Showing papers in "Acta Diabetologica in 2013"

Erythrocyte caspase-3 activation and oxidative imbalance in erythrocytes and in plasma of type 2 diabetic patients.

Abstract: An increased oxidative stress and a decreased life span of erythrocytes (RBCs) are reported in patients with diabetes. Aim of this study was to assess in RBCs from patients with type 2 diabetes whether downstream effector mechanisms of apoptosis, such as activation of caspase-3, is operative, and whether an iron-related oxidative imbalance, occurring inside RBCs and in plasma, could be involved in caspase-3 activation. In 26 patients with type 2 diabetes and in 12 healthy subjects, oxidative stress was evaluated by means of different markers; non-protein-bound iron, methemoglobin and glutathione were determined in RBCs, and non-protein-bound iron was also determined in plasma. Erythrocyte caspase-3 activation was evaluated by an immunosorbent enzyme assay. Arterial hypertension, demographic and standard biochemical data were also evaluated. The results show, for the first time, that type 2 diabetic RBCs put into motion caspase-3 activation, which is significantly higher than in control RBCs. Such an effector mechanism of “eryptosis” was positively correlated to blood glucose levels and to the increased plasma NPBI level. Caspase-3 activation was also positively correlated to occurrence of arterial hypertension. The results suggest that an extracellular oxidative milieu can be responsible for erythrocyte caspase-3 activation in patients with type 2 diabetes. In turn, caspase-3 activation can be envisaged as a novel mechanism which, by impairing the maintenance of erythrocyte shape and function, might contribute to the shortened life span of RBCs from patients with type 2 diabetes and to hemorheological disorders observed in these patients.

Pathophysiology and treatment of diabetic retinopathy.

Abstract: In the past years, the management of diabetic retinopathy (DR) relied primarily on a good systemic control of diabetes mellitus, and as soon as the severity of the vascular lesions required further treatment, laser photocoagulation or vitreoretinal surgery was done to the patient. Currently, even if the intensive metabolic control is still mandatory, a variety of different clinical strategies could be offered to the patient. The recent advances in understanding the complex pathophysiology of DR allowed the physician to identify many cell types involved in the pathogenesis of DR and thus to develop new treatment approaches. Vasoactive and proinflammatory molecules, such as vascular endothelial growth factor (VEGF), play a key role in this multifactorial disease. Current properly designed trials, evaluating agents targeting VEGF or other mediators, showed benefits in the management of DR, especially when metabolic control is lacking. Other agents, directing to the processes of vasopermeability and angiogenesis, are under investigations, giving more hope in the future management of this still sight-threatening disease.

The association of pancreatitis with antidiabetic drug use: gaining insight through the FDA pharmacovigilance database.

Abstract: In patients with diabetes, disease per se, co-morbidities and drugs, including novel agents acting on the incretin system, have all been associated with pancreatitis with controversial data. We investigated the publicly available FDA Adverse Event Reporting System (FDA_AERS) database to gain insight into the possible association between antidiabetic agents and pancreatitis. To this aim, a case/non-case method was retrospectively performed on the FDA_AERS database (2004–2009 period). Cases were defined as reports of pancreatitis according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology. All other reports associated with antidiabetics were considered non-cases. The Reporting Odds Ratio (RORs), with corresponding 95% confidential interval (CI) and Mantel–Haenszel corrected P value, was calculated as a measure of disproportionality, with subsequent time-trend analysis. We retrieved 86,938 reports related to antidiabetics, corresponding to 159,226 drug-report combinations: 2,625 cases and 156,601 non-cases. Disproportionality was found only for exenatide (number of cases, 709; ROR, 1.76; 95% CI, 1.61–1.92; P MH < 0.001) and sitagliptin (128; 1.86; 1.54–2.24; <0.001). For exenatide, significant disproportionality appeared in the first quarter of 2008 (ROR, 1.24; 95% CI, 1.10–1.40; P MH < 0.001), soon after the FDA alert; for sitagliptin in the second quarter of 2008 (1.41; 1.05–1.90; 0.021). This temporal analysis found a striking influence of relevant FDA warnings on reporting of pancreatitis (the so-called notoriety bias) and is, therefore, recommended to avoid transforming a pharmacovigilance signal of alert automatically into an alarm. The precise quantification of the risk of pancreatitis associated with antidiabetics deserves assessment through specific disease-based registries.

Association between glucose variability as assessed by continuous glucose monitoring (CGM) and diabetic retinopathy in type 1 and type 2 diabetes

Abstract: There is a growing debate in the literature on whether glucose variability contributes, as well as high HbA1c levels and longstanding diabetes, to the onset and progression of diabetic retinopathy (DR) in patients with diabetes types 1 (DM1) and 2 (DM2). Few data, obtained only by self-monitoring of blood glucose, support this hypothesis. We used continuous glucose monitoring (CGM) to investigate the association between DR and glucose variability parameters (SD, CONGA 2, MAGE), acute hyperglycemia (HBGI) and chronic exposure to glucose (AG and AUC tot). We studied 68 patients from 19 to 69 years old, 35 with DM1 and 33 with DM2. The prevalence of retinopathy was 43 % in DM 1 patients and 39 % in DM 2 patients. The values of all indicators were obtained by CGM for 72 h. DR was diagnosed on direct or indirect ophthalmoscopic examination, after inducing mydriasis with tropicamide. HbA1c was measured at the baseline and 6 weeks after CGM to test the stability of the patients’ glycemic control. Univariate analysis showed a close association between DR and duration of diabetes (OR 1.11; 1.04–1.19), intensive insulin therapy (OR 5.6, CI 1.14–27.30), SD (OR 1.03; CI 1.01–1.06) and CONGA 2 (OR 1.02; CI 1.00–1.04)—both indicators of variability and HBGI (OR 1.1, CI 1.01–1.18)—a parameter reflecting acute hyperglycemia. There was no significant correlation with HbA1c (p = 0.070). Multivariate regression analysis showed that disease duration is the parameter most significantly correlating with DR (OR 1.05; 1.01–1.15). These results reinforce the evidence that longstanding disease is the factor most closely associated with DR. Our data also suggest, however, that glucose variability—regardless of HbA1c—may also have a role as a risk factor for DR, particularly in the case of acute fluctuations (as represented by CONGA 2 and SD) and acute hyperglycemia (as represented by HBGI).

