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The aim of therapy in type 2 diabetes in terms of blood glucose control is to reduce to target levels HbA1c and to reduce glycaemic variability in order to avoid both hypoglycaemia and wide excursions of postprandial glucose. The first approach to reduce glycaemic variability should consider a dietary and behavioural approach aiming to limit the glycaemic index and the glycaemic load of food and the prescription and implementation of a physical activity plan appropriate for the subject. From the pharmacological point of view, the diabetes specialist has now a much richer therapeutic armamentarium. The therapeutic algorithms can help the physician to choose the most appropriate drug. The traditional approach involves: i) metformin, acting mainly on fasting blood glucose; ii) sulphonylureas, that have shown a number of drawbacks, including the high risk of hypoglycemia; iii) pioglitazone, with a substantial effect on fasting and postprandial glucose and a low risk of hypoglycaemia; iv) insulin, that can be utilized with the basal or prandial approach. The new drugs belonging to the class of dipeptidyl peptidase-4 inhibitors have shown the reduction of postprandial glucose, a neutral effect on weight increase, a good safety profile and preliminary positive cardiovascular effects. When excess weight prevails, the glucagon-like peptide-1 agonists may be the preferred choice for their effect on weight reduction, reduction of hyperinsulinism and glycaemic variability. [ABSTRACT FROM AUTHOR]

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 ≤ 60 ml/min/1.73 m2), 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. [ABSTRACT FROM AUTHOR]

AIMS: To estimate the prevalence of cardiovascular disease (CVD) in Type 2 diabetic patients with and without non-alcoholic fatty liver disease (NAFLD), and to assess whether NAFLD is independently related to prevalent CVD. METHODS: We studied 400 Type 2 diabetic patients with NAFLD and 400 diabetic patients without NAFLD who were matched for age and sex. Main outcome measures were prevalent CVD (as ascertained by medical history, physical examination, electrocardiogram and echo-Doppler scanning of carotid and lower limb arteries), NAFLD (by ultrasonography) and presence of the metabolic syndrome (MetS) as defined by the World Health Organization or Adult Treatment Panel III criteria. RESULTS: The prevalences of coronary (23.0 vs. 15.5%), cerebrovascular (17.2 vs. 10.2%) and peripheral (12.8 vs. 7.0%) vascular disease were significantly increased in those with NAFLD as compared with those without NAFLD (P < 0.001), with no differences between sexes. The MetS (by any criteria) and all its individual components were more frequent in NAFLD patients (P < 0.001). In logistic regression analysis, male sex, age, smoking history and MetS were independently related to prevalent CVD, whereas NAFLD was not. CONCLUSIONS: The prevalence of CVD is increased in patients with Type 2 diabetes and NAFLD in association with an increased prevalence of MetS as compared with diabetic patients without NAFLD. Follow-up studies are necessary to determine whether this higher prevalence of CVD among diabetic patients with NAFLD affects long-term mortality. [ABSTRACT FROM AUTHOR]

Aims To estimate the prevalence of cardiovascular disease (CVD) in Type 2 diabetic patients with and without non-alcoholic fatty liver disease (NAFLD), and to assess whether NAFLD is independently related to prevalent CVD. Methods We studied 400 Type 2 diabetic patients with NAFLD and 400 diabetic patients without NAFLD who were matched for age and sex. Main outcome measures were prevalent CVD (as ascertained by medical history, physical examination, electrocardiogram and echo-Doppler scanning of carotid and lower limb arteries), NAFLD (by ultrasonography) and presence of the metabolic syndrome (MetS) as defined by the World Health Organization or Adult Treatment Panel III criteria. Results The prevalences of coronary (23.0 vs. 15.5%), cerebrovascular (17.2 vs. 10.2%) and peripheral (12.8 vs. 7.0%) vascular disease were significantly increased in those with NAFLD as compared with those without NAFLD ( P < 0.001), with no differences between sexes. The MetS (by any criteria) and all its individual components were more frequent in NAFLD patients ( P < 0.001). In logistic regression analysis, male sex, age, smoking history and MetS were independently related to prevalent CVD, whereas NAFLD was not. Conclusions The prevalence of CVD is increased in patients with Type 2 diabetes and NAFLD in association with an increased prevalence of MetS as compared with diabetic patients without NAFLD. Follow-up studies are necessary to determine whether this higher prevalence of CVD among diabetic patients with NAFLD affects long-term mortality. Diabet. Med. (2006) [ABSTRACT FROM AUTHOR]

