Effects of aerobic or resistance exercise training on cardiovascular autonomic function of subjects with type 2 diabetes: A pilot study.

BACKGROUND AND AIMS: Both aerobic (AER) and resistance (RES) training improve metabolic control in patients with type 2 diabetes (T2DM). However, information on the effects of these training modalities on cardiovascular autonomic control is limited. Our aim was to compare the effects of AER and RES training on cardiovascular autonomic function in these subjects. METHODS AND RESULTS: Cardiovascular autonomic control was assessed by Power Spectral Analysis (PSA) of Heart Rate Variability (HRV) and baroreceptors function indexes in 30 subjects with T2DM, randomly assigned to aerobic or resistance training for 4 months. In particular, PSA of HRV measured the Low Frequency (LF) and High Frequency (HF) bands of RR variations, expression of prevalent sympathetic and parasympathetic drive, respectively. Furthermore, we measured the correlation occurring between systolic blood pressure and heart rate during a standardized Valsalva maneuver using two indexes, b2 and b4, considered an expression of baroreceptor sensitivity and peripheral vasoactive adaptations during predominant sympathetic and parasympathetic drive, respectively. After training, the LF/HF ratio, which summarizes the sympatho-vagal balance in HRV control, was similarly decreased in the AER and RES groups. After AER, b2 and b4 significantly improved. After RES, changes of b2 were of borderline significance, whereas changes of b4 did not reach statistical significance. However, comparison of changes in baroreceptor sensitivity indexes between groups did not show statistically significant differences. CONCLUSION: Both aerobic and resistance training improve several indices of the autonomic control of the cardiovascular system in patients with T2DM. Although these improvements seem to occur to a similar extent in both training modalities, some differences cannot be ruled out. CLINICAL TRIAL REGISTRATION NUMBER: NCT01182948, clinicaltrials.gov.

Psychological distress, self-efficacy and glycemic control in type 2 diabetes.

AIM: To investigate the association of glycemic control with depression, anxiety, self-efficacy and other diabetes-specific psychological measures in a cohort of adult patients with type 2 diabetes (T2D) free of severe chronic diabetes-related complications. METHODS AND RESULTS: In 172 T2D outpatients consecutively recruited at the Diabetes Center of Verona City Hospital, we performed a standard medical assessment and completed the Beck Depression Inventory-II (BDI-II), the Beck Anxiety Inventory (BAI) and the Multidimensional Diabetes Questionnaire (MDQ) Age, body mass index (BMI) and glycosylated hemoglobin (HbA1c) were (median [IQR]): 64.0 [58.0-69.0] years, 31.0 [28.0-34.4] kg/m2, and 7.3 [6.7-8.0] %, respectively. The overall prevalence of anxiety and depression was 14.5% and 18.6%, respectively. Higher levels of HbA1c were significantly (p < 0.001) associated with a number of MDQ dimensions, such as higher perceived interference with daily activities (Spearman's rho coefficient = 0.33), higher perceived diabetes severity (rho = 0.28) and lower self-efficacy (rho = -0.27), but not with depression or anxiety. These three variables were also independent predictors of higher HbA1c levels, when entered in a multivariable stepwise-forward regression model that also included age, BMI, diabetes duration and diabetes-specific social support as covariates. CONCLUSION: Lower self-efficacy and higher diabetes distress were closely associated with poorer glycemic control. No direct association between HbA1c and clinical psychological symptoms was detected. These results highlight that a number of diabetes-specific psychological variables may play a role amidst psychological distress and glycemic control. Further studies are needed to elucidate the relevance of diabetes distress and self-efficacy to the achievement of individual glycemic targets.

Effect of moderate aerobic exercise on sympatho-vagal balance in Type 2 diabetic patients.

