One-year caloric restriction and 12-week exercise training intervention in obese adults with type 2 diabetes: emphasis on metabolic control and resting metabolic rate.

PURPOSE: The effect of combined lifestyle interventions (LSI) including dietary and physical activity on metabolic health, energy metabolism and VO2max in diabetic patients has provided mixed results. We evaluated the impact of 1-year caloric restriction (CR), and 12-week supervised structured exercise training (SSET) on metabolic health, RMR and VO2max in obese adults with type 2 diabetes. METHODS: After 1-month education for LSI, 33 participants had anthropometric, biochemical and metabolic assessments. They then started CR based on RMR, and 3-month SSET during the months 1-3 (Early-SSET) or 4-6 (Late-SSET). Reassessments were planned after 3, 6 and 12 months. Using a per-protocol analysis, we evaluated parameter changes from baseline and their associations for the 23 participants (11 Early-SSET, 12 Late-SSET) who completed the study. RMR was adjusted (adjRMR) for age, sex, fat-free mass (FFM) and fat mass (FM). RESULTS: Compared with baseline, after 6 months we found significant increases in VO2max (+ 14%) and HDL-cholesterol (+ 13%), and reduction in body mass index (- 3%), FM (- 8%) and glycated hemoglobin (HbA1c, - 7%). Training-related caloric expenditure negatively correlated with changes in body weight (p < 0.001), FM (p < 0.001) and HbA1c (p = 0.006). These results were confirmed at the 12-month follow-up. Pooling together all follow-up data, adjRMR changes correlated with changes in glycemia (r = 0.29, p = 0.02), total-cholesterol (r = 0.29, p = 0.02) and VO2max (r = - 0.26,p = 0.02). No significant differences emerged between the Early- and Late-SSET groups. CONCLUSIONS: Combined intervention with SSET and CR improved metabolic control. Changes in metabolic health and fitness correlated with changes of adjRMR, which was reduced improving fitness, glycemia and cholesterolemia. CLINICAL TRIAL REGISTRY: Trial registration number: NCT03785379. URL of registration: http://clinicaltrials.gov .

Vitamin D status and non-alcoholic fatty liver disease in patients with type 1 diabetes.

PURPOSE: In patients with type 1 diabetes (T1D), the prevalence of non-alcoholic fatty liver disease (NAFLD) ranges from 10 to 53% and contrasting evidence suggests that vitamin D deficiency may favor liver fat accumulation. Here, we investigated the association between vitamin D status and NAFLD in adults with T1D. METHODS: 220 consecutive adult T1D patients on multiple daily injections or continuous subcutaneous insulin infusion and not taking calcium or vitamin D supplements were included. Patient characteristics, 25(OH)D serum levels, and metabolic parameters were analyzed. Vitamin D status was defined as sufficiency ( ≥ 75 nmol/L; 30 ng/ml), insufficiency (50-75 nmol/L; 20-30 ng/ml), or deficiency ( < 50 nmol/L; 20 ng/ml). NAFLD was diagnosed at ultrasound examination and graded 0-3. RESULTS: NAFLD was present in 57 patients (29.5%): 51 grade 1, 5 grade 2, and 1 grade 3. Median 25(OH)D levels were 53 nmol/L (IQR 38-70) in patients with NAFLD and 50 nmol/L (34-69) in patients without (p = 0.46). At multivariable analysis, NAFLD was not associated with 25(OH)D levels (p = 0.42) or vitamin D deficiency (p = 0.55), while BMI (OR 1.16, 95% CI 1.07-1.27) and serum triglycerides (OR 1.02, 95% CI 1.01-1.03) were independently associated with NAFLD. CONCLUSIONS: Vitamin D status appears to have no link with low-grade NAFLD in patients with type 1 diabetes.

The role of point-of-care 3-hydroxybutyrate testing in patients with type 2 diabetes undergoing coronary angiography.

