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Background and aims To investigate diabetes treatment initiation and continuation in the next sixth months in newly diagnosed Italian subjects. Methods and results We analyzed administrative claims of 11,300,750 Italian residents. Subjects with incident diabetes were identified by glucose lowering drug prescriptions, disease-specific co-payment exemptions and hospital discharge codes occurring in 2018 but not in 2017. Incident cases were 65,932 of whom 91.4% received the prescription of a glucose lowering drug. Among the latter, those receiving a prescription of a noninsulin medication but no insulin were 84.8%, those receiving a prescription of insulin only were 9.4%, and those receiving prescriptions of both insulin and noninsulin drugs were 5.8%. Metformin was the most frequently drug initially prescribed in noninsulin treated subjects (~85%) and sulphonylurea receptor (SUR) agonists collectively ranked as second (~13%). Lispro (35%) and glargine (34%) were the most frequently prescribed molecules in subjects who were insulin treated. Differences in prescriptions were found in age categories, with increased use of SUR agonists across decades. In the first six months, as many as 50% of noninsulin treated patients continued with the initial drug, ~15% added a second agent, ~5% switched to another medication, and ~30% discontinued any glucose lowering treatment. Conclusions These data document that current guidelines are often neglected because prescriptions of SUR agonists as first agent are still quite common and insulin is prescribed more than expected. They point out the urgent need to improve the dissemination and implementations of guidelines in diabetes care.

In spite of being at target for glucose (1) or traditional cardiovascular (CV) risk factors (2), individuals with type 1 diabetes (T1D) still have an excess of CV mortality and morbidity implying a role for other mechanisms including insulin resistance (IR). Impaired insulin action in T1D was established by clamp technique long ago (3). Estimated glucose disposal rate (eGDR) correlates well with the clamp technique (4) and is a risk marker for microangiopathy (5,6), diabetic kidney disease (DKD) (6), CV risk, and mortality (5,7). In this observational single-center study, we investigated to what extent eGDR is a predictor of CV events, coronary artery disease (CAD), and all-cause mortality irrespective of CV risk factors and DKD in 774 subjects with T1D over a 10-year follow-up, as previously described (8). eGDR (mg/kg/min) was calculated at baseline as follows (4): eGDR = 21.158 − (0.09 × WC) − (3.407 × HTN) − (0.551 × HbA1c), where WC is waist circumference (cm), HTN is hypertension (yes = 1, no = 0), and HbA1c is in %. Follow-up data were retrieved from the national and regional health care registers (ICD-9, Clinical Modification, codes) by searching for CV outcomes (primary outcome) up to 31 December 2017 and for all-cause death up to 31 October 2018. Incidence of CV outcomes was available for 736 participants (95.1%), and vital status was available for all individuals (8). We used univariate and multivariate Cox proportional hazards models to …

Backgrounds and aims To investigate relevant indicators of quality of care in a large population-based sample of people with diabetes representative of clinical practice in Italy in 2018. Methods and results We analyzed data from 11,300,750 subjects. All administrative healthcare claims collected in 2018 were scrutinized to identify subjects with diabetes and investigate several indicators of quality of care. Subjects with diabetes were identified by anti-hyperglycemic drug prescriptions, disease-specific co-payment exemption and hospital discharge codes. Indicators of quality of care pertained to monitoring (HbA1c, creatinine, lipid profile, microalbuminuria, eye examination, ECG, ultrasonography of carotid and lower limb arteries) and diabetes treatment (anti-hyperglycemic agents in subjects with cardiovascular disease, CVD). Subjects attending and nonattending Diabetes Clinics were compared. We identified 697,208 individuals with diabetes. HbA1c was assessed at least once in the year in 62.7%, creatinine in 62.3%, total cholesterol in 59.6%, microalbuminuria in 34.3%. Frequency of eye examination was 8.2%, ECG 23.5%, carotid ultrasonography 14.3%, lower limb ultrasonography 7.6%. Among anti-hyperglycemic drugs, SGLT-2 inhibitors were prescribed to ~5% and GLP-1 receptor agonists to ~5% although the proportion of subjects with CVD was ~45%. Subjects attending Diabetes Clinics had higher figures for all these monitoring and treatment indicators. Conclusions The implementation of national and international guidelines regarding disease monitoring and treatment is far from being satisfactory, especially among subjects nonattending Diabetes Clinics. Further efforts and investments are needed for better disseminating guidelines, more efficaciously engaging healthcare professionals and more strongly empowering the healthcare system to improve diabetes care.

IntroductionDiabetes is a highly prevalent disease worldwide and represents a challenge for patients and healthcare systems. This population-based study evaluated diabetes burden in Italy in 2018 by assessing all aspects of outpatient and hospital care.Research design and methodsWe investigated data of 11 300 750 residents in local health districts contributing to ARNO Diabetes Observatory (~20% of Italian inhabitants). All administrative healthcare claims were analyzed to gather information on access to medical resources. Subjects with diabetes, identified by antihyperglycemic drug prescriptions, disease-specific copayment exemption and hospital discharge codes, were compared with age, sex and residency-matched non-diabetic individuals.ResultsWe identified 697 208 subjects with ascertained diabetes, yielding a prevalence of 6.2% (6.5% in men vs 5.9% in women, p2-fold higher in subjects with diabetes, mainly driven by hospitalizations and outpatient care related to chronic complications rather than to glucose-lowering drugs, diabetes-specific devices, or metabolic monitoring.ConclusionsThe burden of diabetes in Italy is particularly heavy and, as a systemic disease, it includes all aspects of clinical medicine, with consequent high expenses in all areas of healthcare.

Aims Albuminuric and non-albuminuric phenotypes of chronic kidney disease (CKD) may have different cardiovascular risk and survival in type 1 diabetes (T1DM). Herein we estimated risk of major vascular outcomes by the EURODIAB PCS score and determined all-cause mortality rate in 774 T1DM according to CKD phenotypes. Methods We evaluated the distribution of CKD phenotypes [no CKD, stages 1–2, non-albuminuric stage ≥3 (Alb−CKD), albuminuric stage ≥3 (Alb+CKD)], the EURODIAB risk score for major vascular outcomes [low- (LS), intermediate- (IS), and high- (HS) risk] and all-cause mortality over a follow-up of 8.25 ± 2.34 years. Results Out of 774 subjects, 692 (89.4%) had no CKD, 53 (6.8%) CKD stages 1–2, 17 (2.2%) Alb−CKD and 12 (1.6%) Alb+CKD; 466 (60.2%) had LS, 205 (26.5%) IS and 103 (13.3%) HS. Distribution of HS was: no CKD, 9.1%; CKD stages 1–2, 34.0%; Alb−CKD, 64.7%; Alb+CKD, 91.7% (P Conclusions In our T1DM cohort, one fifth of those with CKDs were non-albuminuric. This phenotype was associated with higher risk of major outcomes and similar rate of mortality as compared to CKD stages 1–2. The greatest risk and highest mortality occur in patients with Alb+CKD.