Body composition changes and cardiometabolic benefits of a balanced Italian Mediterranean Diet in obese patients with metabolic syndrome

Abstract: Metabolic syndrome (MS) is a cluster of metabolic alteration associated with a higher risk of cardiovascular disease and overall mortality than the single alterations alone. The Italian Mediterranean Diet (IMD) can exert a positive effect on cardiovascular risk and related morbidity and mortality. The aim was to evaluate the benefits of dietary intervention based on a typical IMD on body composition, cardiometabolic changes and reduction in cardiovascular disease in patients with MS. Eighty White Italian subjects with MS were prescribed a balanced hypocaloric IMD. We investigated dietary habits and impact of the diet on health status, blood biochemical markers, anthropometric measurements and body composition during a 6-month follow-up period. Body composition, fat mass and distribution were assessed by Dual X-ray absorptiometry. Adherence to the IMD led to a decrease in body weight (102.59 ± 16.82 to 92.39 ± 15.94 kg, p < 0.001), body mass index (BMI) (38.57 ± 6.94 to 35.10 ± 6.76, <0.001) and waist circumference (112.23 ± 12.55 vs 92.42 ± 18.17 cm, p < 0.001). A significant loss of total body fat especially in waist region was observed. The MS was resolved in 52 % of the patients. Significant improvements in systolic and diastolic blood pressure and fasting glucose occurred. Low-density lipoprotein cholesterol was reduced from 128.74 ± 33.18 to 108.76 ± 38.61 mg/dl (p < 0.001), triglycerides from 169.81 ± 80.80 to 131.02 ± 63.88 mg/dl (p < 0.001). The present results suggest that a dietary intervention based on a typical IMD effectively promotes weight loss and reduces the growing burden of cardiovascular risk factors that typifies patients with MS.

Clinical frailty and long-term mortality in elderly subjects with diabetes

Abstract: Elderly subjects are characterized by a high prevalence of diabetes and clinical frailty. This study aimed to examine the predictive role of clinical frailty on long-term mortality in elderly subjects with and without diabetes. The study evaluated mortality after 12-year follow-up in 188 subjects with diabetes and 1,100 subjects without diabetes selected in 1992. Clinical frailty was assessed according to the “Frailty Staging System” and stratified in tertiles. After 12-year follow-up, mortality was 50.5 % in subjects without and 66.5 % in subjects with diabetes (p < 0.001). With increasing frailty, mortality increases from 57.9 to 79.0 % (p for trend <0.01) in subjects without and from 75.9 to 87.0 % in subjects with diabetes (p for trend <0.001). Multivariate analysis shows that both diabetes (hazard ratio = 1.38; 95 % confidence interval = 1.12–1.95; p = 0.02) and frailty score (hazard ratio = 1.58 for each unit of increase; 95 % confidence interval = 1.41–2.35; p = 0.04) are predictive of long-term mortality. Moreover, when Cox regression analysis was performed by selecting sex, frailty increases the risk of long-term mortality for each unit of increase by 14 % (hazard ratio = 1.14; 95 % confidence interval = 1.10–1.18; p < 0.01) in women and by 60 % in men (hazard ratio = 1.60; 95 % confidence interval = 1.21–2.12; p < 0.001) in the absence and by 31 % (Hazard ratio = 1.31, 95 % confidence interval = 1.03–1.85, p = 0.03) in women and by 60 % in men (hazard ratio = 1.99, 95 % confidence interval = 1.75–3.05, p < 0.001) in the presence of diabetes, respectively. We concluded that diabetes predicts long-term mortality in elderly subjects. Moreover, clinical frailty significantly predicts mortality in subjects without and even more in those with diabetes. This phenomenon is particularly evident in men. Thus, clinical frailty may be considered a new prognostic factor to identify subjects with diabetes at high risk of mortality.

Relationship between urinary bisphenol A levels and prediabetes among subjects free of diabetes.

Abstract: Bisphenol A (BPA) is a high volume production chemical used in the manufacture of polycarbonate plastics and epoxy resins. Recent experimental studies have suggested that BPA affects glucose metabolism through diverse mechanisms including insulin resistance, pancreatic β-cell dysfunction, adipogenesis, inflammation and oxidative stress. Prediabetes is a stage earlier in the hyperglycemia continuum associated with increased future risk of developing diabetes. Therefore, we examined the association between BPA exposure and prediabetes among subjects free of diabetes. We examined the association between urinary BPA levels and prediabetes in 3,516 subjects from the National Health and Nutritional Examination Survey 2003-2008. Urinary BPA levels were examined in tertiles. Prediabetes was defined as fasting glucose concentration 100-125 mg/dL or 2-h glucose concentration of 140-199 mg/dL or an A1C value of 5.7-6.4 %. Overall, we observed a positive association between higher levels of urinary BPA and prediabetes, independent of potential confounders including body mass index, alcohol intake, blood pressure and serum cholesterol levels. Compared to tertile 1 (referent), the multivariate-adjusted odds ratio (95 % confidence interval) of prediabetes associated with tertile 3 of BPA was 1.34 (1.03-1.73), p-trend = 0.02. In subgroup analysis, this association was stronger among women and obese subjects. Higher urinary BPA levels are found to be associated with prediabetes independent of traditional diabetes risk factors. Future prospective studies are needed to confirm or disprove this finding.

