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.

Type 2 diabetes mellitus: a disease of the governance of the glucose-insulin system: an experimental metabolic control analysis study.

BACKGROUND AND AIMS: The relatives role of each component of the glucose-insulin system in determining hyperglycemia in type 2 diabetes is still under debate. Metabolic Control Analysis (MCA) quantifies the control exerted by each component of a system on a variable of interest, by computing the relevant coefficients of control (CCs), which are systemic properties. We applied MCA to the intravenous glucose tolerance test (IVGTT) to quantify the CCs of the main components of the glucose-insulin system on intravenous glucose tolerance. METHODS AND RESULTS: We combined in vivo phenotyping (IVGTT/euglycaemic insulin clamp) and in silico modeling (GLUKINSLOOP.1) to compute the CCs of intravenous glucose tolerance in healthy insulin-sensitive (n = 9, NGR-IS), healthy insulin-resistant (n = 7, NGR-IR) and subdiabetic hyperglycemic (n = 8, PreT2DM) individuals and in patients with newly diagnosed type 2 diabetes (n = 7, T2DM). Altered insulin secretion and action were documented in NGR-IR and PreT2DM groups, but only 1st phase insulin secretion was significantly lower in T2DM than in PreT2DM (p < 0.05). The CCs changed little in the nondiabetic groups. However, several CCs were significantly altered in the patients (e.g. CCs of beta cell: -0.75 ± 0.10, -0.64 ± 0.15, -0.56 ± 0.09 and -0.19 ± 0.04 in NGR-IS, NGR-IR, PreT2DM and T2DM, respectively; p < 0.01 by MANOVA), and they could not be corrected by matching in silico nondiabetic and T2DM groups for 1st phase secretion. CONCLUSIONS: Type 2 diabetes is characterized not only by loss of function of the elements of the glucose-insulin system, but also by changes in systemic properties (CCs). As such, it could be considered a disease of the governance of the glucose-insulin system.

Variants and haplotypes of TCF7L2 are associated with ß-cell function in patients with newly diagnosed type 2 diabetes: the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 1.

CONTEXT: Intronic variants of TCF7L2 are confirmed genetic risk factors for type 2 diabetes and are associated to alterations in beta cell function in nondiabetic individuals. OBJECTIVE: The objective of the study was to test whether TCF7L2 variability may affect ß-cell function also in patients with type 2 diabetes. DESIGN: This was a cross-sectional association study. SETTING: The study was conducted at a university hospital referral center for diabetes. PATIENTS: Patients included 464 (315 males and 149 females) glutamic acid decarboxylase-negative patients [age: median 59 yr (interquartile range: 52-65); body mass index: 29.3 kg/m(2) (26.5-32.9); fasting plasma glucose: 7.0 mmol/liter (6.1-8.0)] with newly diagnosed type 2 diabetes. INTERVENTION(S): Interventions included frequently sampled oral glucose tolerance test and euglycemic insulin clamp. MAIN OUTCOME MEASURE(S): ß-Cell function (derivative control and proportional control); insulin sensitivity; genotypes of the following TCF7L2 single-nucleotide polymorphisms: rs7901695, rs7903146, rs11196205, and rs12255372. RESULTS: Both rs7901695 and rs7903146 diabetes risk alleles were associated with reduced proportional control of ß-cell function (P = 0.019 and P = 0.022, respectively). Two low-frequency haplotypes were associated with extreme (best and worst) phenotypes of ß-cell function (P < 0.01). No associations between TCF7L2 genotypes and insulin sensitivity were detected. CONCLUSIONS: TCF7L2 diabetes risk variants, either as single-nucleotide polymorphisms or as haplotypes, detrimentally influence ß-cell function and might play a role in determining the metabolic phenotype of patients with newly diagnosed type 2 diabetes.

Glomerular filtration rate, albuminuria and risk of cardiovascular and all-cause mortality in type 2 diabetic individuals.