Aims Patients with a positive microvolt T-wave alternans (TWA) are at increased risk of ventricular arrhythmias and sudden cardiac death. Although Type 2 diabetes is associated with an increased risk of these events, there is a dearth of available data on measurements of TWA in people with Type 2 diabetes. Methods We studied 43 Type 2 diabetic volunteers who were free of diagnosed cardiovascular disease (CVD). Microvolt TWA analysis was performed non-invasively using the CH 2000 system during submaximal exercise with the patients sitting on a bicycle ergometer. Results TWA analysis was positive in 9 (21%) patients, negative in 32 (74.4%) and indeterminate in 2 (4.6%) subjects. TWA positive patients had significantly higher HbA1c levels than those with TWA negativity (8.1 ± 0.9 vs. 7.2 ± 0.8%, P < 0.01). Age, sex, BMI, blood pressure, lipids, 24-h heart rate variability, QTc interval duration, smoking history, diabetes duration and treatment, and microvascular complication status did not differ between the groups. In regression logistic analysis, HbA1c was the only significant predictor of TWA positivity (odds ratio 5.7, 95% CI 1.3–26, P = 0.023) after controlling for potential confounders. Conclusions These results suggest that in Type 2 diabetic patients without clinically manifest CVD, TWA positivity is common (approximately 20%) and is closely correlated with glycaemic control. [ABSTRACT FROM AUTHOR]

Aims To compare plasma biomarkers of inflammation and endothelial dysfunction in individuals with and without non-alcoholic hepatic steatosis (HS), and to evaluate whether such differences were mediated by the adverse metabolic pattern, typically found in these subjects. Methods HS (by ultrasound and computed tomography), visceral fat (by computed tomography), insulin resistance (by homeostasis model assessment—HOMA), plasma biomarkers of inflammation and endothelial dysfunction (hs-C reactive protein, fibrinogen, von Willebrand factor, plasminogen activator inhibitor-1 activity) were measured in 100 non-smoking, healthy, male volunteers. Results Plasma hs-CRP, fibrinogen, v-WF and plasminogen activator inhibitor-1 (PAI-1) activity levels were markedly higher ( P < 0.01 or less) in subjects with non-alcoholic HS ( n = 35) than in those without HS ( n = 65). The former also had significantly higher values for body mass index (BMI), visceral fat, diastolic blood pressure, HOMA insulin resistance score, plasma insulin (both fasting and after glucose load), triglycerides, liver enzymes, and lower high-density lipoprotein (HDL)-cholesterol concentration. While the marked differences in these pro-inflammatory biomarkers observed between the groups were little affected by adjustment for age, BMI, blood pressure values, HOMA insulin resistance score, plasma triglyceride and liver enzyme concentrations, they were completely abolished after controlling for visceral fat. Similarly, in multivariate regression analyses, increased visceral fat significantly predicted the pro-inflammatory biomarkers, independently of HS and other potential confounders. Conclusions These results indicate that, in non-smoking, non-diabetic men, the significant increase of plasma biomarkers of inflammation and endothelial dysfunction in the presence of non-alcoholic HS is largely mediated by abdominal visceral fat accumulation. [ABSTRACT FROM AUTHOR]

AIMS: To examine the association of non-alcoholic hepatic steatosis (HS) with the activity of the hypothalamo-pituitary-adrenal (HPA) axis in Type 2 diabetic individuals. METHODS: The activity of the HPA axis, as measured by 24-h urinary free cortisol (UFC) excretion and serum cortisol levels after 1.0 mg dexamethasone, was measured in 40 diet-controlled, predominantly overweight, Type 2 diabetic patients with non-alcoholic HS and in 40 diabetic patients without HS who were comparable for age, sex and body mass index (BMI). RESULTS: Subjects with non-alcoholic HS had significantly higher 24-h UFC excretion (191 +/- 4 vs. 102 +/- 3 nmol/24 h; P < 0.001) and post-dexamethasone cortisol concentrations (29.1 +/- 2 vs. 14.4 +/- 1 nmol/l; P < 0.001) than those without HS. Patients with HS had significantly higher values for HOMA insulin resistance score, plasma triglycerides and liver enzymes. Age, sex, BMI, waist-hip ratio (WHR), diabetes duration, HbA1c, LDL-cholesterol and blood pressure values were not different between the groups. The differences in urinary and serum cortisol concentrations between the groups remained significant after adjustment for age, sex, BMI, WHR, HOMA insulin resistance score, plasma triglycerides, HbA1c and liver enzymes. In multiple logistic regression analyses, 24-h UFC or serum cortisol concentrations (P < 0.05 and P = 0.02, respectively), along with age and HOMA insulin resistance, predicted the presence of HS, independently of potential confounders. CONCLUSIONS: These results demonstrate that non-alcoholic HS is closely associated with a subtle, chronic overactivity of the HPA axis in diet-controlled Type 2 diabetic individuals. [ABSTRACT FROM AUTHOR]