Estimated Glucose Disposal Rate (eGDR), a validated tool to estimate insulin sensitivity (IS) in T1DM [eGDR = 21.158 - (0.09 x WC, cm) - (3.47 x hypertension, yes = 1) - (0.551 x HbA1c, %)], has been associated to all-cause death. The relationship between eGDR and major vascular (CV) events was evaluated in 736 T1DM enrolled in an observational, single-centre study over a 10-year follow-up. Incidence of CV and coronary events were obtained by interrogating hospital discharge registers. Mean eGDR was 7.51±2.26 (M±SD) mg/kg/min (median 8.26; IQR 5.53-9.29). According to the “Swedish National Diabetes Register,” eGDR was stratified in: C1: ≥8.0 (N. 399, 54.2%, ref); C2: 6.0-7.99 (N. 121, 16.4%); C3: 4.0-5.99 (N. 144, 19.6%) and C4: Disclosure M. Garofolo: None. E. Gualdani: None. R. Giannarelli: None. M. Aragona: None. F. Campi: None. D. Lucchesi: None. G. Daniele: None. R. Miccoli: None. P. Francesconi: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Board Member; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited. G. Penno: None.

We report results from the clinical use of IDegLira compared to basal-bolus (BB) insulin regimen in T2DM patients admitted to our department because of DFU and CLI. We retrospectively identified 44 consecutive T2DM patients admitted to our diabetes ward because of DFU (M/F: 24/20; age: 67.3±9.5 years; BMI: 30.6±5.2 Kg/m2; diabetes duration (DD): 23.5±9.9 years; HbA1c 71.7±24.5 mmol/mol). During hospitalization, 28 patients (Group A: M/F: 15/13; age: 65.7±8.9 years; BMI: 32.6±4.8 Kg/m2; DD: 21.1±9.9 years; HbA1c 76.1±25.2 mmol/mol) previously on BB (63.7±33.9 U/day), were started on IDegLira (IDeg 22.8±7.8 U/day, liraglutide 0.82±0.3 mg/day) while the remaining 16 (Group B; M/F: 9/7; age: 70.4±10.1 years; BMI: 30.3±2.2 Kg/m2; DD: 27±9.2 years; HbA1c 63.9±22.0 mmol/mol; all p=NS vs. Group A) continued BB (43±18 U/day), allowing comparison over a mean follow-up period of 3 months. Patients were comparable with respect to distal lesions, pain-relieving, antibiotic therapies, revascularization procedures and surgical treatments performed. In Group A, BMI, HbA1c and LDL-C improved significantly (26.4±10.1 Kg/m2; 54±11 mmol/mol; 61.5±32 mg/dl; p Disclosure P. Falcetta: None. F.S. Indovina: None. R. Giannarelli: None. A. Piaggesi: None. G. Penno: None. R. Miccoli: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Board Member; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited. A. Coppelli: None.

BackgroundMicrovascular complications (MC) have been claimed to increase the risk for cardiovascular disease in diabetic subjects. However, the effect of MC burden on the risk of major vascular outcomes and all-cause mortality in type 1 diabetes is still poorly explored. We evaluated the relationship between microvascular complications burden and incidence of major cardiovascular events and all-cause mortality in subjects with type 1 diabetes.MethodsWe recruited 774 participants with type 1 diabetes in a single-center observational study over a follow-up of 10.8 ± 2.5 years. Hazard ratios (HR) for cardiovascular outcomes and all-cause death associated with microvascular complications were determined by unadjusted and adjusted Cox regression analysis.ResultsOut of 774 individuals, 54.9% had no-MC, 32.3% 1 MC, 9.7% 2 MC and 3.1% 3 MC. A total of 54 deaths (7.0%) occurred. Death rate increased from no-MC 2.1% (Ref) to 1 MC 7.2% (HR 3.54 [95% CI 1.59–7.87]), 2 MC 14.7% (HR 6.41 [95% CI 2.65–15.49]) and 3 MC 66.7% (HR 41.73 [95% CI 18.42–94.57], p ConclusionsIn type 1 diabetes, microvascular complications burden increases in an independent dose-dependent manner the risk of major cardiovascular outcomes and all-cause mortality. The presence and number of microvascular complications should be considered in stratifying overall cardiovascular risk in type 1 diabetes.

Background: To which extent the presence of one or more microvascular complication (MC) affects cardiovascular (CV) outcomes and mortality in diabetes is still debated. We evaluated the relationship between MC and incidence of major CV events and all-cause mortality in type 1 diabetes. Methods: We recruited 774 participants with type 1 diabetes in a single-center observational study over a follow-up of 10*8±2*5 years. Hazard Ratios (HR) for outcomes were determined by unadjusted and adjusted Cox regressions. Findings: Out of 774 individuals, 54·9% had no-MC, 32·3% 1 MC, 9·7% 2 MC and 3·1% 3 MC. A total of 54 deaths occurred. Death rate increased from no-MC 2·1% (Ref) to 1-MC 7·2% (HR 3·54 [95% CI 1·59–7·87]), 2-MC 14·7% (6·41 [2·65–15·49]) and 3-MC 66·7% (41·73 [18·42–94·57]; p

Gonzalez-Clemente et al. (1) claim that a simpler though efficient assessment of cardiovascular risk in people with type 1 diabetes (T1D) is much needed. Since we showed that the estimated glucose disposal rate (eGDR) was an independent predictor of cardiovascular (CVD) and coronary artery disease (CAD) in people with T1D, they evaluated whether cutoff eGDR values could be calculated to be used in clinical practice to stratify CVD risk. They used the Steno Type 1 Risk Engine (ST1RE) (2) in 179 T1D subjects without CVD to identify 10-year risk level for a first CVD event: low (

Large cardiovascular outcome trials (CVOTs) have lent support to a cardiovascular protection with the use of SGLT2-inhibitors (SGLT2is) and GLP1-Receptor Agonists (GLP1-RAs) in subjects with type 2 diabetes. These two classes of novel glucose lowering agents have been shown to have a similar effect on the risk reduction of Major Adverse Cardiovascular Events (MACE: nonfatal myocardial infarction, nonfatal stroke, cardiovascular mortality). Nonetheless, they may not be simply interchangeable. Rather, careful evaluation of all the results of CVOTs leads identification of different effects that may allow profiling of the ideal individuals with T2DM who may benefit most from the use of one or the other class of agents. These differences include effect on heart failure, stroke and diabetic kidney disease that have prompt recent guidelines and recommendation for the treatment of type 2 diabetes to suggest the preferential use of SGLT2is in those with evidence of heart failure and impaired kidney function, while both SGLT2i and GLP1-RAs with proven effect could be use in those with prevalent atherosclerotic cardiovascular disease. This review discusses all these elements of differentiation along with others that in the future may help establishing the best cardiorenal benefit for individuals with T2DM.

