Hyperproinsulinaemia in impaired glucose tolerance is associated with a delayed insulin response to glucose

Summary In subjects with impaired glucose tolerance hyperproinsulinaemia has been shown to be predictive for progression to Type II (non-insulin-dependent) diabetes mellitus. These findings are often interpreted as early indicators of an impaired beta-cell function. The aim of our study was to assess the potential determinants of hyperproinsulinaemia in subjects with impaired glucose tolerance. The study group consisted of 110 subjects, 45–74 years of age with mean 2 h plasma glucose concentrations between 8.6 and 11.1 mmol/l following two oral glucose tolerance tests. Subsequently, the hyperglycaemic clamp technique (10 mmol/l, with a priming infusion of 20 % glucose solution, 150 mg/kg) was used to assess the beta-cell function (time needed to reach the insulin peak) and insulin sensitivity (M/I value: glucose metabolised divided by insulin response, 150–180 min). Results showed that the intact-proinsulin:insulin ratio increased with increasing time needed to reach the insulin peak (0.065, 0.079 and 0.101; time needed to reach the insulin peak ≤ 5 min, 5 to 15 min, > 15 min; p < 0.05). The split-proinsulin:insulin ratio showed a similar association with the time needed to reach the insulin peak. These associations were independent of age, sex, body mass index and waist:hip ratio. In conclusion, this study shows that relative hyperproinsulinaemia is associated with an impaired beta-cell function in a study group of subjects with impaired glucose tolerance selected after two oral glucose tolerance tests. [Diabetologia (1999) 42: 177–180] Received: 5 June 1998 and in final revised form: 5 October 1998     

Relation between impaired antiplatelet response to clopidogrel and possible pleiotropic effects

Background The study was designed to determine whether impaired antiplatelet response to clopidogrel but not to aspirin may be responsible for loss of pleiotropic effects of the drug. Methods Study included 34 consecutive patients with STEMI undergoing primary percutaneous coronary intervention (PCI) with stent implantation treated with aspirin (loading dose 300 mg followed by 75 mg/day) and clopidogrel (loading dose 600 mg followed by 75 mg/day). On the basis of Platelet Function Analyzer (PFA)-100 test which measured closure times (CT) in test with collagen/epinephrine (CEPI-CT) or collagen/adenosine diphosphate (CADP-CT) patients were stratified after 7 days from admission as full aspirin or clopidogrel responders (CEPI-CT or CADP-CT = 300 sec., respectively) and non-full aspirin or clopidogrel responders (CEPI-CT or CADP-CT < 300 sec., respectively). High sensitivity C-reactive protein (hs-CRP) was measured at baseline and after 7 days of treatment. Results All patients received comparable statin treatment. Median and interquartile ranges (IQR) of hs-CRP increased significantly from 2.5 mg/L (0.4–44.8) at baseline to 8.05 mg/L (1.4–33.9) at day 7 (P = .002) in non-full clopidogrel responders subgroup and only slightly in the full clopidogrel responders subgroup (2.45 mg/L, IQR 0.4–48.3 vs. 4.2 mg/L, IQR 1.9–17.5) (P = .3) remaining within reference intervals. On the contrary median and IQR of hs-CRP increased significantly in both non-full aspirin responders (2.4 mg/L, IQR 1.3–3.3 vs. 5.8 mg/L, IQR 3.2–14.8, P = .01) and full aspirin responders (2.9 mg/L, IQR 2.0–3.7 vs. 5.6 mg/L, IQR 4.3–12.9, P = .04). Conclusions Impaired antiplatelet response to clopidogrel but not to aspirin may contribute to smaller anti-inflammatory response in patients with ST-elevation myocardial infarction.     