PURPOSE: Ketone bodies, 3-hydroxybutyrate (3BOHB), and acetoacetate derive from increased free fatty acid beta-oxidation, thus reflecting marked insulin deprivation with or without decompensated diabetes. Objectives of this study were (1) to determine circulating levels of 3BOHB in patients with and without type 2 diabetes (T2DM), before and after an elective coronary angiography; (2) to detect 3BOHB modification during the procedure; (3) to study possible associations between 3BOHB and clinical parameters/outcomes. METHODS: Sixteen T2DM (72 ± 11 years) and 22 matched controls (71 ± 12 years) undergoing elective coronary angiography were enrolled. In all subjects, biohumoral parameters were determined at hospital admission. Point-of-care determinations of 3BOHB, glucose, and creatinine were performed, at 7 a.m, immediately before and after the procedure. The duration of the fasting period and of the procedure was recorded. RESULTS: T2DM had significantly higher fasting (0.538 ± 0.320 vs 0.255 ± 0.197 mM/l; p = 0.005) and pre-procedural (0.725 ± 0.429 vs 0.314 ± 0.205; p = 0.002) 3BOHB concentrations than controls. Similarly, absolute increment of 3BOHB from the morning value was significantly greater in T2DM (0.369 ± 0.252 vs 0.127 ± 0.135 in controls; p = 0.002). Significant correlations were observed between pre-procedure 3BOHB and glucose levels (r = 0.586; p < 0.0001) and between pre-procedure 3BOHB and fasting creatinine concentrations (r = 0.364; p = 0.029). CONCLUSIONS: An overnight fasting period and a concomitantly stressful condition induce inappropriate 3BOHB increase in T2DM. Point-of-care capillary 3BOHB may be useful before any procedural/surgical intervention in these patients.

Hypovitaminosis D is associated with lower urinary tract symptoms and benign prostate hyperplasia in type 2 diabetes.

Lower urinary tract symptoms (LUTS) may develop more commonly in men with type 2 diabetes mellitus (T2DM). LUTS are often associated with benign prostate hyperplasia (BPH), in general population. An association between LUTS and hypovitaminosis D, and between hypovitaminosis D and type 2 diabetes (T2DM), has also been suggested. Thus, we aim to evaluate possible relationships between hypovitaminosis D, LUTS, and BPH in T2DM men. In this prospective observational study, 67 T2DM males (57.9 ± 9.28 years) underwent medical history collection, International Prostate Symptom Score (IPSS) questionnaire, that allows the identification and grading of LUTS, physical examination, biochemical/hormonal blood tests (fasting plasma glucose, glycated haemoglobin, total cholesterol, high-density lipoprotein cholesterol, triglycerides, creatinine, LH, total testosterone, estradiol (E2 ), 25-OH-vitamin D, PTH, calcium, phosphate, and PSA) and ultrasound transrectal prostate examination. Subdividing patients into three groups, on the base of 25-OH-vitamin D concentration (sufficiency ≥50; insufficiency >25 < 50; and deficiency ≤25 nm), a significant progressive increase of prostate volume (p = 0.037), IPSS score (p = 0.019), diastolic blood pressure (p = 0.018), and a significant decrease in HDL cholesterol (p = 0.038) were observed. 25-OH-Vitamin D levels were inversely correlated with both IPSS (R = -0.333; p = 0.006) and prostate volume (R = -0.311; p = 0.011). At multivariate analysis, hypovitaminosis D remained an independent predictor of both IPSS and prostate volume. In conclusion, we showed, for the first time, an association between 25-OH-vitamin D deficiency, LUTS, and BPH in T2DM men.

Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial.