Background High-density lipoproteins (HDLs) can exert anti-atherogenic effects. On top of removing excess cholesterol through reverse cholesterol transport, HDLs play beneficial actions on endothelial function and integrity. In particular, HDLs are strong determinant of endothelial progenitor cells (EPCs) number and function. To gain further insights into such an effect we characterized in vitro functionality of circulating “early” EPCs obtained from 60 type 2 diabetes individuals with low HDL-cholesterol (HDL-C) and 59 with high HDL-C levels. Methods After an overnight fast, venous blood was drawn in EDTA tubes and processed within 2-h from sampling. Peripheral blood mononuclear cells were isolated and plated on fibronectin coated culture dishes; after 3 days culture, adherent cells positive for Dil-ac-LDL/Lectin dual fluorescent staining were identified as monocytic angiogenic cells (MACs). After 5–7 days culture in EBM-2 medium, adherent cells were evaluated for viability/proliferation (MTT assay), senescence (beta-galactosidase activity detection), migration (modified Boyden chamber using VEGF as chemoattractant), adhesion capacity (on fibronectin-coated culture dishes) and ROS production (ROS-sensitive fluorescent probe CM-H2DCFDA). Results MACs obtained from diabetic individuals with high HDL-C had 23% higher viability compared to low HDL-C (111.6 ± 32.7% vs. 90.5 ± 28.6% optical density; p = 0.002). H2O2 exposure impaired MACs viability to a similar extent in both groups (109.2 ± 31.7% vs. 74.5 ± 40.8% in high HDL-C, p

Background Hypoglycaemia is a major burden of the pharmacological therapy of diabetes and is associated with increased morbidity, mortality and treatment costs. Methods We screened all admissions to the emergency room of the Pisa University Hospital from 1 January 2009 to 31 December 2013, selecting individuals with a discharge diagnosis of hypoglycaemia. We retrieved 500 admissions involving adult diabetic patients: age 71 ± 16 years; M/F 50.2/49.8%; 70.2% type 2 diabetes (T2DM). Results Among T2DM, 42.2% were on insulin, 10.8% on insulin plus oral anti-diabetes drugs and 38.2% on oral anti-diabetes drugs alone (92% sulphonylureas/glinides ± insulin-sensitizers). Glibenclamide was the most frequently used sulphonylurea (69%). Individuals treated with oral anti-diabetes drugs were older than those on insulin (79 ± 11 versus 74 ± 12 years; p

Background and aims An intra-islet incretin system has been recently suggested to operate through modulation of the expression and activity of proconvertase 1/3 and 2 (PC1/3, PC2) in pancreatic alpha-cell accounting for local release of GLP-1. Little is known, whether this alpha-cell activity can be affected by the metabolic alterations occurring in type 2 diabetes, such as hyperglycemia, hyperlipidemia or hyperglucagonemia. Materials and methods AlphaTC1/6 cells from a mice pancreatic cell line were incubated in the presence of two glucose (G) concentration (5.5 and 16.7 mM) for 16 h with or without free fatty acid, IL6 or glucagon. GLP-1 secretion was measured by ELISA and expression of PC1/3 and PC2 by RT-PCR and western blot; cell viability was determined by MTT method, Reactive Oxygen Species generation (ROS) by H2DCFDA fluorescence and apoptosis by Annexin staining and Propidium Iodine (PI) fluorescence. Results Upon 16.7G incubation, GLP-1 secretion (total and active) was significantly increased in parallel with a significant increment in PC1/3 expression, a slight increase in cell viability and ROS generation and by a decrement in PC2 expression with no change in cell apoptosis. When cells were incubated at 5.5mM glucose with FFA, also an increment in GLP-1 secretion and PC1/3 expression was observed together an increment in ROS generation, a decrement in cell viability, and a modest increment in apoptosis. When incubated with 16.7mM glucose with FFA, the increment in GLP-1 secretion was reduced to basal, accompanied by an increment in apoptosis and ROS generation. This was also observed with IL-6, but in this case, no modification in ROS generation or apoptosis was observed when compared to 16.7mM glucose. The presence of glucagon did not modify any of the parameters studied. Conclusion These data suggest that under hyperglycemic, hyperlipidemia or inflammatory conditions, alpha cells can increase expression PC1/3 and activate GLP-1 secretion, which may contribute protecting both alpha and beta-cells from glucose and lipotoxicity, while this effect seems to be lost in the presence of both pathophysiological conditions.

Aims: To assess whereas prevalence, treatment and direct costs of drug-treated dia-betes were similar in migrants and in people of Italian citizenship under the universalistic Italian health care system. Methods and results: Drug-treated diabetic individuals were identified in the population-based multiregional ARNO Observatory on the basis of 2010 prescriptions. Migrants were identified by the country-of-birth code on the fiscal identification code. Diabetes prevalence was calculated for Italians (n Z 7,328,383) and migrants (n Z 527,965). To assess the odds of migrants of having diabetes compared to Italians, we individually matched all migrants to Italians for major con-founders (age, sex and place of residence). Finally, all migrants with diabetes were individually matched for confounders to Italians with diabetes to compare prescriptions, hospitalization rates, services use and direct costs for the National Health System. We identified 368,797 sub-jects with diabetes among Italians and 10,336 among migrants, giving prevalence of 5.03% and 1.96%, respectively. Migrants with diabetes were younger than Italians (52 13 years vs. 68 14 years, P < 0.001); after matching, their risk of disease was higher (odds ratio, 1.55, 95% confidence interval, 1.50e1.60). The total cost was 27% lower in migrants, due to lower cost of drugs (29%), hospital admission (27%) and health services (22%). The number of packages/treated person-year of all glucose-lowering drugs was also lower in migrants (15%) (P < 0.001). Conclusions: Compared to subjects of Italian ancestry, migrants to Italy show a higher risk of diabetes but less intense treatment. Inequalities in health care use are likely and are maintained also in a universalistic system.

OBJECTIVE To evaluate the feasibility and effectiveness of an intensive, multifactorial cardiovascular risk reduction intervention in a clinic-based setting. RESEARCH DESIGN AND METHODS The study was a pragmatic, cluster randomized trial, with the diabetes clinic as the unit of randomization. Clinics were randomly assigned to either continue their usual care (n = 5) or to apply an intensive intervention aimed at the optimal control of cardiovascular disease (CVD) risk factors and hyperglycemia (n = 4). To account for clustering, mixed model regression techniques were used to compare differences in CVD risk factors and HbA1c. Analyses were performed both by intent to treat and as treated per protocol. RESULTS Nine clinics completed the study; 1,461 patients with type 2 diabetes and no previous cardiovascular events were enrolled. After 2 years, participants in the interventional group had significantly lower BMI, HbA1c, LDL cholesterol, and triglyceride levels and significantly higher HDL cholesterol level than did the usual care group. The proportion of patients reaching the treatment goals was systematically higher in the interventional clinics (35% vs. 24% for LDL cholesterol, P = 0.1299; 93% vs. 82% for HDL cholesterol, P = 0.0005; 80% vs. 64% for triglycerides, P = 0.0002; 39% vs. 22% for HbA1c, P = 0.0259; 13% vs. 5% for blood pressure, P = 0.1638). The analysis as treated per protocol confirmed these findings, showing larger and always significant differences between the study arms for all targets. CONCLUSIONS A multifactorial intensive intervention in type 2 diabetes is feasible and effective in clinical practice and it is associated with significant and durable improvement in HbA1c and CVD risk profile.

