Autonomic and hemodynamic responses to insulin in lean and obese humans

To study the acute effects of insulin on autonomic control of cardiac function, we performed spectral analysis of heart rate variability and measured cardiac dynamics (by two-dimensional echocardiography) in 18 obese (BMI = 35 +/- 1 kg.m-2) and 14 lean (BMI = 24 +/- 1 kg.m-2) subjects in the basal state and in response to physiological hyperinsulinemia (1 mU.min-1.kg-1 insulin clamp). In the lean group, insulin promptly (within 20 min) and consistently depressed spectral powers, both in the low-frequency and high-frequency range. These changes were twice as large as accounted for by the concomitant changes in heart rate (68 +/- 2 to 70 +/- 2 beats/min). At the end of the 2-h clamp, stroke volume (67 +/- 4 to 76 +/- 9 ml.min-1) and cardiac output (4.45 +/- 0.21 to 5.06 +/- 0.55 l.min-1) rose, whereas peripheral vascular resistance fell. The low-to-high frequency ratio increased from 1.7 +/- 0.2 to 2.3 +/- 0.3 (P < 0.01), indicating sympathetic shift of autonomic balance. In the obese group, all basal spectral powers were significantly lower (by 40% on average) than in the lean group, and were further reduced by insulin administration. The low-to-high frequency ratio was higher than in controls at baseline (2.4 +/- 0.4, P < 0.03), and failed to increase after insulin (2.2 +/- 0.3, P = ns). Furthermore, obesity was associated with higher resting stroke volume (89 +/- 5 vs. 67 +/- 4 ml.min-1, P < 0.01) and cardiac output (6.01 +/- 0.31 vs. 4.45 +/- 0.21 l.min-1, P = 0.001) but lower peripheral vascular resistance (15.1 +/- 0.8 vs. 19.2 +/- 1.1 mmHg.min.L-1, P = 0.002), whereas mean arterial blood pressure was similar to control (90 +/- 2 vs. 86 +/- 2 mmHg, P = not significant). We conclude that physiological hyperinsulinemia causes acute desensitization of sinus node activity to both sympathetic and para-sympathetic stimuli, sympathetic shift of autonomic balance, and a high-output, low-resistance hemodynamic state. In the obese, these changes are already present in the basal state, and may therefore be linked with chronic hyperinsulinemia.     

The diagnostic value of the rate-corrected QT interval in long-term type-1 diabetes mellitus

OBJECTIVE: To assess the relationship between rate-corrected QT interval (QTc interval) and cardiac reflex tests in order to determine the value of QTc interval measurements in the diagnosis of diabetic cardiac autonomic neuropathy. INVESTIGATIONS: The QTc interval was measured in the resting ECG of 97 type 1 diabetics (58 women, 39 men; mean age 35 +/- 12 years; duration of diabetes 18 +/- 10 years; HbA1c 7.8 +/- 1.8%). Age-related results were compared with five cardiac function tests (heart rate variation at rest and on forced breathing; 30/15 ratio of heart rate; Valsalva manoeuvre; orthostasis). RESULTS: The QTc interval was not prolonged ( < or = 440 ms) in 68 patients (70%), while in 29 (30%) it was prolonged ( > 440 ms). No significant differences regarding QTc interval were found between patients with autonomic cardiac neuropathy ( > or = 2 abnormal function tests) and those without ( < 2 abnormal function tests) (QTc interval 436 +/- 25 vs 426 +/- 19 ms). QTc intervals correlated with the coefficients of variation for heart rate variation at rest and on forced breathing and the 30/15 ratio of heart rate (p = 0.001; p = 0.001; p = 0.03), but not with the results of the Valsalva manoeuvre and the orthostasis test. CONCLUSION: Prolongation of the QTc interval in longstanding type 1 diabetes does not provide a reliable indication of cardiac autonomic neuropathy and this measure cannot replace conventional reflex tests for its diagnosis.     

Assessment of insulin sensitivity and secretion with the labelled intravenous glucose tolerance test: improved modelling analysis

