Gestational diabetes and thyroid autoimmunity.

Background. About 10% of pregnancies are complicated by previously unknown impairment of glucose metabolism, which is defined as gestational diabetes. There are little data available on prevalence of thyroid disorders in patients affected by gestational diabetes, and about their postgestational thyroid function and autoimmunity. We therefore investigated pancreatic and thyroid autoimmunity in gestational diabetic patients and in women who had had a previous gestational diabetic pregnancy. Methods. We investigated 126 pregnant women at the time of a 100-g oral glucose tolerance test: 91 were classified as gestational diabetics, and 35 were negative (controls). We also studied 69 women who had delivered a baby 18-120 months prior to this investigation and who were classified at that time gestational diabetics (38 women) or normally pregnant (31 women; controls). Results. Our data show no differences for both thyroid function and prevalence of autoimmune disorders during pregnancy; however, a significant increase in thyroid autoimmunity was seen in women previously affected by gestational diabetes. This increased prevalence of thyroid autoimmunity was not associated with the development of impaired glucose metabolism after pregnancy. Conclusions. Our data suggest that maternal hyperglycemia is a risk factor for the development of thyroid autoimmunity, a conclusion that should now be confirmed in a larger cohort of patients.

Mechanisms of uremic erythrocyte-induced adhesion of human monocytes to cultured endothelial cells.

In end-stage renal disease (ESRD) endothelium may represent a key target for the action of circulating elements, such as modified erythrocytes (RBC) and/or plasmatic factors, that may facilitate inflammation and the vasculopathy associated with uremia. We have previously demonstrated that phosphatidylserine (PS) exposure on the surface of RBC from ESRD patients increases RBC-human umbilical vein endothelial cell (HUVEC) interactions and causes decreased nitric oxide (NO) production. We postulated that, besides the pro-inflammatory effects due to decreased NO bio-availability, enhanced ESRD-RBC-HUVEC interactions might directly stimulate pro-inflammatory pathways leading to increased vascular adhesion molecule expression. ESRD-RBC-endothelial cell interactions induced a time-dependent up-regulation of VCAM-1 and ICAM-1 (measured by Western blot (WB) and real-time PCR), associated with mitogen-activated protein kinase (MAPK) activation and impairment of the Akt/endothelial nitric oxide synthase (eNOS) signaling cascade, measured by WB. In reconstitution experiments, normal RBC incubated with uremic plasma showed increased PS exposure and significantly increased VCAM-1 and ICAM-1 mRNA levels when incubated on HUVEC. Interestingly, ESRD-RBC induced increased expression of adhesion molecules was prevented by Annexin-V (AnV, able to mask PS on RBC surface), anti-integrin-alpha(v)beta3, anti-thrombospondin-1 (TSP-1), and PD98059 (a selective inhibitor of MAPK phosphorylation). Moreover, AnV reversed the ESRD-RBC effects on MAPK and Akt/eNOS signaling pathways. Our data demonstrate that, possibly via a direct interaction with the endothelial thrombospondin-(alpha(v)beta3) integrin complex, ESRD-RBC-HUVEC adhesion induces a vascular inflammatory phenotype. Thus, intervention targeting ESRD-RBC increased adhesion to endothelium and/or MAPK and Akt/eNOS pathways may have the potential to prevent vascular lesions under uremic conditions.

Selective insulin resistance affecting nitric oxide release but not plasminogen activator inhibitor-1 synthesis in fibroblasts from insulin-resistant individuals.

OBJECTIVE: Insulin activates several processes potentially dangerous for the arterial wall and hyperinsulinemia might be atherogenic. However, other insulin effects are protective for the vessel wall and thus anti-atherogenic. Aim of this study was to investigate whether insulin effects on potentially pro-atherogenic and anti-atherogenic processes were differently affected in cells from insulin-resistant individuals. METHODS AND RESULTS: We determined insulin effect on nitric oxide (NO) production and plasminogen activator inhibitor (PAI)-1 synthesis in 12 fibroblast strains obtained from skin biopsy samples of 6 insulin-sensitive (IS) (clamp M >7 mg/kg body weight per minute) and 6 insulin-resistant (IR) (clamp M <5 mg/kg body weight per minute) healthy volunteers. Insulin effects on NO release and Akt phosphorylation were significantly impaired in fibroblasts from IR as compared with IS individuals. Conversely, there was not any difference between IR and IS strains in insulin ability to increase PAI-1 antigen levels and, after 24-hour insulin incubation, PAI-1 mRNA increase in IR strains was only slightly less than in IS strains. Insulin ability to induce MAPK activation was also comparable in IR and IS cells. CONCLUSIONS: We conclude that in cells from IR individuals, insulin action on anti-atherogenic processes, such as NO release, is impaired, whereas the hormone ability to stimulate atherogenic processes, such as PAI-1 release, is preserved.

[The "problem obesity": viewpoint of the internist]. / Il "problema obesità" visto dall'internista.