The study explores the degree of control of hyperglycaemia and cardiovascular (CV) disease risk factors in men and women with type 2 diabetes and the impact thereon of obesity, central adiposity, age and use of medications.A cross-sectional survey was conducted at 10 hospital-based outpatients diabetes clinics. 1297 men and 1168 women with no previous CV events were studied. Women were slightly (only one year) older and more obese than men: average BMI was respectively 30.7 ± 5.7 vs 28.6 ± 4.1 kg/m(2) (p0.001), and prevalence of abdominal obesity was 86% vs 44% (p0.001). Women smoked less, but had higher HbA1c, LDL cholesterol, non-HDL cholesterol, systolic blood pressure and serum fibrinogen than men. Accordingly optimal targets for HbA1c (7%), LDL cholesterol (100 mg/dL), HDL cholesterol (40 for men,50 for women, mg/dL), and systolic blood pressure (130 mmHg) were less frequently achieved by women than men (respectively 33.8% vs 40.2%; 14.6% vs 19.2%; 34.1% vs 44.5%; 68.8% vs 72%; p0.05 for all). Findings were confirmed after stratification for waist circumference (or ≥ 88 cm for women;or ≥ 102 cm for men), BMI (or ≥ 25 kg/m(2)) or age (or ≥ 65 years). As for treatment, women were more likely than men to take insulin, alone or in combination with oral hypoglycaemic drugs, to be under anti-hypertensive treatment, whereas the use of lipid lowering drugs was similar in men and women.Control of hyperglycaemia and major CVD risk factors is less satisfactory in women than men. The gender disparities are not fully explained by the higher prevalence of total and central obesity in women; or by a less intensive medical management in women.

To assess temporal trend in incidence (2003-12) and prevalence (2002-12) of type 1 diabetes in children and young adults, direct costs and selected indicators of quality of care under the coverage of the universalistic Italian National Health System (NHS).The ARNO Observatory, a healthcare monitoring system based on administrative data, identified a population-based multiregional cohort of subjects aged 0-29 years. Type 1 diabetes was defined by at least two prescriptions of insulin over 12 months and continuous insulin-treatment in the following year. Indicators of quality of care and directs costs were assessed in persons with diabetes and in people without diabetes, individually matched for age, gender and health unit (1:4 ratio). We identified 2357 incident cases of type 1 diabetes aged 0-29 years (completeness of ascertainment, 99%). Incidence rates were similar in ages 0-14 (15.8, 95% CI 14.9-16.8) and 15-29 years (16.3, 15.4-17.2), with no significant trend. Prevalence increased from 137 to 166.9/100,000, particularly in the age 15-29 years. Direct costs accounted for € 2117 in persons with diabetes and € 292 in control individuals. A statistically significant decreasing trend in hospitalization for acute complications was evident (p 0.001), which was almost completely due to ketoacidosis. People with at least one HbA1c measurement over the year were 48.5%.We showed high incidence and increasing prevalence of type 1 diabetes in young adults in Italy, which impact on direct costs under the universalistic coverage of the NHS.

The paper presents a post-hoc analysis of the intensity of dyslipidaemia care operated in the first 2 years of Multiple-Intervention-in-type-2-Diabetes.ITaly (MIND.IT) study.MIND.IT is a multicentric, randomized, two-parallel arm trial involving 1461 type 2 diabetic patients at high cardiovascular (CV) risk. The study compares the usual care (UC) of CV prevention with a multifactorial intensive care (IC) approach aiming at achieving target values for the main CV risk factors according to a step-wise treat-to-target approach.Proportion of patients on target for low-density lipoprotein cholesterol (LDL-C) was about 10% at baseline and increased significantly more with IC than UC (43 vs. 27%; p 0.001). However, the majority (57%) of patients, in this intended intensively treated cohort, failed to achieve the proposed target. Average LDL-C decreased from 144 ± 35 to 108 ± 31 mg/dl with IC and from 142 ± 28 to 118 ± 32 with UC (p-for-interaction0.0001). IC was associated with a significantly greater increase in statin prescription and lower withdrawal from treatment than UC (43 vs. 11% and 28 vs. 61%, respectively; both p 0.001). However, the new treatments were characterized in both groups by the use of low starting doses (≤ 10 mg of atorvastatin, equivalent dose in more than 90% of patients) without increase in case of missed target.The application of a multifactorial treat-to-target intervention is associated with a significant improvement in LDL-C beyond usual practice. However, the change in LDL-C appears to be more related to an increased number of treated patients and a decreased treatment withdrawal than to a true treat-to-target approach.

OBJECTIVE To ascertain to which extent the use of HbA1c and oral glucose tolerance test (OGTT) for diagnosis of glucose tolerance could identify individuals with different pathogenetic mechanisms and cardiovascular risk profile. RESEARCH DESIGN AND METHODS A total of 844 subjects (44% men; age 49.5 ± 11 years; BMI 29 ± 5 kg/m2) participated in this study. Parameters of β-cell function were derived from deconvolution of the plasma C-peptide concentration after a 75-g OGTT and insulin sensitivity assessed by homeostasis model assessment of insulin resistance (IR). Cardiovascular risk profile was based on determination of plasma lipids and measurements of body weight, waist circumference, and blood pressure. Glucose regulation categories by OGTT and HbA1c were compared with respect to insulin action, insulin secretion, and cardiovascular risk profile. RESULTS OGTT results showed 42% of the subjects had prediabetes and 15% had type 2 diabetes mellitus (T2DM), whereas the corresponding figures based on HbA1c were 38 and 11%, with a respective concordance rate of 54 and 44%. Subjects meeting both diagnostic criteria for prediabetes presented greater IR and impairment of insulin secretion and had a worse cardiovascular risk profile than those with normal glucose tolerance at both diagnostic methods. In a logistic regression analyses adjusted for age, sex, and BMI, prediabetic subjects, and even more T2DM subjects by OGTT, had greater chance to have IR and impaired insulin secretion. CONCLUSIONS HbA1c identifies a smaller proportion of prediabetic individuals and even a smaller proportion of T2DM individuals than OGTT, with no difference in IR, insulin secretion, and cardiovascular risk profile. Subjects fulfilling both diagnostic methods for prediabetes or T2DM are characterized by a worse metabolic profile.

Type 2 diabetes is a chronic and progressive condition associated with the risk of invalidating micro- and macrovascular complications. Hyperglycemia is the hallmark of the condition and, despite much discussion, glycemic control remains a main goal of treatment in the attempt to prevent chronic complications. A beneficial effect of glycemic control was initially supported by the UK Diabetes Prospective Study showing that intensive treatment, compared with conventional therapy, resulted in an average HbA1c level of 7% and was associated with a 24% relative risk reduction of any diabetes-related end point and a 37% reduction in the risk of microvascular disease. Moreover, a nonsignificant 16% reduction ( P = 0.052) in the risk of acute myocardial infarction was reported (1). Similar results were confirmed in the Kumamoto study (2), whereas the results of more recent intervention trials remain questionable. In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study (3), a lower mean HbA1c level was achieved in the intensive-control group than in the standard-control group (6.6 vs. 7.3%). Intensive control reduced the incidence of combined major macro- and microvascular events (hazard ratio [HR] 0.90; 95% CI 0.82–0.98; P = 0.01), as well as that of major microvascular events (HR 0.86; 0.77–0.97; P = 0.01). However, there was no significant effect of glucose control on major macrovascular events, death from cardiovascular causes, or death from any cause. In the Veteran Administration Diabetes Trial (VADT) (4), median HbA1c levels were 8.4% in the standard therapy group and 6.9% in the intensive therapy group. There was no significant difference between the two groups in the rate of cardiovascular events or in the rate of death from any cause (HR 1.07; 0.81–1.42; P = 0.62). No differences between the two groups were observed for microvascular …

Epidemiologic data support the hypothesis of a direct and independent relationship between hyperglycemia and cardiovascular disease. The lack of a clear-cut threshold value in diabetic patients, and the persistence of the relationship in nondiabetic population as well, suggest that glycemia is a continuous variable, similarly to other cardiovascular risk factors. Moreover, increased plasma glucose levels contribute to cardiovascular risk by activating multiple atherogenic mechanisms. In spite of evident plausibility for hyperglycemia as a cardiovascular risk factor per se, intervention data remain controversial. Results of recent large-scale intervention trials, such as ACCORD, ADVANCE, and VADT, seem to undermine the concept that tight glycemic control confers some protection against cardiovascular disease in patients with type 2 diabetes, while maintenance of near-normal glycemic control from earlier stage of the disease and during acute coronary events seems to be more beneficial. However, individualized therapies remain the cornerstone of strategies aimed to reduce cardiovascular risk associated to hyperglycemia.