BACKGROUND AND AIMS: To assess all-cause and cardiovascular mortality in type 2 diabetic individuals according to estimated glomerular filtration rate (eGFR) and albuminuria. METHODS AND RESULTS: We followed 2823 type 2 diabetic outpatients for a median period of 6 years for the occurrence of all-cause and cardiovascular mortality. eGFR was estimated using the abbreviated Modification of Diet in Renal Disease study equation. At baseline, an eGFR < 60 ml/min/1.73 m² and abnormal albuminuria were present in 22.5% and 26.0% of participants, respectively. During follow-up, a total of 309 patients died, 53% of deaths were secondary to cardiovascular causes. Risks of all-cause and cardiovascular mortality increased progressively with decreasing eGFR and increasing albuminuria. After adjustment for age, sex, body mass index, smoking, hypertension, diabetes duration, hemoglobin A1c, plasma lipids, medications use (hypoglycemic, anti-hypertensive, anti-platelet or lipid-lowering drugs) and albuminuria, the hazard ratios of all-cause and cardiovascular mortality per 1-SD decrease in eGFR were 1.53 (95%CI 1.2-2.0; p < 0.0001) and 1.51 (95%CI 1.05-2.2; p=0.023), respectively. A similar pattern in the risk of all-cause and cardiovascular mortality was seen for albuminuria (1.14, 1.01-1.3, p=0.028 and 1.19, 1.01-1.4, p=0.043 per 1-SD increase in albuminuria, respectively) after adjustment for eGFR and other potential confounders. CONCLUSIONS: These findings suggest that both decreasing eGFR and rising albuminuria are associated with all-cause and cardiovascular mortality in type 2 diabetic individuals, independently of traditional risk factors and diabetes-related variables.

Incidence of severe nocturnal hypoglycemia in patients with type 1 diabetes treated with insulin lispro or regular human insulin in addition to basal insulin glargine.

BACKGROUND AND AIMS: Once-daily (OD) basal insulin glargine (GLA) can be used as part of a multiple daily injection regimen in patients with type 1 diabetes mellitus. This randomized, multicenter study compared GLA+prandial regular human insulin (RHI) with GLA+prandial insulin lispro (LIS) in reducing the incidence of severe nocturnal hypoglycemia at endpoint. In addition, the effects on glycemic control of both treatments were investigated. METHODS AND RESULTS: Patients (489) previously on neutral protamine Hagedorn (NPH) insulin or GLAR plus RHI/LIS were switched to, or continued on GLA (target fasting blood glucose [FBG]=5.0-6.7 mmol/L [90-120 mg/dL]) for 8 weeks (qualification phase) prior to randomization; patients continued with their previous bolus insulin. Patients (n=395) were then randomized to LIS (n=193) or RHI (n=202) and treated for 16 weeks. The proportion of patients experiencing severe nocturnal hypoglycemia at the end of the study was 1.55% (n=3) in the RHI group and 1.11% (n=2) in the LIS group (p=0.938 between groups); the mean difference was 0.44% (95% CI: -1.77, 2.21), suggesting non-inferiority of RHI versus LIS. At the end of the study, both treatments did not differ with respect to glycemic control, as measured by hemoglobin A(1c) and FBG. CONCLUSION: These results suggest that GLA+LIS and GLA+RHI treatments were associated with a similar and low rate of severe nocturnal hypoglycemia. Further studies with greater patient sizes are necessary to verify the findings from the current study.

Abnormal serum alanine aminotransferase levels are associated with impaired insulin sensitivity in young women with polycystic ovary syndrome.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) are both associated with insulin resistance.We assessed whether NAFLD is associated with impaired insulin sensitivity in PCOS women independently of age and total adiposity. SUBJECTS AND METHODS: We enrolled 14 young PCOS women with NAFLD, 14 women with PCOS alone and 14 healthy controls, who were matched for age, body mass index, and total body fat (by bio-impedance analyzer). NAFLD was diagnosed by the surrogate measure of abnormal serum alanine aminotransferase (ALT) concentrations (defined as ALT>19 U/l) after excluding other secondary causes of liver disease (alcohol, virus, and medications). Insulin sensitivity was measured by euglycemic hyperinsulinemic clamp. RESULTS: Insulin sensitivity was markedly decreased (p<0.001) in PCOS women with abnormal ALT levels, whereas it was similar between PCOS women with normal ALT levels andmatched healthy controls (8.3+/-2.5 vs 12.1+/-1.7 vs 13.2+/-1.8 mg/min x kg of fat-free mass, respectively). PCOS women with abnormal ALT levels also had higher plasma triglycerides and lower HDLcholesterol concentrations than those with PCOS alone. There was a strong inverse association between serum ALT levels and insulin sensitivity in the whole group of PCOS women (r=-0.59, p=0.0013). CONCLUSIONS: Abnormal serum ALT levels, as surrogate measure of NAFLD, are closely associated with impaired insulin sensitivity in young PCOS women in a manner that is independent from the contribution of age and total adiposity. Early recognition of NAFLD by radiological imaging tests in this group of young patients is warranted.

