The potential of glucose management indicator for the estimation of glucose disposal rate in people with type 1 diabetes.

BACKGROUND AND AIMS: Insulin resistance is a growing feature in type 1 diabetes (T1D). It can be quantified by calculating the estimated glucose disposal rate (eGDR) with the Epstein's formula, which includes laboratory-measured glycated hemoglobin (HbA1c). We aimed the current research to assess the agreement between the conventional eGDR formula and an alternative one (eGDR-GMI) incorporating the glucose management indicator (GMI) derived from continuous glucose monitoring (CGM). We also explored the relationship between eGDR-GMI, cardiovascular risk factors, and the prevalence of diabetes-related complications. METHODS AND RESULTS: We designed a cross-sectional study that included adults with T1D. eGDR-GMI and eGDR (mg/kg/min) were calculated using GMI or HbA1c, waist circumference, and hypertensive state. Clinical data were collected from electronic medical records. The analyses encompassed 158 participants with a mean age of 39 ± 13 years. The Bland-Altman analysis showed a good agreement between eGDR-GMI and eGDR. When we divided participants in eGDR-GMI tertiles we found a higher prevalence of diabetes-related complications and a less favorable metabolic profile in the lowest eGDR-GMI tertile. The relative risk of retinopathy, nephropathy, and neuropathy significantly increased by approximately 1 unit with each decrease in eGDR-GMI, regardless of age, sex, disease duration, lipids, and smoking habit. CONCLUSIONS: eGDR-GMI represents a valid and robust alternative to the eGDR to assess insulin resistance in T1D. Low eGDR-GMI is associated with diabetes complications and a less favorable metabolic profile. Incorporating the eGDR-GMI into clinical practice can enhance the characterization of T1D people and allow for a more personalized treatment approach.

Elevated blood flow in people with type 1 and type 2 diabetes.

AIMS: The study aimed to evaluate blood flow (BF) and microvascular function in the forearm of people with type 1 and type 2 diabetes at rest and after ischemia. Microvascular function plays a crucial role in regulating BF in peripheral tissues based on metabolic demand. METHODS: People with diabetes and sex-matched healthy controls were recruited. Brachial artery diameter and blood velocity were continuously measured at rest and after ischemia by an automatic tracking system. BF and vascular conductance were then calculated. RESULTS: Forty-nine people with diabetes and 49 controls were enrolled. BF at rest and after ischemia was significantly higher in people with diabetes than controls: Type 1, 243 ± 116 and 631 ± 233 ml/min; controls, 180 ± 106 and 486 ± 227 ml/min; Type 2, 332 ± 149 and 875 ± 293 ml/min; controls 222 ± 106 and 514 ± 224 ml/min. Vascular conductance was significantly higher in Type 2 than in controls at rest and after ischemia. CONCLUSIONS: People with diabetes exhibited significantly increased BF, with Type 2 also showing heightened vascular conductance. Activating metabolic pathways triggered by hyperglycemia may lead to distinct vascular redistribution, potentially impairing blood flow over time. These findings of the study underscore the importance of understanding overall vascular dynamics in diabetes and its implications for vascular health.

Effect of Extra Virgin Olive Oil and Butter on Endothelial Function in Type 1 Diabetes.

Post-prandial hyperglycemia can be relevant in developing early manifestations of atherosclerosis. EVOO (Extra Virgin Olive Oil), rich in saturated fatty acids and commonly used in the Mediterranean diet, seems to control post-prandial hyperglycemia better than butter. Subjects with type 1 diabetes are at higher risk of developing cardiovascular disease and show endothelial dysfunction, an early manifestation of atherosclerosis in the first years of the disease. Our study aims to evaluate whether EVOO and butter influence endothelial function in subjects with type 1 diabetes when added to a single high glycemic index (HGI) meal. In this exploratory cross-over study, 10 subjects with type 1 diabetes and 6 healthy subjects were scheduled to receive two types of HGI meals: one enriched with EVOO and one with butter. Before and after each test meal at different time points, all subjects underwent the evaluation of endothelial function by flow-mediated dilation technique, glucose and lipids measurements, and gastric emptying assessment by ultrasound. Flow-mediated dilation significantly increased after EVOO-enriched meal compared with butter in subjects with type 1 diabetes (two-way-repeated measurements ANOVA, p = 0.007). In patients with type 1 diabetes, the add-on of EVOO to HGI meal improves vascular function compared to butter, which has detrimental effects.