Background To test the association between gamma-glutamyltransferase level and glucose regulation. Methods We performed a cross-sectional analysis of 500 subjects [199 men/301 women, age 47 ± 11 years, body mass index (BMI) 28.6 ± 5.5 kg/m2] referred to Diabetes Clinics because of potential risk of type 2 diabetes mellitus (T2DM). Results The prevalence of all glucose intolerance categories was higher in the top quartile of gamma-glutamyltransferase than in the first. Subjects with normal glucose tolerance showed lower gamma-glutamyltransferase levels compared with those with impaired glucose tolerance (IGT), impaired fasting glucose (IFG)+ IGT and T2DM (ANOVA, p < 0.0001), but not those with IFG. Homeostasis model assessment-insulin resistance (HOMA-IR) increased with increasing levels of gamma-glutamyltransferase, while the insulinogenic index/HOMA-IR ratio decreased. In an age- and sex-adjusted analysis, the top gamma-glutamyltransferase quartile was independently associated with IFG + IGT [odds ratio (OR) 2.41; 95% confidence interval (CI): 1.13–5.15] and T2DM (OR 2.77; 95% CI: 1.47–5.22). After further adjustment for BMI, alcohol intake, family history of diabetes, cigarette smoking and physical activity, the top quartile of gamma-glutamyltransferase remained an independent predictor of IFG + IGT (OR 2.62; 95% CI: 1.13–6.07) and T2DM (OR 2.39; 95% CI: 1.20–4.76). Only when transaminases and HOMA-IR have been added to the model, the top quartile of gamma-glutamyltransferase resulted no more independently associated to IFG + IGT or T2DM. Conclusions Gamma-glutamyltransferase is closely related to insulin resistance, reduced beta-cell function and deterioration of glucose tolerance. Copyright © 2010 John Wiley & Sons, Ltd.

Athough type 2 diabetes is a heterogeneous condition encompassing multiple metabolic and vascular alterations, it can be easily described as a disease characterized by chronic hyperglycemia and increased cardiovascular (CV) risk. Hyperglycemia is the diagnostic criterion for diabetes, the target for antidiabetic therapy, and, together with A1C, the marker of glycemic control. Progressive worsening of glycemic control has been described in type 2 diabetic patients irrespective of initial form of treatment, leading the U.K. Prospective Diabetes Study (UKPDS) investigators to describe such changes as the “natural history” of the disease (1). Still, maintaining good glycemic control is crucial, since it is associated with marked reduction in the risk of developing retinopathy, nephropathy, and neuropathy in both type 1 (2) and type 2 diabetic patients (1). But it is CV disease that worsens long-term prognosis in type 2 diabetes (3), to the point that diabetes has been proposed as a CV risk equivalent owed to the observation that 10-year risk for major coronary events approximates the risk in CHD in patients without diabetes with previous CV events (4), increased case fatality rate after myocardial infarction, and worse overall prognosis after CHD (5). In diabetic patients, even after correction for known CV risk factors, the incidence of myocardial infarction or stroke is two- to threefold higher than in the nondiabetic population, with a twofold increase in risk of death (6), suggesting that some feature of diabetes must confer excessive propensity toward CV disease. Can this feature be hyperglycemia? No better issue can be chosen for debate. From an epidemiological point of view, there is evidence that the risk of CV mortality increases with the increase of plasma glucose concentrations (7) and A1C values (8). Moreover, multiple atherogenic mechanisms have been identified that can be activated by hyperglycemia (9). In spite of evident …

Cardiovascular disease accounts for a great majority of deaths in patients with type 2 diabetes. According to the World Health Organization, the prevalence of cardiovascular disease in diabetic patients ranges from 26 to 36%. Fatality rate after myocardial infarction is greater in diabetic patients, and overall prognosis after coronary heart disease is worse. Based on these observations, it has been proposed that diabetes should be considered as a coronary heart disease risk equivalent. If that is the case, prevention of diabetes and early intervention should be pursued. This view is supported by the notion that cardiovascular risk is already increased in people with impaired glucose tolerance. Moreover, higher-than-optimum blood glucose is a major cause of cardiovascular mortality in most world regions of the world. Whether dysglycemia is a marker for a more complex metabolic condition or may directly contribute to excess cardiovascular risk is still a matter of debate. However, experimental work has shown how increased glucose level can trigger multiple mechanisms of susceptibility to atherosclerosis, and diabetes prevention trials have indicated that along with reduction of the rate of conversion toward diabetes, significant improvement in cardiovascular risk factors occurs. Moreover, in the STOP-NIDDM trial, targeting postprandial glucose was associated with reduction in new cases of hypertension, myocardial infarction, and any cardiovascular events. In conclusion, dysglycemia should be included in the list of established cardiovascular risk factors and early treatment introduced in the attempt to improve cardiovascular morbidity and mortality.

This study evaluated the prevalence of peripheral arterial disease (PAD) in type 2 diabetes and its association with traditional and non-traditional cardiovascular (CV) risk factors.In 1610 type 2 diabetics PAD was defined as ankle-brachial pressure index (ABPI)0.9.PAD prevalence was 17%, increased with age, diabetes duration, HbA 1c levels, previous CV events. There were no significant differences in the prevalence of traditional CV risk factors between patients with and without PAD. PAD patients had higher levels of fibrinogen (10.88+/-2.32 versus 10.2+/-2.23micromol/L; p0.0001), uric acid (327.1+/-89.2 versus 315.2+/-83.3micromol/L, p0.01), pulse pressure (70+/-18 versus 60+/-16mm Hg, p0.0001), higher rate of microalbuminuria (21.3% versus 13.7%; p0.05) and lower glomerular filtration rate (GFR, 80.7+/-24 versus 89.9+/-22 ml/min/1.73 m2; p0.001) than those without. In age-gender-adjusted analysis, smoking (OR 1.5; CI: 1.07-2.2), HbA 1c (OR 1.45; CI: 1.07-2.08), high pulse pressure (OR 2.81; CI: 1.63-4.82), reduced GFR (OR 2.16; CI: 1.4-3.3), microalbuminuria (OR 1.62; CI: 1.11-2.36), high fibrinogen levels (OR 2.03; CI: 1.34-3.07) were associated with PAD. In multivariate analysis age, male sex, smoking, high pulse pressure, low GFR, high fibrinogen levels, previous CV events were independent risk factors for PAD.PAD prevalence is high in Type 2 diabetic patients. Non-traditional cardiovascular risk factors may be involved in the development of this complication.