AIMS: The purpose of the study was to determine long-term cardiovascular autonomic adaptation to moderate endurance aerobic exercise in people with Type 2 diabetes in order to test the hypothesis of an enhanced vagal drive. METHODS: We analysed the power spectral density of heart rate cyclic variations at rest, while lying, and while standing in 12 sedentary, non-smoking, Type 2 diabetic individuals. Testing was performed before and after a 6-month, supervised, progressive, aerobic training programme, twice weekly. Heart rate variability was assessed by autoregressive power spectral analysis (PSA); this method allows reliable quantification of low-frequency (LF) and high-frequency (HF) components, which are considered to be under mainly sympathetic and purely parasympathetic control, respectively. RESULTS: In 10-min electrocardiogram recordings, mean RR intervals values lying and standing were similar before and after physical exercise. Likewise, total heart rate variability, expressed as total power spectral density (PSD), was not altered by exercise. In contrast, on standing, the HF component, expressed in normalized units, was significantly higher (20.1 +/- 4 vs. 30.4 +/- 5, P < 0.01), whereas the LF component was significantly lower (68.1 +/- 7 vs. 49.8 +/- 8, P < 0.01) after exercise; hence, on standing, the LF/HF ratio, reflecting the sympathetic vs. parasympathetic balance, was markedly lower (16.2 +/- 11 vs. 5.2 +/- 3.2, P = 0.003). No significant exercise-related changes in these PSA components were observed on lying. CONCLUSIONS: A twice-weekly, 6-month, moderate, aerobic exercise programme, without a concomitant weight loss diet, is associated with significant improvements in cardiovascular autonomic function in overweight, non-smoking, Type 2 diabetic individuals.

Power spectral analysis of heart rate in hypothyroidism.

OBJECTIVE: The aim of the present study was to evaluate the impact of hypothyroidism on the autonomic regulation of the cardiovascular system by analysing separately sympathetic and parasympathetic influences on the heart. DESIGN: In seven newly diagnosed untreated hypothyroid patients we analysed power spectral density of heart rate cyclic variations at rest, while lying, and while standing. The same protocol was repeated after the induction of stable euthyroidism by levothyroxine (L-T(4)) treatment. The results were also compared with those obtained from seven age-, sex- and body mass index-matched control subjects. METHODS: Heart rate variability was evaluated by autoregressive power spectral analysis (PSA). This method allows reliable quantification of low frequency (LF) and high frequency (HF) components of the heart rate power spectral density. These are considered to be under mainly sympathetic and purely parasympathetic control respectively. In addition, heart rate variations during deep breathing, lying to standing, and Valsalva's manoeuvre were assessed. RESULTS: PSA showed a sharp reduction in the HF (parasympathetic) component in hypothyroid subjects compared with controls (lying, 29.4+/-5.4 vs 47.7+/-6.3 normalized units (NU) (means +/- s.e.m.), P<0.05; standing, 14.0+/-3.5 vs 32.1+/-3.6NU, P<0.005). Conversely, the LF (mainly sympathetic) component was higher in hypothyroid subjects than in controls (lying, 61.6+/-6.4 vs 45.4+/-6.7 NU; standing, 71.7+/-8.0 vs 53.1+/-5.6NU), this difference being significant in the standing position. Hence, the LF/HF ratio, which is considered an index of sympathovagal balance, was increased in hypothyroid subjects while both lying (2.75+/-0.6 vs 1.16+/-0.3; P<0.05) and standing (10.0+/-3.7 vs 1.85+/-0.3; P<0. 02). Total heart rate variability, expressed as total power spectral density, was lower in hypothyroid patients than in control subjects, this difference being significant in the lying position (574+/-126 vs 2302+/-994ms(2), P<0.05). In patients re-examined after L-T(4) therapy, complete normalization of cardiovascular parameters was observed (LF/HF ratio, lying, 1.26+/-0.4; standing, 2.56+/-0.8, both P<0.01 vs baseline values). The response to conventional cardiovascular autonomic tests was not significantly different between hypothyroid patients and healthy controls, and did not change in patients after therapy. CONCLUSIONS: These results suggest that, contrary to the clinical picture, thyroid hormone deficiency is associated with an increased sympathetic influence on the autonomic cardiovascular system. The changes in sympathetic function could be explained by a secondary adaptation to an altered cardiovascular responsiveness.

Cigarette smoking and plasma total homocysteine levels in young adults with type 1 diabetes.