Functional and morphological cardiovascular alterations associated with neurofibromatosis 1.

Subjects with Neurofibromatosis 1 (NF1) develop vascular complications. The protein product of the gene affected in NF1, neurofibromin, physiologically modulates endothelial function and preserves vascular and myocardial structure. Our study aimed to verify whether subjects with NF1 have early, preclinical abnormalities of carotid artery structure, brachial artery function, and cardiac function. We recruited 22 NF1 subjects without previous cardiovascular events and 22 healthy control subjects. All subjects underwent measurement of carotid artery intima-media thickness (IMT), evaluation of brachial artery endothelial function after ischemia and exercise, and cardiac function. Mean IMT was 543 ± 115 µ in NF1 subjects and 487 ± 70 µ in Controls (p < 0.01). Endothelial function was significantly dumped in NF1 subjects. The dilation after ischemia and exercise was respectively 7.5(± 4.8)% and 6.7(± 3.0)% in NF1 versus 10.5(± 1.2)% and 10.5(± 2.1)% in control subjects (p < 0.02; p < 0.002). Left ventricular systolic function assessed by Global Longitudinal Strain was significantly different between NF1 subjects and Controls: - 19.3(± 1.7)% versus - 21.5(± 2.7)% (p < 0.008). These findings demonstrate that NF1 patients have early morphological and functional abnormalities of peripheral arteries and systolic cardiac impairment and suggest the need for a tight cardiovascular risk evaluation and primary prevention in subjects with NF1.

The Strategic Alliance between Clinical and Molecular Science in the War against SARS-CoV-2, with the Rapid-Diagnostics Test as an Indispensable Weapon for Front Line Doctors.

Our work concerns the actual problem of spread of SARS- CoV-2 outbreak which requires fast and correct as possible answer. In current scenario, the need of rapid answer put away the imperative of proper methodology. We focus on the serogical immunoassay for diagnosis of Covid-19 as an important weapon not only for diagnostic purpose, but also for epidemiologic one. The right equilibrium between high speed, low cost and accuracy is obtained with easy-to-use decentralized point-of-care test as the colloidal gold-based immunochromatographic strip assay which detects IgM and IgG antibodies directed against SARS-CoV-2. As our aim is to evaluate the efficacy of Covid-19 rapid tests and of serological assays in real-life settings, we designed a research protocol aimed to establish how to use correctly these diagnostics, taking into account the different possible clinical and epidemiological scenarios.

Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial.

BACKGROUND: The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. METHODS: TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50-75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2-3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15-45 mg) or a sulfonylurea (5-15 mg glibenclamide, 2-6 mg glimepiride, or 30-120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. FINDINGS: Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74-1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups. INTERPRETATION: In this long-term, pragmatic trial, incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycaemia events. FUNDING: Italian Medicines Agency, Diabete Ricerca, and Italian Diabetes Society.

Body fat and blood rheology: Evaluation of the association between different adiposity indices and blood viscosity.

