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Aims To assess the association between circulating levels of soluble CD40 ligand (sCD40L), an emerging cardiovascular risk factor, and γ-glutamyltransferase (GGT) activity concentrations in Type 1 diabetic subjects. Methods Plasma concentrations of sCD40L and GGT activity, a marker of liver dysfunction, were measured in 54 non-smoking, non-drinking, young Type 1 diabetic patients, who were free of diagnosed cardiovascular disease. Results When participants were grouped according to tertiles of GGT, plasma sCD40L concentrations steadily increased across GGT tertiles ( P = 0.007 for trend). Similarly, plasma sCD40L concentrations were positively correlated with plasma GGT levels in the whole group of participants ( r = 0.532; P < 0.0001). In multivariate linear regression analysis, plasma GGT activity levels were positively associated with sCD40L (standardized beta coefficient = 0.342; P = 0.027) independently of age, gender, diabetes duration, glycated haemoglobin, total cholesterol and systolic blood pressure. Further adjustment for the presence of diabetic retinopathy and microalbuminuria did not appreciably attenuate this association. Conclusions Our findings suggest that there is a strong, graded, relationship between plasma GGT activity and sCD40L concentrations in non-smoking, non-drinking, young Type 1 diabetic individuals. This association appears to be independent of numerous confounding factors. Further studies are required to confirm the reproducibility of these results. [ABSTRACT FROM AUTHOR]

BACKGROUND: The effect of insulin on glucose, protein metabolism, circulating fatty acids (FFA), potassium (K(+)) and C-peptide concentrations were investigated in a 12-year-old girl with leprechaunism. The mutations do not affect the insulin-receptor binding affinity and insulin-stimulated auto-phosphorylation of the receptor. METHODS: The subject was studied with a primed-continuous infusion of [6,6 - (2)H(2)] glucose and [1-(13)C] leucine during a basal period followed by two steps of insulin infusion (1 and 10 mU/kg/min) of 2 h each, during which plasma glucose level decreased from 131 to 115 and then to 95 mg/dL. RESULTS: Whole body glucose disposal was virtually unaffected by insulin, slightly decreasing from 21 micromol/kg/min in the basal period to 20 and to 19 micromol/kg/min during the two steps of insulin infusion, respectively. The endogenous leucine flux, an index of proteolysis, was completely insensitive to insulin, being 182, 189 and 180 micromol/kg/min, in the three periods, respectively. The FFA concentration (an indirect index of lipolysis) decreased from 1135 to 799 during step 1. During step 2 the FFA concentration rebounded to 917 micromol/L. The concentration of K(+) decreased from 4.2 to 3.2 mmol/L and an infusion of 20 mEq/h of KCl was necessary to prevent further hypokalemia (final value 3.3 mmol/l). The C-peptide concentration declined from 1.85 to 0.97 and then to 0.29 pmol/mL. CONCLUSIONS: The dissociation of control exerted by insulin on K+ uptake and on beta-cell secretion may rely on a differential expression and folding of the mutated receptors in the different insulin target tissues. Copyright (c) 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Non-alcoholic liver steatosis is associated with metabolic syndrome and type 2 diabetes. The prevalence of this condition in type 2 diabetes is estimated to be between 28 and 55%. Non-alcoholic liver steatosis is not a benign disease because of its potential progression to liver fibrosis, cirrhosis and cancer. The Verona diabetes study, a population-based observational study, on 7148 type 2 diabetic patients after 5 years of follow-up has reported an increased risk of death from gastrointestinal diseases, particularly from chronic liver cirrhosis. Moreover, in the same population after 10 years of follow-up a higher risk of mortality from liver cancer was observed and this risk increased significantly in obese patients (body mass index >30 kg/m2). Of note is that obese diabetic patients suffer an even higher prevalence of non-alcoholic liver steatosis. In conclusion, the Verona diabetes study showed an increased risk of mortality from liver cirrhosis and liver cancer in type 2 diabetic patients. Diverse pathophysiological mechanisms can be responsible, i.e. higher alcohol consumption, hepatitis and others but, considering the high prevalence of non-alcoholic liver steatosis in these patients, it is plausible to hypothesize that non-alcoholic liver steatosis may play a significant role in predisposing the liver of diabetics to chronic diseases. [ABSTRACT FROM AUTHOR]