BACKGROUND AND AIMS: Prediabetes increases cardiovascular risk and is associated with excess mortality. In preclinical models, metformin has been shown to exert anti-ageing effects. In this study, we sought to assess whether metformin modulates putative effector longevity programs in prediabetic subjects. METHODS AND RESULTS: In a randomized, single-blind, placebo-controlled trial, 38 prediabetic subjects received metformin (1500 mg/day) or placebo for 2 months. At baseline and after treatment, we collected anthropometric and metabolic parameters. Gene and protein levels of SIRT1, mTOR, p53, p66Shc, SIRT1 activity, AMPK activation, telomere length, and SIRT1 promoter chromatin accessibility were determined in peripheral blood mononuclear cells (PBMCs). Plasma N-glycans, non-invasive surrogate markers of ageing, were also analysed. Compared to baseline, metformin significantly improved metabolic parameters and insulin sensitivity, increased SIRT1 gene/protein expression and SIRT1 promoter chromatin accessibility, elevated mTOR gene expression with concomitant reduction in p70S6K phosphorylation in subjects' PBMCs, and modified the plasma N-glycan profile. Compared to placebo, metformin increased SIRT1 protein expression and reduced p70S6K phosphorylation (a proxy of mTOR activity). Plasma N-glycans were also favourably modified by metformin compared to placebo. CONCLUSION: In individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. ClinicalTrials. gov identifier: NCT01765946 - January 2013.

Hypoglycemia affects the changes in endothelial progenitor cell levels during insulin therapy in type 2 diabetic patients.

PURPOSE: Hypoglycemia is a barrier to the achievement of glycemic targets and limits the beneficial effects of improved glucose control on cardiovascular outcomes in type 2 diabetes (T2D). Circulating endothelial progenitor cells (EPCs) participate in cardiovascular homeostasis and predict future cardiovascular events. Therefore, we herein analyzed the association between occurrence of hypoglycemia and EPC changes in T2D patients after optimization of glucose control with basal insulin therapy. METHODS: In the NCT00699686 trial, 42 T2D insulin-naïve patients received a 3 + 3-month cross-over therapy with glargine and detemir. There were 43 minor and 2 severe hypoglycemic episodes in 19 patients (45.2 %, 0.54 episodes/patient/year). Changes in EPCs were analyzed in relation to the occurrence of hypoglycemia during the trial. RESULTS: Patients with hypoglycemia had a higher final HbA1c at 6 months than patients without, although absolute HbA1c changes were not significantly different. Though PCs increased at study end, in patients experiencing at least 1 hypoglycemic episode, the changes in CD34(+), CD133(+) progenitor cells and CD34(+)KDR(+) EPCs were significantly lower than the respective changes in patients without incident hypoglycemia, even after correcting for confounders. During treatment with detemir, which induced >twofold less hypoglycemia than glargine, CD34(+)KDR(+) EPCs increased significantly more than during treatment with glargine. CONCLUSIONS: In naïve T2D patients initiating basal insulin, hypoglycemia prevents the increase in vasculoprotective PCs. Clinically, these data strengthen the importance of avoiding hypoglycemia to improve cardiovascular outcomes during the treatment of T2D.

Dipeptidyl peptidase-4 inhibitors can minimize the hypoglycaemic burden and enhance safety in elderly people with diabetes.

The prevalence of type 2 diabetes mellitus (T2DM) among elderly people is increasing. Often associated with disabilities/comorbidities, T2DM lowers the chances of successful aging and is independently associated with frailty and an increased risk of hypoglycaemia, which can be further exacerbated by antihyperglycaemic treatment. From this perspective, the clinical management of T2DM in the elderly is challenging and requires individualization of optimum glycaemic targets depending on comorbidities, cognitive functioning and ability to recognize and self-manage the disease. The lack of solid evidence-based medicine supporting treatment guidelines for older people with diabetes further complicates the matter. Several classes of medicine for the treatment of T2DM are currently available and different drug combinations are often required to achieve individualized glycaemic goals. Many of these drugs, however, carry disadvantages such as the propensity to cause weight gain or hypoglycaemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a recent addition to the pharmacological armamentarium, have become widely accepted in clinical practice because of their efficacy, low risk of hypoglycaemia, neutral effect on body weight, and apparently greater safety in patients with kidney failure. Although more information is needed to reach definitive conclusions, growing evidence suggests that DPP-4 inhibitors may become a valuable component in the pharmacological management of elderly people with T2DM. The present review aims to delineate the potential advantages of this pharmacological approach in the treatment of elderly people with T2DM.

