Effect of nateglinide on the incidence of diabetes and cardiovascular events.

BACKGROUND: The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. METHODS: In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. RESULTS: After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. CONCLUSIONS: Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

Effect of valsartan on the incidence of diabetes and cardiovascular events.

BACKGROUND: It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. METHODS: In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. RESULTS: The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). CONCLUSIONS: Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

Role of anti-polyethylene glycol (PEG) antibodies in the allergic reactions to PEG-containing Covid-19 vaccines: Evidence for immunogenicity of PEG.

A small fraction of recipients who receive polyethylene-glycol (PEG)-containing COVID-19 mRNA-LNP vaccines (Comirnaty and Spikevax) develop hypersensitivity reactions (HSRs) or anaphylaxis. A causal role of anti-PEG antibodies (Abs) has been proposed, but not yet been proven in humans.We used ELISA for serial measurements of SARS-CoV-2 neutralizing Ab (anti-S) and anti-PEG IgG/IgM Ab levels before and after the first and subsequent booster vaccinations with mRNA-LNP vaccines in a total of 291 blood donors. The HSRs in 15 subjects were graded and correlated with anti-PEG IgG/IgM, just as the anti-S and anti-PEG Ab levels with each other. The impacts of gender, allergy, mastocytosis and use of cosmetics were also analyzed. Serial testing of two or more plasma samples showed substantial individual variation of anti-S Ab levels after repeated vaccinations, just as the levels of anti-PEG IgG and IgM, which were over baseline in 98-99 % of unvaccinated individuals. About 3-4 % of subjects in the strongly left-skewed distribution had 15-45-fold higher values than the median, referred to as anti-PEG Ab supercarriers. Both vaccines caused significant rises of anti-PEG IgG/IgM with >10-fold rises in about âˆ¼10 % of Comirnaty, and all Spikevax recipients. The anti-PEG IgG and/or IgM levels in the 15 vaccine reactors (3 anaphylaxis) were significantly higher compared to nonreactors. Serial testing of plasma showed significant correlation between the booster injection-induced rises of anti-S and anti-PEG IgGs, suggesting coupled anti-S and anti-PEG immunogenicity.Conclusions: The small percentage of people who have extremelevels of anti-PEG Ab in their blood may be at increased risk for HSRs/anaphylaxis to PEGylated vaccines and other PEGylated injectables. This risk might be further increased by the anti-PEG immunogenicity of these vaccines. Screening for anti-PEG Ab "supercarriers" may help predicting reactors and thus preventing these adverse phenomena.

Crystal structure of zwitterionic 3,3'-[1,1'-(butane-1,4-di-yl)bis-(1H-imidazol-3-ium-3,1-di-yl)]bis-(propane-1-sulfonate) dihydrate.

The crystal structure of the title compound, C16H26N4O6S2·2H2O, a water-soluble di-N-heterocyclic carbene ligand precursor was determined using a single crystal grown by the slow cooling of a hot N,N-di-methyl-formamide solution of the compound. The dihydrate crystallizes in the monoclinic space group P21/c, with half of the zwitterionic mol-ecule and one water mol-ecule of crystallization in the asymmetric unit. The remaining part of the mol-ecule is completed by inversion symmetry. In the mol-ecule, the imidazole ring planes are parallel with a plane-to-plane distance of 2.741 (2) Å. The supra-molecular network is consolidated by hydrogen bonds of medium strength between the zwitterionic mol-ecules and the water mol-ecules of crystallization, as well as by π-π stacking inter-actions between the imidazole rings of neighbouring mol-ecules and C-H⋯O hydrogen-bonding inter-actions.

Abnormal glucose tolerance is associated with diminished postload change in leptin levels in women.

BACKGROUND: It is generally accepted that the metabolic effects of leptin are diminished in the obese due to leptin resistance. Hormone resistance may develop if diurnal (including meal-related) changes in hormone levels are disrupted. We sought to describe leptin changes after a 75 g oral glucose tolerance test (OGTT) in women with a prior diagnosis of gestational diabetes mellitus (a high risk group for the metabolic syndrome) compared to that in healthy controls. METHODS: In 2000 a retrospective cohort study was performed on women who had been diagnosed with gestational diabetes mellitus (WHO criteria 1985, n = 57) between 1996 and 1998 and on a healthy control female group (n = 36) all of whom had had a prior pregnancy without any diagnosis of diabetes. All the women underwent a standard 75 g OGTT. Serum leptin was measured by radioimmunoassay before and 90 min after the OGTT. RESULTS: Using multilevel models of change, fasting leptin levels were shown to be associated with body mass index; 10.1% (95% CI 8.1-12.1%) increase per 1 kg/m(2) increase in body mass index), homeostasis model assessment insulin sensitivity; 0.4% (95% CI 0.2-0.7%) decrease per 1% increase in insulin sensitivity); abnormal glucose tolerance (24% decrease, 95% CI 8-37%); and smoking (31% decrease, 95% CI 16-44%). Postload (90 min) leptin levels decreased significantly in women with normal glucose tolerance by 13% (95% CI 8-18%), while no significant change in postload leptin level was apparent in women with abnormal glucose tolerance (3% increase, 95% CI -4% to 29%). CONCLUSIONS: Disturbed leptin changes were found following an OGTT in women with abnormal glucose tolerance that might be either a cause or a consequence of leptin resistance.