Diabetes is due to the concomitant presence of insulin resistance and impaired insulin secretion. β-Cell dysfunction begins during the prediabetic period, is progressive and not modified by the used therapy. It seems to be determined also by the genetic pattern, and some variants of TCF7L2 gene show in recent reports the strongest association with the alteration of both β-cell function and mass. New therapeutic approaches should therefore improve not only the function but also the β-cell mass. To this aim, strict glycemic control, insulin-sensitizers such as thiazolidinediones and incretin mimetic molecules can be used.

Background: Early identification of impairment in renal function is crucial in diabetic patients. Serum cystatin C may be the most sensitive indicator of glomerular filtration rate (GFR) in the clinical setting. Methods: We compared cystatin C with creatinine, the Cockcroft-Gault (C-G) formula, and the Modification of Diet in Renal Disease (MDRD) study equation for the assessment of early decreased renal function in 288 diabetic patients (125 type 1, 163 type 2) with renal impairment [GFR: 4–222 mL · min−1 · (1.73 m2)−1]. Relationships of cystatin C, creatinine, and iohexol clearance were linearized by plotting their reciprocals in a simple regression model. Diagnostic efficiency was calculated from ROC curves. Results: In this study population, cystatin C (P = 0.0013) was better correlated with GFR (r = 0.857) than were creatinine (r = 0.772), C-G (r = 0.750), and MDRD (r = 0.806), a result replicated in patients with normal renal function (P = 0.023, type 1; P = 0.011, type 2), but not in those with decreased GFR. Mean cystatin C concentrations showed step-by-step statistically significant increases as GFR decreased, allowing very early detection of reduction in renal function. At 90 mL · min−1 · (1.73 m2)−1 and 75 mL · min−1 · (1.73 m2)−1 cut-points, diagnostic efficiencies of cystatin C (89% and 92%) were better than those of the other variables (79%–82% and 85%–86%, respectively; P = 0.01). Conclusions: All data supported the value of serum cystatin C compared with conventional estimates based on serum creatinine measurement for detecting very early reduction of renal function. Use of cystatin C to measure renal function will optimize early detection, prevention, and treatment strategies for diabetic nephropathy.

The aim of this study was to determine whether early myocardial structural and functional systolic and diastolic alterations in asymptomatic and uncomplicated patients with type 1 diabetes mellitus (DM) could be detected using the new highly sensitive echocardiographic techniques of integrated backscatter and color Doppler myocardial imaging. Forty asymptomatic and uncomplicated patients with type 1 DM and 40 gender- and age-matched normal controls were studied. All patients were analyzed by conventional and new echocardiographic techniques (integrated backscatter and color Doppler myocardial imaging). Patients with DM showed reduced systolic function compared with controls, evidenced by significantly lower peak strain, strain rates, and cyclic variation indexes at the septum (p

Insulin is a common treatment option for many patients with type 2 diabetes, and is generally used late in the natural history of the disease. Its injectable delivery mode, propensity for weight gain and hypoglycaemia, and the paucity of trials assessing the risk-to-safety ratio of early insulin use are major shortcomings associated with its use in patients with type 2 diabetes. Development of new insulins-such as insulin analogues, including long-acting and short-acting insulins-now provide alternative treatment options to human insulin. These novel insulin formulations and innovative insulin delivery methods, such as oral or inhaled insulin, have been developed with the aim to reduce insulin-associated hypoglycaemia, lower intraindividual pharmacokinetic and pharmacodynamic variability, and improve imitation of physiological insulin release. Availability of newer glucose-lowering drugs (such as glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose co-transporter-2 inhibitors) also offers the opportunity for combination treatment; the results of the first trials in this area of research suggest that such treatment might lead to use of reduced insulin doses, less weight gain, and fewer hypoglycaemic episodes than insulin treatment alone. These and future developments will hopefully offer better opportunities for individualisation of insulin treatment for patients with type 2 diabetes.

Low insulin sensitivity and a selective loss of acute insulin release identify those individuals at the highest risk of developing type 2 diabetes. Normally, the rapid release of insulin after the ingestion of a meal is critical for post-prandial glucose regulation as first-phase insulin modulates suppression of endogenous glucose production and, therefore, limits meal-related plasma glucose excursions. The loss of first-phase insulin secretion contributes to the development of glucose intolerance. Indeed, postprandial hyperglycaemia represents the first and more evident perturbation of glucose homeostasis in about 60% of newly diagnosed type 2 diabetic patients. In these individuals, restoration of first-phase insulin secretion may result in more efficient inhibition of hepatic glucose production and improved glucose tolerance. In the light of these considerations, therapeutic intervention either alone or in combination with improvement of insulin resistance should be considered early in the course of the disease to prevent excessively rapid deterioration of glycaemic control.

Type 2 diabetes mellitus (T2DM) is one of the most common chronic disorders in older adults and the number of elderly diabetic subjects is growing worldwide. Nonetheless, the diagnosis of T2DM in elderly population is often missed or delayed until an acute metabolic emergency occurs. Accumulating evidence suggests that both aging and environmental factors contribute to the high prevalence of diabetes in the elderly. Clinical management of T2DM in elderly subjects presents unique challenges because of the multifaceted geriatric scenario. Diabetes significantly lowers the chances of “successful” aging, notably it increases functional limitations and impairs quality of life. In this regard, older diabetic patients have a high burden of comorbidities, diabetes-related complications, physical disability, cognitive impairment and malnutrition, and they are more susceptible to the complications of dysglycemia and polypharmacy. Several national and international organizations have delivered guidelines to implement optimal therapy in older diabetic patients based on individualized treatment goals. This means appreciation of the heterogeneity of the disease as generated by life expectancy, functional reserve, social support, as well as personal preference. This paper will review current treatments for achieving glycemic targets in elderly diabetic patients, and discuss the potential role of emerging treatments in this patient population.

Prevention of long-term complications remains the main challenge in the treatment of diabetes. A strong relationship between glucose control and development of complications is apparent in all epidemiologic studies. Yet, intervention trials have yielded questionable results, particularly when intensive treatment was introduced in patients with long-standing diabetes. It has been postulated that in these subjects, prior exposure to chronic hyperglycemia may have generated a negative “metabolic memory,” preventing full exertion of the beneficial effects of any subsequent improvement of glucose control. This phenomenon has been replicated in animal models and it recognizes a molecular basis in the role of oxidative stress, advanced glycation processes, and epigenetic mechanisms accounting for self-perpetuating modifications of gene expression. Conversely, early intervention in both type 1 and type 2 diabetes has proven that good glycemic control reduces the risk of development and progression of complications with a beneficial effect that extends well beyond the duration of near-normoglycemia. This has brought up the concept of “metabolic legacy,” an advantage handed down by early and effective implementation of treatments designed to reduce blood glucose levels as safely as possible along with multifactorial intervention of all cardiovascular risk factors. The evidence, nature, and clinical implication of these concepts are reviewed.