A new modelling analysis was developed to assess insulin sensitivity with a tracer-modified intravenous glucose tolerance test (IVGTT). IVGTTs were performed in 5 normal (NGT) and 7 non-insulin-dependent diabetic (NIDDM) subjects. A 300 mg/kg glucose bolus containing [6,6-(2)H2]glucose was given at time 0. After 20 min, insulin was infused for 5 min (NGT, 0.03; NIDDM, 0.05 U/kg). Concentrations of tracer, glucose, insulin and C-peptide were measured for 240 min. A circulatory model for glucose kinetics was used. Glucose clearance was assumed to depend linearly on plasma insulin concentration delayed. Model parameters were: basal glucose clearance (Cl(b)), glucose clearance at 600 pmol/l insulin concentration (Cl600), basal glucose production (Pb), basal insulin sensitivity index (BSI = Cl(b)/basal insulin concentration); incremental insulin sensitivity index (ISI = slope of the relationship between insulin concentration and glucose clearance). Insulin secretion was calculated by deconvolution of C-peptide data. Indices of basal pancreatic sensitivity (PSIb) and first (PSI1) and second-phase (PSI2) sensitivity were calculated by normalizing insulin secretion to the prevailing glucose levels. Diabetic subjects were found to be insulin resistant (BSI: 2.3 +/- 0.6 vs 0.76 +/- 0.18 ml x min(-1) x m(-2) x pmol/l(-1), p < 0.02; ISI: 0.40 +/- 0.06 vs 0.13 +/- 0.05 ml x min(-1) x m(-2) x pmol/l(-1), p < 0.02; Cl600: 333 +/- 47 vs 137 +/- 26 ml x min(-1) x m(-2), p < 0.01; NGT vs NIDDM). Pb was not elevated in NIDDM (588 +/- 169 vs 606 +/- 123 micromol x min(-1) x m(-2), NGT vs NIDDM). Hepatic insulin resistance was however present as basal glucose and insulin were higher. PSI1 was impaired in NIDDM (67 +/- 15 vs 12 +/- 7 pmol x min x m(-2) x mmol/l(-1), p < 0.02; NGT vs NIDDM). In NGT and in a subset of NIDDM subjects (n = 4), PSIb was inversely correlated with BSI (r = 0.95, p < 0.0001, log transformation). This suggests the existence of a compensatory mechanism that increases pancreatic sensitivity in the presence of insulin resistance, which is normal in some NIDDM subjects and impaired in others. In conclusion, using a simple test the present analysis provides a rich set of parameters characterizing glucose metabolism and insulin secretion, agrees with the literature, and provides some new information on the relationship between insulin sensitivity and secretion.     

Influence of chronic Naltrexone treatment on growth hormone and insulin secretion in obese subjects

OBJECTIVE: Recent studies have demonstrated the restoration of a normal 24 h GH profile induced by a reduction of insulinaemia after weight loss, suggesting a reciprocal relationship between plasma insulin and GH concentrations. We aimed to clarify if an opiate-induced reduction in plasma insulin could affect GH secretion in obesity. DESIGN: We have studied the insulin response to an oral glucose tolerance test (OGTT) and the GH response to GHRH before and after prolonged treatment with Naltrexone (NTX). C-peptide, IGF-I, IGFBP-3 plasma levels and the IGF-I/IGFBP-3 molar ratio were also determined. SUBJECTS: Twelve obese women (aged 25-41 y; Body mass index (BMI): 31-39 kg/m2) and six lean normal women (aged 25-38; BMI: 19.8-23.1 kg/m2). MEASUREMENT: GH was determined by the IRMA method; insulin, C-peptide, IGF-I and IGFBP-3 were assayed by the RIA method. For molar comparison between IGF-I and IGFBP-3 we have considered 30.5 kDa the molar weight of IGFBP-3. Results are expressed as mean +/- s.e.m. RESULTS: We observed a significant decrease in basal concentration of both insulin (230.1 +/- 34.9 vs 133.2 +/- 16.9 pmol/L; P < 0.005) and C-peptide (3.7 +/- 0.3 vs 2.4 +/- 0.1 micrograms/L; P < 0.02). No modifications in the insulin secretory response to the OGTT were observed. A significant increase of the GHRH-induced GH peak response (7.7 +/- 1.4 vs 19.7 +/- 3.1 micrograms/L; P < 0.01) and GH-AUC (533 +/- 151 vs 1415 +/- 339 micrograms/L/120 min; P < 0.01) was found after NTX treatment. A negative correlation was found between basal insulin and GH peak values, both before (r = -0.641, P = 0.027) and after NTX (r = -0.714, P = 0.013). No modifications were found in IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio. Moreover, NTX affected neither the insulin response to OGTT or IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio in a group of six lean controls. Conversely, NTX significantly reduced the GH response to GHRH, when expressed as both peak and AUC values. CONCLUSIONS: The opiate antagonist significantly reduced basal insulin concentrations and augmented the GH response to GHRH in obese subjects. In the absence of modifications in IGF-I and IGFBP-3 plasma levels and their molar ratio, we propose that insulin may exert a negative feedback on GH secretion.     