Oxidative stress and antioxidant status in patients with late-onset gestational diabetes mellitus

Abstract: The relationship between late-onset gestational diabetes mellitus [GDM] and oxidative stress is not well known, and the importance of the oxidant/antioxidant equilibrium in the clinical evolution and its complications require elucidation. The aim of the study was to evaluate the relationships between maternal levels of markers of oxidative stress in women with late-onset GDM that, potentially, may have considerable clinical implications in the pathogenesis and/or the evolution of GDM. Pregnant women (n = 78; 53 with GDM, 25 controls), between the 24th and 29th week of gestation, were enrolled. Both groups were analysed for demographic data, perinatal and obstetrics outcomes together with the levels of the marker’s oxidative stress and antioxidant status. Control versus patient results in the univariate analysis were the following: pre-gestational body mass index [BMI] 23.31 ± 4.2 vs. 27.13 ± 4.6 kg/m2 (P = 0.001); weeks at delivery 39.2 ± 3.05 vs. 38.9 ± 1.8 (P = 0.09); Caesarean delivery 12.5 vs. 43% (P = 0.004); macrosomia 4 vs. 9.4% (P = 0.6); lipoperoxides [LPO] 2.06 ± 1.00 vs. 3.14 ± 1.55 μmol/mg (P = 0.001); catalase 3.23 ± 1.41 vs. 2.52 ± 1.3 nmol/min/ml (P = 0.03); superoxide dismutase [SOD] 0.11 ± 0.04 vs. 0.08 ± 0.01 U/ml (P = 0.0003); glutathione peroxidase [GPX] 0.03 ± 0.006 vs. 0.025 ± 0.006 nmol/min/ml (P = 0.01); glutathione reductase [GSH] 0.004 ± 0.002 vs. 0.004 ± 0.004 nmol/min/ml (P = 0.9)]; and glutathione transferase [GST] 0.0025 ± 0.0012 vs. 0.0027 ± 0.00017 nmol/min/ml (P = 0.7). Multivariate analysis showed catalase might have a protective effect against GDM development and LPO seems to be a risk factor for the disease. These data suggest an increase in oxidative stress and a decrease in antioxidative defence in women with late-onset GDM and, as such, may have considerable clinical implications in the pathogenesis and/or the course of the pregnancy in these patients.

Glyco-oxidation and cardiovascular complications in type 2 diabetes: a clinical update

Abstract: Diabetes is associated with a greatly increased risk of cardiovascular disease (CVD), which cannot be explained only by known risk factors, such as smoking, hypertension, and atherogenic dyslipidemia, so other factors, such as advanced glycation end-products (AGEs) and oxidative stress, may be involved. In this frame, hyperglycemia and an increased oxidative stress (AGE formation, increased polyol and hexosamine pathway flux, and protein kinase C activation) lead to tissue damage, thus contributing to the onset of cardiovascular complications. Several studies have identified in various cell systems, such as monocytes/macrophages and endothelial cells, specific cellular receptors (RAGE) that bind AGE proteins. The binding of AGEs on RAGE induces the production of cytokines and intracellular oxidative stress, thus leading to vascular damage. Soluble RAGE levels have been identified as hypothetical markers of CVD, but, in this regard, there are sparse and conflicting data in the literature. The purpose of this review was to examine all the available information on this issue with a view to clarifying or at least highlighting the points that are still weak, especially from the point of clinical view.

Serum levels of bone resorption markers are decreased in patients with type 2 diabetes.

Abstract: Previous studies of bone turnover markers in diabetes are limited, and the results are conflicting. Our aim was to evaluate differences in bone turnover markers and i-PTH between T2DM and non-diabetes subjects. Cross-sectional study including 133 subjects (78 T2DM, 55 without diabetes). BMD were measured by dual X-ray absorptiometry. Bone turnover markers were determined in serum. Serum levels of bone resorption markers (CTX and TRAP5b) were lower in T2DM compared with non-diabetes subjects. There were no differences in bone formation markers. i-PTH serum levels were lower in T2DM: 38.35 ± 18.20 pg/ml versus 50.22 ± 18.99 pg/ml, P < 0.05. TRAP5b and CTX were positively correlated with i-PTH (CTX: r = 0.443, P < 0.001; TRAP5b: r = 0.180, P = 0.047). There was an inverse relationship between TRAP5b levels and diabetes duration (r = −0.269, P = 0.021). T2DM patients have lower levels of bone resorption markers, and i-PTH compared with subjects without diabetes. Lower levels of PTH may induce a low turnover state as reflected by lower levels of bone resorption markers, and this situation may influence the higher risk of fracture of T2DM.

Regulation of TIMP3 in diabetic nephropathy: a role for microRNAs

Abstract: Diabetic nephropathy (DN) is the major cause of chronic kidney disease in developed countries and contributes significantly to increased morbidity and mortality among diabetic patients. Morphologically, DN is characterized by tubulo-interstitial fibrosis, thickening of the glomerular basement membrane and mesangial expansion mainly due to accumulation of extracellular matrix (ECM). ECM turnover is regulated by metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs) activities. In diabetic conditions, TIMP3 expression in kidney is strongly reduced, but the causes of this reduction are still unknown. The aim of this study was to elucidate at least one of these mechanisms which relies on differential expression of TIMP3-targeting microRNAs (miRs) in a hyperglycemic environment either in vitro (MES13 cell line) or in vivo (mouse kidney and human biopsies). Among the TIMP3-targeting miRs, miR-21 and miR-221 were significantly upregulated in kidneys from diabetic mice compared to control littermates, and in a mesangial cell line grown in high glucose conditions. In human samples, only miR-21 expression was increased in kidney biopsies from diabetic patients compared to healthy controls. The expression of miR-217, which targets TIMP3 indirectly through downregulation of SirT1, was also increased in diabetic kidney and MES13 cell line. In agreement with these result, SirT1 expression was reduced in mouse and human diabetic kidneys as well as in MES13 mesangial cell line. TIMP3 deficiency has recently emerged as a hallmark of DN in mouse and human. In this study, we demonstrated that this reduction is due, at least in part, to increased expression of certain TIMP3-targeting miRs in diabetic kidneys compared to healthy controls. Unveiling the post-transcriptional mechanisms responsible for TIMP3 downregulation in hyperglycemic conditions may orient toward the use of this protein as a possible therapeutic target in DN.