OBJECTIVE: The purposes of this study were to compare plasma total homocysteine (tHcy) levels, a recognized cardiovascular risk factor, in nondiabetic subjects and type 1 diabetic patients, and to evaluate whether chronic cigarette smoking had a deleterious effect on plasma tHcy levels in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: Plasma tHcy concentrations were measured in 60 young type 1 diabetic patients without clinical evidence of macroangiopathy and in 30 healthy control subjects who were matched for age, sex, BMI, and smoking habit. RESULTS: Plasma tHcy levels were significantly higher in type 1 diabetic patients than in control subjects (12.5 +/- 4.8 vs. 10.3 +/- 2.2 micromol/l, P = 0.01). After stratification by smoking status, diabetic smokers had values for age, sex, BMI, lipids, creatinine, blood pressure, glycometabolic control, diabetes duration, and microvascular complications that were superimposable on their nonsmoking counterparts. Nevertheless, plasma tHcy levels were markedly elevated in diabetic smokers versus nonsmokers (15.5 +/- 5.7 vs. 10.6 +/- 3 pmol/l, P < 0.0001) in a dose-dependent fashion (P < 0.0001, by analysis of variance when subjects were categorized for the number of cigarettes smoked daily). CONCLUSIONS: Chronic cigarette smoking seems to adversely affect plasma tHcy levels in young adults with type 1 diabetes.

Chronic cigarette smoking is associated with increased plasma circulating intercellular adhesion molecule 1 levels in young type 1 diabetic patients.

OBJECTIVE: The purposes of this study were to compare plasma concentrations of circulating intercellular adhesion molecule 1 (cICAM-1), a marker of endothelial dysfunction, in nondiabetic subjects and type 1 diabetic patients and to evaluate whether chronic cigarette smoking had a deleterious effect on plasma cICAM-1 levels in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: Plasma cICAM-1 concentrations were measured in 54 young type 1 diabetic patients without clinical macroangiopathy and in 20 healthy control subjects who were matched for age, sex, BMI, and smoking habit. RESULTS: Type 1 diabetic patients had significantly higher plasma levels of cICAM-1 than control subjects (280.4 +/- 59 vs. 224 +/- 53.6 ng/ml, respectively) (P < 0.001). After stratification by smoking status, diabetic smokers had values for age, sex, BMI, lipids, blood pressure, glycemic control, diabetes duration, and chronic complications of diabetes that were super-imposable on their nonsmoking counterparts. Nevertheless, plasma cICAM-1 levels were markedly elevated in type 1 diabetic smokers (321.4 +/- 64.2 vs. 257.3 +/- 41.5 ng/ml, respectively) (P < 0.001) in a dose-dependent fashion (P < 0.001 by analysis of variance when subjects were categorized by number of cigarettes smoked per day). CONCLUSIONS: Chronic cigarette smoking has a deleterious effect on plasma cICAM-1 levels in young type 1 diabetic patients, which further supports the clinical importance of discouraging the initiation of smoking and promoting its cessation in people with type 1 diabetes.

Comparative assessment of peripheral sympathetic function by postural vasoconstriction arteriolar reflex and sympathetic skin response in NIDDM patients.

PURPOSE: The aim of the study was to compare peripheral sympathetic adrenergic and cholinergic nerve function in NIDDM (non-insulin-dependent diabetes mellitus) patients with various degrees of diabetic neuropathy and neuropathic foot ulceration. The parameters used were postural vasoconstriction arteriolar reflex (VAR) and sympathetic skin response (SSR), respectively. PATIENTS AND METHODS: Forty-seven NIDDM patients were studied. No patients had clinically significant peripheral vascular disease. They were divided according to peripheral somatic neuropathy, assessed by clinical score and vibration perception threshold (VPT). Twenty-two patients showed no significant evidence of peripheral neuropathy and normal VPT (DN-); 15 had signs and symptoms of neuropathy and VPT alteration (DN+); 10 had diabetic neuropathy and foot ulceration (DNU). Twenty-two normal subjects were also examined as a control group. Resting arteriovenous shunt skin blood flow, measured using laser-Doppler flowmetry, and the VAR of the big toe on lowering the foot were studied. Sympathetic skin response was assessed by an EMG apparatus. Autonomic function was also investigated by using standard cardiovascular reflex tests. RESULTS: Resting blood flow values were similar in the three NIDDM groups and in the control group. VAR to foot lowering was significantly impaired in all NIDDM groups by comparison with controls (72.8 +/- 2.1%, mean +/- SEM), this impairment being progressively more pronounced in DN- (58.8 +/- 2.3%, P < 0.001), DN+ (33.3 +/- 3.0%, P < 0.001 versus DN-) and DNU (8.6 +/- 2.7%, P < 0.001 versus DN+). Sympathetic skin response was assessed in 28 patients and was significantly impaired in DN-compared with the control group (2.53 +/- 0.04 versus 2.71 +/- 0.04 log mcV, P < 0.01). This impairment was severe in the DNU compared with the DN+ group (1.36 +/- 0.05 versus 2.26 +/- 0.04 log mcV, P < 0.005). A positive correlation was found between VAR values and SSR (P < 0.001), and these measurements were also closely correlated with several parameters of central autonomic and somatic neuropathy. CONCLUSION: These results indicate that peripheral sympathetic adrenergic and cholinergic fibers simultaneously undergo early alterations in diabetic patients, even when there is no clinical neuropathy. Our data also show almost complete abolition of peripheral sympathetic activity in NIDDM patients with foot ulceration.

