LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro.

AIMS/HYPOTHESIS: Activation of inflammatory pathways is involved in the pathogenesis of type 2 diabetes mellitus. On the basis of its role in vascular inflammation and in metabolic disorders, we hypothesised that the TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) could be involved in the pathogenesis of type 2 diabetes mellitus. METHODS: Plasma levels of LIGHT were measured in two cohorts of type 2 diabetes mellitus patients (191 Italian and 40 Norwegian). Human pancreatic islet cells and arterial endothelial cells were used to explore regulation and relevant effects of LIGHT in vitro. RESULTS: Our major findings were: (1) in both diabetic cohorts, plasma levels of LIGHT were significantly raised compared with sex- and age-matched healthy controls (n = 32); (2) enhanced release from activated platelets seems to be an important contributor to the raised LIGHT levels in type 2 diabetes mellitus; (3) in human pancreatic islet cells, inflammatory cytokines increased the release of LIGHT and upregulated mRNA and protein levels of the LIGHT receptors lymphotoxin ß receptor (LTßR) and TNF receptor superfamily member 14 (HVEM/TNFRSF14); (4) in these cells, LIGHT attenuated the insulin release in response to high glucose at least partly via pro-apoptotic effects; and (5) in human arterial endothelial cells, glucose boosted inflammatory response to LIGHT, accompanied by an upregulation of mRNA levels of HVEM (also known as TNFRSF14) and LTßR (also known as LTBR). CONCLUSIONS/INTERPRETATION: Our findings show that patients with type 2 diabetes mellitus are characterised by increased plasma LIGHT levels. Our in vitro findings suggest that LIGHT may contribute to the progression of type 2 diabetes mellitus by attenuating insulin secretion in pancreatic islet cells and by contributing to vascular inflammation.

ENPP1 Q121 variant, increased pulse pressure and reduced insulin signaling, and nitric oxide synthase activity in endothelial cells.

OBJECTIVE: Insulin resistance induces increased pulse pressure (PP), endothelial dysfunction (ED), and reduced bioavailability of endothelium-derived nitric oxide (NO). The genetic background of these 3 cardiovascular risk factors might be partly common. The ENPP1 K121Q polymorphism is associated with insulin resistance and cardiovascular risk. METHODS AND RESULTS: We investigated whether the K121Q polymorphism is associated with increased PP in white Caucasians and with ED in vitro. In 985 individuals, (390 unrelated and 595 from 248 families), the K121Q polymorphism was associated with PP (P=8.0 x 10(-4)). In the families, the Q121 variant accounted for 0.08 of PP heritability (P=9.4 x 10(-4)). This association was formally replicated in a second sample of 475 individuals (P=2.6 x 10(-2)) but not in 2 smaller samples of 289 and 236 individuals (P=0.49 and 0.21, respectively). In the individual patients' data meta-analysis, comprising 1985 individuals, PP was associated with the Q121 variant (P=1.2 x 10(-3)). Human endothelial cells carrying the KQ genotype showed, as compared to KK cells, reduced insulin-mediated insulin receptor autophosphorylation (P=0.03), Ser(473)-Akt phosphorylation (P=0.03), and NO synthase activity (P=0.003). CONCLUSIONS: Our data suggest that the ENPP1 Q121 variant is associated with increased PP in vivo and reduced insulin signaling and ED in vitro, thus indicating a possible pathogenic mechanism for the increased cardiovascular risk observed in ENPP1 Q121 carriers.

Body mass index represents a good predictor of vitamin D status in women independently from age.