BACKGROUND: In recent years, new measures of body adiposity have been introduced: lipid accumulation product (LAP), body adiposity index (BAI) and body shape index (ABSI). These indices have been demonstrated to better associate with cardiovascular disease than other measures of adiposity. OBJECTIVES: The aim of the present study was to evaluate if LAP or BAI better associate with blood viscosity than other measures of adiposity (body mass index, BMI; waist circumference, WC; waist-to-hip ratio, W/HR; waist-to-height ratio, W/HtR). METHODS: 344 subjects were recruited for the present investigation. Exclusion criteria were: diabetes, elevated triglycerides, smoking and drug use. Blood lipids and glucose were measured by routine methods. Blood and plasma viscosity were measured by a cone-plate viscometer. Adiposity measures were computed as previously described. RESULTS: In simple correlation analyses, blood viscosity (BV) correlated with BMI, BAI, and LAP in males and with LAP in females. Correlations between plasma viscosity and adiposity indices were weak and not statistically significant. Other variables significantly related with BV were: gender, HDL- and LDL-Cholesterol, and triglycerides (p < 0.05). In multiple regression analysis only LAP was associated with BV. CONCLUSIONS: Our data suggest that LAP index is strongly associated to blood viscosity. This result, along with previous evidence, identifies LAP index as a potential cardiovascular risk marker.

Red blood cell distribution width predicts two-hours plasma glucose levels during OGTT.

OBJECTIVE: Red blood cell distribution width (RDW) is a numerical measure, reported as part of a standard complete blood count, usually employed for differential diagnosis of anemic state. Some lines of evidence demonstrate that RDW associates with type 2 diabetes incidence and its complications. To further explore the role of RDW as predictor of abnormal glucose metabolism, we have analyzed the relationship between RDW and 2-hours plasma glucose concentration during an oral glucose tolerance test (OGTT). METHODS: Forty-five outpatients were enrolled for the present study. Participants underwent 75 g OGTT and measurements of hematological parameters. Cardiovascular disease risk factors (blood pressure, blood lipids, cigarette smoking, obesity) were evaluated by routine methods. RESULTS: In simple regression analysis 2-hours post-load glucose was directly associated with age (r = 0.36, p = 0.01), fasting glucose levels (r = 0.40, p = 0.002) and RDW (r = 0.31, p = 0.037). In multiple regression analysis fasting glucose, RDW, triglycerides and age significantly and independently predicted 2-hours plasma glucose (p <  0.01 for all coefficients). CONCLUSION: The present findings demonstrate that RDW associates with plasma glucose concentration after a 75-g oral glucose tolerance test. Our results highlight the role of RDW as predictor of glucose metabolism disturbance.

Plasma viscosity is increased in subjects with elevated ankle brachial index.

OBJECTIVE: Peripheral artery occlusive disease (PAOD) is associated with increased cardiovascular risk (CVR). Recently it has been reported that also the increased stiffness of lower limb arteries is associated with increased CVR. In particular, subjects with poorly compressible arteries (PCA) appear to have a CVR even higher than that of subjects with PAOD. Limited data are available on the role of hemorheological factors in determining increase in arterial stiffness. Our study aimed to investigate possible association between blood and plasma viscosity and elevated ankle brachial index (ABI). METHODS: Subjects were free-living participants to a cardiovascular disease screening campaign. Sixty-two subjects with ABI ranging 1.3-1.4, and 20 with ABI >1.4 were matched with 124 and 40 control subjects, respectively. Cardiovascular disease risk factors (blood pressure, blood lipids, glucose, cigarette smoking, obesity) were evaluated by routine methods. Blood and plasma viscosities were measured by a cone-plate viscometer. Ankle-brachial index was computed as measure of arterial stiffness. RESULTS: Compared with controls, who were carefully matched for age, sex and all cardiovascular risk factors, subjects with elevated ABI values had increased levels of plasma viscosity (1.42 ± 0.11 vs. 1.35 ± 0.10 cP, p <  0.001, for subjects with ABI ranging 1.3-1.4, and 1.41 ± 0.10 vs. 1.33 ± 0.10 cP, p <  0.01, for subjects with ABI >1.4). No difference in blood viscosity was observed. CONCLUSION: The present investigation provides evidence that plasma viscosity is increased in subjects with elevated ABI values, independently of other cardiovascular risk factors. This finding contributes to explain the high CVR of patients with PCA.