Determinants of serum leptin levels in Cushing's syndrome

Corticosteroids and insulin increase leptin expression in vivo and in vitro. To investigate whether increased serum cortisol influences serum leptin concentrations in humans, we analyzed fasting serum leptin and insulin levels in 50 patients with Cushing's syndrome [34 female patients: 27 with the pituitary form and 7 with the adrenal form; age, 41.6 +/- 2.7 yr; body mass index (BMI), 29.6 +/- 1.2 kg/m2; 16 male patients all with the pituitary form; age, 39.2 +/- 3.1 yr; BMI, 26.3 +/- 2.3 kg/m2] and in controls matched for BMI, age, and gender. Serum leptin levels were higher in female than in male patients in both the Cushing (P < 0.01) and control (P < 0.001) groups. Disease-specific differences in serum leptin levels were only detected in male (106 vs. 67 pmol/L; Cushing's syndrome vs. control, P < 0.05), not female, patients. Multiple stepwise regression analysis of both patient groups revealed insulin as the best predictor of serum leptin concentrations, accounting for 37% of the variance in serum leptin levels, in contrast to BMI or mean serum cortisol (as measured by sampling in 10-min intervals over 24 h). In the subgroup of patients (n = 9) with pituitary adenoma, serum leptin levels were reduced after tumor resection, with concurrent decreases in serum cortisol, insulin, and BMI. In conclusion, chronic hypercortisolemia in Cushing's syndrome appears not to directly affect serum leptin concentrations, but to have an indirect effect via the associated hyperinsulinemia and/or impaired insulin sensitivity.     

Ontogeny of humoral immunity in northern elephant seal (Mirounga angustirostris) neonates

OBJECTIVE: To assess relations of left ventricular (LV) geometry and function to insulin resistance in obesity-a condition associated with volume overload and abnormal LV relaxation. DESIGN: Cross-sectional relational study. SUBJECTS: 27 healthy overweight-obese subjects (18 women, body mass index (BMI) = 35.0+/-4.0 kg/m2) and 31 age-matched normal-weight controls (21 women, BMI = 22.6+/-2.4 kg/m2). MEASUREMENTS: Subjects were studied by Doppler-echocardiography the same day and hour (08.00 h) as measurements of fasting insulin and blood glucose were made. Insulin resistance was determined by the 'Homeostasis Assessment Model'. RESULTS: Twelve obese subjects with insulin resistance (IR) had higher body size than 15 patients without IR and higher blood pressure than normal-weight controls (all P < 0.01). Relative IR was related to isovolumic relaxation time. This relation was not maintained after controlling for age, blood pressure, weight and height. Isovolumic relaxation time was, however, positively related to diastolic blood pressure, a measure of load, in normal controls (r=0.44) and obese without IR (r=0.62) but not in insulin resistant subjects (r=0.14). CONCLUSION: IR does not independently influence myocardial relaxation in uncomplicated obesity, but modulates the effect of load on active diastole.     

Serum lipoprotein lipid profile in women with the polycystic ovary syndrome: relation to anthropometric, endocrine and metabolic variables

OBJECTIVE: Although often associated with insulin resistance and glucose intolerance, various lipoprotein abnormalities have been found in polycystic ovary syndrome (PCOS) but not invariably so when the degree of obesity is taken into account. We have therefore investigated the serum lipid profile in a group of women with polycystic ovary syndrome with and without obesity. DESIGN: Cross-sectional study of serum lipoprotein lipids and plasma free fatty acids in relation to anthropometric, metabolic and hormonal variables in women with PCOS and weight-matched controls. PATIENTS: Twenty-four obese (Pob, mean BMI +/- SD 30.6 +/- 3.3 kg/m2) and 25 non-obese (Pnob, 22.2 +/- 2.3 kg/m2) women with PCOS. Twenty obese (Cob, 30.2 +/- 3.5 kg/m2) and 20 non-obese (Cnob, 21.4 +/- 1.5 kg/m2) controls. MEASUREMENTS: Fasting concentrations of plasma free fatty acids, serum cholesterol and triglycerides in high density lipoproteins (HDL), low density lipoproteins (LDL) and very low density lipoproteins (VLDL) in relation to insulin sensitivity index (M/I; assessed with the euglycaemic insulin clamp), glucose tolerance (k-value; intravenous glucose tolerance test), basal serum hormone concentrations, and body fat distribution (skinfolds and waist hip ratio). RESULTS: Plasma concentrations of free fatty acids were markedly higher in Pob than in the other groups (all P < 0.001). The lipoprotein lipids did not differ between Pob and Cob, or between the non-obese groups, whereas both obese groups had higher serum concentrations of triglycerides, totally and in VLDL, and lower HDL-cholesterol than their non-obese counterparts. Pob also had higher serum levels of total and LDL-cholesterol than Pnob. Pob had a more pronounced subcutaneous truncal-abdominal adiposity, higher fasting insulin levels and lower M/I than the other groups, and a lower k-value than Cob. Cob had higher levels of fasting insulin than Cnob. Free fatty acid levels correlated with the k-value (inversely) in both women with PCOS and controls, and with M/I (inversely), age and testosterone levels in PCOS. Stepwise regression analysis for the total population, comparing endocrine, anthropometric and metabolic explanatory variables, showed that the serum levels of HDL-cholesterol and triglycerides were mainly correlated with body fat distribution (both) and fasting insulin levels (triglycerides), and levels of total and LDL-cholesterol with BMI and age. CONCLUSIONS: Plasma free fatty acid correlations were markedly increased in obese women with PCOS, closely associated with the lower insulin sensitivity and lower glucose tolerance in these women. In spite of these profound metabolic aberrations, the lipoprotein lipid profile was not significantly more abnormal in obese women with PCOS than in their weight-matched controls.     