[Metabolic syndrome after pregnancy complicated with gestational diabetes: four-year follow-up]. / Metabolikus szindróma gesztációs diabéteszt követôen: négyéves utánkövetés.

Although clustering of cardiovascular risk factors is unquestionable, the importance of the "metabolic syndrome" as a distinct cardiovascular risk marker has been debated recently. In the authors' previous report a high frequency of glucose intolerance was described 8 years after a pregnancy complicated by gestational diabetes, often associated with other unfavorable metabolic parameters. In the present study the objective was to estimate the prevalence of metabolic syndrome in a cohort of previously gestational diabetes women, using different diagnostic criteria, 4 years after delivery. Those data were compared to a control group of 39 women with normal glucose tolerance during pregnancy. Irrespective of the criteria used, metabolic syndrome was found more frequently among women with prior gestational diabetes. The prevalence of metabolic syndrome increased by degree of deterioration of glucose tolerance in the prior gestational diabetes group. Overweight women in both group had 10-fold increased risk of metabolic syndrome compared to normal-weight women. According to our results a clustering of cardiovascular risk factors might be observed in previous gestational diabetes women, 4 yrs after delivery. These data highlight the importance of regular follow-up of these women, and the possible advantage of early and aggressive treatment of each component of metabolic syndrome.

Carbohydrate metabolism and cardiovascular risk factors 4 years after a pregnancy complicated by gestational diabetes.

AIMS: The aim of the present study was to determine the prevalence of abnormal glucose tolerance and the metabolic syndrome in a cohort of previously gestational diabetic (GDM) women 4 years after delivery. METHODS: Sixty-eight prior GDM and a control group of 39 women with normal glucose tolerance during pregnancy were invited to participate in a follow-up study. RESULTS: The prevalence of diabetes, impaired glucose tolerance and impaired fasting glucose (IFG) was 21%, 16%, and 6% among prior GDM women and 0%, 15%, and 0% among controls respectively (P=0.0039). Independently of the metabolic syndrome criteria used this status was found more frequently among women with prior GDM (all P<0.05). The prevalence of the metabolic syndrome showed a dose-response relationship with the level of weight categories (P<0.005) as well as with the level of glucose intolerance (P=0.024). CONCLUSION: According to our results a disturbed carbohydrate metabolism and a clustering of cardiovascular risk factors might be observed in previous GDM women 4 years after delivery.

Maternal glycemia and risk of large-for-gestational-age babies in a population-based screening.

OBJECTIVE: Gestational diabetes is a risk factor for large-for-gestational-age (LGA) newborns, but many LGA babies are born to mothers with normal glucose tolerance. We aimed to clarify the association of maternal glycemia across the whole distribution with birth weight and risk of LGA births in mothers with normal glucose tolerance. RESEARCH DESIGN AND METHODS: We undertook a population-based gestational diabetes screening in an urban area of Hungary in 2002-2005. All singleton pregnancies of mothers >or=18 years of age, without known diabetes or gestational diabetes (World Health Organization criteria) and data on a 75-g oral glucose tolerance test at 22-30 weeks of gestation, were included (n = 3,787, 78.9% of the target population). LGA was determined as birth weight greater than the 90th percentile using national sex- and gestational age-specific charts. RESULTS: Mean +/- SD maternal age was 30 +/- 4 years, BMI was 22.6 +/- 4.0 kg/m(2), fasting blood glucose was 4.5 +/- 0.5 mmol/l, and postload glucose was 5.5 +/- 1.0 mmol/l. The mean birth weight was 3,450 +/- 476 g at 39.2 +/- 1.2 weeks of gestation. There was a U-shaped association of maternal fasting glucose with birth weight (P(curve) = 0.004) and risk of having an LGA baby (lowest values between 4 and 4.5 mmol/l, P(curve) = 0.0004) with little change after adjustments for clinical characteristics. The association of postload glucose with birth weight (P = 0.03) and the risk of an LGA baby (P = 0.09) was weaker and linear. CONCLUSIONS: Both low and high fasting glucose values at 22-30 weeks of gestation are associated with increased risk of an LGA newborn. We suggest that the excess risk related to low glucose reflects the increased use of nutrients by LGA fetuses that also affects the mothers' fasting glucose.

Current controversies in the mechanisms and treatment of gestational diabetes.

Gestational diabetes mellitus (GDM) is a heterogeneous entity, including carbohydrate intolerance of variable severity with onset or first recognition during pregnancy. Insulin resistance and beta-cell dysfunction are thought to be major determinants of its development. Its pathomechanism in many ways resembles that of type 2 diabetes. There is an evolving body of evidence from the last decade presenting similarities between gestational diabetes and the metabolic (insulin resistance) syndrome. These new observations suggest that GDM might be an early manifestation of the metabolic syndrome. The desired treatment target of GDM is normoglycemia. It can be reached by dietary treatment; however, if it fails, maternal glycemic monitoring or combined fetal-maternal monitoring, or even insulin (if required) can help reach it. Multiple daily insulin regimens are becoming more widely accepted for the treatment of GDM. Insulin analogues, however, need some more evidence to support their usefulness and safety during pregnancy. The screening for GDM, the reclassification, regular care, and follow-up of these women after pregnancy are of the utmost importance to delay or prevent not only type 2 diabetes but cardiovascular complications as well.