Relationship between fasting insulin and cardiovascular risk factors is already present in young men: the Verona Young Men Atherosclerosis Risk Factors Study.

The associations between fasting plasma insulin concentration and risk factors for cardiovascular disease were examined in 979 18-year-old men participating in the Verona Young Men Atherosclerosis Risk Factors Study, a cross-sectional population-based study. Body mass index (BMI), waist-to-hip ratio (WHR), plasma triglycerides and uric acid concentrations, and blood pressure values significantly increased, and the high-density lipoprotein (HDL)-total cholesterol ratio decreased, across quartiles of fasting insulin. Total and low-density lipoprotein cholesterol, concentrations did not change significantly with the increase in fasting insulin levels. After adjustment for BMI, WHR, smoking, alcohol intake and physical activity, only plasma triglycerides significantly increased across insulin quartiles (F = 7.1; P < 0.001). However, systolic blood pressure and uric acid were close to statistical significance (P = 0.06-0.07). Multiple linear regression analysis confirmed that plasma insulin was independently correlated with plasma triglycerides and, to a lesser extent, with blood pressure and uric acid concentration. This analysis pointed out that BMI was a stronger independent predictor of all cardiovascular disease risk factors than fasting insulin. When subjects were categorized according to the number of metabolic and haemodynamic disorders occurring within the same individual, subjects with multiple disorders (i.e, three or four) had higher plasma insulin levels than those with none or few disorders, even after adjusting for BMI, WHR and behavioural variables (F = 4.0; P < 0.01). These results indicate that hyperinsulinaemia is already associated with a cluster of cardiovascular disease risk factors in young adulthood, the strongest independent association being with plasma triglycerides.

Relationship of uric acid concentration to cardiovascular risk factors in young men. Role of obesity and central fat distribution. The Verona Young Men Atherosclerosis Risk Factors Study.

OBJECTIVE: To examine the relationships of serum uric acid concentration with several risk factors of cardiovascular diseases (CVD). SUBJECTS: 957 men 18 y old participating in the Verona Young Men Atherosclerosis Risk Factors Study, a cross-sectional population-based study. MEASUREMENTS: Body mass index (BMI), waist/hip ratio (WHR), serum uric acid, serum lipids, blood pressure, fasting insulin and behavioural variables. RESULTS: Serum uric acid concentration showed positive associations with BMI (r = 0.24; P < 0.0001), WHR (r = 0.19; P < 0.0001) and serum triglyceride levels (r = 0.19; P < 0.0001); it was also significantly correlated to systolic (r = 0.08; P < 0.01) and diastolic (r = 0.11; P < 0.001) blood pressure, fasting insulin (r = 0.11; P < 0.001), total (r = 0.12; P < 0.001) and LDL cholesterol (r = 0.10; P < 0.01) plasma concentrations. Life-style characteristics, such as smoking and physical activity did not show any significant association, while daily alcohol intake was positively associated with uric acid concentration (r = 0.09; P < 0.01). While the adjustment for fasting insulin did not substantially change these results, the magnitude of the correlations between uric acid and CVD risk factors markedly decreased when allowance was made for BMI and WHR. Only triglycerides maintained an independent correlation with uric acid levels (r = 0.17; P < 0.0001). In multivariate regression analysis, serum triglycerides, BMI and WHR (at borderline significance) were independent positive predictors of uric acid (R2 of the model 0.122, P < 0.001), while fasting insulin concentration did not give any independent contribution to explain the variability uric acid levels. CONCLUSIONS: These data indicate that, already in young, essentially health subjects, hyperuricaemia associates with several components of the so-called insulin resistance syndrome, thus suggesting that increased levels of uric acid might be another member of this syndrome. In addition, these data suggest that obesity and central body fat distribution, rather than hyperinsulinaemia/insulin resistance, play a major role in linking hyperuricaemia with CVD risk factors clustering in the insulin resistance syndrome. Nevertheless, hypertrigliceridemia is related to hyperuricemia independently of obesity and central body fat distribution.