Effect of aerobic training on baroreflex regulation of cardiac and sympathetic function

To investigate the effect of aerobic exercise training on baroreflex regulation of muscle sympathetic nerve activity (MSNA) and cardiac R-R intervals in a middle-aged to older population, 10 healthy men > 40 yr of age underwent tests of autonomic function before and after 12 wk of high-intensity training. Cardiac and peripheral baroslopes were determined from the R-R interval vs. mean arterial pressure (MAP) and peroneal MSNA vs. diastolic pressure relationships, respectively, during sequential bolus injections of nitroprusside and phenylephrine. Maximal oxygen uptake increased (P < 0.05) 17% with training. Resting R-R interval increased (881 +/- 23 to 956 +/- 38 ms, P < 0.05), MAP decreased (96 +/- 2 to 91 +/- 3 mmHg, P < 0.05), and MSNA was unaltered (23.1 +/- 2.3 to 23.6 +/- 1.9 bursts/min) with training. Before and after training, respectively, cardiac baroslopes determined with decreasing (8.7 +/- 0.9 to 9.9 +/- 5.5 ms/mmHg) and increasing MAP (9.6 +/- 2.1 to 9.9 +/- 2.2 ms/mmHg) and the peripheral sympathetic baroslope (-3.3 +/- 0.4 to -3.5 +/- 0.6 bursts.min-1 x mmHg-1) did not differ. The results suggest that short-term aerobic training does not alter resting MSNA or neurocirculatory responses to baroreceptor challenges in middle-aged and older men.     

Alterations in glucose metabolism in patients with Alzheimer's disease

OBJECTIVE: To determine the alterations in glucose metabolism that occur in patients with Alzheimer's Disease (AD). DESIGN: Cross-sectional comparison of AD and healthy controls. SETTING: A University teaching hospital. PATIENTS: Healthy controls (n = 14, BMI: 24.9 +/- 0.5 kg/M2, age 73 +/- 1 years) and patients with AD (n = 12, BMI: 23.9 +/- 1.0 kg/M2, age 72 +/- 1 years). All controls and patients with AD had a normal history and physical examination, a negative family history of diabetes, and took no medications. MEASUREMENTS: All patients and controls underwent an assessment of their dietary intake and physical activity, a 3-hour oral glucose tolerance test (OGTT), and a 2-hour hyperglycemic glucose clamp study. RESULTS: Total caloric intake (AD: 27.1 +/- 1.3 kcal/kg/day; Control: 23.6 +/- 1.6 kcal/kg/day; P = ns) and intake of complex carbohydrates (AD: 5.9 +/- 0.4 kcal/kg/day; Control: 6.5 +/- 0.3 kcal/kg/day; P = ns) were not different between groups. Leisure time physical activity was greater in controls (AD: 2970 +/- 411 kcal/week; Control: 5229 +/- 864 kcal/week; P < 0.05). Patients with AD had higher fasting glucose (AD: 5.9 +/- 0.2 mmol/L; Control: 5.1 +/- 0.1 mmol/L; P < 0.01) and insulin (AD: 144 +/- 20 pmol/L; Control: 100 +/- 6 pmol/L; P < 0.05) values. In response to the OGTT, the area under the curve for glucose and insulin was similar in both groups. During the hyperglycemic clamp, steady-state glucose values were higher in the Alzheimer's patients (AD: 11.5 +/- 0.2 mmol/L; Control: 10.9 +/- 0.1 mmol/L, P < 0.01). First- and second-phase insulin responses were similar in each group. The insulin sensitivity index (units: mL/kg.min per pmol/L x 100), a measure of tissue sensitivity to insulin, was reduced in the patients with AD (AD: 0.59 +/- 0.06; Control: 0.79 +/- 0.07; P < 0.05). CONCLUSIONS: We conclude that early AD is characterized by alterations in peripheral glucose metabolism, which may relate, in part, to alterations in physical activity.     