IL-6 induction of TLR-4 gene expression via STAT3 has an effect on insulin resistance in human skeletal muscle.

Abstract: We investigated the cytokines and mechanisms involved in the induction of insulin resistance in human skeletal muscle. Ten subjects with impaired glucose tolerance (IGT) and 10 control subjects were recruited. We performed biopsies on the vastus lateralis muscle and used immunoblotting to determine levels of inflammatory cytokines, Toll-like receptor (TLR) gene expression, and insulin signaling. We also used a human myotube culture system to examine the mechanisms underlying TLR-4 gene expression. To identify inflammatory cytokines associated with insulin resistance, we measured the levels of IL-6, TNF-α, TLR-2, and TLR-4 in skeletal muscle from non-obese patients with IGT and control subjects. Levels of IL-6, TNF-α, and TLR-4, but not TLR-2, were significantly increased in the IGT group. Insulin resistance decreased significantly in HSMMs following long-term IL-6 treatment. TLR-4 gene expression was significantly increased in human skeletal muscle myoblasts (HSMMs) treated with IL-6. To determine the main signaling pathway for IL-6-induced TLR-4 gene expression, we examined several signaling factors associated with IL-6 signaling pathways. We found that the active form of “signal transducer and activator of transcription 3” (STAT3) was increased. “Stattic” (a STAT3 inhibitor) markedly inhibited TLR-4 gene expression. IL-6 induction of TLR-4 gene expression via STAT3 is one of the main mechanisms underlying insulin resistance in human skeletal muscle.

"Normoalbuminuric" diabetic nephropathy: tubular damage and NGAL.

Abstract: The aim of this study was to demonstrate that neutrophil gelatinase-associated lipocalin (NGAL) increased before the onset of microalbuminuria in patients with type 1 diabetes mellitus (T1DM), representing an important biochemical parameter with high sensitivity and specificity to make a precocious diagnosis of “normoalbuminuric” diabetic nephropathy (DN). Serum NGAL (sNGAL) and urinary NGAL (uNGAL) levels were evaluated in a cohort of fifty patients affected by T1DM. They had no signs of clinical nephropathy. Thirty-five healthy subjects (HS) were recruited. sNGAL levels were significantly higher compared with those measured in HS [193.7 (103.2–405.4) vs. 46.4 (39.8–56.2) ng/ml; p < 0.0001], as were uNGAL levels [25.5 (14.2–40.2) vs. 6.5 (2.9–8.5) ng/ml; p < 0.0001]. sNGAL was found to be directly correlated with glycated hemoglobin. uNGAL also positively correlated with albuminuria, whereas an inverse correlation was found with uric acid. After multivariate analysis, significance was maintained for the correlation between uNGAL and microalbuminuria. In ROC analysis, sNGAL showed a good diagnostic profile such as uNGAL. NGAL increases in patients with T1DM, even before diagnosis of microalbuminuria representing an early biomarker of “normoalbuminuric” DN with a good sensitivity and specificity. NGAL measurement could be useful for the evaluation of early renal involvement in the course of diabetes.

Alcohol use of diabetes patients: the need for assessment and intervention.

Abstract: It is well known that diabetes self-care behaviors are critical to disease progression. Unfortunately, many patients do not adhere to diabetes self-care recommendations despite their importance. Alcohol use has been identified as a barrier to diabetes self-care adherence. Excessive alcohol consumption not only negatively impacts diabetes self-care adherence but also affects the course of diabetes. Diabetes patients who are at-risk drinkers are likely to have poor diabetes treatment adherence, leading to increased morbidity and mortality. Alcohol consumption by diabetes patients is often inadequately assessed and addressed in their medical care. Brief interventions to reduce at-risk drinking have been well validated in a variety of patient populations and offer the potential to improve diabetes treatment adherence and outcome. Assessment and treatment of at-risk drinking could be readily incorporated into routine diabetes care. Strategies for brief assessment of and intervention for at-risk drinking are offered.

TCF7L2 gene polymorphisms and type 2 diabetes: association with diabetic retinopathy and cardiovascular autonomic neuropathy

Abstract: Type 2 diabetes (T2DM) is a complex disease resulting from the contribution of both environmental and genetic factors. Recently, the list of genes implicated in the susceptibility to T2DM has substantially grown, also as a consequence of the great development of the genome-wide association studies in the last decade. Common polymor- phisms in TCF7L2 gene have shown to have a strong effect with respect to many other involved genes. The aims of our study were to confirm the role of TCF7L2 in the suscepti- bility to T2DM in the Italian population and to investigate whether TCF7L2 genotypes also contribute to the clinical phenotypes variability and to diabetic complications development. Three TCF7L2 polymorphisms (rs7903146, rs7901695 and rs12255372) have been analyzed by allelic discrimination assays in a cohort of 154 Italian patients with T2DM and 171 healthy controls. A case-control association study and a genotype-phenotype correlation study have been carried out. Consistent with previous studies, all three SNPs showed a strong association with susceptibility to T2DM, both at genotypic (P = 0.003, P = 0.004 and P = 0.012) and at allelic level (P = 0.0004, P = 0.0004 and P = 0.003). Moreover, we observed associations between TCF7L2 variants and the following diabetic com- plications: diabetic retinopathy, cardiovascular disease and coronary artery disease. We also found a strong correlation between the rs7903146 and the presence of cardiovascular autonomic neuropathy (P = 0.02 with a high OR = 8.28). In conclusion, our study, in addition to confirming the involvement of TCF7L2 gene in the T2DM susceptibility, has shown that TCF7L2 genetic variability also contributes to the development of diabetic complications such as reti- nopathy and cardiovascular autonomic neuropathy.