To examine the association of non-alcoholic hepatic steatosis (HS) with the activity of the hypothalamo-pituitary-adrenal (HPA) axis in Type 2 diabetic individuals. The activity of the HPA axis, as measured by 24-h urinary free cortisol (UFC) excretion and serum cortisol levels after 1.0 mg dexamethasone, was measured in 40 diet-controlled, predominantly overweight, Type 2 diabetic patients with non-alcoholic HS and in 40 diabetic patients without HS who were comparable for age, sex and body mass index (BMI). Subjects with non-alcoholic HS had significantly higher 24-h UFC excretion (191 ± 4 vs. 102 ± 3 nmol/24 h; P < 0.001) and post-dexamethasone cortisol concentrations (29.1 ± 2 vs. 14.4 ± 1 nmol/l; P < 0.001) than those without HS. Patients with HS had significantly higher values for HOMA insulin resistance score, plasma triglycerides and liver enzymes. Age, sex, BMI, waist–hip ratio (WHR), diabetes duration, HbA1c, LDL-cholesterol and blood pressure values were not different between the groups. The differences in urinary and serum cortisol concentrations between the groups remained significant after adjustment for age, sex, BMI, WHR, HOMA insulin resistance score, plasma triglycerides, HbA1c and liver enzymes. In multiple logistic regression analyses, 24-h UFC or serum cortisol concentrations ( P < 0.05 and P = 0.02, respectively), along with age and HOMA insulin resistance, predicted the presence of HS, independently of potential confounders. These results demonstrate that non-alcoholic HS is closely associated with a subtle, chronic overactivity of the HPA axis in diet-controlled Type 2 diabetic individuals. Diabet. Med. 22, 1146 –1150 (2005) [ABSTRACT FROM AUTHOR]

AIMS: To evaluate whether plasma biomarkers of inflammation and endothelial dysfunction differed in Type 1 diabetic patients as compared with those in non-diabetic subjects, and to examine the association of these biomarkers with early stages of microvascular complications. METHODS: Plasma biomarkers of inflammation [fibrinogen, hs-C-reactive protein (hs-CRP)] and endothelial dysfunction [von Willebrand factor (v-WF), intercellular adhesion molecule-1, plasminogen activator inhibitor-1 (PAI-1) activity] were measured in 88 non-smoking young patients with Type 1 diabetes without clinical macrovascular disease and in 40 healthy controls. RESULTS: Plasma levels of hs-CRP, fibrinogen, v-WF, soluble intracellular adhesion molecule-1 (sICAM-1) and PAI-1 activity were markedly higher (P < 0.01 or less) in Type 1 diabetic patients than in healthy controls; these results were essentially unchanged when healthy controls were compared with patients without complications. After stratification by microvascular complication status, plasma biomarkers of inflammation and endothelial dysfunction were significantly increased in those with more advanced disease compared with those with early complications or without complications, respectively. However, while the significant differences in these biomarkers were little affected by adjustment for sex, age, BMI and blood pressure values, they were totally abolished after additional adjustment for diabetes duration and glycaemic control. CONCLUSIONS: These results indicate that in Type 1 diabetes there is a subclinical, chronic inflammation which is, at least partly, independent of clinically manifest macro- and microvascular complications, smoking or other traditional cardiovascular risk factors; this subclinical inflammation is closely correlated to the magnitude and duration of hyperglycaemia. [ABSTRACT FROM AUTHOR]

To evaluate whether plasma biomarkers of inflammation and endothelial dysfunction differed in Type 1 diabetic patients as compared with those in non-diabetic subjects, and to examine the association of these biomarkers with early stages of microvascular complications. Plasma biomarkers of inflammation [fibrinogen, hs-C-reactive protein (hs-CRP)] and endothelial dysfunction [von Willebrand factor (v-WF), intercellular adhesion molecule-1, plasminogen activator inhibitor-1 (PAI-1) activity] were measured in 88 non-smoking young patients with Type 1 diabetes without clinical macrovascular disease and in 40 healthy controls. Plasma levels of hs-CRP, fibrinogen, v-WF, soluble intracellular adhesion molecule-1 (sICAM-1) and PAI-1 activity were markedly higher ( P < 0.01 or less) in Type 1 diabetic patients than in healthy controls; these results were essentially unchanged when healthy controls were compared with patients without complications. After stratification by microvascular complication status, plasma biomarkers of inflammation and endothelial dysfunction were significantly increased in those with more advanced disease compared with those with early complications or without complications, respectively. However, while the significant differences in these biomarkers were little affected by adjustment for sex, age, BMI and blood pressure values, they were totally abolished after additional adjustment for diabetes duration and glycaemic control. These results indicate that in Type 1 diabetes there is a subclinical, chronic inflammation which is, at least partly, independent of clinically manifest macro- and microvascular complications, smoking or other traditional cardiovascular risk factors; this subclinical inflammation is closely correlated to the magnitude and duration of hyperglycaemia. Diabet. Med. 22, 999–1004 (2005) [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]

A letter to the editor is presented regarding the International Diabetes Federation's (IDF) definition of the metabolic syndrome that independently predicts future cardiovascular events in Type 2 diabetic patients.

Evaluates interleukin-6 levels in type 1 diabetic patients without microvascular and macrovascular complications. Procedure; Differences in fibrinogen concentration; Significance.

Focuses on a study which assessed the effects of chronic smoking on leptin levels in type 1 diabetics. Information on serum leptin; Methods; Conclusions.