Physiological insulinemia acutely modulates plasma leptin

Whether insulin acutely regulates plasma leptin in humans is controversial. We examined the dosage-response and time-course characteristics of the effect of insulin on leptin in 10 men (age 42+/-2 years [mean+/-SE]; BMI 29.3+/-2.0 kg/m2). Each individual underwent four 9-h euglycemic clamps (insulin at 20, 40, 80, and 400 mU x m[-2] x min[-1) and a control saline infusion. Although plasma glucose and insulin levels remained constant, leptin diminished from 9.1+/-3.0 to 5.9+/-2.1 ng/ml (P < 0.001) by the end of the control experiment. Conversely, plasma leptin showed a dosage-dependent increase during the insulin infusions that was evident within 30-60 min. The insulin-induced increase in leptin was proportionately lower in obese insulin-resistant men. Free fatty acids (FFAs) decreased during insulin and did not change during saline infusions. ED50 (the dose producing half-maximal effect) for insulin's effect on leptin and FFA was similar (138+/-36 vs. 102+/-24 pmol/l, respectively; P=0.11). To further define the role of physiological insulinemia, we compared the effect of a very low dosage insulin infusion (10 mU x m[-2] x min[-1]) with that of a control saline infusion in another group of 10 men (mean age 39+/-3 years; BMI 27.1+/-1.0 kg/m2). Plasma leptin remained stable during that insulin infusion, but fell by 37+/-2% in the control experiment. Thus physiological insulinemia can acutely regulate plasma leptin. Insulin could mediate the effect of caloric intake on leptin and could be a determinant of its plasma concentration. Inadequate insulin-induced leptin production in obese and insulin-resistant subjects may contribute to the development or worsening of obesity.     

Relation of obesity to insulin secretion and clearance in adolescents: the Bogalusa Heart Study

OBJECTIVE: Earlier we found elevated insulin levels in obese children and adolescents. The present study examines whether alterations in insulin secretion and/or clearance contribute to hyperinsulinemia in obese adolescents. METHODS: Fasting circulating insulin and C-peptide concentrations were examined in 1157 adolescents, aged 11-18 y, from a biracial (black/white) community. In this epidemiologic study, plasma C-peptide was used as a noninvasive measure of insulin secretion by beta cells, C-peptide to insulin ratio as an indicator of hepatic insulin extraction, and insulin to glucose ratio as a measure of insulin sensitivity. Body mass index (BMI) was used as an index of obesity, since it is strongly associated with insulin levels and the C-peptide to insulin ratio more so than with measures of skinfolds and percent body fatness. RESULTS: Obese individuals (BMI > 90th P) had higher levels of plasma insulin (23.7 mu/ml vs 11.7 mu/ml), C-peptide (2.7 ng/ml vs 1.7 ng/ml), and insulin to glucose ratio (0.29 vs 0.15), and lower C-peptide to insulin ratio (0.13 vs 0.16) than non-obese adolescents (all P < 0.001). Elevated C-peptide and decreased C-peptide to insulin ratio were noted in subjects with both obesity and hyperinsulinemia (insulin > 90th P) versus those without these conditions (P < 0.001). Individuals with obesity and low insulin clearance (C-peptide/insulin < 10th P) had 18-fold higher prevalence of hyperinsulinemia versus those without these conditions. Although black adolescents, despite their lower percent body fat, had higher insulin and lower C-peptide and C-peptide to insulin ratio than their white counterparts, BMI related positively to insulin and C-peptide, and inversely with C-peptide to insulin ratio in both races. CONCLUSIONS: These data suggest that both increased insulin secretion and decreased insulin clearance contribute to hyperinsulinema in obese adolescents.     

Non-invasive continuous glucose monitoring in Type I diabetic patients with optical glucose sensors. Non-Invasive Task Force (NITF)

Glucose intolerance is influenced by body fat mass, as well as muscle fiber composition. To examine the relation between the metabolic profile and muscle morphology in this condition, we performed muscle biopsies and hyperglycemic clamps to determine insulin secretion and clearance, and the insulin effects on glucose disposal and nonesterified fatty acids (NEFA) in 45 glucose intolerant persons (body mass index [BMI], 27.8 +/- 3.0 kg/m2) and 45 normoglycemic controls (BMI, 25.8 +/- 2.7 kg/m2) (P = .001). After adjustment for BMI, glucose-intolerant subjects had lower first-phase insulin release (726 v 954 pmol/L, P = .04). Glucose-intolerant subjects and controls differed in fasting insulin, insulin clearance, and insulin sensitivity to glucose disposal before, but not after, standardizing for BMI. During the clamp, glucose-intolerant subjects had less NEFA suppression and elevated levels of NEFA compared with controls (85% +/- 9% v 90% +/- 6%, P = .02; and 70 +/- 42 micromol/L v 45 +/- 28 micromol/L, P = .01). Glucose-intolerant subjects also had a higher percentage of insulin-insensitive, type 2b muscle fibers, which are not adapted for fat oxidation (7% +/- 9% v 9% +/- 9%, P = .003). BMI was not associated with NEFA suppression or the percentage of type 2b muscle fibers in either group. In conclusion, glucose-intolerant persons have impaired first-phase insulin release, an elevated percentage of type 2b muscle fibers, and increased NEFA availability. Reduced insulin clearance, hyperinsulinemia, and insulin resistance were associated with small increments in BMI.     

