions associated with tissue injury, including exercise-induced inflammation, and thus is a potential marker for athletic overtraining. Methods: We measured free plasma DNA along with C-reactive protein (CRP), creatine kinase (CK), and uric acid (UA) in 17 recreationally trained men participating in a 12-week resistance training regimen (8 resistance multi-joint exercises selected to stress the entire musculature: bench press, squat, leg press, snatch, hang clean, dead lifts, barbell arm curls, and rowing), consisting of 4 training periods (t1, t2, t3, and t4). Results: Plasma DNA concentrations increased markedly after t1, t2, and t3 and returned to baseline after t4. There were substantial differences between t2 and t1 and between t3 and t2 plasma DNA concentrations. CRP increased by 300% after t2 and by 400% after t3 (there was no difference between t2 and t3 CRP values) compared with baseline (t0). CK increased only after t3. UA increased after t2 and t3, with a greater increase after t3. Conclusions: This study demonstrates that, after chronic excessive resistance exercise, plasma DNA concentrations increase in proportion to training load, suggesting that plasma DNA may be a sensitive marker for overtraining-induced inflammation.

Background: Circulating free plasma DNA is implicated in conditions associated with tissue injury, including exercise-induced inflammation, and thus is a potential marker for athletic overtraining. Methods: We measured free plasma DNA along with C-reactive protein (CRP), creatine kinase (CK), and uric acid (UA) in 17 recreationally trained men participating in a 12-week resistance training regimen (8 resistance multi-joint exercises selected to stress the entire musculature: bench press, squat, leg press, snatch, hang clean, dead lifts, barbell arm curls, and rowing), consisting of 4 training periods (t1, t2, t3, and t4). Results: Plasma DNA concentrations increased markedly after t1, t2, and t3 and returned to baseline after t4. There were substantial differences between t2 and t1 and between t3 and t2 plasma DNA concentrations. CRP increased by 300% after t2 and by 400% after t3 (there was no difference between t2 and t3 CRP values) compared with baseline (t0). CK increased only after t3. UA increased after t2 and t3, with a greater increase after t3. Conclusions: This study demonstrates that, after chronic excessive resistance exercise, plasma DNA concentrations increase in proportion to training load, suggesting that plasma DNA may be a sensitive marker for overtraining-induced inflammation. (c) 2006 American Association for Clinical Chemistry.

Adiponectin and leptin are closely related to weight control and energy balance, whereas exercise affects elderly metabolic regulation and functional capacity.The objective of this study was to investigate leptin and adiponectin responses in elderly males after exercise training and detraining.The study design was a 1-yr randomized controlled trial.The study was performed at the Laboratory of Physical Education and Sport Science Department.Fifty inactive men [age, 65-78 yr; body mass index (BMI), 28.7-30.2 kg/m2] were recruited from a volunteer database by word of mouth and fliers sent to medical practitioners, physiotherapists, and nursing homes in the local community.Participants were randomly assigned to a control (n = 10), low-intensity (n = 14), moderate-intensity (n = 12), or high-intensity training (HI; n = 14) group. Resistance training (6 months, 3 d/wk, 10 exercises/three sets) was followed by 6 months of detraining.Strength, exercise energy cost, skinfold sum, body weight, maximal oxygen consumption, resting metabolic rate (RMR), and plasma leptin and adiponectin were determined at baseline and after training and detraining.Strength, maximal oxygen consumption, RMR, and exercise energy cost increased (P0.05) after training in an intensity-dependent manner. Skinfold sum and BMI were reduced by resistance training (P0.05), with HI being more effective (P0.05) than moderate-intensity/low-intensity training. Leptin was diminished (P0.05) by all treatments, whereas adiponectin increased (P0.05) only in HI. Detraining maintained training-induced changes only in HI. The percent leptin decrease was associated (P0.05) with the percent BMI decrease and the percent RMR increase, whereas the percent adiponectin increase was associated (P0.05) with the percent BMI decrease.Resistance training and detraining may alter leptin and adiponectin responses in an intensity-dependent manner. Leptin and adiponectin changes were strongly associated with RMR and anthropometric changes.