Stage of change and motivation to healthy diet and habitual physical activity in type 2 diabetes.

Lifestyle changes to healthy diet (HD) and habitual physical activity (HPA) are recommended in type 2 diabetes mellitus (T2DM). Yet, for most people with diabetes, it may be difficult to start changing. We investigated the stage of change toward healthier lifestyles according to Prochaska's model, and the associated psychological factors in T2DM patients, as a prerequisite to improve strategies to implement behavior changes in the population. A total of 1,353 consecutive outpatients with T2DM attending 14 tertiary centers for diabetes treatment completed the validated EMME-3 questionnaire, consisting of two parallel sets of instruments to define the stage of change for HD and HPA, respectively. Logistic regression was used to determine the factors associated with stages that may hinder behavioral changes. A stage of change favoring progress to healthier behaviors was more common in the area of HD than in HPA, with higher scores in action and maintenance. Differences were observed in relation to gender, age and duration of disease. After adjustment for confounders, resistance to change toward HD was associated with higher body mass index (BMI) (odds ratio (OR) 1.05; 95 % confidence interval (CI) 1.02-1.08). Resistance to improve HPA also increased with BMI (OR 1.06; 95 % CI 1.03-1.10) and decreased with education level (OR 0.74; 95 % CI 0.64-0.92). Changing lifestyle, particularly in the area of HPA, is not perceived as an essential part of treatment by many subjects with T2DM. This evidence must be considered when planning behavioral programs, and specific interventions are needed to promote adherence to HPA.

Development of metabolic syndrome and electrocardiographic features of left ventricular hypertrophy in middle-aged working subjects.

BACKGROUND AND AIMS: Metabolic syndrome (MS) leads to excess cardiovascular disease, including heart failure. Left ventricular hypertrophy (LVH) is common in MS patients, but it is unknown whether onsets of MS and LVH coincide. Herein, we tested the association between development of MS and of electrocardiographic LVH in a cohort of middle-aged individuals. METHODS: We included 303 working subjects (mean age 43.0 ± 6.2; 41% males), followed- up for 4.3 ± 0.8 yr. ATP-III MS components were determined. Electrocardiographic LVH features were assessed by Sokolow and Cornell voltage indexes and Romhilt-Estes (RE) score. RESULTS: At baseline, Cornell index was significantly higher in subjects with (no.=55; 18.2%) than in those without MS (12.8 ± 6.4 vs 10.9 ± 5.4 mm; p=0.023), while Sokolow index and RE score were not different. At followup, individuals who developed (no.=51) compared to those who did not develop MS showed a significant increase in Cornell voltage index (1.0 ± 0.6 vs -0.55 ± 0.3 mm; p=0.035) and RE score (0.17 ± 0.17 vs -0.08 ± 0.04; p=0.028). The change in Cornell index over time was directly correlated with the change in the number of MS components (r=0.133; p=0.02) and in homeostasis model assessment of insulin resistance (r=0.117; p=0.046). The association between MS onset and the increase in Cornell index/RE score was independent from confounders. CONCLUSIONS: In a young population of working subjects, the development of MS is associated with worsening features of LVH. Early LVH electrocardiographic screening in young subjects who develop MS should be considered and performed using Cornell voltage index.

The limited clinical value of a specific diabetic cardiomyopathy.