Autonomic neuropathy in diabetic children

OBJECTIVE: Evaluate the presence of cardiovascular autonomic nerve dysfunction in children and adolescents with insulin-dependent diabetes mellitus. METHODOLOGY: We studied 110 patients (54 male, 56 female) and 100 healthy sex and age-matched children. Autonomic nerve function was assessed by standard cardiovascular reflex tests: (1) Fall in systolic blood pressure in response to standing. (2) Heart rate in response to standing. (3) Beat-to-beat rate variation during deep breathing. (4) Quotient of heart rate during and after Valsalva manoeuvre. (5) Change in blood pressure response to sustained handgrip. The coefficient of variation of heart rate was determined from 150 systoles using a microcomputer-based technique. The lower limits of normal were defined according to statistical analysis taking into account the relationship between heart rate variability and age. RESULTS: Forty-seven of the 110 diabetic children and adolescents studied showed one or more abnormal tests for cardiovascular autonomic dysfunction; many patients had an abnormality in more than one test. Twenty-two patients showed early involvement, 18 patients had definite and 7 severe involvement. No correlation was found between sex, glycaemic control, duration of diabetes or presence of retinopathy and persistent microalbuminuria and the autonomic nerve function. CONCLUSIONS: In the paediatric age group also, autonomic nerve dysfunction can be present in asymptomatic diabetic patients. Heart rate variation during Valsalva manoeuvre and maximum/minimum 30:15 ratio are the most sensitive indices to detect autonomic abnormalities in children.     

Caffeine enhances modulation of parasympathetic nerve activity in humans: quantification using power spectral analysis

We investigated changes in autonomic nerve activity following caffeine intake by power spectral analysis of R-R intervals of heartbeats in humans. A beverage containing 240 mg of caffeine or a control beverage was given to 10 healthy volunteers, and R-R intervals were measured while subjects were sitting and controlling their respiration at a constant rate. After consumption of the caffeine-containing beverage, a transient and significant increase (P < 0.001) in spectral integrated values (areas under the curve) of high frequency power (high component, HC) was observed, and at 30 min the value was significantly greater than in controls (P < 0.02), suggesting an increase in vagal autonomic nerve activity. The effect of caffeine was also examined using decaffeinated coffee supplemented with exogenous caffeine (2 mg/kg body wt). A transient and significant increase (P < 0.0001) in HC was observed, and the value was significantly greater (P < 0.02) than when subjects consumed decaffeinated coffee without supplemental caffeine. The ratio of HC to total integrated value (which is also used as a selective indicator of vagal activity) was also significantly higher (P < 0.04) after caffeine consumption. Physiological variables accompanying the change in autonomic nerve activity (i.e., blood pressure, surface body temperature and heart rate) were not significantly affected by caffeine intake. These results suggest that power spectral analysis of heartbeat R-R intervals is an effective and noninvasive method for detecting subtle changes in autonomic nerve activity in response to food intake.     

Insulin sensitivity, insulin action, and fibrinolysis activity in nondiabetic and diabetic obese subjects

Because inconsistencies occur with regard to the relative contribution of insulin to the hypofibrinolysis characteristic of obesity and diabetes, we explored the relationship between insulin and fibrinolysis, assessing both insulin sensitivity and insulin action. Seventeen markedly obese subjects (body mass index [BMI], 34.0+/-1.6 kg/m2; 12 nondiabetic and five diabetic) were studied using the three-step euglycemic-hyperinsulinemic clamp technique. Since the circadian rhythm of the fibrinolytic system may obscure a true effect of insulin, variations in fibrinolysis parameters observed during the glucose clamp were compared with those occurring spontaneously because of the circadian rhythm. Compared with six normal-weight subjects (BMI, 21.0+/-0.9 kg/m2), all obese subjects exhibited basal hyperinsulinism (fasting plasma insulin, 16.0+/-1.4 v 9.8+/-1.3 microU/microL, P < .001; fasting plasma C-peptide, 1.4+/-0.2 v 0.5+/-0.2 ng/mL, P < .001), hypofibrinolysis (euglobulin lysis time [ELT], 378+/-29 v 222+/-31 minutes, P=.01; tissue plasminogen activator [tPA] antigen, 7.8+/-0.9 v 4.2+/-0.5 ng/mL, P=.04; plasminogen activator inhibitor type 1 [PAI-1] activity, 22.2+/-2.5 v3.9+/-0.6 AU/mL, P=.004), and marked insulin resistance (M value, ie, the maximal glucose disposal rate, 9.1+/-0.6 v 18.6+/-0.8 mg/(kg x min), P < .001). The M value correlated inversely with tPA antigen (r=-.46, P=.05). During insulin infusion, values for fibrinolysis parameters decreased, but were not different compared with variations due to the circadian rhythm. In conclusion, our findings together with previously reported data reinforce the idea that chronic hyperinsulinism is linked to hypofibrinolysis, but insulin does not seem to acutely regulate the fibrinolysis system.     