Acute effect of insulin on autonomic regulation of the cardiovascular system: a study by heart rate spectral analysis.

Insulin is suggested to have direct effects on the cardiovascular system but these are not well described. We assessed the possible influence of insulin on autonomic control of heart function. A 2-h hyperinsulinaemic euglycaemic clamp was performed in 10 healthy women (mean age 21.7 +/- 1.3 years), at two different insulin infusion rates: 80 mU m-2 and 400 mU m-2 min-1, in 7 and 3 subjects, respectively. Saline alone was infused in 4 controls. Power spectral analysis (PSA) of heart rate was recorded before and after 90-120 min of insulin infusion, as were blood pressure and heart rate. Although there were no significant changes in heart rate or blood pressure, PSA showed marked reductions of high frequency (HF) bands after insulin (2.60 +/- 0.12 vs 2.09 +/- 0.16 log ms2, p < 0.005), as at both low and high infusion rates (2.46 +/- 0.13 to 2.14 +/- 0.23 log ms2, p < 0.05, and 2.92 +/- 0.18 to 1.98 +/- 0.06 log ms2, p < 0.01, respectively). There were no significant changes of low frequency (LF) bands. Densities at LF and HF did not change significantly in control studies. As HF and LF are considered to reflect parasympathetic and mainly sympathetic control respectively, our observation of an increased LF/HF ratio (0.13 +/- 0.10 vs 0.63 +/- 0.13, p < 0.005) may be considered an index of relative sympathetic predominance induced by insulin infusion. We conclude that insulin affects the cardiovascular system, reducing vagal influence on the heart and inducing a relative hypersympathetic tone.

Power spectral analysis of heart rate in hyperthyroidism.

The aim of the present study was to evaluate the impact of hyperthyroidism on the cardiovascular system by separately analyzing the sympathetic and parasympathetic influences on heart rate. Heart rate variability was evaluated by autoregressive power spectral analysis. This method allows a reliable quantification of the low frequency (LF) and high frequency (HF) components of the heart rate power spectral density; these are considered to be under mainly sympathetic and pure parasympathetic control, respectively. In 10 newly diagnosed untreated hyperthyroid patients with Graves' disease, we analyzed power spectral density of heart rate cyclic variations at rest, while lying, and while standing. In addition, heart rate variations during deep breathing, lying and standing, and Valsalva's maneuver were analyzed. The results were compared to those obtained from 10 age-, sex-, and body mass index-matched control subjects. In 8 hyperthyroid patients, the same evaluation was repeated after the induction of stable euthyroidism by methimazole. Heart rate power spectral analysis showed a sharp reduction of HF components in hyperthyroid subjects compared to controls [lying, 13.3 +/- 4.1 vs. 32.0 +/- 5.6 normalized units (NU; P < 0.01); standing, 6.0 +/- 2.7 vs. 15.0 +/- 4.0 NU (P < 0.01); mean +/- SEM]. On the other hand components were comparable in the 2 groups (lying, 64.0 +/- 6.9 vs. 62.0 +/- 6.5 NU; standing, 77.0 +/- 6.5 vs. 78.0 +/- 5.4 NU). Hence, the LF/HF ratio, which is considered an index of sympathovagal balance, was increased in hyperthyroid subjects while both lying (11.3 +/- 4.5 vs. 3.5 +/- 1.1; P < 0.05) and standing (54.0 +/- 12.6 vs. 9.8 +/- 2.6; P < 0.02). This parameter was positively correlated with both T3 (r = 0.61; P < 0.05) and free T4 (r = 0.63; P < 0.05) serum levels. Among traditional cardiovascular autonomic tests, the reflex response of heart rate during lying to standing was significantly lower in hyperthyroid patients than in controls (1.12 +/- 0.03 vs. 1.31 +/- 0.04; P < 0.002). No statistically significant difference in reflex responses between the two groups was found in deep breathing or Valsalva's maneuver. In the 8 patients reexamined after methimazole treatment, we observed complete normalization of altered cardiovascular parameters, with slight predominance of the vagal component compared with controls. These results suggest that thyroid hormone excess may determine reduced parasympathetic activity and, thus, a relative hypersympathetic tone.