Aims In poorly controlled diabetes, increased renal glucose uptake has been implicated in the pathogenesis of diabetic nephropathy by promoting nonenzymatic glycosylation of proteins, activation of protein kinase C, and increased polyol pathway flux. However, whether glucose uptake by the diabetic kidney is actually increased, especially in patients with Type 1 diabetes, is unclear. Methods To examine this question, we used a combination of net balance and isotopic techniques to compare renal glucose uptake in 12 subjects with Type 1 diabetes before and after restoration of near normoglycaemia by infusion of insulin with that in 15 postabsorptive nondiabetic volunteers. Results Prior to insulin infusion, the diabetic subjects were markedly hyperglycaemic (arterial glucose 15.8 +/- 0.9 vs. 4.4 +/- 0.1 mM) and their renal tissue glucose uptake (i.e. total glucose disappearance across the kidney minus glycosuria) was increased more than 2(1)/(2)-fold (388 +/- 43 vs. 148 +/- 12 mu mol/min, P < 0.001). This was wholly explained by the mass action effects of hyperglycaemia since the diabetic subjects had normal renal blood flow (1575 +/- 82 vs. 1492 +/- 68 mL/min, P = 0.46) and reduced renal tissue glucose fractional extraction (1.7 +/- 0.2 vs. 2.3 +/- 0.1%, P = 0.027). Insulin infusion for three hours, which restored near normoglycaemia (arterial glucose 7.6 +/- 0.7 mM), reduced renal tissue glucose uptake toward normal (258 +/- 41 mu mol/min, P = 0.006) without altering renal blood flow (1557 +/- 110, P = 0.63) or renal tissue glucose fractional extraction (2.1 +/- 0.3%, P = 0.35). Renal and hepatic glucose release, which had been increased (419 +/- 49 and 960 +/- 54 vs. 204 +/- 9 and 734 +/- 32 mu mol/min, both P < 0.001), were suppressed by insulin to 138 +/- 22 and 520 +/- 53 mu mol/min, respectively (both P < 0.001). Conclusions In poorly controlled Type 1 diabetes, renal glucose uptake is markedly increased, which provides a link between hyperglycaemia and biochemical processes implicated in the pathogenesis of diabetic nephropathy. Its reversal by restoration of near normoglycaemia with insulin may explain the benefit of intensive insulin therapy in preventing diabetic nephropathy.

Made available in DSpace on 2022-04-28T18:55:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2004-08-09 Background: Increased fasting plasma glucose (FPG) and 2-hour postchallenge plasma glucose (PCPG) levels with normal hemoglobin A1c (HbA 1c) levels are recognized as risk factors for cardiovascular disease. We undertook this study to determine the relationships between FPG and 2-hour PCPG levels over the normal HbA1c range and to assess the need to control FPG and 2-hour PCPG levels to achieve HbA1c targets recommended by the American Diabetes Association (ADA), International Diabetes Federation (IDF), and American College of Endocrinology (ACE). Methods: The data of all healthy individuals with HbA1c values less than 7.0% (N=457) who underwent oral glucose tolerance tests between 1986 and 2002 for either screening as potential research volunteers (93%) or diagnostic purposes (7%) were analyzed. Results: Of 404 individuals with normal HbA1c levels (

In a cross-sectional study, we assessed β-cell function and insulin sensitivity index (ISI) with hyperglycemic clamps (10 mmol/l) in 24 subjects with impaired fasting glycemia (IFG, fasting plasma glucose [FPG] between 6.1 and 7.0 mmol/l), 15 type 2 diabetic subjects (FPG >7.0 mmol/l), and 280 subjects with normal fasting glycemia (NFG, FPG 11.1 mmol/l) had a lower ISI than their respective IGT counterparts (P < 0.05). We conclude that the early stages of glucose intolerance are associated with disturbances in β-cell function, while insulin resistance is seen more markedly in later stages.