BACKGROUND & AIMS: Vitamin D is a pleiotropic hormone targeting several tissues and is involved in basic homeostatic processes, including bone mineralization, immune response and muscle strength. Although hypovitaminosis D is common in Europe and North America, representing a risk factor for several chronic diseases, the contribution of factors other than sun exposure is largely underestimated. METHODS: In our study, we retrospectively collected data from medical records of women with age between 19 and 80 screened in Central Italy (42°N) for increased risk of metabolic syndrome. Vitamin D status was evaluated by serum 25-hydroxyvitamin D (25(OH)D) measurement and the association among vitamin D status and anthropometric and clinic variables was tested by multivariate logistic analysis. RESULTS: More than 80% of women presented serum 25(OH)D concentration lower than 30 ng/mL (75 nM), with the majority of values falling between 10 and 20 ng/mL. 25(OH)D concentration was dependent on season, with the highest 25(OH)D mean value measured in September and the lowest mean value in March. Among different clinical characteristics, body mass index (BMI) demonstrated the highest significant inverse correlation with serum 25(OH)D values, independently from season and age. Serum 25(OH)D values demonstrated a seasonal-directed sinusoidal trend and they raised during spring/summer in a similar manner in both obese and non-obese women. However, the obese group had lower mean values of vitamin D respect to overweight and to normal weight groups in both winter and summer, reaching frequently the status of vitamin D deficiency (<10 ng/mL). CONCLUSIONS: In conclusion, at our latitude, seasonal UV irradiance availability determines an obligate sinusoidal trend in vitamin D status. However, body mass is able to reduce proportionally circulating vitamin D over calendar months determining vitamin D deficiency. These results suggest taking in particular account BMI in clinical management of vitamin D status in overweight and obese women.

[Incretin therapies and multifactorial clinical approach to cardiometabolic patients]. / Le terapie incretiniche e l'approccio clinico multifattoriale del paziente cardiometabolico.

Atherogenic dyslipidemia, hypertension and obesity are frequently present in type 2 diabetes mellitus (T2DM) and contribute to the overall increase in cardiovascular (CV) morbidity and mortality associated with this disease. It is therefore highly desirable that treatments aimed to improving glucose control in T2DM do not negatively impact such risk factors. It would be very helpful, instead, if treatments implemented to lower blood glucose could also be efficacious in mitigating hypertension, obesity and dyslipidemia, so to improve global CV risk profile in these patients. Glucagon-like peptide 1 receptor agonists (GLP-1RA) can efficiently ameliorate blood glucose profile in diabetic subjects with no or minimal risk of hypoglycemia: besides, the use of these agents is associated with weight loss, decreased blood pressure and a modestly but significantly improved lipid profile. Clinical trials and meta-analyses have also demonstrated that patients treated with exenatide and, to a larger extent, with liraglutide are significantly more likely to achieve the composite endpoint of glycated hemoglobin <7%, no hypoglycemia and no weight gain as compared to patients exposed to other diabetes treatment, including dipeptidyl peptidase-4 inhibitors and insulin glargine. Thus, even if randomized controlled outcome trials definitely demonstrating a reduction in CV events in GLP-1RA treated subjects are still lacking, it is nevertheless evident that treatment with GLP-1RA, by its action on CV risk factors, could contribute to mitigate the risk profile in T2DM.

Increased circulating resistin is associated with insulin resistance, oxidative stress and platelet activation in type 2 diabetes mellitus.

Resistin is an adipokine that promotes inflammation and insulin resistance by targeting several cells including platelets. We hypothesised that in type 2 diabetes (T2DM), resistin may foster in vivo oxidative stress, thromboxane-dependent platelet activation and platelet-derived inflammatory proteins release, key determinants of atherothrombosis. A cross-sectional comparison of circulating resistin, sCD40L, as a marker of platelet-mediated inflammation, asymmetric dimethylarginine (ADMA), endothelial dysfunction marker, Dickkopf (DKK)-1, reflecting the inflammatory interaction between platelets and endothelial cells, and urinary 8-iso-PGF2α and 11-dehydro-TxB2, reflecting in vivo lipid peroxidation and platelet activation, respectively, was performed between 79 T2DM patients and 30 healthy subjects. Furthermore, we investigated the effects of the α-glucosidase inhibitor acarbose and the PPARγ agonist rosiglitazone, targeting hyperglycaemia or insulin resistance, versus placebo, in 28 and 18 T2DM subjects, respectively. Age- and gender-adjusted serum resistin levels were significantly higher in patients than in controls. HOMA (ß=0.266, p=0.017) and 11-dehydro-TXB2 (ß=0.354, p=0.002) independently predicted resistin levels. A 20-week treatment with acarbose was associated with significant reductions (p=0.001) in serum resistin, DKK-1, urinary 11-dehydro-TXB2 and 8-iso-PGF2α with direct correlations between the change in serum resistin and in other variables. A 24-week rosiglitazone treatment on top of metformin was associated with significant decreases in resistin, DKK-1, 11-dehydro-TXB2 and 8-iso-PGF2α, in parallel with HOMA decrease. In conclusion, resistin, antagonising insulin action in part through PPARγ activation, may favour insulin resistance and enhance oxidative stress, endothelial dysfunction and platelet activation. The adipokine-platelet interactions may be involved in platelet insulin resistance and their consequent pro-aggregatory phenotype in this setting.