To evaluate the cardiovascular risk associated with the presence of the Metabolic Syndrome in Type 2 diabetic subjects. Subjects with the Metabolic Syndrome, defined by WHO criteria, were identified in a large sample of non-insulin-treated Type 2 diabetic patients examined within the Verona Diabetes Complications Study ( n = 946). At baseline and after a mean of 4.5 years follow-up, cardiovascular disease (CVD) was assessed by medical history, physical examination, electrocardiogram (ECG) and echo-duplex of carotid and lower limb arteries. Death certificates and medical records of subjects who died during the follow-up were scrutinized in order to identify CVD deaths. In statistical analyses, CVD was considered as an aggregate end-point, including fatal and non-fatal coronary, cerebrovascular and peripheral vascular disease as well as ischaemic ECG abnormalities and vascular lesions at the echo-duplex. The proportion of subjects with the Metabolic Syndrome was very high (92.3%). At the baseline, 31.7% of subjects were coded positive for CVD, which was more prevalent in subjects with the Metabolic Syndrome (32.9 vs. 17.8%, P = 0.005). Among subjects free of CVD at the baseline ( n = 559), CVD events during the follow-up were significantly increased in patients with the Metabolic Syndrome as compared with those without it (19.9% vs. 3.9%, P < 0.001). Multiple logistic regression analysis showed that, along with sex, age, smoking and HbA1c, the presence of the Metabolic Syndrome independently predicted prevalent (OR 2.01, P = 0.045) and incident CVD (OR 4.89, P = 0.031). In Type 2 diabetes, the presence of the Metabolic Syndrome is associated with an almost 5-fold increase in CVD risk. Diabet. Med. **, ***–*** (2003) [ABSTRACT FROM AUTHOR]

Abstract Aims To identify the independent predictors of insulin sensitivity in Type 2 diabetes, and to establish whether isolated Type 2 diabetes (i.e. diabetes without overweight, dyslipidaemia and hypertension) is a condition of insulin resistance. Methods We examined 45 patients with non-insulin-treated Type 2 diabetes undergoing a 4-h euglycaemic hyperinsulinaemic clamp (20 mU/m2 per min) combined with 3 H-3-D-glucose and 14 C-U-glucose infusions and indirect calorimetry. We also examined 1366 patients with non-insulin-treated Type 2 diabetes randomly selected among those attending the Diabetes Clinic and in whom insulin resistance was estimated by Homeostasis Model Assessment (HOMA-IR). Results In the 45 patients undergoing glucose clamp studies, insulin-mediated total glucose disposal (TGD) was independently and negatively associated with systolic blood pressure (standardized β coefficient = -0.407, P = 0.003), plasma triglycerides (β= -0.355, P = 0.007), and HbA1c (β= -0.350, P = 0.008). The overall variability of TGD explained by these variables was 53%. Overweight diabetic subjects with central fat distribution, hypertension, hypertriglyceridaemia and poor glycometabolic control had insulin-mediated TGD values markedly lower than their lean counterparts without hypertension, with normal triglycerides, and with good glycometabolic control (16 ± 5 vs. 31 ± 10 µmol/min per kg lean body mass, P < 0.01). Nevertheless, the latter still were markedly insulin-resistant when compared with sex- and age-matched non-diabetic control subjects (31 ± 10 vs. 54 ± 13 µmol/min per kg lean body mass, P < 0.01). In the 1366 Type 2 diabetic patients of the epidemiological study, HOMA-IR value was independently associated with HbA1c (β = 0.283, P < 0.0001), plasma triglycerides (β = 0.246, P < 0.0001), body mass index (β = 0.139, P < 0.001), waist girth (β... [ABSTRACT FROM AUTHOR]