AIMS: Diabetic patients show a higher likelihood of developing heart failure (HF), independently of the atherosclerotic process, than their nondiabetic counterparts. This suggests the presence of an intrinsic vulnerability of the heart in patients with diabetes mellitus. DATA SYNTHESIS: A cardiomyopathy specific to the diabetic patient was first hypothesized by Rubler and co-workers, in 1972 and recognized as a nosologic entity by the World Health Organization (WHO) in 1995. All patients falling under Rubler's definition had ascertained diabetic glomerusclerosis, but were unaffected by major coronary artery disease (CAD). Notably, the mean plasma glucose in those patients was 417 ± 209 mg/dl. Since then, several studies conducted in both animals and in humans have focused on pathogenetic mechanisms, clinical manifestations, diagnostic as well as therapeutic approaches utilized for the treatment of diabetic cardiomyopathy (DCM). Despite the large body of literature available, the clinical entity and significance of this diabetic complication continue to be elusive. CONCLUSIONS: In the present report, recent pathophysiological findings and diagnostic strategies to treat DCM are reviewed. Particular attention is dedicated to the clinical manifestation of DCM, that is to heart failure (HF), and to the implications of co-morbidities and metabolic control on its evolution.

An unbalanced monocyte polarisation in peripheral blood and bone marrow of patients with type 2 diabetes has an impact on microangiopathy.

AIM/HYPOTHESIS: Monocytes/macrophages play important roles in adipose and vascular tissues and can be polarised as inflammatory M1 or anti-inflammatory M2. We sought to analyse monocyte polarisation status in type 2 diabetes, which is characterised by chronic inflammation. METHODS: We enrolled 60 individuals without diabetes and 53 patients with type 2 diabetes. We quantified standard monocyte subsets defined by cluster of differentiation (CD)14 and CD16. In addition, based on the phenotype of polarised macrophages in vitro, we characterised and quantified more definite M1 (CD68(+)CCR2(+)) and M2 (CX3CR1(+)CD206(+)/CD163(+)) monocytes. We also analysed bone marrow (BM) samples and the effects of granulocyte-colony stimulating factor (G-CSF) stimulation in diabetic and control individuals. RESULTS: We found no alterations in standard monocyte subsets (classical, intermediate and non-classical) when comparing groups. For validation of M1 and M2 phenotypes, we observed that M2 were enriched in non-classical monocytes and had lower TNF-α content, higher LDL scavenging and lower transendothelial migratory capacity than M1. Diabetic patients displayed an imbalanced M1/M2 ratio compared with the control group, attributable to a reduction in M2. The M1/M2 ratio was directly correlated with waist circumference and HbA1c and, among diabetic patients, M2 reduction and M1/M2 increase were associated with microangiopathy. A decrease in M2 was also found in the BM from diabetic patients, with a relative M2 excess compared with the bloodstream. BM stimulation with G-CSF mobilised M2 macrophages in diabetic but not in healthy individuals. CONCLUSIONS/INTERPRETATION: We show that type 2 diabetes markedly reduces anti-inflammatory M2 monocytes through a dysregulation in bone-marrow function. This defect may have a negative impact on microangiopathy.

The increased dipeptidyl peptidase-4 activity is not counteracted by optimized glucose control in type 2 diabetes, but is lower in metformin-treated patients.

AIM: Dipeptidyl peptidase (DPP)-4 in responsible for incretin degradation and some observations suggest that DPP-4 activity is increased in type 2 diabetes (T2D). We aimed to assess the effect of T2D and glucose control on DPP-4 activity. METHODS: In the first set (SET1) of patients, we compared plasma DPP-4 activity between 30 T2D and 20 age- and sex-matched non-diabetic subjects. In the second set (SET2), we measured serum DPP-4 activity in 42 T2D patients before and after a trial of glucose control achieved by add-on basal insulin therapy (NCT00699686). Serum/plasma DPP-4 activity was determined using chromogenic and fluorigenic substrates, as well as several positive and negative controls. RESULTS: In SET1, plasma DPP-4 activity was significantly higher in T2D vs. controls (32.2 ± 1.2 U/l vs. 21.2 ± 1.1 U/l, p < 10(-6)). From a meta-analysis of the literature, we found that T2D is associated with a 33% increase in DPP-4 activity compared to controls. In SET2, serum DPP-4 activity was not lowered by intensified glucose control, despite an average haemoglobin A1c (HbA1c) reduction of 1.5%. In both sets of diabetic patients, the use of metformin was associated with a significantly lower DPP-4 activity, independently of age, sex, body mass index and HbA1c. CONCLUSION: DPP-4 activity is increased in T2D, but is not lowered by glucose control, suggesting that hyperglycaemia is not a direct determinant of DPP-4 activity. However, metformin may indirectly reduce DPP-4 activity.