Higher HDL cholesterol levels are associated with a lower incidence of chronic kidney disease in patients with type 2 diabetes.

BACKGROUND AND AIMS: Type 2 diabetes is one of the most important risk factor for the development of chronic kidney disease (CKD). Recently, it has been shown that lower high-density lipoprotein cholesterol (HDL-C) levels predicted the development of microalbuminuria in type 2 diabetic individuals. We have prospectively assessed the effects of plasma HDL-C levels on the incidence of CKD in a large cohort of type 2 diabetic patients. METHODS AND RESULTS: We followed 1987 type 2 diabetic outpatients with normal or near-normal kidney function at baseline for 5 years for the occurrence of incident CKD defined as glomerular filtration rate < or = 60 mL/min/1.73 m(2) (as estimated by the abbreviated Modified Diet and Renal Disease Study equation). Cox proportional hazards models were used to examine the independent relationship between plasma HDL-C levels and incident CKD. During a median follow-up of 5 years, 11.8% (n=234) of participants developed incident CKD. In multivariate regression analysis, higher HDL-C levels were associated with a lower risk of incident CKD (multiple-adjusted hazard ratio 0.76; 95% coefficient intervals 0.61-0.96; p=0.025) independently of age, gender, body mass index, hypertension, smoking history, diabetes duration, hemoglobin A1c, plasma triglycerides, LDL-cholesterol, presence of diabetic retinopathy, baseline albuminuria, and current use of medications (anti-hypertensive, anti-platelet, lipid-lowering and hypoglycemic drugs). CONCLUSIONS: Higher plasma levels of HDL-C are associated with a lower risk of incident CKD in a large cohort of type 2 diabetic adults independently of numerous confounding factors.

Is fasting glucose variability a risk factor for retinopathy in people with type 2 diabetes?

AIMS: Fasting plasma glucose variability strongly predicts the incidence of cardiovascular events in type 2 diabetic patients. We prospectively assessed whether fasting plasma glucose variability predicts the development/progression of retinopathy in a large cohort of type 2 diabetic outpatients. METHODS: In the period 1996-1999, 1019 type 2 diabetic participants (aged 69+/-11 years) in the Verona Diabetes Study underwent at least 3 fasting plasma glucose (FPG) determinations and an eye examination by retinography. Of these, 746 underwent a 2nd eye examination in the period 2000-2004, while 273 did not (102 patients had died before undergoing the 2nd eye examination). For each patient, the mean (M-FPG) and the coefficient of variation of FPG (CV-FPG) were computed. RESULTS: By the 2nd eye examination, 124 patients had either developed new retinopathy (79 patients) or progressed to a more severe degree of retinopathy (45 patients). In a multivariable logistic regression analysis, the development/progression of retinopathy was independently predicted by average glycaemia over time, expressed as glycated haemoglobin (odds ratio [OR] 1.82, 95%CI 1.40-2.38 for 1 SD increase) or M-FPG (OR 1.88, 1.47-2.41), but not by CV-FPG. Among other independent variables, HDL-cholesterol was inversely associated with the development/progression of retinopathy. CONCLUSIONS: These results suggest that in elderly type 2 diabetic patients the magnitude of hyperglycaemia, but not fasting plasma glucose variability, strongly predicts the development/progression of diabetic retinopathy independently of other known risk factors.

Relationship between soluble CD40 ligand and gamma-glutamyltransferase concentrations in non-drinking, young Type 1 diabetic individuals.