The Verona diabetes study: a population-based survey on known diabetes mellitus prevalence and 5-year all-cause mortality.

This population-based survey aimed to determine the prevalence of known diabetes mellitus on 31 December 1986, and to assess all-cause mortality in the subsequent 5 years (1987-1991) in Verona, Italy. In the study of prevalence, 5996 patients were identified by three independent sources: family physicians, diabetes clinics, and drug prescriptions for diabetes. Mortality was assessed by matching all death certificates of Verona in 1987-1991 with the diabetic cohort. Overall diabetes prevalence was 2.61% (95% confidence interval 2.56-2.67). Prevalence of insulin-dependent and non-insulin-dependent diabetes mellitus was 0.069% (0.059-0.078) and 2.49% (2.43-2.54), respectively. Diabetes prevalence sharply increased after age 35 years up to age 75-79, and finally declined. Prevalence was higher in men up to age 69 years, in women after age 75 years. Of the diabetic cohort 1260 patients (592 men, 668 women) died by 31 December 1991, yielding an overall standardized mortality ratio of 1.46 (CI 1.38-1.54). Even though the differences narrowed with age, mortality rates in the diabetic cohort were higher than in the non-diabetic population at all ages. Women aged 65-74 years showed observed/expected ratio higher than men (2.27, CI 1.92-2.66, vs 1.50, CI 1.30-1.72), while in other age groups the sex-related differences were not significant. Pharmacological treatment of diabetes was associated with an excess mortality, while treatment with diet alone showed an apparent protective effect on mortality (observed/expected ratio 0.73, CI 0.58-0.92).(ABSTRACT TRUNCATED AT 250 WORDS)

Mononuclear leukocytes from obese patients with type II diabetes have reduced activity of hexokinase, 6-phosphofructokinase and glucose-6-phosphate dehydrogenase.

In the present study we measured the activity of some cytosolic enzymes involved in intracellular glucose metabolism in mononuclear leukocytes from 77 obese subjects of which 39 were nondiabetic and 38 had newly-diagnosed untreated type II diabetes mellitus. 28 subjects (19 nondiabetic and 18 diabetic) had also a study of insulin binding to monocytes. 35 subjects (14 nondiabetic, 21 diabetic) underwent an insulin tolerance test for the evaluation of in vivo insulin action. Mononuclear leukocytes from diabetic obese patients showed significantly lower activities of hexokinase (HK), 6-phosphofructokinase (PFK) and glucose-6-phosphate dehydrogenase (G6PDH), while pyruvate kinase (PK) and 6-phosphogluconate dehydrogenase (6PGDH) activities were similar in the two groups. In the whole population HK and G6PDH activities inversely correlated with fasting and 2-h OGTT plasma glucose levels. Neither plasma insulin levels nor maximal specific insulin binding to monocytes were significantly correlated with any of the enzyme activities measured. Conversely, the parameter of insulin action generated by insulin tolerance test significantly correlated with HK, G6PDH and 6PGDH. These results indicate that in obese subjects the presence of diabetes is associated with a reduced activity of some enzymes of glucose metabolism in mononuclear leukocytes. This multiple enzymatic defect is correlated with the impairment of in vivo insulin action.

Influence of body fat and its regional localization on risk factors for atherosclerosis in young men.

A study was carried out in 1988 in Verona, Italy, to examine the relation of body fat and its localization to several risk factors for atherosclerosis in young men. Total body fat (bioelectrical impedance), waist and hip circumferences, and waist/hip circumference ratio were measured in 1,293 18-year-old men. Fasting serum levels of total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, and insulin, as well as systolic and diastolic blood pressure, were also measured. Significant differences were found in all metabolic and hemodynamic variables among quartiles of total body fat. Most of these differences remained significant after the authors controlled for the independent effect of fat localization and behavioral factors such as smoking, alcohol intake, and physical activity. Triglycerides, insulin, and blood pressure were significantly different among quartiles of waist/hip ratio, but these differences disappeared after the authors controlled for the independent effect of total body fat. These results indicate that in young men, irrespective of its regional localization, an excess of body fat is associated with a poor profile of risk for atherosclerosis. On the other hand, the prevalent localization of fat in the central part of the body is not independently associated with any risk factor.