Oral tolerance induction with altered forms of ovalbumin

The mechanism of insulin resistance in obesity was examined in ten obese (BMI 33 +/- 1 kg/m2) and nine lean (BMI 22 +/- 1 kg/m2) Caucasian women during a hyperglycemic-hyperinsulinemic clamp using 13C and 31P nuclear magnetic resonance (NMR) spectroscopy to measure rates of muscle glycogen synthesis and intramuscular glucose-6-phosphate (G-6-P) concentrations. Under similar steady-state plasma concentrations of glucose (approximately 11 mmol/l) and insulin (approximately 340 pmol/l), rates of muscle glycogen synthesis were reduced approximately 70% in the obese subjects (52 +/- 8 micromol/[l muscle-min]) as compared with the rates in the lean subjects (176 +/- 22 micromol/[l muscle-min]; P < 0.0001). Basal concentrations of intramuscular G-6-P were similar in the obese and lean subjects; but during the clamp, G-6-P failed to increase in the obese group (deltaG-6-P obese 0.044 +/- 0.011 vs. lean 0.117 +/- 0.011 mmol/l muscle; P < 0.001), reflecting decreased muscle glucose transport and/or phosphorylation activity. We conclude that insulin resistance in obesity can be mostly attributed to impairment of insulin-stimulated muscle glycogen synthesis due to a defect in glucose transport and/or phosphorylation activity.     

Ovarian hyperandrogenism is associated with insulin resistance to both peripheral carbohydrate and whole-body protein metabolism in postpubertal young females: a metabolic study

The role of endogenous androgens in enhancing the body's protein anabolic capacity has been controversial. To examine this question we chose to study whole-body protein and glucose kinetics in a group of 21 young, postpubertal females (16.3 +/- 0.6 yr), 8 of whom had clinical and laboratory evidence of ovarian hyperandrogenism (OH) (BMI = 37.8 +/- 1.3 kg/m2). We used L-[1-13C]leucine and [6,6,2H2]glucose tracer infusions before and after suppression of their endogenous androgens with estrogen/progesterone supplementation in the form of Triphasil for 4 weeks. Their baseline data were also compared with those of similar aged girls, 7 obese (OB) (BMI = 36.4 +/- 1.5) and 6 lean (LN) (BMI = 20.9 +/- 0.7) who were normally menstruating and had no evidence of androgen excess. Despite comparable glucose concentrations, both OH and OB groups had significant hyperinsulinemia (OH > OB), both basally and after iv glucose stimulation, as compared to LN controls (basal insulin: OH, 252 +/- 52 pmol/L; OB, 145 +/- 41; LN, 60 +/- 9, P = 0.009 OH vs. LN; peak insulin: OH, 2052 +/- 417; OB, 1109 +/- 127, LN, 480 +/- 120, P = 0.0009 OH vs. LN). The rate of appearance (Ra) of glucose, a measure of glucose production, was greater in the LN controls than in the OH or OB groups (OH, 2.0 +/- 0.1 mg/kg.fat free mass.min; OB, 1.9 +/- 0.1; LN, 3.3 +/- 0.1, P < 0.004 vs. LN). Calculated total rates of whole-body protein breakdown (leucine Ra), oxidation, and protein synthesis (nonoxidative leucine disposal) were substantially higher in the OH and OB groups as compared with LN controls (P < 0.04 vs. LN); however, when data are expressed on a per kilogram of fat free mass basis, the OH group had higher rates of proteolysis than the OB and LN, with indistinguishable rates between the latter two groups. None of the above-mentioned parameters changed after 1 month of administration of Triphasil, despite marked improvement in circulating testosterone and free testosterone concentrations after treatment (testosterone, -50%, P = 0.003; free testosterone, -70%, P = 0.02). We conclude that obesity in young postpubertal females is associated with insulin resistance for both peripheral carbohydrate and protein metabolism, and that patients with the OH syndrome have even greater insulin resistance as compared with simple obesity, regardless of treatment for the androgen excess. Carefully designed studies targeting interventions to improve both the hyperandrogenic and hyperinsulinemic state may prove useful even in the early juvenile stages of this disease.     