The Emerging Risk Factors Collaboration (1) has recently confirmed that type 2 diabetes remains associated with substantial premature mortality. Compared with nondiabetic individuals, those with diabetes have a hazard ratio (HR) of 1.80 (95% CI 1.71–1.90) for death from any cause, 1.25 (1.19–1.31) for death from cancer, 2.32 (2.11–2.56) for death from vascular causes, and 1.73 (1.62–1.85) for death from other causes. As is apparent, the greater risk is owing to cardiovascular (CV) disease, which accounts for >60% of the years of life lost because of diabetes. Although this increase in CV risk is largely attributable to the coexistence of multiple metabolic and hemodynamic disorders, elevation of plasma glucose levels remains strongly associated with increased CV morbidity and mortality (2–4). In support of a potential direct effect of plasma glucose elevation is the association between fasting plasma glucose levels >100 mg/dL (5.6 mmol/L) and vascular death (1). Since this a near-linear association (1,5) it has been postulated that reduction of plasma glucose levels should exert a positive impact on CV morbidity and mortality. In the UK Prospective Diabetes Study (UKPDS), improvement of glycemic control was associated with a 16% reduction in the risk of myocardial infarction without achieving statistical significance ( P < 0.052) (6). Glycemic control in that seminal trial was, however, relatively unsuccessful. Though intensively treated patients achieved an average A1C of 7%, a progressive worsening in glycemic control occurred after the initial improvement. A more aggressive and successful approach was adopted in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) (7) and Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) (8) trials and Veterans Affairs Diabetes Trial (VADT) (9). In all these three large studies, glycemic control was achieved (A1C 6.5–7.0%) and maintained over a substantial period of …

We investigated cross-sectionally whether the type 2 diabetes (T2DM) risk alleles of rs1801282 (PPARG2) and rs4607103 (ADAMTS9) were associated with T2DM and/or insulin sensitivity (IS) and beta cell function (βF) in Italians without and with newly diagnosed T2DM. In 676 nondiabetic subjects (336 NGR and 340 IGR) from the GENFIEV study and in 597 patients from the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS), we (1) genotyped rs1801282 and rs4607103, (2) assessed βF by C-peptide/glucose modeling after OGTT, and (3) assessed IS by HOMA-IR in both studies and by euglycemic insulin clamp in VNDS only. Logistic, linear, and two-stage least squares regression analyses were used to test (a) genetic associations with T2DM and with pathophysiological phenotypes, (b) causal relationships of the latter ones with T2DM by a Mendelian randomization design. Both SNPs were associated with T2DM. The rs4607103 risk allele was associated to impaired βF (p

Cardiovascular diseases still represent the leading cause of mortality and hospitalization, worldwide. As a consequence of the marked demographic changes observed in the general population, the improved survival rate after an acute cardiovascular event and the progressive rise of costs (mostly due to technological and pharmacological innovations), the estimated burden of cardiovascular diseases will be soon become insurmountable for national healthcare systems. In this view, an integrated approach aimed at improving strategies for cardiovascular disease prevention and, thus, limiting the negative outcomes, would probably be successful. Such an approach may not only achieve long-term benefits, but even significant advantages in the short to medium term, mostly in asymptomatic high-risk individuals. Indeed, this latter population of asymptomatic high-risk individuals would mostly benefit from extensive application and improvement of strategies for cardiovascular disease prevention with a favourable cost-benefit ratio. The Italian Society for Cardiovascular Disease Prevention — Societa Italiana per la Prevenzione Cardiovascolare (SIPREC) — has recognized this strategic aim, focusing a significant part of its institutional actions on the effort for providing educational supports and consensus documents, which represent an overview of the scientific knowledge and personal clinical expertise by national and international key opinion leaders. Expert committees periodically generate ‘state-of-the-art’ documents on specific scientific topics with relevant socioeconomic implications and large clinical impact. The present article is dedicated to healthcare professionals, is based on the available evidence, and provides information on diagnostic algorithms and therapeutic options on abnormal glucose regulation (or dysglycaemia). The relationship between abnormalities in glucose metabolism and cardiovascular complications represents an important and relatively early target for cardiovascular disease prevention. SIPREC identified, even in this clinical setting, a group of scientific experts in order to form a multidisciplinary ‘task force’. This group has been asked to explain in a short, simple and effective fashion the epidemiological impact and the pathophysiological nature of the problem, its clinical features, potential diagnostic algorithms and therapeutic options, and its influence on the clinical practice of both specialist physicians and general practitioners. This work provides the background for discussing novel future strategies for cardiovascular prevention. It is also aimed at highlighting the importance of an emerging marker of cardiovascular risk, which is often not recognized and underestimated.

BACKGROUND: Chronic hyperglycemia is a major contributor to in vivo platelet activation in diabetes mellitus. OBJECTIVES: To evaluate the effects of acarbose, an alpha-glucosidase inhibitor, on platelet activation and its determinants in newly diagnosed type 2 diabetic patients. METHODS: Forty-eight subjects (26 males, aged 61 +/- 8 years) with early type 2 diabetes (baseline hemoglobin A(1c) < or = 7% and no previous hypoglycemic treatment) were randomly assigned to acarbose up to 100 mg three times a day or placebo, and evaluated every 4 weeks for 20 weeks. The main outcome measures were urinary 11-dehydro-thromboxane (TX)B(2) (marker of in vivo platelet activation) and 8-iso-prostaglandin (PG)F(2alpha) (marker of in vivo lipid peroxidation) excretion rate, 2-h postprandial plasma glucose (PPG) after a test meal, and assessment of glucose fluctuations by mean amplitude of glycemic excursions (MAGE). RESULTS: Baseline measurements revealed biochemical evidence of enhanced lipid peroxidation and platelet activation. As compared with the placebo group, patients treated with acarbose had statistically significant reductions in urinary 11-dehydro-TXB(2) and 8-iso-PGF(2alpha) excretion rate as early as after 8 weeks and at each subsequent time point (between-group P < 0.0001 at 12, 16 and 20 weeks), following earlier decreases in PPG and MAGE. Multiple regression analyses in the acarbose group revealed that PPG was the only significant predictor of 11-dehydro-TXB(2) urinary excretion rate (beta = 0.39, P = 0.002) and MAGE the only predictor of 8-iso-PGF(2alpha) urinary excretion rate (beta = 0.42, P = 0.001). CONCLUSIONS: Postprandial hyperglycemia is associated with enhanced lipid peroxidation and platelet activation in early type 2 diabetes. A moderate decrease in PPG achieved with acarbose causes time-dependent downregulation of these phenomena, suggesting a causal link between early metabolic abnormalities and platelet activation in this setting.