AIMS: To assess the association between circulating levels of soluble CD40 ligand (sCD40L), an emerging cardiovascular risk factor, and gamma-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.

Diabetic retinopathy is associated with an increased incidence of cardiovascular events in Type 2 diabetic patients.

AIMS: We investigated the association of diabetic retinopathy with the risk of incident cardiovascular disease (CVD) events in a large cohort of Type 2 diabetic adults. METHODS: Our study cohort comprised 2103 Type 2 diabetic outpatients who were free of diagnosed CVD at baseline. Retinal findings were classified based on fundoscopy (by a single ophthalmologist) to categories of no retinopathy, non-proliferative retinopathy and proliferative/laser-treated retinopathy. Outcomes measures were incident CVD events (i.e. non-fatal myocardial infarction, non-fatal ischaemic stroke, coronary revascularization procedures or cardiovascular death). RESULTS: During approximately 7 years of follow-up, 406 participants subsequently developed incident CVD events, whereas 1697 participants remained free of diagnosed CVD. After adjustment for age, body mass index, waist circumference, smoking, lipids, glycated haemoglobin, diabetes duration and medications use, patients with non-proliferative or proliferative/laser-treated retinopathy had a greater risk (P < 0.001 for all) of incident CVD events than those without retinopathy [hazard ratio 1.61 (95% confidence interval 1.2-2.6) and 3.75 (2.0-7.4) for men, and 1.67 (1.3-2.8) and 3.81 (2.2-7.3) for women, respectively]. After additional adjustment for hypertension and advanced nephropathy (defined as overt proteinuria and/or estimated glomerular filtration rate < or = 60 ml/min/1.73 m(2)), the risk of incident CVD remained markedly increased in those with proliferative/laser-treated retinopathy [hazard ratio 2.08 (1.02-3.7) for men and 2.41 (1.05-3.9) for women], but not in those with non-proliferative retinopathy. CONCLUSIONS: Diabetic retinopathy (especially in its more advanced stages) is associated with an increased CVD incidence independent of other known cardiovascular risk factors.

Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients.

AIMS/HYPOTHESIS: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease in type 2 diabetes. Currently, there is a lack of information on associations between NAFLD and microvascular complications of diabetes. We assessed the associations between NAFLD and both chronic kidney disease (CKD) and retinopathy in a large cohort of type 2 diabetic individuals using a cross-sectional design. METHODS: Prevalence rates of retinopathy (by ophthalmoscopy) and CKD (defined as overt proteinuria and/or estimated GFR

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.

Clinical efficacy and tolerability of alpha-blocker doxazosin as add-on therapy in patients with hypertension and impaired glucose metabolism.