[Cardiovascular risk reduction in the management of diabetic patients: what has changed since the '90s in the clinical approach?]. / Ridurre il rischio cardiovascolare nel trattamento del paziente diabetico: cos'è cambiato dagli anni '90 ad oggi nell'approccio clinico?

Cardiovascular (CV) diseases are the main driver of morbidity and mortality in type 2 diabetes. Mitigating CV risk is therefore one of the main objectives when deciding which therapeutic strategy to adopt when treating diabetic patients. Several lines of evidence suggest nowadays that tight glucose control is associated with a significant reduction in CV risk only when implemented early in the course of the disease and obtained with minimal hypoglycemia risk. This is why glycemic targets "personalized" or "tailored" according to patient clinical characteristics are more and more advised by guidelines and scientific societies. Furthermore, hyperglycemia not only could directly induce vascular wall damage, but it might also act as a potential multiplier of the deleterious effects of all CV risk factors. Therefore, without treating to target all the coexistent risk factors, a CV risk reduction could hardly be achieved. Thus, when deciding which therapeutic strategy to adopt to treat hyperglycemia in diabetes, molecules should ideally be selected which do not worsen extra-glycemic risk factors (obesity, dyslipidemia, hypertension) or which, even better, could help mitigating them. Incretin-based therapies, and glucagon-like peptide-1 (GLP-1) receptor agonists in particular, seem to be able to induce weight loss, ameliorate lipid profile and reduce blood pressure. Furthermore, GLP-1 receptor agonist treatment is associated with a very low hypoglycemia risk. In theory, therefore, using this class of drugs for treating hyperglycemia should help mitigating CV risk in diabetes. Firm evidence of this is not so far available: however, should it convincingly emerge in the next future, it would definitely change our overall approach to CV risk in diabetes.

Circulating dickkopf-1 in diabetes mellitus: association with platelet activation and effects of improved metabolic control and low-dose aspirin.

BACKGROUND: Dickkopf-1 (DKK-1) is a major regulator of the Wnt signaling pathway, involved in inflammation, atherogenesis, and the regulation of glucose metabolism. Because platelets are major contributors to circulating levels of DKK-1 in other clinical settings, we aimed at characterizing the platelet contribution to DKK-1 in type 2 diabetes mellitus (T2DM) and evaluating associations of DKK-1 with glucose metabolism, platelet activation, and endothelial dysfunction. METHODS AND RESULTS: A cross-sectional comparison of DKK-1, soluble CD40L (sCD40L; reflecting platelet-mediated inflammation), asymmetric dimethylarginine (ADMA; marker of endothelial dysfunction), and urinary 11-dehydro-thromboxane B2 (in vivo marker of platelet activation) was performed among 214 diabetic patients (90 receiving aspirin at 100 mg/day) and 30 healthy controls. Plasma DKK-1 levels were markedly higher in patients with T2DM than in healthy patients (P<0.0001). DKK-1 levels were significantly lower in diabetic patients receiving compared with those not on aspirin treatment (P=0.008); in the latter, DKK-1 was significantly correlated with 11-dehydro-thromboxane B2, ADMA, and CD40L (ρ=0.303. P<0.0001, ρ=0.45. P<0.0001, and ρ=0.37, P<0.0001, respectively) but not with glycemic control or DM duration. Among patients not receiving aspirin, improvement of metabolic control in a subgroup of newly diagnosed patients treated with acarbose for 20 weeks and in a group treated with rosiglitazone for 24 weeks was associated with concurrent significant reductions in DKK-1 (P=0.005 and P=0.004) and 11-dehydro-thromboxane B2 (P=0.005 and P=0.004). CONCLUSIONS: Circulating DKK-1 is increased in T2DM and associated with endothelial dysfunction and platelet activation. Plasma DKK-1 levels are reduced with improvement of glycemic control and low-dose aspirin treatment.