To test the hypothesis that physiologic hyperinsulinemia activates the sympathetic nervous system in humans, we measured changes in plasma norepinephrine as well as epinephrine concentrations during euglycemic hyperinsulinemic clamp experiments in which normal volunteers were infused with insulin for up to 12 hours, at rates chosen to simulate the basal and postprandial hyperinsulinemia seen in insulin-resistant states. Infusions of insulin increased plasma insulin threefold (to approximately 200 pmol/L) and 15-fold (to approximately 1,000 pmol/L) in simulations of fasting and postprandial hyperinsulinemia. In neither experiment did plasma norepinephrine or epinephrine change significantly. In control experiments in which saline was infused for 12 hours, plasma epinephrine increased twofold (P less than .05), but plasma norepinephrine did not change. Therefore, we conclude that hyperinsulinemia of the magnitude seen in the insulin-resistant humans does not increase sympathetic nervous system activity.

We performed hyperglycemic clamps in 283 nondiabetic Caucasians and, with multiple linear regression, determined the contribution of beta-cell function and tissue insulin sensitivity to variations in glycemia and insulinemia during oral glucose tolerance tests (OGTTs). Impaired glucose tolerance (IGT) subjects had reduced insulin sensitivity(P < .02) and beta-cell function (P < .0001). Normal glucose tolerance (NGT) subjects with first-degree type 2 diabetic relatives had reduced first and second phase insulin secretion (both, P < .05), but normal insulin sensitivity(P = .37). beta-Cell function and insulin sensitivity accounted for one fourth of the variability in glucose tolerance. Fasting plasma glucose in subjects with NGT (n = 185) was a function of both phases of insulin secretion and of insulin sensitivity tall, P < .05), whereas, in IGT subjects (n = 98), it was a function of first phase insulin secretion and insulin sensitivity(P < .01). Two-hour glycemia was a function of second phase secretion and insulin sensitivity (P < .01). Fasting and 2-hour plasma insulin levels were determined by insulin sensitivity land glycemia) in NGT subjects (P < .001), but by second phase secretion in IGT (P < .001). We conclude that beta-cell function is reduced in subjects with IGT; glycemia and insulinemia are not regulated by the same mechanisms in IGT and NGT; insulin sensitivity does not contribute to insulinemia in IGT; family history of diabetes influences beta-cell function, but not insulin sensitivity in Caucasians. Copyright (C) 2000 by W.B. Saunders Company.

Recent studies using a combination of isotope and balance techniques have shown that, in the postabsorptive state, the human kidney contributes substantially to overall glucose production and consumption. The kidney may contribute as much as the liver to gluconeogenesis and play an important role in the counterregulation of hypoglycemia. Furthermore, increased renal glucose production may contribute to fasting hyperglycemia found in type I and type II diabetes mellitus. Finally, loss of renal tissue as a consumer of glucose could explain the insulin resistance of uremia. We hypothesize that the human kidney may play a more important role in human carbohydrate metabolism than previously appreciated.

Recent studies using a combination of isotope and balance techniques have shown that, in the postabsorptive state; the human kidney contributes substantially to overall glucose production and consumption. The kidney may contribute as much as the liver to gluconeogenesis and play an important role in the counterregulation of hypoglycemia. Furthermore, increased renal glucose production may contribute to fasting hyperglycemia found in type I and type II diabetes mellitus. Finally, loss of renal tissue as a consumer of glucose could explain the insulin resistance of uremia. We hypothesize that the human kidney may play a more important role in human carbohydrate metabolism than previously appreciated.