BACKGROUND AND AIM: The aim of this trial was to evaluate the effect of doxazosin as add-on therapy in patients with hypertension not adequately controlled on current antihypertensive therapy, and impaired glucose metabolism. The effect of doxazosin administered as add-on therapy was to be considered significant both from clinical and statistical viewpoints if the proportion of patients with adequate control of blood pressure (BP<130/85 mmHg) would be at least 30% after 16 weeks of combined therapy. METHOD AND RESULTS: It was an open, multicenter phase IV study, lasting 19 weeks: 3-week qualifying/placebo run-in period+16-week dose titration/add on therapy period, involving 264 out-patients (158 m and 106 f; mean age+/-SD: 60.9+/-8.6 years; mean BMI+/-SD: basal 29.5+/-5.1, final 30.2+/-4.6) with blood pressure still >130/85 mmHg in spite of the antihypertensive treatment (ACE inhibitors 44%, AT II antagonists 21%, Ca antagonists 12%, other drugs 8%, polytherapy 15%) and affected by type 2 diabetes (n=219), impaired fasting glucose (IFG; n=16) or impaired glucose tolerance (IGT; n=29). Following a run-in, 3-week qualifying phase during which placebo was added to ongoing antihypertensive treatment, 16-week treatment with doxazosin was added at dosages from 1 up to 8 mg/day. Main outcome measures were: the percentage of patients with blood pressure <130/85 mmHg at the end of treatment; the effects of the combination therapy on glyco-lipidic metabolism: fasting plasma glucose, fasting insulin, glycated hemoglobin, insulin resistance (HOMA-R), plasma lipids; and the effect on the 10-year CHD risk (Framingham equation). RESULTS: 35% of patients were responsive (BP<130/85 mmHg) to add-on treatment with doxazosin (CI 90%: 30.3%-40.4%; P<0.05, stat. an. intention to treat). During the run-in phase with placebo, mean SBP/DBP (+/-SD) decreased from 155.6+/-13.2/91.8+/-6.8 mmHg (Week -3) to 151.9+/-12.9/90.1+/-7.2 mmHg (Week -1) and to 151.2+/-11.5/90.1+/-6.9 mmHg (Week 0). During add-on treatment with doxazosin, mean SBP/DBP (+/-SD) further decreased to 144.9+/-15.2/86.3+/-8.3 mmHg (Week 4), 139.7+/-15.3/83.4+/-7.9 mmHg (Week 8), 135.5+/-14.3/81.7+/-7.6 mmHg (Week 12) and 136.4+/-14.5/81.0+/-7.0 mmHg (Week 16). Overall, mean BP changes reached a plateau of about -15 mmHg (SBP) and -9 mmHg (DBP) after 16 weeks of treatment; at each visit the mean decreases from baseline were statistically significant. The following mean values of metabolic parameters were reduced during the study: fasting plasma glucose (-4.1mg/dl; -2.8%), fasting insulin (-2 microU/ml; -12.3%; P<0.05), glycated hemoglobin (-0.12%; -1.7%), HOMA-R (-1.03; -18.2%; P<0.05), total cholesterol (-1.85 mg/dl; -1.1%), LDL cholesterol (-1.35 mg/dl; -0.8%) and triglycerides (-5.64 mg/dl; -2.4%); mean HDL cholesterol increased (+1.79 mg/dl; +3.9%; P<0.01). At the end of study treatment, the percentage of patients with lab values returned within normal ranges, in comparison with basal values, was statistically significant (P<0.05) for the following parameters: fasting plasma glucose (6.3%), fasting insulin (7.5%), LDL cholesterol (6.0%). Ten-year CHD risk (+/-SD) decreased from 16.4+/-7.8% to 13.6+/-7.4% (final vs. basal: -2.87+/-3.9; -17%; P<0.01). Six patients (2.3%) reported 8 adverse drug reactions: dizziness (3), edema (2), headache (2), asthenia (1). In one out of these 6 patients, in whom doxazosin was associated to the ACE inhibitor quinapril, adverse reaction (peripheral edema) led to treatment withdrawal. CONCLUSION: In patients not responsive to antihypertensive treatment and concomitantly affected by impaired glucose metabolism, achievement of target BP was obtained in more than one third of cases after 16-week add-on treatment with doxazosin. Changes in glyco-lipidic parameters and reduction of 10-year CHD risk observed during the study, although of moderate extent, confirm the overall favourable effect of antihypertensive combinations including doxazosin.

Review article: type 2 diabetes and chronic liver disease in the Verona diabetes study.

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.

Validation of the Italian version of the WHO-Well-Being Questionnaire (WHO-WBQ) and the WHO-Diabetes Treatment Satisfaction Questionnaire (WHO-DTSQ).