[Anti-diabetes agents and hypoglycemia]. / Farmaci antidiabete ed ipoglicemia.

Hypoglycemia risk is probably the most important limiting factor when attempting to treat to target diabetic subjects. Therefore, one needs always to consider how much a given treatment is likely to induce iatrogenic hypoglycemia when choosing a therapeutic strategy for type 2 diabetes. At present, a surprisingly scant amount of data is available about how frequent hypoglycemia is relative to the use of a particular drug. Furthermore, these data are not easy to interpret, having been collected in different ways and being often related to different ways of defining and detecting hypoglycemia. The available literature does suggest, however, that metformin and thiazolidinedione treatments are associated with a negligible hypoglycemia risk. On the other hand, sulphonylurea use (in particular glybenclamide use) is associated with a frequency of hypoglycemia far greater than commonly thought. Newer therapies (like incretin-based therapies) are instead associated with a very low hypoglycemia risk. With these agents, it appears that a significant hypoglycemia risk is detected only when they are used as add-on therapy to insulin or sulphonylureas.

Decreased in vivo oxidative stress and decreased platelet activation following metformin treatment in newly diagnosed type 2 diabetic subjects.

BACKGROUND: In type 2 diabetes, metformin reduces cardiovascular risk beyond the effect of glycaemic control. Since oxidative stress and the consequent enhanced platelet activation contribute to accelerated atherosclerosis in diabetes, we hypothesized that metformin could reduce oxidative stress in this condition. METHODS: We randomized 26 newly diagnosed type 2 diabetic subjects to assume either metformin (M, n = 13) or gliclazide (G, n = 13) for 12 weeks. Drugs were titrated as needed to achieve good glycaemic control. Before and after treatment, we determined blood glucose, insulin, HbA(1c), vitamin A and E levels and 8-iso-PGF(2alpha) and 11-dehydro-thromboxane B(2) urinary excretion, an in vivo oxidative stress and a thromboxane-dependent platelet activation marker, respectively. RESULTS: Notwithstanding a comparable improvement in metabolic control, 8-iso-PGF(2alpha) (M from 708 +/- 32 to 589 +/- 45 pg/mg cr, p < 0.001; G from 646 +/- 80 to 665 +/- 79, pg/mg cr, p = ns) and 11-dehydro-thromboxane B(2) (M from 2190 +/- 196 to 1753 +/- 150 pg/mg cr, p < 0.05; G from 2048 +/- 202 to 1923 +/- 223, pg/mg cr, p = ns) urinary excretion decreased after metformin but not after gliclazide treatment. After metformin, vitamin A and E levels significantly increased while they remained unchanged after gliclazide. CONCLUSIONS: These data suggest that metformin could improve oxidative stress, preserve antioxidant function and restrain platelet activation in type 2 diabetes.

Wide expressivity variation and high but no gender-related penetrance in two dopa-responsive dystonia families with a novel GCH-I mutation.

We describe the clinical and molecular correlates in two Italian families with dopa-responsive dystonia (DRD) and the same novel mutation of GTP-cyclohydrolase I (GCH-I) gene. Thirty-five subjects were examined and the genotype correlated to phenotype. Childhood onset foot dystonia is present in 7 subjects currently under the age of 40. In 1 patient bilateral foot dystonia was evident at birth suggesting that dystonia may be active as early as in utero. In another patient, dystonia spontaneously remitted in adolescence, to relapse 8 years later, as writer's cramp. Dystonia and parkinsonian signs are present in 5 other patients. In 2 subjects an isolated parkinsonism started over the age of 45. A 5-base pair insertion at codon 242 within exon 6 of GTP-cyclohydrolase I (GCH-I) gene that shifts the reading frame and results in a premature stop at codon 247 with truncation of the polypeptide has been detected in 21 subjects. Considering dystonia and parkinsonism the overall penetrance is 0.71 and not significantly different in men (0.69) and women (0.75). Genealogical studies seem to exclude that these families are related but haplotype analysis suggests a single founder. Our findings in subjects with the same mutation indicate a wide intrafamilial variation in expressivity and high penetrance in DRD but do not confirm the reported influence of gender on GCH-I gene mutation penetrance.