Neural network subtyping of depression

OBJECTIVE: To examine the mechanisms by which weight loss improves glycemic control in overweight subjects with NIDDM, particularly the relationships between energy restriction, improvement in insulin sensitivity, and regional and overall adipose tissue loss. RESEARCH DESIGN AND METHODS: Hyperinsulinemic glucose clamps were performed in 20 subjects (BMI = 32.0 +/- 0.5 [SEM] kg/m2, age = 48.4 +/- 2.7 years) with normal glucose tolerance (NGT) (n = 10) or mild NIDDM (n = 10) before and on the 4th (d4) and 28th (d28) days of a reduced-energy (1,100 +/- 250 [SD] kcal/day) formula diet. Body composition changes were assessed by dual energy x-ray absorptiometry and insulin secretory changes were measured by insulin response to intravenous glucose before and after weight loss. RESULTS: In both groups, energy restriction (d4) reduced fasting plasma glucose (FPG) (delta FPG: NGT = -0.4 +/- 0.2 mmol/l and NIDDM = -1.1 +/- 0.03 mmol/l, P = 0.002), which was independently related to reduced carbohydrate intake (partial r = 0.64, P = 0.003). There was a marked d4 increase in percent of insulin suppression of hepatic glucose output (HGO) in both groups (delta HGO suppression: NGT = 28 +/- 15% and NIDDM = 32 +/- 8%, P = 0.002). By d28, with 6.3 +/- 0.4 kg weight loss, FPG was further reduced (d4 vs. d28) in NIDDM only (P = 0.05), and insulin sensitivity increased in both groups (P = 0.02). Only loss of abdominal fat related to improvements in FPG (r = 0.51, P = 0.03) and insulin sensitivity after weight loss (r = 0.48, P = 0.05). In contrast to insulin action, there were only small changes in insulin secretion. CONCLUSIONS: Both energy restriction and weight loss have beneficial effects on insulin action and glycemic control in obesity and mild NIDDM. The effect of energy restriction is related to changes in individual macronutrients, whereas weight loss effects relate to changes in abdominal fat.     

NIDDM in the elderly

OBJECTIVE: We conducted this study to assess the metabolic alterations in elderly patients with NIDDM. RESEARCH DESIGN AND METHODS: Healthy, lean (n = 15; age, 73 +/- 1 years; BMI, 23.8 +/- 0.5 kg/m2), and obese (n = 10; age, 71 +/- 1 years; BMI, 28.9 +/- 1.2 kg/m2) control subjects and lean (n = 10; age, 75 +/- 2 years; BMI, 24.0 +/- 0.5 kg/m2) and obese (n = 23; age, 73 +/- 1 years; BMI, 29.9 +/- 0.7 kg/m2) NIDDM patients underwent a 3-h glucose tolerance test, a 2-h hyperglycemic glucose clamp study, and a 3-h euglycemic glucose clamp study with tritiated glucose methodology to measure glucose production and disposal rates. RESULTS: Waist-to-hip ratio (WHR) was greater in both lean and obese NIDDM patients than in control subjects. Insulin responses during the oral glucose tolerance test were similar in obese subjects (control subjects: 417 +/- 64 pmol/l; NIDDM patients: 392 +/- 47 pmol/l) but were reduced in lean NIDDM patients (control subjects: 374 +/- 34 pmol/l; NIDDM patients: 217 +/- 20 pmol/l, P < 0.01). Lean and obese NIDDM patients had absent first-phase insulin responses during the hyperglycemic clamp. Second-phase insulin responses were reduced in lean (P < 0.01 vs. control subjects by analysis of variance) but not obese NIDDM patients. Hepatic glucose output was not increased in lean or obese NIDDM patients. Steady-state (150-180 min) glucose disposal rates were 16% less in lean NIDDM patients (control subjects: 8.93 +/- 0.37 mg.kg LBM (lean body mass)-1.min-1; NIDDM patients: 7.50 +/- 0.28 mg.kg LBM-1.min-1, P < 0.05) and 37% less in obese NIDDM patients (control subjects: 8.17 +/- 0.38 mg.kg LBM-1.min-1; NIDDM patients: 5.03 +/- 0.36 mg.kg LBM-1.min-1, P < 0.001). CONCLUSIONS: Lean elderly NIDDM patients have a profound impairment in glucose-induced insulin release but mild resistance to insulin-mediated glucose disposal. Obese elderly NIDDM patients have adequate circulating insulin, but marked resistance to insulin-mediated glucose disposal. Hepatic glucose output is not increased in elderly NIDDM patients.