AIM: To validate the Italian version of the World Health Organization (WHO)-Well-Being Questionnaire (WBQ) and the WHO-Diabetes Treatment Satisfaction Questionnaire (DTSQ) in Type 1 and Type 2 diabetic patients. METHODS: The cultural adaptation of the questionnaires was performed by using standard forward/backward techniques. Internal consistency reliability was estimated by Cronbach's alpha coefficient. Construct validity was evaluated using the Short Form-36 (SF-36) Health Status Questionnaire. Finally, the discriminative properties of the questionnaires were evaluated relative to the patients' characteristics. The questionnaires were administered to a random sample of patients identified in twelve outpatient diabetes clinics. RESULTS: Overall, 412 subjects were recruited, of whom 96 (23%) with Type 1 diabetes. Item-scale correlations were >0.40 for all the items. Cronbach's alpha coefficient was 0.86 for the WHO-DTSQ and ranged between 0.79 and 0.91 for the WHO-WBQ. High correlations were found between WHO-WBQ scales and the mental dimensions of the Short Form-36 (SF-36) questionnaire, but not between WHO-DTSQ and SF-36 scores. Women, obese subjects, those with longer diabetes duration and multiple complications showed a worse quality of life in all of the four areas of the WHO-WBQ. In Type 2 diabetic subjects, SF-36 scores, but not WHO-WBQ scores, were able to discriminate the population according to the treatment modalities. Lower levels of treatment satisfaction were related to female gender, longer diabetes duration, insulin treatment, presence of diabetes complications and HbA1c levels >7.0%. The flexibility of the treatement was perceived as a major problem even among patients treated with oral agents. CONCLUSIONS: The WHO-DTSQ can be considered as a valuable instrument to be used internationally for the description of diabetes treatment satisfaction. The WHO-WBQ also shows adequate psychometric properties, but additional data are needed to clarify whether it is more sensitive than SF-36, the most widely used generic instrument.

Insulin sensitivity and hepatic steatosis in obese subjects with normal glucose tolerance.

BACKGROUND AND AIM: Hepatic steatosis has recently been associated with insulin resistance and other metabolic abnormalities as a possible feature of the metabolic syndrome, but it is still uncertain how hepatic steatosis and insulin sensitivity are connected. Furthermore, obesity is a well characterized insulin resistant condition that is often associated with hepatic steatosis. The aim of this study was to verify whether hepatic steatosis further worsens insulin sensitivity in obese subjects by comparing the degree of insulin sensitivity in obese subjects with normal glucose tolerance on the basis of the presence or absence of hepatic steatosis. METHODS AND RESULTS: We analyzed 86 obese patients whose alcohol intake was less than 20 g/day and who showed no signs of viral hepatopathy. All of the subjects had normal glucose tolerance as shown by an oral glucose tolerance test. Insulin resistance was estimated using the homeostasis model assessment (HOMA) method and the diagnosis of steatosis was determined by an ultrasound scan of the liver. The subjects were comparable in terms of body mass index (BMI), lipid profile and serum uric acid levels; those with hepatic steatosis were slightly older and tended to have higher systolic blood pressure and fasting glycemia levels. The HOMA values were significantly higher in the group with hepatic steatosis (4.48 +/- 2.22 vs 3.11 +/- 1.47, p=0.002). There was no linear correlation between HOMA and alanine aminotransferase (ALT) levels, but a close linear correlation between HOMA and BMI (r=0.40; p<0.001). The effect of hepatic steatosis on HOMA remained significant after adjusting for age and gender (covariance analysis, p=0.006). When BMI was added to the covariance analysis, hepatic steatosis retained its statistical significance. CONCLUSION: Our data suggest that hepatic steatosis can increase insulin resistance independently of obesity.

The Metabolic Syndrome is an independent predictor of cardiovascular disease in Type 2 diabetic subjects. Prospective data from the Verona Diabetes Complications Study.

AIMS: To evaluate the cardiovascular risk associated with the presence of the Metabolic Syndrome in Type 2 diabetic subjects. METHODS: 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. RESULTS: 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). CONCLUSIONS: In Type 2 diabetes, the presence of the Metabolic Syndrome is associated with an almost 5-fold increase in CVD risk.

Metabolic syndrome: epidemiology and more extensive phenotypic description. Cross-sectional data from the Bruneck Study.