The prevalence of obesity has reached epidemic dimension in industrialized countries and it is known that obesity is associated with increased risk of cardiovascular morbidity and mortality. Commonly, obesity is defined by the Body Mass Index (BMI). However, BMI fails to consider body fat distribution. The relationship between the risk of metabolic-cardiovascular diseases and body fat distribution indices such as the waist-to-hip ratio (WHR) and the waist circumference, rather than measures of the degree of body fatness as expressed by BMI, has long been recognized. Recently, clinical and epidemiological research has found waist circumference to be the best anthropometric indicator of both total body fat and intra-abdominal fat mass. Android or visceral obesity is associated with metabolic syndrome and increased cardiovascular morbidity and mortality through a variety of molecular mechanisms possibly linking the metabolic syndrome to hemostatic and vascular abnormalities. Obesity guidelines suggest the need for weight reduction using behavioural change to reduce caloric intake and increasing physical activity. A realistic goal for weight reduction is to reduce body weight by 5% to 10% over a period of 6 to 12 months. Combined intervention of a low calories diet, increased physical activity, and behaviour therapy provides better outcomes for long-term weight reduction and weight maintenance than programs that use only one or two of these modalities. The drugs used to promote weight loss have been anorexic drugs or appetite suppressants. All classes of anorexic drugs affect neurotransmitters in the brain. The new agent sibutramine has norepinephrine and serotonin effects. Another new agent, orlistat, has a different mechanism of action, the reduction of fat absorption. Weight loss drugs approved by the FDA for long-term use may be useful as an adjunct to diet, physical activity and behaviour therapy for patients with a BMI of > or =30 with no concomitant obesity-related risk factors or diseases, and for patients with a BMI of > or =27 with concomitant obesity-related risk factors or diseases.

Effects of combined antiviral therapy on asymptomatic mixed cryoglobulinemia in naive patients with chronic hepatitis C virus infection: a preliminary study.

The clinical spectrum of mixed cryoglobulinemia embraces several manifestations: recurrent vascular purpura, weakness, arthralgia/arthritis, glomerulonephritis, peripheral neuropathies, and Raynaud's phenomenon. Mixed cryoglobulinemia is currently treated with steroids, low-antigen content diet, immunosuppressors, plasma exchange, and antiviral therapy, namely, alpha -interferon alone or, more recently, in association with ribavirin. In the present research, we verified the effectiveness of combined therapy with interferon and ribavirin on asymptomatic mixed cryoglobulinemia in naïve (never treated before) patients with chronic hepatitis C. We enrolled 50 consecutive patients, 31 males and 19 females, with chronic hepatitis C who showed a sustained response to combined antiviral therapy (interferon and ribavirin). Before treatment, cryoglobulins were detected in 25 subjects (50%). Only 1 of the 25 patients with asymptomatic mixed cryoglobulinemia had persistence of cryoglobulins at the end of the follow-up period. Unexpectedly, in 7 of 25 subjects without mixed cryoglobulinemia before treatment, cryoglobulins became detectable after antiviral therapy. Our present study first reports the onset of asymptomatic mixed cryoglobulinemia in hepatitis C virus patients after clearance of the virus from blood obtained with a combined antiviral treatment. Possible explanations are discussed. Our data also suggest that the appearance of a clinically evident mixed cryoglobulinemia cannot be excluded in this kind of subject.

Probabilistic approach to developing nephropathy in diabetic patients with retinopathy.

It is well known that diabetes is a risk factor for many complications including diabetic retinopathy and nephropathy. An interesting question is whether a diabetic patient who has developed a retinopathy develops a nephropathy sooner. We approached this problem by calculating the conditional probability that a diabetic patient will develop a second complication, given that they had already developed the first complication. We also propose the application of Bayes' formula to estimate the probability of developing the second complication, given that the first complication had developed previously. We compared these two methods by applying them to analyse 5473 patients with type 2 diabetes. The results of our experience are described.

Phenotype modulation in cultures of vascular smooth muscle cells from diabetic rats: association with increased nitric oxide synthase expression and superoxide anion generation.

Proliferative modification of vascular smooth muscle cell (vSMC) and impaired bioavailability of nitric oxide (NO) have both been proposed among the mechanisms linking diabetes and atherosclerosis. However, diabetes induced modifications in phenotype and nitric oxide synthase(s) (NOS) expression and activity in vSMC have not been fully characterized. In this study, cell morphology, proliferative response to serum, alpha-SMactin levels, eNOS expression and activity, cGMP intracellular content, and superoxide anion release were measured in cultures of vSMC obtained from aorta medial layer of ten diabetic (90% pancreatectomy, DR) and ten control (sham surgery, CR) rats. Vascular SMC from DR showed a less evident "hill and valley" culture morphology, increased growth response to serum, greater saturation density, and lower levels of alpha-SMactin. In the same cells, as compared to CR cells, eNOS mRNA levels and NOS activity were increased, while intracellular cGMP level was lower and superoxide anion production was significantly greater. These data indicate that chronic hyperglycemia might induce, in the vascular wall, an increased number of vSMC proliferative clones which persist in culture and are associated with increased eNOS expression and activity. However, upregulation of eNOS and increased NO synthesis occur in the presence of a marked concomitant increase of O(2-) production. Since NO bioavailability, as reflected by cGMP levels, was not increased in DR cells, it is tempting to hypothesize that the proliferative phenotype observed in DR cells is associated with a redox imbalance responsible quenching and/or trapping of NO, with the consequent loss of its biological activity.