Studies on the mechanism of action of sulphonylureas in type II diabetic subjects: gliquidone.

The mechanism of action of sulphonylureas is not completely understood. In the present study we evaluated the effects of gliquidone, a second-generation compound, on several metabolic parameters in 22 patients with untreated newly-diagnosed type II (noninsulin-dependent) diabetes mellitus. After either 1 or 6 months of treatment with gliquidone plus isocaloric diet we observed: 1) a significant decrease in fasting plasma glucose and glycemic profile after oral glucose load; 2) unchanged fasting and postglucose plasma insulin levels; 3) no change in fasting C-peptide levels but a significant increase in C-peptide concentrations after glucose challenge; 4) a significant increase in glucose disappearance rate from plasma following iv insulin injection; 5) an increase in the insulin-induced reduction of plasma levels of free-fatty acids; 6) no change in plasma C-peptide levels following iv insulin injection; 7) a significant increase in specific insulin binding to monocytes. After 6 but not 1 month of gliquidone therapy we also found an increase in the activity of hexokinase in circulating mononuclear leukocytes. These results suggest that the hypoglycemic effect of gliquidone occurs through either an increased beta cell response to glucose stimulus or an enhanced insulin sensitivity. The latter effect seems to depend on both receptor and postreceptor mechanisms.

Normal inhibition by somatostatin of glucose-stimulated B cell secretion in the obese subjects.

Aim of the present study was to evaluate whether the inhibitory effect of somatostatin on pancreatic B-cell secretion is normal in nondiabetic obese subjects. For this purpose plasma C-peptide concentrations were measured in 10 nondiabetic obese subjects and 10 nonobese healthy controls during a 4-h hyperglycemic (11 mmol/l) glucose clamp. Somatostatin was infused (2.5 nmol/min) during the third hour of the study period in order to inhibit glucose-stimulated B-cell secretion. Fasting C-peptide averaged 0.46 +/- 0.04 nmol/l (mean +/- SEM) in nonobese subjects, and 0.85 +/- 0.08 nmol/l in obese patients (P less than 0.001). In the period 0-120 min the area under the plasma C-peptide curve was significantly higher in obese than in nonobese subjects (292 +/- 23 vs. 230 +/- 17 nmol/l x 120 min, P less than 0.05), however, in the last 20 min of the glucose infusion period without somatostatin (100-120 min) plasma C-peptide was not significantly different in the two groups (2.94 +/- 0.32 nmol/l in nonobese subjects and 3.21 +/- 0.19 nmol/l in obese patients, p = NS). During somatostatin infusion while maintaining hyperglycemia, plasma C-peptide decreased in both groups, and in the period 160-180 min it averaged 0.89 +/- 0.12 nmol/l in control subjects and 0.93 +/- 0.08 nmol/l in obese patients (P = NS), with a percent reduction similar in the two groups (70 +/- 2% in controls and 71 +/- 2% in obese patients). After discontinuing somatostatin infusion, plasma C-peptide increased to concentrations which were higher in obese than in nonobese subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma concentrations of glucagon during hyperglycemic clamp with or without somatostatin infusion in obese subjects.

The aim of the present study was to evaluate whether the inhibitory effect on pancreatic A-cell exerted by hyperglycemic hyperinsulinemia and/or by somatostatin administration is impaired in human obesity. For this purpose plasma glucagon concentrations were measured in 8 obese and 8 nonobese nondiabetic subjects during a 4-h hyperglycemic clamp. Synthetic cyclic somatostatin-14 was infused at the rate of 2.5 nmol/min during the third hour of the study. Fasting plasma glucagon was higher in obese than in nonobese subjects (242 +/- 32 vs 163 +/- 15 pg/ml, p less than 0.05) (mean +/- SEM). In the last 20 min of the glucose infusion period preceding somatostatin administration (100-120 min of the study) plasma glucagon averaged 195 +/- 26 pg/ml in obese and 122 +/- 13 pg/ml in nonobese subjects (p less than 0.05), with a reduction of 19 +/- 3% in the former and 28 +/- 4% in the latter (p = n.s.). In both groups somatostatin infusion did not result in a further decrease in plasma glucagon, which averaged 192 +/- 27 pg/ml in obese and 123 +/- 16 pg/ml in nonobese subjects (p less than 0.05) in the 160-180 min period of the study. Also after discontinuing somatostatin infusion plasma glucagon levels did not change. These results suggest that in human obesity hyperglycemic hyperinsulinemia has a normal inhibitory effect on pancreatic A-cell and that somatostatin administration has no additive effect on hyperglycemia and hyperinsulinemia in either obese or nonobese nondiabetic subjects.