OBJECTIVES: The present study aimed at evaluating the prevalence of the Metabolic Syndrome and at identifying its additional clinical features. RESEARCH DESIGN AND METHODS: Within a prospective population-based survey examining 888 subjects aged 40-79 y, subjects were identified fulfilling the WHO and the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria for diagnosing the Metabolic Syndrome. In these subjects and in the rest of the sample (controls), several metabolic and nonmetabolic biochemical parameters were compared. RESULTS: The prevalence of the Metabolic Syndrome by WHO criteria was 34.1% (95% CI 31.0-37.2) and by NCEP-ATPIII criteria 17.8% (15.5-20.3). The prevalence was significantly higher in older subjects and in those less physically active. Subjects with the Metabolic Syndrome either by WHO or by NCEP-ATPIII criteria showed higher levels of oxidized low-density lipoprotein, apolipoprotein B, urate, leptin, fibrinogen, leukocytes, erythrocyte sedimentation rate, GOT, gamma-GT and soluble endothelial adhesion molecules (E-selectin, vascular adhesion molecule-1 and intercellular adhesion molecule-1) and lower apolipoprotein A concentrations. Insulin resistance, as assessed by the Homeostasis Model Assessment, increased with the increase in the number of traits composing the syndrome found within the single individual. Subjects with insulin resistance had more pronounced abnormalities in several parameters, including the additional features of the syndrome (eg fibrinogen and soluble adhesion molecules). CONCLUSIONS: The Metabolic Syndrome occurs very frequently in the general population aged 40-79 y, and is associated with several additional metabolic and nonmetabolic abnormalities that likely contribute to an increased cardiovascular risk. Insulin resistance seems to play a major role in classic and additional abnormalities featuring the Metabolic Syndrome.

Self-reported exercise and quality of life in young type 1 diabetic subjects.

Evaluation of quality of life is important in treatment strategies of chronic illnesses, such as diabetes mellitus. The present study aimed at measuring the impact of self-reported exercise on quality of life in T1DM patients. Fifty-three young T1DM patients on intensive insulin-treatment regime who were regularly attending the Diabetes Clinic were selected. At the end of the scheduled clinic visit, they were asked to fill in an Italian version of the Diabetes Quality of Life (DQOL) questionnaire; 30 patients exercised regularly, whereas 23 were sedentary. Patients with clinical and laboratory evidence of major eye, renal and cardiovascular diseases were excluded. A significant difference in the scale of satisfaction (1.9 +/- 0.3 vs 2.2 +/- 0.5; p = 0.009), along with a better HbA1c level (7.0 +/- 1.0 vs 7.8 +/- 1.2; p = 0.014), was observed in physically active patients as compared to sedentary ones, whereas there were no differences between the 2 groups with respect to the impact and worry scale. Moreover, there were no significant correlations between glucose control parameters and the quality of life scores. In conclusion, we showed that self-reported exercise is associated with both a better quality of life and a better metabolic control in young T1DM patients. Further efforts should however be made to recognize all factors that can help motivate patients to exercise.

Body mass index and the risk of mortality in type II diabetic patients from Verona.

OBJECTIVE: The relation between body weight and mortality in type II diabetic patients has not been fully elucidated. The aim of the present study was to evaluate the impact of body weight on mortality in a well-characterized type II diabetic cohort. RESEARCH DESIGN AND METHODS: We examined a cohort of 3398 type II diabetic patients, alive on December 1986 and followed up for 10 years, to assess mortality and its causes and to investigate the relationship between body mass index (BMI) and mortality from all and specific causes. For this purpose, survival in the different quartiles of BMI was evaluated by a Cox model, controlling for sex, age, treatment, smoking, duration of diabetes, hypertension, and fasting plasma glucose. The Cox model was applied either excluding (model 1) or including (model 2) the last three variables. RESULTS: During the 10 ys of follow-up, 1212 deaths (639 women, 573 men) occurred in the cohort under study. Since the interaction between BMI and age was statistically significant (P = 0.002), survival was studied separately in people aged <65 and > or =65 y (median age of the cohort = 65.9 y). Under 65 y, a significantly higher all-cause mortality was observed in obese patients, that is, in the IV quartile (BMI> or =30.9 kg/m(2); RR = 1.74; CI 95% = 1.26-2.40), in model 1. The inclusion of hypertension, duration of diabetes, and fasting plasma glucose in the model (model 2) slightly decreased the relative risk (RR = 1.52; CI 95% = 1.10-2.11). After 65 y, higher body weight was associated with a better outcome, especially in patients belonging to the IV quartile of BMI (RR = 0.74; CI 95% = 0.62-0.90). CONCLUSIONS: In older type II diabetic patients, a moderate excess weight predicts a better survival, while obesity is a negative prognostic factor in patients younger than 65 y. In the latter patients, the effect of obesity on mortality seems to be partly mediated by hypertension, duration of diabetes, and fasting plasma glucose.