Optimized glycaemic control achieved with add-on basal insulin therapy improves indexes of endothelial damage and regeneration in type 2 diabetic patients with macroangiopathy: a randomized crossover trial comparing detemir versus glargine.

AIMS: In diabetes, endothelial damage promotes macroangiopathy and endothelial regeneration is impaired, owing to reduced endothelial progenitor cells (EPCs). Given that insulin influences endothelial biology, we compared the effects of add-on basal insulin analogues on endothelial damage and regeneration in type 2 diabetes (T2D). METHODS: This was a 6-month randomized crossover trial comparing add-on insulin detemir versus glargine in poorly controlled T2D with macroangiopathy. At baseline, crossover (3 months) and study end (6 months), we measured HbA1c, EPCs, circulating endothelial cells (CECs), VCAM-1, ICAM-1 and E-selectin. Body weight and hypoglycaemic episodes were also recorded. RESULTS: Forty-two patients completed the study, randomly assigned to the glargine-detemir (n = 21) or the detemir-glargine (n = 21) schedule. At crossover, EPC levels did not change compared with baseline, but significantly increased at study end. CECs decreased over time and were significantly reduced at study end. ICAM-1, VCAM-1 and E-selectin were significantly reduced at crossover and further decreased at study end. No differences were seen in these effects between detemir and glargine. HbA1c showed a carryover effect and its reduction was similar with detemir and glargine in the first arm. Incidence of hypoglycaemia and weight gain was lower with detemir than with glargine in both arms. CONCLUSION: Optimized glycaemic control by add-on basal insulin improved indexes of endothelial damage and regeneration. Compared to glargine, detemir achieved similar endothelial protection with lower weight gain and less hypoglycaemia. These results might have implications for therapy of aging T2D patients with cardiovascular disease.

Microangiopathy is independently associated with presence, severity and composition of carotid atherosclerosis in type 2 diabetes.

BACKGROUND AND AIMS: Common mechanisms for the development of micro- and macroangiopathic diabetic complications have been suggested. We aimed to cross-sectionally investigate strength and characteristics of the association between carotid atherosclerosis and microangiopathy in type 2 diabetic patients. METHODS AND RESULTS: Common carotid artery intima-media thickness (cIMT), carotid plaque (CP) type and degree of stenosis were evaluated by ultrasound, along with the determination of anthropometric parameters, HbA1c, lipid profile, assessment of diabetic retinopathy and nephropathy, in 662 consecutive patients with type 2 diabetes mellitus (T2DM). Patients were divided according to high/low cIMT, presence/absence of CP and of retinopathy and nephropathy. Patients with CP were older, more prevalently males, past smokers, had longer diabetes duration, significantly lower HDL cholesterol and more prevalent ischemic heart disease (all p<0.05) as compared to those with cIMT < 1 mm. Microangiopathies were more prevalent in patients with CP than in those without. At multivariate logistic regression, factors independently associated with the presence of CP were age, past smoke, HDL cholesterol, retinopathy and retinopathy plus nephropathy. A significant independent correlation of CP stenosis with stage of retinopathy and nephropathy was found. Finally, echolucent CPs were associated with a lower prevalence of proliferative retinopathy than CP containing calcium deposits. CONCLUSION: In T2DM, retinopathy, alone or in combination with nephropathy, is independently associated to CP, and severity of microangiopathy correlates with severity of carotid atherosclerosis. These observations, together with the different prevalence of proliferative retinopathy according to CP types, point to possible common pathogenic mechanisms in micro- and macrovascular complications.