Pancreatitis associated with the use of GLP-1 analogs and DPP-4 inhibitors: a case/non-case study from the French Pharmacovigilance Database

Abstract: In the recent past, concerns have raised regarding the potential risk of acute pancreatitis among type 2 diabetic patients using incretin-based drugs such as glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors. The aim of this study is to investigate the association between exposure to incretin-based drugs and the occurrence of pancreatitis reported in the French Pharmacovigilance Database. The case/non-case method was performed from serious adverse drug reactions (ADRs) involving antihyperglycemic agents (except insulin alone) reported to the French pharmacovigilance system between March 2008 (first marketing of an incretin-based drug in France) and March 2013. Cases were defined as reports of pancreatitis, and all other serious ADRs were considered non-cases. Disproportionality was assessed by calculating reporting odds ratios (ROR) adjusted for age, gender, history of pancreatitis, other antihyperglycemic drugs and other drugs associated with a higher risk of pancreatitis. Among 3,109 serious ADRs, 147 (4.7 %) reports of pancreatitis were identified as cases and 2,962 reports (95.3 %) of other ADRs as non-cases. Among the cases, 122 (83.0 %) involved incretin-based drugs. Disproportionality was found for all incretin-based drugs (adjusted ROR: 15.7 [95 % CI 9.8–24.9]), all GLP-1 analogs (29.4 [16.0–53.8]), exenatide (28.3 [12.8–62.3]), liraglutide (30.4 [15.4–60.0]), all DPP-4 inhibitors (12.1 [7.3–20.0]), sitagliptin (12.4 [7.3–21.0]), saxagliptin (15.1 [4.3–52.7]), and vildagliptin (7.4 [3.1–17.6]). Temporal analysis found disproportionality for incretin-based drugs since their first year of marketing in France. Compared with other antihyperglycemic agents, use of incretin-based drugs is associated with an increased risk of reported pancreatitis in France.

MicroRNA genetic variations: association with type 2 diabetes

Abstract: MicroRNAs are small single-stranded molecules that have emerged as important genomic regulators in different pathways. Different studies have shown that they are implicated in the metabolism and glucose homeostasis, and therefore, they could also be involved in the pathogenesis of metabolic disorders such as type 2 diabetes (T2DM). The aim of this study was to verify whether genetic variations in candidate microRNA (miRNA or miR) genes could contribute to T2DM susceptibility. We have selected 13 miRNAs as candidate loci according to literature data and to a computational analysis. MicroRNA genes were analyzed by direct sequencing in a cohort of 163 Italian T2DM patients and 185 healthy controls. We identified 6 novel variants never described before and 9 SNPs already described in databases. Five newly identified variants were found only in the cases group. We performed a case/control association study to test the associations of particular alleles/genotypes of identified SNPs with the disease. Two polymorphisms were associated with T2DM susceptibility: in particular, the G allele of rs895819 in hsa-mir-27a has shown a significantly protective effect (OR = 0.58 and P = 0.008), while the G allele of rs531564 in hsa-mir-124a appears to be a risk allele (OR = 2.15, P = 0.008). This is the first report indicating that genetic polymorphisms in miRNA regions could contribute to T2DM susceptibility.

Salsalate improves glycemic control in patients with newly diagnosed type 2 diabetes

Abstract: Chronic inflammation contributes to insulin resistance and type 2 diabetes mellitus (T2DM). We investigated whether treatment with salsalate, an anti-inflammatory medication, improves glycemia in a group of newly diagnosed drug-naive patients with T2DM. The study was a randomized, double-blind, placebo-controlled trial. Diagnosis of T2DM was made within 2 months of enrollment, and participants had not received any anti-glycemic agent. Sixty adults were randomized to receive salsalate (3 g/day) or placebo for 12 weeks. Fasting plasma glucose and insulin, glucose 2 h after 75 g oral glucose, HbA1C, lipid profile, HOMA-IR, and HOMA-B were determined before and after treatment. Salsalate reduced fasting glucose from 6.3 ± 0.2 mmol/l to 5.4 ± 0.2 mmol/l (P < 0.01) and TG from 1.9 ± 0.2 mmol/l to 1.5 ± 0.2 mmol/l (P < 0.03). Fasting insulin levels were increased in the salsalate group from 18.8 ± 1.6 to 21.6 ± 3.9, while they decreased in the placebo group. HbA1c rose in the placebo group from 6.2% ± 0.2 to 7.9% ± 1.1 mmol/mol, but decreased in the intervention group from 6.1% ± 0.5 to 5.6% ± 0.2 mmol/mol (P < 0.04 for between-group comparison). HOMA-IR did not change but HOMA-B increased ~1.7-fold (P = 0.06) in the salsalate group. The results show that salsalate is effective in improving glycemic control in newly diagnosed naive patients with T2DM. The optimal duration of treatment with salsalate and sustainability of its effect requires further study (IRCT138709011465N1).

The gut microbiota profile is associated with insulin action in humans

Abstract: The role of the gut microbiota in the induction of metabolic diseases has now been increasingly recognized worldwide. Indeed, a specific gut microbiota has been shown to characterize lean versus obese phenotypes both in humans and mice. We have also recently demonstrated that a precise gut microbiota is associated with the host’s responsiveness to a high-fat diet. Therefore, we hypothesized that insulin resistance in humans could also be linked to a specific gut microbiota. To this aim, microbial DNA and RNA were extracted from the appendix contents of insulin-resistant versus insulin-sensitive obese subjects, matched for body mass index and age, and analyzed by DNA- and RNA-DGGE. Microbial DNA analysis showed that the patients fully segregated according to their degree of insulin action. Conversely, microbial RNA investigation showed that some degree of homology still existed between insulin-sensitive and insulin-resistant patients. Quantitative trait analysis, ordinary least squares regression, principal components regression, partial least squares, canonical correlation analysis, and canonical correspondence analysis also showed a net separation of the two phenotypes analyzed. We conclude that a specific gut microbial profile is associated with insulin action in humans.