BACKGROUND Elevated levels of the proinflammatory cytokine soluble CD40 ligand (sCD40L) were reported in subjects with diabetes, impaired glucose tolerance, metabolic syndrome (MS), obesity, and insulin resistance. Metabolic abnormalities might also account for increased sCD40L in subjects with essential hypertension. METHODS Several metabolic and vascular correlates of sCD40L levels have been investigated in 90 nondiabetic never-treated essential hypertensive men. RESULTS Median sCD40L level was 8.7 ng/ml (interquartile range: 4.9-11.7). On the basis of sCD40L, subjects were divided by tertiles (thresholds at 6.6 and 11.0 ng/ml). The three groups did not differ for age, body mass index (BMI), smokers, blood pressure (BP), prevalence of nondippers, lipids and lipoproteins, renal function, and albuminuria. Carotid intima-media thickness (IMT: 0.79 +/- 0.22, 0.83 +/- 0.29, and 0.85 +/- 0.30 mm) and percentage of subjects with wall thickening (IMT >0.9 to

Dr. Daniele: The case record presented here is that of D.S., a woman who is now 35 years. Her case report begins when she was 14 years (1987) at which time she underwent screening for diabetes because of her obesity (weight 95 kg, BMI 36 kg/m) and her family history of diabetes (mother and maternal grandmother). Based on her fasting glucose level (160 mg/dl), she was diagnosed with diabetes mellitus. At that time, her level of HbA1c was 7.8%. D.S. began treatment with a low calorie diet with which she obtained a moderate weight reduction (about 10–15 kg). During the following years, she has had several weight fluctuations until she reached 67 kg in 1995. Throughout that period, she had several medical visits, but there is no available information regarding her glucose levels. At 22 years of age (1996), she was admitted into the hospital following a hyperglycemic crisis, accompanied by polyuria and polydipsia. This hospitalization resulted in the diagnosis of insulin-dependent diabetes mellitus and subsequently, she began insulin treatment. On that occasion, diabetic retinopathy was found. The following years she saw an improvement in her glucose levels (HbA1c 6.5%) but a worsening of the retinopathy (diffuse microaneurysms, microhemorthages, and hard exudates) that required bilateral laser therapy. Concurrently, she developed a peripheral motor and sensory neuropathy, and then microalbuminuria but with preserved renal function. She continued insulin with four daily injections and maintained good metabolic control (HbA1c \ 6.5–7%), although her body weight rose continuously until she again reached 95 kg in 2000. In 2003, her HbA1c levels increased (7.8%) and she gained an additional 5 kg.

Based on the results of the U.K. Prospective Diabetes Study (UKPDS), “… treatment of type 2 diabetes [should] include aggressive efforts to lower blood glucose levels as close to normal as possible. …” This was the recommendation the American Diabetes Association promulgated based on the results of the UKPDS when published (1). The suggestion was soon adopted by official guidelines in every region of the world (2). They are generally consistent in recommending an A1C goal of 10,000 subjects with type 2 diabetes and vascular disease, or multiple CV risk factors, to an intensive treatment program targeting normal blood glucose values and A1C

Background and aims The aims of this study were to establish the prevalence of metabolic syndrome (MS), in type 2 diabetes mellitus (DM), according to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, and to assess the association of MS with other cardiovascular (CV) risk factors in these patients. Methods and results A cross-sectional study was conducted in 1610 patients with type 2 DM. Glycated hemoglobin A1c (HbA1c), total cholesterol, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), uric acid, fibrinogen, creatinine, and albumin/creatinine ratios were measured. The risk of coronary heart disease (CHD) was calculated using the UKPDS Risk Engine. Seventy percent of the diabetic population met the criteria for MS; central obesity and hypertension were the most common criteria. Subjects with MS had higher levels of HbA1c, LDL-C, non-HDL-C, uric acid, and fibrinogen compared to patients without MS. Similarly, microalbuminuria and a high triglyceride (Tg)/HDL-C ratio (a marker of small LDL-C) occurred more frequently in patients with MS. When patients with no history of CHD events were considered, mean CHD risk was greater in those with, than those without, MS. Conclusions MS is highly prevalent in type 2 DM and is commonly associated with non-traditional CV risk factors. The diagnosis of MS seems to confer additional CHD risk in patients with type 2 diabetes.

We randomly administered thyrotropin-releasing hormone (200 micrograms, as an i.v. bolus) or control saline (in isovolumic amount) to 30 male diabetic subjects (23 IDDM, 7 NIDDM) in fair metabolic control (HbA1 9.7 +/- 0.3%, means +/- SEM) and to 12 healthy male controls on two different mornings. While GH in the basal state was similar in IDDM, NIDDM and normal subjects, TRH administration evoked a significant GH release only in a single IDDM individual. The only GH-responder to TRH was a newly-diagnosed (two weeks) IDDM patient, still with a high glycated hemoglobin level (HbA1 11.1%), despite normal plasma glucose levels. Saline infusion did not affect GH concentrations either in normals or in diabetics. Exaggerated GH responses to TRH are uncommon in diabetic patients in good metabolic conditions.

We evaluated the possible association between early vascular abnormalities and the metabolic syndrome (MS) in 77 normotensive subjects (mean age: 50 years) at risk of developing diabetes for family history of diabetes, obesity, or impaired fasting glucose. Fifty healthy subjects were recruited as controls. MS was defined according to the ATP III criteria. Brachial artery endothelium-dependent and -independent vasodilation were assessed as flow-mediated dilation (FMD) and response to glyceryl trinitrate (GTN, 25 μg sublingual), respectively, by automatic computerized edge detection system. Carotid-femoral pulse wave velocity (PWV) and radial augmentation index (AIx) were assessed by applanation tonometry. PWV was significantly ( P P P

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.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.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.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.

The impact of the diabetes epidemic will be staggering in terms of costs to individuals and society. Social educational initiatives are imperative to altering the lifestyle trends that drive the growth of the epidemic. Targeted lifestyle or drug interventions aimed at preventing progression from prediabetes to type 2 diabetes mellitus carry costs and risks that need to be considered in the context of expected benefits, which also need to be carefully defined. In terms of pharmacological intervention as part of a primary prevention programme, the risk/benefit assessment must include the potential for adverse effects in a large population of asymptomatic individuals, a significant proportion of whom would not progress to diabetes in the absence of treatment and in whom impaired glucose regulation may reflect different underlying pathogenetic mechanisms. Improving the balance of risks and benefits in drug interventions will require a greater ability to determine which treatments are likely to safely improve glucose regulation and prevent diabetes and its adverse cardiovascular outcomes in individual patients.

Objectives We hypothesized that molecules active in vascular remodeling (i.e. MMPs and their TIMPs) could be modified in diabetic patients, as indirect markers of the diabetes related generalized abnormality of vascular activity. To test this hypothesis, we measured the plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 in type 2 diabetic patients and in healthy subjects. Methods We enrolled 181 diabetic patients and 165 controls. We measured body mass index (BMI), glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), fasting plasma insulin (FPI), homeostasis model assessment index (HOMA index), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), lipoprotein(a) [Lp(a)], plasminogen activator inhibitor-1 (PAI-1), homocysteine (Hct) fibrinogen (Fg), high sensitivity C-reactive protein (hs-CRP), and plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2. Results A significant increase (P < 0.0001) of BMI, HbA1c, FPG, FPI, HOMA index, SBP, DBP, TC, LDL-C, Tg, Lp(a), PAI-1, Hct, Fg, and hs-CRP was present in the diabetic group, with a significant decrease (P < 0.0001) of HDL-C levels compared to healthy subjects. MMP-2 and MMP-9 levels were significantly higher (P < 0.0001) in diabetic patients. Significant TIMP-1, and TIMP-2 increase was also observed (P < 0.0001) in the diabetic group. Conclusion Plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 are increased in diabetic patients which may reflect abnormal extracellular matrix (ECM) metabolism.