Decreased platelet aggregation by shear stress-stimulated endothelial cells in vitro: description of a method and first results in diabetes.

The interaction between platelets and endothelium in vivo is a complex phenomenon. Our aim was to develop an in vitro system that mimics the in vivo environment and investigate platelet function in a common pathological condition. Human umbilical vein endothelial cells were used and platelets from 28 type 2 diabetes patients were studied under shear stress conditions. Mean coefficient of variation of platelet aggregation was 10% in dynamic conditions in the presence of endothelium. Endothelial cells increased the concentration of inductor needed to achieve 50% platelet aggregation to adenosine diphosphate from 2.6 ± 1.3 in static conditions to 3.7 ± 1.3 µM in dynamic conditions. A similar pattern was observed when collagen was used for platelet activation. Incubation of endothelium with a nitric oxide inhibitor abolished this effect, indicating platelet inhibitory effect of endothelial cells is nitric oxide mediated. Platelet reactivity of healthy controls was less influenced by the presence of endothelial cells and displayed reduced basal platelet reactivity compared with platelets from diabetes patients. We show that platelet aggregation in diabetes as commonly reported in vitro may not fully reflect the in vivo pathophysiological process. Future studies are warranted to investigate other pathological conditions and analyse the effects of antiplatelet agents using this system.

Lipid-polymer nanoparticles encapsulating curcumin for modulating the vascular deposition of breast cancer cells.

Vascular adhesion and endothelial transmigration are critical steps in the establishment of distant metastasis by circulating tumor cells (CTCs). Also, vascular inflammation plays a pivotal role in steering CTCs out of the blood stream. Here, long circulating lipid-polymer nanoparticles encapsulating curcumin (NANOCurc) are proposed for modulating the vascular deposition of CTCs. Upon treatment with NANOCurc, the adhesion propensity of highly metastatic breast cancer cells (MDA-MB-231) onto TNF-α stimulated endothelial cells (HUVECs) reduces by ~70%, in a capillary flow. Remarkably, the CTCs vascular deposition already reduces up to ~50% by treating solely the inflamed HUVECs. The CTCs arrest is mediated by the interaction between ICAM-1 on HUVECs and MUC-1 on cancer cells, and moderate doses of curcumin down-regulate the expression of both molecules. This suggests that NANOCurc could prevent metastasis and limit the progression of the disease by modulating vascular inflammation and impairing the CTCs arrest. FROM THE CLINICAL EDITOR: In this novel study, lipid nanoparticles encapsulating curcumin were able to prevent metastasis formation and limited the progression of the disease by modulating vascular inflammation and impairing the circulating tumor cells' arrest as a result of down-regulation of ICAM1 and MUC1 in a highly metastatic breast cancer cell line model.

Triglyceride glucose index and common carotid wall shear stress.

OBJECTIVES: Alterations in wall shear stress contribute to both clinical and subclinical atherosclerosis. Several conditions such as hypertension, diabetes, and obesity can impair shear stress, but the role of insulin resistance has never been investigated. The present study was designed to investigate whether insulin resistance assessed by TyG Index associates with wall shear stress in the common carotid artery. METHODS: One hundred six individuals were enrolled. Blood pressure, lipids, glucose, and cigarette smoking were evaluated. TyG Index was calculated as log[fasting triglycerides × fasting glucose / 2]. Subjects underwent blood viscosity measurement and echo-Doppler evaluation of carotid arteries to calculate wall shear stress. The association between TyG Index and carotid wall shear stress was assessed by simple and multiple regression analyses. RESULTS: TyG Index was significantly and inversely associated with carotid wall shear stress both in simple (r = -0.44, P < 0.001) and multiple regression analyses accounting for age, sex, and major cardiovascular risk factors. The association was further confirmed after exclusion of subjects with diabetes, dyslipidemia, fasting blood glucose greater than 100 mg/dL, and triglycerides greater than 150 mg/dL. CONCLUSIONS: The present findings suggest that increasing insulin resistance, as assessed by TyG Index, associates with atherosclerosis-prone shear stress reduction in the common carotid artery.