Very severely obese patients have a high prevalence of type 2 diabetes mellitus and cardiovascular disease

Abstract: The prevalence of very severe obesity has increased progressively and faster than other classes of obesity over the last years. It is unclear whether the prevalence of obesity-related complications and health risks increases progressively or reaches a plateau above a certain degree of obesity. The aim of our study was to investigate whether the severity of obesity was correlated with the prevalence of type 2 diabetes mellitus (T2DM), impaired fasting glucose, impaired glucose tolerance (IGT), metabolic syndrome (MS), and cardiovascular diseases (CVDs) in a large cohort of patients with different degrees of obesity. A cross-sectional study was conducted in 938 obese patients without a previous diagnosis of diabetes. Patients were assigned to different categories of obesity: mild-moderate obesity (BMI 30–39.9 kg/m2), morbid obesity (BMI 40–49.9 kg/m2), and super-obesity (SO, BMI ≥50 kg/m2). The prevalence of IGF, IGT, screen-detected T2DM, MS, and CVD was higher in SO patients than in the other groups. Interestingly, the association between SO and either MS or CVD was independent of glucose tolerance status, indicating that factors other than glucose metabolism also favor cardio-metabolic complications in obese patients. In patients without screen-detected T2DM (n = 807), insulin sensitivity and secretion OGTT-derived indexes indicated that SO patients had the worst glucose homeostasis relative to the other categories of obesity, which was indicated by the most reduced disposition index in these patients, a predictor of future T2DM. In conclusion, SO patients have an extremely high prevalence of glucose metabolism deterioration, and cardio-metabolic complications are more prevalent in these patients compared to less obese patients.

Monocyte–macrophage polarization balance in pre-diabetic individuals

Abstract: Pre-diabetes is characterized by increased cardiovascular risk and chronic inflammation. The activation of monocyte-macrophages plays major roles in vascular biology. Herein, we aimed to analyze monocyte-macrophage polarization status in subjects with IFG and/or IGT compared with normal glucose tolerant (NGT) individuals. We enrolled 87 middle-aged individuals with low prevalence of cardiovascular disease. Based on OGTT, they were divided into 49 NGT and 38 pre-diabetic (IFG and/or IGT). Using flow cytometry analysis of peripheral blood cells, we quantified traditional monocyte subsets based on CD14 and CD16 expression as well as novel monocyte-macrophage pro-inflammatory CD68(+)CCR2(+) M1 and anti-inflammatory CX3CR1(+)CD163(+)/CD206(+) M2 phenotypes. The M1/M2 ratio was taken to represent the polarization balance. There were no differences in traditional classical (CD14(++)CD16(-)), intermediate (CD14(++)CD16(+)) and nonclassical (CD14(+)CD16(+)) monocytes between groups. Rather, compared to NGT, pre-diabetic subjects showed a significant increase in pro-inflammatory M1 cells and percent expression of the oxLDL scavenger receptor CD68, without changes in anti-inflammatory M2 cells. M1 levels and CD68 expression were directly correlated with HbA1c. We show for the first time that otherwise healthy pre-diabetic subjects have excess M1 inflammatory cells in peripheral blood, which may contribute to cardiovascular risk.

Nonalcoholic fatty liver and metabolic syndrome in Italy: results from a multicentric study of the Italian Arteriosclerosis society

Abstract: Nonalcoholic fatty liver disease (NAFLD) is associated with all the components of metabolic syndrome (MS) and might to be considered an additional component of MS itself. The Italian Society for the Study of Atherosclerosis (SISA) in 2005 started a research project aimed to study the NAFLD, using ultrasound (US), in nondiabetic MS subjects matching at least one of the ATP III criteria for HDL-C or triglycerides [TG]. Prevalence of US-NAFLD and its associated risk factors and prevalence of hypertransaminasemia and its possible determinants were evaluated. NAFLD prevalence was 0.78. Men with steatosis compared to men without steatosis were younger (P < 0.05) with higher TG (P < 0.03), homeostasis model assessment insulin resistance (HOMA-R) (P < 0.003), and visceral fat thickness (VFT) (P < 0.0001). Women with steatosis showed higher TG (P < 0.05), HOMA-R (P < 0.04), VFT (P < 0.0001), and lower age (P < 0.05). At multivariate analyses, VFT (P < 0.0001), HOMA-R (P < 0.02), and TG/HDL (P < 0.05) were associated with severity of NAFLD. Age (P < 0.05), LogTG (P < 0.005), and VFT (P < 0.01) were associated with higher ALT. The US prevalence of steatosis in this study (0.78) is the highest reported in patients with MS. Considering the exclusion of severe obese and diabetic patients and the recruitment criteria, this finding highlights the prominent role played by the alterations of lipid metabolism in the pathogenesis of NAFLD.

The prevalence and characteristics of latent autoimmune diabetes in adults (LADA) and its relation with chronic complications in a clinical department of a university hospital in Korea

