Osteopontin levels correlate with severity of diabetic cardiomyopathy in early stage of diabetes.

Diabetic cardiomyopathy (DbCM) is characterized by restrictive pattern and consistent risk of overt heart failure. We here focused osteopontin (OPN), which was tested independently associated with left ventricular diastolic dysfunction (LVDD). Overall, OPN increased with DbCM severity according with the presence of left atrial dilatation, LV hypertrophy and LVDD.

Ancient wheats: beneficial effects on insulin resistance.

Non-alcoholic fatty liver disease and type 2 diabetes mellitus are two conditions that commonly co-exist in the context of metabolic syndrome. Several scientific advances in understanding this association have identified insulin resistance as the key point in the pathogenesis of both diseases. The first line treatment suggested in the management of these diseases is represented by lifestyle changes, and in particular, the modification of alimentary regimen, with the transition to a healthy diet. In this context, several studies have focused their attention on the identification of food products with beneficial actions, like ancient wheat (AW). AW is defined as the early cereals that were domesticated in their places of origin in the "Fertile Crescent" of the Middle East, and played a central role as a main source of food for the early civilizations in that region. The present narrative review aims at providing a systematic overview of the state of the art on the effects of AW on insulin resistance.

Nox2 up-regulation and hypoalbuminemia in patients with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is associated with oxidative stress but the underlying mechanisms promoting oxidative stress as well as its relationship with cardiovascular events is still unclear. In 375 T2DM patients who were followed-up for approximately 5 years we measured the serum levels of soluble NOX2-derived peptide (sNOX2-dp), a marker of Nox2 activation, and albumin, a powerful antioxidant protein. In the entire cohort soluble Nox2 and serum albumin were significantly correlated (r = -0.348, P < 0.0001). During the follow-up 49 cardiovascular events (CVE) were registered, of which 45 were non-fatal myocardial infarction (MI); patients with non-fatal MI had significantly higher soluble NOX2/albumin ratio compared to cardiovascular events-free patients. Cox regression analysis showed a significant association between sNox2-dp/serum albumin ratio and the incidental risk of non-fatal MI (HR 1.106, CI95% 1.020-1.198, P = 0.014). The study suggests that redox status imbalance negatively influences vascular outcomes in T2DM.

Impaired Clinical Efficacy of Aspirin in Hypoalbuminemic Patients With Diabetes Mellitus.

Objective: To investigate the impact of albumin levels on the aspirin efficacy, since aspirin inhibits platelet aggregation (PA) by cyclooxygenase one irreversible acetylation that is less effective in patients with type 2 diabetes mellitus (T2DM). Patients and Methods: A total of 612 aspirin (100 mg/day)-treated T2DM patients were followed-up for 54.4 ± 7.3 months. The primary endpoint, a composite of cardiovascular events (CVEs) including CV death, myocardial infarction, ischemic stroke and coronary revascularization, was analysed according to baseline values of serum albumin (≥ or < 3.5 g/dL). Serum thromboxane (Tx)B2 was also measured. Results: 250 (40.8%) patients had serum albumin < 3.5 g/dL; these patients were overweight and had higher values of fibrinogen (p = 0.009), high sensitivity C-reactive protein (p = 0.001) and fasting plasma glucose (p < 0.0001) compared to those with albumin ≥ 3.5 g/dL. During follow-up, 86 CVEs were recorded, 49 and 37 in patients with serum albumin < or ≥3.5 g/dL, respectively (p = 0.001). At multivariable Cox regression analysis, serum albumin < 3.5 g/dL (hazard ratio [HR] 1.887, 95% confidence interval [CI] 1.136-3.135, p = 0.014), age (HR 1.552 for every 10 years, 95%CI 1.157-2.081, p = 0.003), fasting plasma glucose (HR 1.063, 95%CI 1.022-1.105, p = 0.002) and beta-blocker use (HR 0.440, 95%CI 0.270-0.717, p = 0.001) were associated to CVEs. Serum TxB2 levels (n = 377) were 0.32 ± 0.12 and 0.24 ± 0.12 ng/ml in patients with albumin < or ≥ 3.5 g/dL, respectively (p < 0.001). Conclusion: In T2DM patients, the efficacy of aspirin varies according to albumin levels. Hypoalbuminemia associated with impaired TxB2 inhibition and an increased risk of long-term CVEs.

The polymorphism rs35767 at IGF1 locus is associated with serum urate levels.

Previous studies suggested that the IGF-1/IGF-1 receptor signaling pathway may contribute to regulate uric acid levels. To confirm this hypothesis, we assessed the effects of the IGF-1-raising genetic variant rs35767 on urate levels in serum and urine, and we investigated IGF-1 ability to modulate the expression of transporters involved in reabsorption and secretion of uric acid in the kidney. The study population included 2794 adult Whites. 24-hour urinary uric acid concentration was available for 229 subjects. rs35767 polymorphism was screened using TaqMan genotyping assays. HEK293 (human embryonic kidney-293) cell line was treated with IGF-1 (1, 5, 10, 50 nM) for 24-hours, and differences in the expression of urate transporters were evaluated via Western Blot and real time rtPCR. Individuals carrying the IGF-1-raising allele (rs35767 T) exhibited significantly lower levels of serum urate according to both additive and recessive models, after correction for gender, age, BMI, glucose tolerance, glomerular filtration rate, and anti-hypertensive treatment. TT genotype carriers displayed higher uricosuria than C allele carriers did, after adjusting for confounders. Exposure of HEK293 cells to IGF-1 resulted in a dose-dependent increase of uric acid transporters deputed to uric acid excretion (MRP4, NPT1 and BCRP), and reduction of GLUT9 expression, the major mediator of uric acid reabsorption, both at mRNA and protein level. We observed a significant association between the functional polymorphism rs35767 near IGF1 with serum urate concentrations and we provide a mechanistic explanation supporting a causal role for IGF-1 in the regulation of uric acid homeostasis.