Common carotid and brachial artery hemodynamic alterations in periodontal disease.

AIM: In patients affected by periodontal disease, hypertension and systemic inflammation might cause an arterial hemodynamic derangement; this, in turn, can act as a mediator of the atherogenic process often seen in these patients. This study aimed at a comprehensive hemodynamic evaluation in periodontal patients. METHODS: Fourty-eight subjects participating to a cardiovascular prevention programme were enrolled. Periodontitis, classical risk factors for atherosclerosis, and shear and tensile forces in both carotid and brachial arteries were evaluated. Calculated periodontal indexes were plaque, gingival and pocket deep (PD) indexes. Simple and multiple regression analyses were performed. Afterwards, 30 of them with normal PD index were compared with 30 carefully - matched patients with periodontitis. RESULTS: Brachial and carotid parietal tension were significantly associated with periodontal indexes, especially PD-Sum, in both simple (r = 0.42, p < 0.001 for carotid artery and r = 0.36, p < 0.02 for brachial artery) and multiple regression analyses. Shear stress gave similar results. In case-control analysis, shear stress was lower by 15% and 30%, respectively, in carotid and brachial artery in patients with high PD; common carotid parietal tension was higher. Arterial stiffness resulted not associated with periodontitis. CONCLUSIONS: Periodontal disease is associated to a complex atherosclerotic prone hemodynamic derangement, particularly in large elastic arteries.

The effect of HDL cholesterol on blood and plasma viscosity in healthy subjects.

OBJECTIVE: The influence of lipids on blood and plasma viscosity has not been fully elucidated. In this study we evaluated the contribution of HDL cholesterol to blood and plasma viscosity, in healthy subjects. METHODS: One hundred and forty-four (80 males and 64 females) subjects were enrolled among free-living participants to a cardiovascular disease screening. Exclusion criteria were: diabetes, elevated triglycerides, elevated LDL cholesterol, smoking and drug use. Blood lipids were measured by routine methods. Blood and plasma viscosity were measured by a cone-plate viscometer (Wells-Brookfield DV-III, Stoughton, U.S.A.). Subjects were divided in two groups: at low (<50 mg/dl) and high HDL cholesterol (>50 mg/dl). RESULTS: Blood and plasma viscosity were similar in subjects at low and high HDL cholesterol. In univariate analysis none of the lipid variables was significantly correlated with blood and/or plasma viscosity. In multivariate analysis only LDL cholesterol was marginally associated with blood viscosity. CONCLUSION: HDL cholesterol does not influence blood and plasma viscosity in healthy normolipidemic subjects. LDL cholesterol is marginally associated with blood viscosity.

Exenatide improves endothelial function assessed by flow mediated dilation technique in subjects with type 2 diabetes: results from an observational research.

The GLP-1 receptor agonist exenatide has been approved for adjunctive treatment of type 2 diabetes. Continuous GLP-1 infusion improves endothelial function in vivo; no evidence about a beneficial effect of exenatide on vascular function has been published. The aim of our observational study was to evaluate whether exenatide would improve brachial artery function evaluated by the flow mediated dilation (FMD) technique, compared with glimepiride, in subjects with type 2 diabetes. FMD time course was assessed by ultrasound, after 5 min forearm ischaemia, at baseline and after 16-week treatment. At the end of the study FMD was significantly higher in subjects who assumed exenatide compared with glimepiride (9.1 ± 3.6 vs. 5.6 ± 1.0, p = 0.01). Even if limited by the small number of studied subjects, who were not matched in the two treatment groups, this research study represents the first FMD evidence suggesting that chronic administration of exenatide improves arterial dilation.

Modulating the vascular behavior of metastatic breast cancer cells by curcumin treatment.