Abstract: Few studies were performed to evaluate the prevalence of latent autoimmune diabetes in adults (LADA) and the difference of chronic complications between LADA, T1DM, and T2DM in Korean. The aim of this study is to establish the prevalence of LADA in a diabetic clinic of Soonchunhyang University hospital and to compare the phenotypic characteristics according to DM classification based on positivity of glutamic acid decarboxylase antibodies (GADA). Also, another important point concerns the occurrence of diabetes chronic microvascular complications in LADA. 323 patients who were checked GADA among diabetic patients admitted at Soonchunhyang University hospital were recruited. Twenty-eight patients (8.7%) were identified as positive for GADA. 11.5% (n = 37) were diagnosed with T1DM and 5.3% (n = 17) were diagnosed with LADA. GADA titer showed significant negative correlation with age of onset, total cholesterol (TC), triglyceride (TG), fasting C-peptide, stimulated C-peptide, BMI, and positive correlation with HbA1C and HDL-C. Compared with those that tested negative for GADA, patients with GADA positive had lower values of onset age, BMI, TC, TG, LDL-C, fasting, and stimulated C-peptide levels and higher values of HbA1C. A significant gradual increase of values was observed for the onset age, BMI, SBP, DBP, fasting, and stimulated C-peptide across the T1DM, LADA, and T2DM subgroups. Concerning the chronic complications there was no difference in prevalence of retinopathy, neuropathy and nephropathy between three groups. Of LADA patients, 12 patients were receiving insulin treatment and mean time to insulin initiation was about 37 months. In conclusion, because our study suggests LADA subgroups in Korea appear to have a faster decline in C-peptide levels, it is worth detecting the patients with LADA early and effort to preserve beta cell function. Furthermore, our results showed that the prevalence of microvascular complication was comparable between the subgroups.

Independent glucose and weight-reducing effects of Liraglutide in a real-world population of type 2 diabetic outpatients

Abstract: The GLP-1 receptor agonist Liraglutide is effective in reducing HbA1c in type 2 diabetic (T2D) patients. In addition, treatment with Liraglutide is associated with significant weight loss. In this study, we analyzed the inter-relationships between glycemic and weight effects of Liraglutide treatment in a population of type 2 diabetic outpatients. T2D patients initiating Liraglutide therapy since September 2010 to July 2012 at 3 outpatient clinics were enrolled and followed-up. We collected baseline information about anthropometric data, cardiovascular risk factors, diabetes duration, prevalence of complications and history of anti-diabetic medications. We collected HbA1c and body weight at baseline and every 4 months. A total of 166 patients were included, who were on average 56.6 ± 8.9 (mean ± SD) years old and had a baseline HbA1c of 8.7 ± 1.3 % and BMI 36.3 ± 6.4 kg/m(2). Mean follow-up was 9.4 ± 4.2 months (range 4-16). Patients lost on average 1.5 ± 1.3 % HbA1c and 4.0 ± 5.0 kg body weight. Most patients (73.5 %) improved HbA1c and loosed weight. Significant independent determinants of HbA1c drop were baseline HbA1c (r = 0.673; p < 0.001) and previous insulin therapy (r = -0.251; p < 0.001). The only independent determinant of weight loss was baseline BMI (r = 0.429; p < 0.001). Drop in HbA1c was unrelated to baseline BMI or weight loss. Weight loss was unrelated to baseline HbA1c or drop in HbA1c. Glycemic improvement and weight reduction obtained with Liraglutide treatment in T2D patients in a real-world setting are independent and possibly mediated by different mechanisms.

Polymorphisms in the Selenoprotein S gene and subclinical cardiovascular disease in the Diabetes Heart Study

Abstract: Selenoprotein S (SelS) has previously been associated with a range of inflammatory markers, particularly in the context of cardiovascular disease (CVD). The aim of this study was to examine the role of SELS genetic variants in risk for subclinical CVD and mortality in individuals with type 2 diabetes mellitus (T2DM). The association between 10 polymorphisms tagging SELS and coronary (CAC), carotid (CarCP) and abdominal aortic calcified plaque, carotid intima media thickness and other known CVD risk factors was examined in 1220 European Americans from the family-based Diabetes Heart Study. The strongest evidence of association for SELS SNPs was observed for CarCP; rs28665122 (5′ region; β = 0.329, p = 0.044), rs4965814 (intron 5; β = 0.329, p = 0.036), rs28628459 (3′ region; β = 0.331, p = 0.039) and rs7178239 (downstream; β = 0.375, p = 0.016) were all associated. In addition, rs12917258 (intron 5) was associated with CAC (β = −0.230, p = 0.032), and rs4965814, rs28628459 and rs9806366 were all associated with self-reported history of prior CVD (p = 0.020–0.043). These results suggest a potential role for the SELS region in the development subclinical CVD in this sample enriched for T2DM. Further understanding the mechanisms underpinning these relationships may prove important in predicting and managing CVD complications in T2DM.

Type 1 diabetes and celiac disease in adults: glycemic control and diabetic complications.

Abstract: The prevalence of celiac disease (CD) in patients with type 1 diabetes mellitus (T1DM) is 4.5 %. Objective of the study is to investigate (1) the course of glycemic control at CD diagnosis and after the initiation of a gluten-free diet (GFD) in T1DM patients; (2) the prevalence of diabetic complications in T1DM patients with adult onset of CD. In 20 hospitals in the Netherlands, we identified T1DM patients diagnosed with CD at adult age. We retrospectively collected glycated hemoglobin (HbA1c) levels before CD diagnosis, at CD diagnosis, and the most recent HbA1c levels as well as the presence of nephropathy and retinopathy. The control group consisted of patients with T1DM and negative CD serology matched for age, gender, T1DM duration, and HbA1c levels. Thirty-one patients were eligible with a median duration of T1DM and CD of 27 years (IQR 14–37) and 3 years (IQR 1–8), respectively. The matched control group consisted of 46 patients. HbA1c levels at the moment of CD diagnosis were 7.5 % (IQR 7.1–8) [58 mmol/mol] and at the most recent visit 7.4 % (IQR 6.9–7.9, P = 0.15) [57 mmol/mol] indicating no difference. Prevalence of retinopathy was lower in T1DM + CD group compared with controls, (38.7 vs 67.4 %, P < 0.05), whereas no difference in the prevalence of nephropathy was found between the groups (P = 0.09). In conclusion, T1DM + CD patients have less retinopathy compared to T1DM patients without CD. A GFD possibly favorable affects the development of vascular complications in T1DM patients.