Glycaemic fall after a glucose load. A population-based study.

BACKGROUND AND AIMS: A blood glucose (BG) fall after an oral glucose load has never been described previously at a population level. This study was aimed at looking for a plasma glucose trend after an oral glucose load for possible blood glucose fall if any, and for its impact on coronary mortality at a population level. METHODS AND RESULTS: In subjects from an unselected general population, BG and insulin were detected before and 1 and 2h after a 75-g oral glucose load for insulin sensitivity and ß-cell function determination. Blood pressure, blood examinations and left ventricular mass were measured, and mortality was monitored for 18.8±7.7 years. According to discriminant analysis, the population was stratified into cluster 0 (1-h BG < fasting BG; n=497) and cluster 1 (1-h BG ≥ fasting BG; n=1733). To avoid any interference of age and sex, statistical analysis was limited to two age-gender-matched cohorts of 490 subjects from each cluster (n=940). Subjects in cluster 0 showed significantly higher insulin sensitivity and ß-cell function, lower visceral adiposity and lower blood pressure values. Adjusted coronary mortality was 8 times lower in cluster 0 than 1 (p<0.001). The relative risk of belonging to cluster 1 was 5.40 (95% CI 2.22-13.1). CONCLUSION: It seems that two clusters exist in the general population with respect to their response to an oral glucose load, independent of age and gender. Subjects who respond with a BG decrease could represent a privileged sub-population, where insulin sensitivity and ß-cell function are better, some risk factors are less prevalent, and coronary mortality is lower.

Cerebrovascular disease in diabetes mellitus: the role of carotid intima-media thickness.

BACKGROUND AND PURPOSE: Cerebrovascular disease in diabetes appears to be less considered than coronary and peripheral disease, the reason being the intrinsic difficulty in finding available diagnostic tools for its early identification. Among these, carotid artery intima-media thickness (cIMT) represents the simplest measurable parameter for pre-atherosclerotic lesions in extra-cranic arteries. METHODS: The role of cIMT as a surrogate marker of cerebral atherosclerosis and predictor of stroke, its relationship to microangiopathy and chronic inflammation, along with its role as an outcome parameter in anti-hyperglycemic therapeutical intervention trials in type 2 and 1 diabetes mellitus are discussed in this paper. RESULTS AND CONCLUSIONS: Carotid IMT is increased in diabetes. It is an independent predictor of stroke, in particular of the ischemic subtype, and of stroke recurrence in diabetic, as well as in non-diabetic populations. A possible role of cIMT as a predictor of microangiopathy has also been suggested, but it needs further investigation. A weak association with chronic inflammation has been demonstrated in diabetic patients. Carotid IMT has been successfully employed as an outcome parameter for several anti-hyperglycemic therapeutic trials. However data on cIMT as a predictor of cerebrovascular disease are scarce in diabetic patients, particularly in type 1 diabetes, and more studies are needed to define the risk of cerebrovascular disease in diabetic patients.

Nonalcoholic fatty liver disease (NAFLD) in nonobese patients with diabetes: Prevalence and relationships with hemodynamic alterations detected with Doppler sonography().