OBJECTIVE: The recent EURODIAB Study has identified autonomic neuropathy as an independent risk factor for severe hypoglycemia in patients with type 1 diabetes. We tested the hypothesis that counterregulatory catecholamine responses and awareness of hypoglycemia are impaired to a greater extent in type 1 diabetic patients with autonomic neuropathy (AN+) than in those without autonomic neuropathy (AN-). RESEARCH DESIGN AND METHODS: We studied 22 type 1 diabetic patients (8 AN+, 14 AN-) matched for age, duration of diabetes, glycemic control, and history of hypoglycemic episodes. We also studied 33 nondiabetic control subjects using the stepped hypoglycemic clamp technique and determined glycemic thresholds and magnitudes of counterregulatory hormone responses and of hypoglycemia symptoms. RESULTS: Both groups of diabetic patients had reduced awareness of hypoglycemia as evidenced by an elevated glycemic threshold for autonomic symptoms > or =2 SD above normal but neither the magnitude nor thresholds for symptoms differed in AN+ patients and AN-patients. Both groups also had impaired glucagon, epinephrine, norepinephrine, growth hormone and cortisol responses to hypoglycemia. However, in AN+ patients compared with AN-patients, magnitudes of epinephrine and norepinephrine responses (194+/-49 vs. 784+/-206 pmol/l, P < 0.007, and 316+/-56 vs. 610+/-87 pmol/l, P < 0.02, respectively) and epinephrine and norepinephrine glycemic thresholds (2.33+/- 0.10 vs. 2.82+/-0.10 mmol/l, P < 0.009 and 2.34+/-0.06 vs. 2.79+/-0.10 mmol/l, P < 0.008, respectively) were impaired to a greater extent. This was associated with a 50% greater requirement of exogenous glucose to prevent more severe hypoglycemia during the 2.3 mmol/l glycemic plateau (P < 0.002). No differences were observed between other counterregulatory hormone responses in AN+ and AN- patients. CONCLUSIONS: We conclude that in patients with type 1 diabetes, autonomic neuropathy further reduces counterregulatory catecholamine responses. Since this should increase the risk for severe hypoglycemia, one might consider safer therapeutic goals in these patients.

OBJECTIVE: We tested the hypothesis that impaired tissue sensitivity to catecholamines contributes to hypoglycemia unawareness in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 21 subjects with type 1 diabetes underwent a standardized insulin infusion protocol to produce a stepwise decrease in plasma glucose to 45-min plateaus of 4.3, 3.6, 3.0, and 2.3 mmol/l. Glycemic thresholds, maximum responses for adrenergic and neuroglycopenic symptoms, and counterregulatory hormones were determined. Patients were classified as hypoglycemia unaware if the initiation of adrenergic symptoms occurred at a plasma glucose level 2 SD below that of nondiabetic volunteers. beta-Adrenergic sensitivity was measured as the dose of isoproterenol required to produce an increment in heart rate of 25 beats per minute above baseline (I25) in resting subjects. RESULTS: Subjects with type 1 diabetes and hypoglycemia unawareness experienced the onset of adrenergic symptoms at a lower plasma glucose level than did those with awareness (2.5+/-0.1 vs. 3.7+/-0.1 mmol/l, P < 0.001), whereas neuroglycopenic symptoms occurred at similar glucose levels (2.7+/-0.2 vs. 2.8+/- 0.1 mmol/l). The plasma glucose levels for counterregulatory hormone secretion (epinephrine 2.9+/-0.2 vs. 4.1+/-0.2 mmol/l; norepinephrine 2.7+/-0.1 vs. 3.2+/-0.2 mmol/l; cortisol 2.5+/-0.2 vs. 3.3+/-0.2 mmol/l, P < 0.01) were also lower in subjects with unawareness. The maximal epinephrine (1,954+/-486 vs. 5,332+/- 1,059 pmol/l, P < 0.01), norepinephrine (0.73 +/- 0.14 vs. 1.47+/-0.21 nmol/l, P = 0.04), and cortisol (276+/-110 vs. 579+/-83 nmol/l, P < 0.01) responses were reduced in the unaware group. I25 was greater in unaware subjects than in subjects without unawareness (1.5+/-0.3 vs. 0.8+/-0.2 microg), where I25 was not different from that of controls (0.8 +/-0.2 microg). CONCLUSIONS: We conclude that subjects with type 1 diabetes and hypoglycemia unawareness have reduced beta-adrenergic sensitivity, which may contribute to their impaired adrenergic warning symptoms during hypoglycemia.