The spreading of tumor cells to secondary sites (tumor metastasis) is a complex process that involves multiple, sequential steps. Vascular adhesion and extravasation of circulating tumor cells (CTCs) is one, critical step. Curcumin, a natural compound extracted from Curcuma longa, is known to have anti-tumoral, anti-proliferative, anti-inflammatory properties and affect the expression of cell adhesion molecules, mostly by targeting the NF-κB transcription factor. Here, upon treatment with curcumin, the vascular behavior of three different estrogen receptor negative (ER(-)) breast adenocarcinoma cell lines (SK-BR-3, MDA-MB-231, MDA-MB-468) is analyzed using a microfluidic system. First, the dose response to curcumin is characterized at 24, 48, and 72 h using a XTT assay. For all three cell lines, an IC(50) larger than 20 µM is observed at 72 h; whereas no significant reduction in cell viability is detected for curcumin concentrations up to 10 µM. Upon 24 h treatment at 10 µM of curcumin, SK-BR3 and MDA-MB-231 cells show a decrease in adhesion propensity of 40% (p = 0.02) and 47% (p = 0.001), respectively. No significant change is documented for the less metastatic MDA-MB-468 cells. All three treated cell lines show a 20% increase in rolling velocity from 48.3 to 58.7 µm/s in SK-BR-3, from 64.1 to 73.77 µm/s in MDA-MB-231, and from 57.5 to 74.4 µm/s in MDA-MB-468. Collectively, these results suggest that mild curcumin treatments could limit the metastatic potential of these adenocarcinoma cell lines, possibly by altering the expression of adhesion molecules, and the organization and stiffness of the cell cytoskeleton. Future studies will elucidate the biophysical mechanisms regulating this curcumin-induced behavior and further explore the clinical relevance of these findings.

Exenatide improves glycemic variability assessed by continuous glucose monitoring in subjects with type 2 diabetes.

BACKGROUND: Daily glycemic fluctuation leads to development of long-term complications. The aim of our pilot study was to determine if exenatide reduces glycemic variability, assessed with a continuous glucose monitoring (CGM) system, compared with glimepiride. METHODS: We enrolled six consecutive subjects with type 2 diabetes, for whom exenatide was suggested as second-line treatment, and six control subjects, for whom glimepiride was suggested as second-line treatment. CGM was performed at baseline and after 16 weeks of treatment. As measures of glycemic variability we calculated the total daily mean glucose (MG), SD, and mean amplitude of glycemic excursions (MAGE). RESULTS: Exenatide significantly reduced MG, SD, and MAGE, whereas glimepiride did not. Fasting glucose and glycated hemoglobin were lowered in both groups, even if the reduction was not significant. CONCLUSION: Exenatide can reduce glycemic variability compared with glimepiride, providing additional beneficial effects in controlling glucose homeostasis.

Poor glycemic control is an independent risk factor for low HDL cholesterol in patients with type 2 diabetes.

OBJECTIVE To determine whether the association observed between poor glycemic control and low HDL cholesterol in type 2 diabetes is dependent on obesity and/or hypertriglyceridemia. RESEARCH DESIGN AND METHODS We performed a cross-sectional study of 1,819 patients with type 2 diabetes and triglycerides <400 mg/dl enrolled at three diabetes centers in Italy. The risk for low HDL cholesterol was analyzed as a function of A1C levels. Odds ratios (ORs) were calculated after adjustment for confounding factors. RESULTS A 1% increase in A1C significantly increased the risk for low HDL cholesterol (OR 1.17 [95% CI 1.1-1.2], P = 0.00072); no changes were observed when age, sex, smoking, and lipid-lowering therapy were included in the model (1.17 [1.1-1.2], P = 0.00044). The association remained strong after adjustments for obesity and hypertriglyceridemia in multivariate analysis (1.12 [1.05-1.18], P = 0.00017). CONCLUSIONS Poor glycemic control appears to be an independent risk factor for low HDL cholesterol in type 2 diabetes.