Objective To characterise the performance of Β-cell during a standard oral glucose tolerance test (OGTT). Design Fifty-six subjects were studied. A minimal analogic model of Β-cell secretion during the OGTT was applied to all OGTTs (see below). The amount of insulin secreted over 120′ in response to oral glucose (OGTT-ISR; Insulin Units 120′[sup −1] m[sup −2] BSA) and an index of Β-cell secretory ‘force’ (Β-Index; pmol.min[sup −2] m[sup −2] BSA) were computed with the aid of the model. In protocol A; 10 healthy subjects underwent two repeat 75 g OGTT with frequent (every 10′–15′) blood sampling for glucose and C-peptide to test the reproducibility of OGTT-ISR andΒ-Index with a complete or a reduced data set. In protocol B, 7 healthy subjects underwent three OGTTs (50, 100 or 150 g), to test the stability of the Β-Index under different glucose loads. In protocol C, 29 subjects (15 with normal glucose tolerance, 7 with impaired glucose tolerance and 7 with newly diagnosed type 2 diabetes) underwent two repeat 75 g OGTT with reduced (every 30′ for 120′) blood sampling to compare the reproducibility and the discriminant ratio (DR) of OGTT-ISR and Β-index with the insulinogenic index (IG-Index: ΔInsulin [sub 30prime;] - Basal>/Δ/A Glucose [sub 30′] - Basal>. In protocol D, 20 subjects (14 with normal glucose tolerance, 5 with impaired glucose tolerance and 1 with newly-diagnosed type 2 diabetes) underwent a 75 g 0GTT and an intravenous glucose tolerance test (IVGTT) on separate days to explore the relationships between acute (0′– 10′) insulin response (AIR) during the IVGTT andΒ-index and OGTT-ISR during the OGTT. Results In all protocols, the minimal analogic model of C-peptide secretion achieved a reasonable fit of the experimental data. In protocol A; a good reproducibility of both Β-index and OG... [ABSTRACT FROM AUTHOR]

Background: Ageing is characterized by a decreased functional reserve, a concept defined as homeostenosis. We assessed the impact of long-term exposure to the average value (mean) or to the variability (coefficient of variation) of fasting glycaemia, body mass index (BMI) and pulse pressure on total mortality in a cohort of type 2 diabetic patients., Methods: Fasting glycaemia, BMI and pulse pressure values were collected over a period of 3 years in 1 319 type 2 diabetic patients who were subsequently followed up for 10 years. For each patient, the means and the coefficients of variation of fasting glycaemia, BMI and pulse pressure were computed. The adverse impact of these risk factors on total mortality was assessed in patients aged < 65 years (n = 565) and in those aged > or = 65 years (n = 754), separately., Results: During the 10 years of follow-up, 438 patients died. In younger diabetic patients, the means of fasting glycaemia [hazard ratio (HR) of III tertile versus I tertile = 2.11, 95% confidence interval (CI): 1.22-3.64], BMI (HR = 1.88, 1.12-3.14) and pulse pressure (HR = 2.36, 1.34-4.16) were independently associated with total mortality, while in older patients they were not. In contrast, the coefficients of variation of glycaemia (HR = 1.56, 1.17-2.08), BMI (HR = 1.34, 1.03-1.75) and pulse pressure (HR = 1.34, 1.03-1.74) independently predicted total mortality only in older patients., Conclusions: Our findings suggest that the variability of fasting glycaemia, body weight and blood pressure (BP) is independently associated with an increased risk of all-cause mortality in older type 2 diabetic patients. Future studies are required to confirm the reproducibility of our findings., (Copyright 2008 John Wiley & Sons, Ltd.)