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women of reproductive age; it is associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. This study was designed to assess the long term effects of a pure androgen receptor blocker, flutamide, on the lipid profile in women with PCOS and to examine the possible mechanisms by which androgens may exert their influence. Seventeen women with PCOS (10 obese and 7 lean) were studied. All subjects received a 12-week course of oral flutamide (500 mg/day). The baseline and posttreatment evaluations included lipid profile, androgen levels, insulin sensitivity, and serum catecholamine determinations. The primary outcome was the change in the ratio of low density lipoproteins (LDL) to high density lipoproteins (HDL). Treatment with flutamide was associated with a significant decrease in the LDL/HDL ratio by 23% (P = 0.005), in total cholesterol by 18% (P < 0.0001), in LDL by 13% (P = 0.002), and in triglycerides by 23% (P = 0.002). Flutamide treatment was also associated with a trend toward an increase in HDL (by 14%; P = 0.14). The effects on lipid profile were found regardless of obesity and were not associated with a change in weight. Furthermore, actions of flutamide on lipid metabolism were not associated with significant changes in circulating adrenaline or noradrenaline, glucose metabolism, or insulin sensitivity. This report has demonstrated for the first time that treatment with the pure antiandrogen, flutamide, may improve the lipid profile and that this effect may be due to direct inhibition of androgenic actions.

In a double-blind, randomized study, miglitol (BAY m 1099), an alpha-glucosidase inhibitor, 100 mg tds or placebo was given orally with meals for a period of 24 weeks in 117 patients with Type 2 (non-insulin-dependent) diabetes mellitus (DM) treated with insulin. Fasting and 1 h postprandial plasma glucose and C-peptide were measured at the beginning and at the end of each 4-week interval and glycosylated haemoglobin was determined at day 0 and at the end of the 12th and 24th week. One hour postprandial plasma glucose was significantly lower in the miglitol group at the end of the 24th week (placebo: 11.6 +/- 1.5 vs miglitol: 8.2 +/- 1.5 mmol l-1, mean +/- SD, p = 0.001). Diabetes control improved in the same group as the HbA1 was lowered by 16% (p =0.0001) at the end of the treatment. Mild reversible adverse effects were observed in 37 patients of the miglitol group (mainly flatulence and mild hypoglycaemia) and 2 of the placebo group. Urinary glucose was rendered negative in 41 patients in the miglitol group only. Thus miglitol appears to be a safe and effective adjunct in the management of Type 2 DM, in association with insulin.

Release of glucose by liver and kidney are both increased in diabetic animals. Although the overall release of glucose into the circulation is increased in humans with diabetes, excessive release of glucose by either their liver or kidney has not as yet been demonstrated. The present experiments were therefore undertaken to assess the relative contributions of hepatic and renal glucose release to the excessive glucose release found in type 2 diabetes. Using a combination of isotopic and balance techniques to determine total systemic glucose release and renal glucose release in postabsorptive type 2 diabetic subjects and age-weight-matched nondiabetic volunteers, their hepatic glucose release was then calculated as the difference between total systemic glucose release and renal glucose release. Renal glucose release was increased nearly 300% in diabetic subjects (321+/-36 vs. 125+/-15 micromol/min, P < 0.001). Hepatic glucose release was increased approximately 30% (P = 0.03), but increments in hepatic and renal glucose release were comparable (2.60+/-0.70 vs. 2.21+/-0.32, micromol.kg-1.min-1, respectively, P = 0.26). Renal glucose uptake was markedly increased in diabetic subjects (353+/-48 vs. 103+/-10 micromol/min, P < 0.001), resulting in net renal glucose uptake in the diabetic subjects (92+/-50 micromol/ min) versus a net output in the nondiabetic subjects (21+/-14 micromol/min, P = 0.043). Renal glucose uptake was inversely correlated with renal FFA uptake (r = -0.51, P < 0.01), which was reduced by approximately 60% in diabetic subjects (10. 9+/-2.7 vs. 27.0+/-3.3 micromol/min, P < 0.002). We conclude that in type 2 diabetes, both liver and kidney contribute to glucose overproduction and that renal glucose uptake is markedly increased. The latter may suppress renal FFA uptake via a glucose-fatty acid cycle and explain the accumulation of glycogen commonly found in the diabetic kidney.