Body mass index, metabolic syndrome and carotid atherosclerosis.

OBJECTIVE: Body fatness and fat distribution are widely accepted as coronary heart disease risk factors. In this study, we have evaluated the contribution of generalized adiposity, assessed by body mass index (BMI), to carotid atherosclerosis, in participants with or without metabolic syndrome (MetS). METHODS: We have analysed 840 female and 1002 male participants in a regional Cardiovascular Disease Prevention Campaign. Blood glucose and lipids were analysed by standard methods. According to BMI, calculated as weight (in kilograms)/height (in square metres), participants were divided into normal weight (BMI <25 kg/m2), overweight (BMI between 25 and 29.9 kg/m2) and obese (BMI>29.9 kg/m2). Carotid atherosclerosis was evaluated by echo Doppler. RESULTS: Blood pressure, waist circumference, triglycerides and glucose were significantly higher, and high-density lipoprotein was lower, in overweight and obese participants, compared with normal weight. MetS was more frequent among obese and overweight than normal-weight participants (51.7 vs. 21.5 vs. 9.8%, respectively). The prevalence of carotid atherosclerosis was 45.29% in participants with MetS, significantly higher than in participants without MetS (33.04%, P<0.0001), but it was similar across the three weight categories. Furthermore, in multiple regression analyses BMI was not significantly associated with carotid atherosclerosis. CONCLUSION: The present findings suggest that increasing body weight favours the clustering of coronary heart disease risk factors. Overweight and obesity, however, do not independently associate with carotid atherosclerosis.

The E23K variant of KCNJ11 encoding the pancreatic beta-cell adenosine 5'-triphosphate-sensitive potassium channel subunit Kir6.2 is associated with an increased risk of secondary failure to sulfonylurea in patients with type 2 diabetes.

CONTEXT: Several studies suggest that genetic factors may play a role in the different responses to antidiabetic therapy; however, conclusive evidence is still lacking. OBJECTIVE: The objective of the study was to investigate whether diabetic patients carrying the E23K variant in KCNJ11 are at increased risk for secondary sulfonylurea failure. DESIGN: Secondary sulfonylurea failure was defined as fasting plasma glucose greater than 300 mg/dl despite sulfonylurea-metformin combined therapy and appropriate diet, in the absence of other conditions causing hyperglycemia. SETTING: The study was conducted in an ambulatory care facility. PATIENTS: A total of 525 Caucasian type 2 diabetic patients were enrolled in the study. INTERVENTION: Sulfonylurea treatment was followed by sulfonylurea-metformin combined therapy and then insulin treatment. MAIN OUTCOME MEASURE: Secondary failure was the main outcome measure. RESULTS: Of the diabetic patients enrolled in the study, 38.5% were E23E homozygous, 51.4% were E23K heterozygous, and 10.1% were K23K homozygous. The frequency of carriers of the K allele was 58 and 66.8% among patients treated with oral therapy or secondary sulfonylurea failure, respectively (odds ratio, 1.45; 95% confidence interval, 1.01-2.09; P = 0.04). Adjustment for age, gender, fasting glycemia, glycosylated hemoglobin, age at diagnosis, and duration of diabetes in a logistic regression analysis did not change this association (odds ratio, 1.69; 95% confidence interval, 1.02-2.78; P = 0.04). Islets isolated from carriers of the K allele showed no differences in glucose-stimulated insulin secretion and a tendency toward reduced response upon glibenclamide stimulation (P = 0.09). After 24-h exposure to high (16.7 mmol/liter) glucose concentration, impairment of glibenclamide-induced insulin release was significantly (P = 0.01) worse with the E23K variant. CONCLUSIONS: These data suggest that the E23K variant in KCNJ11 may influence the variability in the response of patients to sulfonylureas, thus representing an example of pharmacogenetics in type 2 diabetes.