Elevated 1-h post-load plasma glucose levels in subjects with normal glucose tolerance are associated with a pro-atherogenic lipid profile.

BACKGROUND AND AIMS: Evidence suggests that plasma glucose concentration ≥155 mg/dl at 1h during an oral glucose tolerance test (OGTT) (NGT 1 h-high) predicts both development of type 2 diabetes (T2DM) and cardiovascular events, among adults with normal glucose tolerance (NGT). An atherogenic lipid profile is detectable in subjects with impaired glucose tolerance (IGT) and T2DM. Whether individuals with NGT-1h-high also exhibit a pro-atherogenic lipid profile is still uncertain. METHODS: The study cohort includes 1011 non-diabetic Caucasian adults participating in the CATAMERI study. All participants were submitted to anthropometrical evaluation before undergoing an OGTT. Subjects were categorized into NGT 1 h-low (1 h glucose < 155 mg/dl), NGT 1 h-high, IGT, and newly diagnosed T2DM. Lipid profile includes triglycerides, total and HDL cholesterol, apolipoprotein B (ApoB) and ApoA-1. RESULTS: 510 subjects were NGT 1 h-low, 211 NGT 1 h-high, 232 IGT and 58 were newly diagnosed T2DM. Triglyceride and ApoB levels were significantly higher in NGT 1 h-high, IGT and T2DM subjects compared to NGT 1 h-low, and HDL cholesterol was significantly lower. Triglycerides-to-HDL cholesterol ratio was significantly higher in NGT 1 h-high, IGT and T2DM groups compared with NGT 1 h-low individuals. The ApoB/ApoA-1 ratio was significantly higher in NGT 1 h-high, IGT and T2DM groups than in the NGT 1 h-low group. NGT 1 h-high, IGT and T2DM subjects exhibited reduced LDL/ApoB ratio compared with NGT 1 h-low. Noticeably, there were no significant differences in ApoB/ApoA-1 and LDL/ApoB ratios when comparing NGT 1 h-high with IGT and T2DM. CONCLUSIONS: Individuals with NGT 1-h-high exhibited an atherogenic lipid pattern qualitatively and quantitatively similar to that observed in individuals with IGT and newly diagnosed T2DM.

Insulin-like growth factor-1 is a negative modulator of glucagon secretion.

Glucagon secretion involves a combination of paracrine, autocrine, hormonal, and autonomic neural mechanisms. Type 2 diabetes often presents impaired glucagon suppression by insulin and glucose. Insulin-like growth factor-I (IGF-1) has elevated homology with insulin, and regulates pancreatic ß-cells insulin secretion. Insulin and IGF-1 receptors share considerable structure homology and function. We hypothesized the existence of a mechanism linking the inhibition of α-cells glucagon secretion to IGF-1. Herein, we evaluated the association between plasma IGF-1 and glucagon levels in 116 nondiabetic adults. After adjusting for age gender and BMI, fasting glucagon levels were positively correlated with 2-h post-load glycaemia, HOMA index and fasting insulin, and were negatively correlated with IGF-1 levels. In a multivariable regression, the variables independently associated to fasting glucagon were circulating IGF-1 levels, HOMA index and BMI, explaining 20.7% variation. To unravel the molecular mechanisms beneath IGF-1 and glucagon association, we investigated whether IGF-1 directly modulates glucagon expression and secretion in an in vitro model of α-cells. Our data showed that IGF-1 inhibits the ability of low glucose concentration to stimulate glucagon expression and secretion via activation of the phosphatidylinositol-3-kinase/Akt/FoxO1 pathway. Collectively, our results suggest a new regulatory role of IGF-1 on α-cells biological function.

Genetic Predictors of Cardiovascular Mortality During Intensive Glycemic Control in Type 2 Diabetes: Findings From the ACCORD Clinical Trial.

OBJECTIVE: To identify genetic determinants of increased cardiovascular mortality among subjects with type 2 diabetes who underwent intensive glycemic therapy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS: A total of 6.8 million common variants were analyzed for genome-wide association with cardiovascular mortality among 2,667 self-reported white subjects in the ACCORD intensive treatment arm. Significant loci were examined in the entire ACCORD white genetic dataset (n = 5,360) for their modulation of cardiovascular responses to glycemic treatment assignment and in a Joslin Clinic cohort (n = 422) for their interaction with long-term glycemic control on cardiovascular mortality. RESULTS: Two loci, at 10q26 and 5q13, attained genome-wide significance as determinants of cardiovascular mortality in the ACCORD intensive arm (P = 9.8 × 10-9 and P = 2 × 10-8, respectively). A genetic risk score (GRS) defined by the two variants was a significant modulator of cardiovascular mortality response to treatment assignment in the entire ACCORD white genetic dataset. Participants with GRS = 0 experienced a fourfold reduction in cardiovascular mortality in response to intensive treatment (hazard ratio [HR] 0.24 [95% CI 0.07-0.86]), those with GRS = 1 experienced no difference (HR 0.92 [95% CI 0.54-1.56]), and those with GRS ≥2 experienced a threefold increase (HR 3.08 [95% CI 1.82-5.21]). The modulatory effect of the GRS on the association between glycemic control and cardiovascular mortality was confirmed in the Joslin cohort (P = 0.029). CONCLUSIONS: Two genetic variants predict the cardiovascular effects of intensive glycemic control in ACCORD. Further studies are warranted to determine whether these findings can be translated into new strategies to prevent cardiovascular complications of diabetes.