AIM: To evaluate the prevalence, severity, and hemodynamic features of nonalcoholic fatty liver disease (NAFLD) in nonobese diabetics. METHODS: We studied 100 consecutive nonobese (body mass index [BMI] < 30) patients with type 1 (n = 17) or type 2 (n = 83) diabetes and no known causes of liver disease. Steatosis was diagnosed and graded with ultrasonography. Digital sonographic images of the liver and right kidney were analyzed with dedicated software (HDI-Lab), and the liver/kidney ratio of grey-scale intensity was calculated as an index of the severity of the steatosis. Severity scores ranging from 0 (none) to 5 (severe) were compared with sonographic and Doppler findings (right liver size, portal vein diameter and flow velocity, hepatic and splenic arterial pulsatility indices, hepatic-vein flow profile and A- and S-wave velocities). RESULTS: The prevalence of steatosis was 24% in type I and 80% in type II diabetes (grade 1 in 17%, grade 2 in 34%, grade 3 in 33%, grade 4 in 9%, grade 5 in 7%). In patients with steatosis (especially those with grades 4-5 disease), hepatic volume was increased (p < 0.005). Portal vein diameter was increased in grade 5 steatosis. The hepatic artery pulsatility index was significantly increased, particularly in grades 4 and 5 (p < 0.0001); portal and A-wave velocities were significantly reduced in grades 3-5 (p < 0.001); and the hepatic vein flow profile was altered in 27% (biphasic: 20%, flat: 7%) patients with steatosis, although there was no correlation with severity. CONCLUSIONS: NAFLD is very frequent in nonobese diabetics with type 2 but not type 1 disease, and it is associated with hepatomegaly and liver hemodynamic alterations only when it is severe.

Glucose tolerance is negatively associated with circulating progenitor cell levels.

AIMS/HYPOTHESIS: Circulating progenitor cells participate in cardiovascular homeostasis. Depletion of the pool of endothelial progenitor cells (EPCs) is associated with increased cardiovascular risk. Furthermore, EPCs are reduced in the presence of classical risk factors for atherosclerotic disease, including diabetes mellitus. This study was designed to evaluate progenitor cell levels in volunteers with different degrees of glucose tolerance. METHODS: Cardiovascular parameters and the levels of circulating CD34(+) and CD34(+) kinase insert domain receptor (KDR)(+) cells were determined in 219 middle-aged individuals with no pre-diagnosed alterations in carbohydrate metabolism. Glucose tolerance was determined by fasting and 2 h post-challenge glucose levels, with IFG and IGT considered as pre-diabetic states. RESULTS: CD34(+) and CD34(+)KDR(+) cells were significantly reduced in individuals who were found to have diabetes mellitus, and were negatively correlated with both fasting and post-challenge glucose in the whole population. While only CD34(+) cells, but not CD34(+)KDR(+) cells, were significantly reduced in pre-diabetic individuals, post-challenge glucose was an independent determinant of the levels of both CD34(+) and CD34(+)KDR(+) cells. CONCLUSIONS/INTERPRETATION: Glucose tolerance was negatively associated with progenitor cell levels in middle-aged healthy individuals. Depletion of endothelial progenitors with increasing fasting and post-meal glucose may be one cause of the high incidence of cardiovascular damage in individuals with pre-diabetes.

Visceral obesity is characterized by impaired nitric oxide-independent vasodilation.

BACKGROUND: Endothelial dysfunction has been described in obesity. This study examines the impact of visceral obesity on nitric oxide-independent relaxation in the human forearm. METHODS AND RESULTS: In ten viscerally obese and ten matched controls forearm blood flow (FBF) was measured by venous occlusion plethysmography during intrabrachial infusion of: (1) sodium nitroprusside; (2) bradykinin, before and after inhibition of vasoactive prostaglandins and nitric oxide; (3) potassium; (4) ouabain (Na(+)/K(+)ATPase inhibitor) alone or (5) in combination with BaCl(2)(K(IR)inhibitor). Baseline FBF and endothelium-independent vasodilatation were similar in the two groups. In obese patients, bradykinin-induced increase of FBF was significantly less than in controls (P<0.01). Irrespective of prostaglandins and nitric oxide inhibition, bradykinin response was lower in the viscerally obese. Intrabrachial potassium determined a significantly blunted response (P<0.05). Ouabain caused a similar, moderate decrease in basal FBF in the two groups; the coinfusion of BaCl(2)caused a more intense decline in FBF which was significantly relevant in obese (-24+/-5%, P<0.01). CONCLUSIONS: In obese patients there is a blunted nitric oxide-independent relaxation determined by a decreased response of inwardly rectifying potassium channels.