Myocardial dysfunction and chronic heart failure in patients with long-lasting type 1 diabetes: a 7-year prospective cohort study

Abstract: The aim of the study is to evaluate the prevalence and incidence of myocardial dysfunction (MD) and heart failure (HF) in long-lasting (≥10 years) type 1 diabetes without cardiovascular disorders or with hypertension or coronary heart disease (CHD). The study included 1,685 patients with type 1 diabetes (mean baseline age, 51 years; diabetes duration, 36 years). In all patients, echocardiography was performed, NT-proBNP levels were measured, and clinical symptoms were evaluated. A 7-year follow-up was conducted to monitor systolic and diastolic manifestations of MD and HF. At the end of the follow-up period, the prevalence of HF in the entire group was 3.7 %, and the incidence was 0.02 % per year. The prevalence of MD was 14.5 % and the incidence –0.1 % per year. MD and HF were observed only in hypertensive or CHD patients. At baseline, subjects with diastolic HF constituted 85 % of the HF population and those with systolic HF the remaining 15 %. Baseline HF predictors included age, diabetes duration, HbA1c levels, CHD, systolic blood pressure >140 mmHg, and GFR <60 mL/min/1.73 m2. In patients with type 1 diabetes, MD and HF occurred only when diabetes coexisted with cardiovascular disorders affecting myocardial function. The prevalence and incidence of HF in patients with hypertension and CHD were relatively low. While the cause of this observation remains uncertain, it could probably be explained, at least partially, by the cardioprotective effect of concomitant treatment.

Nutritional education and carbohydrate counting in children with type 1 diabetes treated with continuous subcutaneous insulin infusion: the effects on dietary habits, body composition and glycometabolic control

Abstract: Carbohydrate counting (CHC) in combination with nutritional education has been used to optimize the insulin dose in patients with type 1 diabetes (T1D). The aim of this study was to test the impact of CHC and nutritional education on changes in dietary habits, body composition and body fat distribution in children with T1D treated with insulin pumps (CSII). Twenty-five children with T1D and CSII were recruited and valuated at baseline and after 18 months of follow-up. They were trained in CHC and following standard nutrition education program (based on American Diabetes Association and International Society of Pediatric and Adolescent Diabetes guidelines); clinical, biochemical and nutritional variables were measured. In the total population, body composition, body fat distribution and biochemical variables did not change, at follow-up; HbA1c was significantly reduced (8.50 ± 0.77 vs 7.92 ± 0.74 %; p < 0.001) without changing insulin/kg/day requirement. In the sub-group of patients with a significant HbA1c reduction (ΔHbA1c ≥ 0.5 %, n = 12), the carbohydrate (CHO) intake was significantly higher at follow-up (53.0 ± 4.0 vs 57.6 ± 2.5 %; p < 0.01); on the contrary, fat (31.3 ± 3.6 vs 28.5 ± 1.6 %; p < 0.05) and protein intake (15.4 ± 1.8 vs 13.3 ± 1.6 %; p < 0.01) significantly decreased. Patients without a significant HbA1c reduction did not show any difference. CHC, in combination with nutritional education, does not affect dietary habits, body composition and body fat distribution in children with T1D treated with CSII. Moreover, the sub-group of subjects showing a significant improvement in glycometabolic control reported an increase in CHO intake and a reduction in fat and protein intake.

Economic status and clinical care in young type 1 diabetes patients: a nationwide multicenter study in Brazil

Abstract: The aim of this study is to evaluate the influence of economic status on clinical care provided to Brazilian youths with type 1 diabetes in daily practice, according to the American Diabetes Association’s guidelines. This was a cross-sectional, multicenter study conducted between 2008 and 2010 in 28 public clinics in Brazil. Data were obtained from 1,692 patients (55.3 % female, 56.4 % Caucasian), with a mean age of 13 years (range, 1–18), a mean age at diagnosis of 7.1 ± 4 years and diabetes duration of 5 ± 3.7 years. Overall, 75 % of the patients were of a low or very low economic status. HbA1c goals were reached by 23.2 %, LDL cholesterol by 57.9 %, systolic blood pressure by 83.9 % and diastolic blood pressure by 73.9 % of the patients. In total, 20.2 % of the patients were overweight and 9.2 % were obese. Patients from very low economic status were less likely to attend tertiary care level when compared with those from low, medium and high economic status, 64.2 % versus 75.5 % versus 78.3 % and 74.0 %; p < 0.001, respectively. The rate of annual screening for retinopathy, nephropathy and for foot alterations was 66.2, 69.7 and 62.7 %, respectively. Insulin dose, age, very low economic status, daily frequency of self-blood glucose monitoring and female gender were independently associated with poor glycemic control. Screening for diabetic complications and attaining glucose, lipid and blood pressure goals present a challenge for young Brazilian type 1 diabetes patients. The low economic status of the majority of our patients may represent a barrier to reaching these goals.

Human subcutaneous adipose tissue Glut 4 mRNA expression in obesity and type 2 diabetes

Abstract: Cellular resistance to insulin caused by reduced glucose transport and metabolism is a primary defect leading to the development of metabolic disease. While the etiology of insulin resistance is multifactorial, reduced insulin action is associated with impaired activity of the glucose transporter GLUT4 in insulin-sensitive tissues. Yet, the role of adipose tissue GLUT4 deregulation in the pathogenesis of insulin resistance, obesity, and diabetes is still unclear. In this study, we assessed the relative GLUT4 level in human subcutaneous adipose tissue from obese, diabetic, and diabetic obese versus control subjects, using a real-time PCR method. GLUT4 mRNA levels were considerably decreased among type 2 diabetic patients compared with those of the controls (P < 0.01), whereas no such difference was found between obese and normal-weight controls. Multiple linear regressions analysis in both diabetic non-obese and diabetic obese groups showed a negative correlation between GLUT4 mRNA expression and both markers of obesity or insulin resistance (P < 0.01). However, in obese group, GLUT4 was inversely associated only with HOMA-IR (P < 0.01). Our findings showed that adipose GLUT4 gene expression changes were more related to insulin resistance and type 2 diabetes rather than to obesity.