Plasma free fatty acid concentration during hyperglycemic glucose clamp with and without somatostatin infusion in obese subjects with normal glucose tolerance.

In the present study we evaluated the regulation of plasma free fatty acid (FFA) concentration by glucose and insulin in human obesity. To this purpose we measured plasma FFA concentration in normoglycemic, normoinsulinemic obese (n = 8) and nonobese (n = 8) healthy subjects during 240 min of exogenous hyperglycemia (hyperglycemic glucose clamp) in presence of both glucose-stimulated (0-120 min and 180-240 min) and somatostatin-inhibited (120-180 min) insulin secretion. We found that plasma FFA curves were roughly parallel in the 0-120 min period and FFA values of obese subjects were constantly higher throughout the experimental period. Moreover, the difference between the two groups was significant when individual data were expressed as a percent of fasting FFA value (P less than 0.0001 from 0 to 120 min). Plasma insulin levels were similar in the two groups during the entire study. The amount of glucose metabolized during the 80-120 min period was significantly lower in obese than in nonobese subjects (172 +/- 7 v. 341 +/- 11 mg/m2.min, P less than 0.01; means +/- s.e.). During the somatostatin period (120-180 min) plasma insulin was lowered close to basal values in both groups (116 +/- 15 and 109 +/- 11 pmol/l) and plasma FFA concentrations rose in a linear fashion. Our data suggest that suppression of plasma FFA concentrations by glucose and insulin is qualitatively similar in healthy nonobese and obese subjects, the latter having higher FFA values. Insulin action on FFA metabolism isn ot grossly impaired in obese subjects who are clearly insulin resistant as far as glucose metabolism is concerned.

Enzymatic activities related to intermediary metabolism of glucose in circulating mononuclear cells from obese humans: relationship to enzyme activity in adipose tissue.

In order to assess whether enzyme activities of glucose metabolism measured in mononuclear blood cells reflect those in a typical insulin target tissue, we studied hexokinase, 6-phosphofructokinase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase activities in lymphomonocytes and in hypogastric adipose tissue from 15 nondiabetic obese women. Statistically significant relationships were found in the activities of hexokinase (r = 0.53, p less than 0.05), 6-phosphofructokinase (r = 0.85, p less than 0.01), and 6-phosphogluconate dehydrogenase (r = 0.72, p less than 0.01) between the two tissues. These results suggest that mononuclear blood cells may be suitable as a model for studying cytosolic key enzymes involved in the glucose metabolism of humans.

Estimates of in vivo insulin action in man: comparison of insulin tolerance tests with euglycemic and hyperglycemic glucose clamp studies.

We compared estimates of in vivo insulin action derived from insulin tolerance tests (ITT) and euglycemic and hyperglycemic glucose clamp studies in 17 normal subjects and 19 patients with various diseases characterized by insulin resistance. Fifteen subjects underwent an ITT and a euglycemic clamp study, 17 subjects underwent an ITT and a hyperglycemic clamp study, and 4 subjects underwent all 3 tests. The ITT consisted of a bolus iv injection of regular insulin (0.1 U/kg BW). The plasma glucose disappearance rate during the 3- to 15-min period following the insulin injection was taken as a measure of insulin action. In both euglycemic and hyperglycemic clamp studies, which were carried out with standard techniques, the ratio between the amount of glucose infused to maintain glycemia at the desired level and the mean plasma insulin concentration from 60-120 min (M) (euglycemic clamp studies) or 20-120 min (I) (hyperglycemic clamp studies) was used as a measure of insulin action. A close correlation was found between plasma glucose disappearance rate and the M/I ratio during either the euglycemic (r = 0.811; P less than 0.001) or the hyperglycemic (r = 0.826; P less than 0.001) clamp studies. These results suggest that the 15-min ITT is suitable as a simple and rapid estimation of in vivo insulin action when glucose clamp studies are not feasible, as in large series of subjects or serial studies.