Outcomes associated with combined antiplatelet and anticoagulant therapy

BACKGROUND: The use of antiplatelet therapy in combination with oral anticoagulants remains controversial. The objective of this study was to estimate and compare the incidence of adverse and coronary event rates between patients receiving warfarin monotherapy or warfarin and antiplatelet combination therapy. METHODS: This was a retrospective, longitudinal, pharmacoepidemiologic analysis. Adult patients receiving warfarin managed by an anticoagulation service who had documented the use of antiplatelet agents (eg, aspirin, clopidogrel, and/or dipyridamole) [ie, the combination-therapy cohort] or their nonuse (ie, the monotherapy cohort) were identified as of September 30, 2005. Utilizing integrated, electronic medical records, anticoagulation-related adverse events (eg, death, hemorrhage, or thrombosis) and coronary events were identified during a 6-month follow-up period (October 2005 through March 2006). The proportions of events were compared between cohorts. Independent associations between the cohorts and the outcomes were assessed with adjustment for potential confounding factors. RESULTS: Data from 2,560 patients in the monotherapy cohort and 1,623 patients in the combination-therapy cohort were analyzed. Patients in the combination-therapy cohort were more likely to have had anticoagulation-related hemorrhages (4.2% vs 2.0%, respectively; unadjusted p < 0.001) and coronary events (0.9% vs 0.3%, respectively; p = 0.009), but not death (0.1% vs 0.2%, respectively; unadjusted p = 0.186) or thrombotic events (0.3% vs 0.4%, respectively; unadjusted p = 0.812). With adjustment, combined warfarin and antiplatelet use was independently associated with hemorrhagic events (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.44 to 5.28), but not with coronary events (OR, 0.99; 95% CI, 0.37 to 2.62). CONCLUSIONS: At the population level, the hemorrhagic risk associated with warfarin therapy combined with antiplatelet therapy appears to outweigh the benefits. These findings suggest that clinicians should carefully consider the risks and benefits when recommending combined antiplatelet therapy for patients receiving warfarin who do not meet the evidence-based criteria for such therapy.     

Glutamic acid decarboxylase antibody positivity is associated with an impaired insulin response to glucose and arginine in nondiabetic patients with autoimmune thyroiditis

To study whether antibodies to glutamic acid decarboxylase (GADab) are associated with subclinical beta-cell damage and impaired insulin secretion, we screened 441 nondiabetic patients with autoimmune thyroiditis (AT) for GADab, and 15 (3.4%) were found positive. Antibodies to IA-2 were found in two GADab+ and one GADab- patients. We matched 11 GADab+ and 13 GADab- AT patients who were euthyroid on thyroxin supplementation, and 13 control subjects for sex, age, and body mass index and measured insulin, C-peptide, and glucagon response to glucose and arginine at three blood glucose concentrations (fasting, 14 mmol/liter, >25 mmol/liter). In the fasting state, all groups had similar blood glucose concentration and HbA1c level, but the serum insulin concentration was higher in the AT patients compared with the control subjects (P < 0.04). The acute insulin response to arginine was lower in GADab+ than in GADab- thyroiditis subjects at glucose concentration of 14 and >25 mmol/liter (AIR(14): 76.8 +/- 52.0 vs. 158.2 +/- 118.2 mU/liter, P = 0.040; AIR(>25): 84.3 +/- 64.4 vs. 167.9 +/- 101.5 mU/liter, P = 0.035). In conclusion, GADab were associated with a decreased insulin secretion capacity in nondiabetic subjects with thyroiditis, which suggests that GADab positivity could be a marker of subclinical insulitis.     

Hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation

Adiponectin may have an antiatherogenic effect by reducing endothelial activation. We hypothesized that plasma adiponectin levels were correlated with endothelial function. Plasma adiponectin level was determined by an in-house RIA assay using a rabbit polyclonal antibody in 73 type 2 diabetic patients and 73 controls. Endothelium-dependent and independent vasodilation of the brachial artery was measured by high-resolution vascular ultrasound. Plasma adiponectin level was lower in diabetic patients than in controls (4.73 +/- 1.96 vs. 7.69 +/- 2.80 microg/ml, respectively; P < 0.001), and they also had impaired endothelium-dependent (5.6 +/- 3.6 vs. 8.6 +/- 4.5%, respectively; P < 0.001) and -independent vasodilation (13.3 +/- 4.9 vs. 16.5 +/- 5.6%, respectively; P < 0.001). Plasma adiponectin correlated with endothelium-dependent vasodilation in controls (P = 0.02) and diabetic patients (P = 0.04). On general linear-model univariate analysis, brachial artery diameter, the presence of diabetes, plasma adiponectin, and high-density lipoprotein were significant independent determinants of endothelium-dependent vasodilation. In vitro experiments showed that endothelial cells expressed adiponectin receptors, and adiponectin increased nitric oxide production in human aortic endothelial cells. In conclusion, low plasma adiponectin level is associated with impaired endothelium-dependent vasodilation, and the association is independent of diabetes mellitus. Adiponectin may act as a link between adipose tissue and the vasculature.     

Resistance to antiplatelet therapy

Cardiovascular mortality continues to be high and events continue to occur in patients taking antiplatelet medications. Aspirin and clopidogrel have become integral parts of management in patients with coronary artery disease and after percutaneous angioplasty. However, the platelet responses to aspirin and clopidogrel are not uniform. Diminished or lack of response to these agents has been termed aspirin resistance and clopidogrel resistance. These phenomena have tremendous clinical significance as together they may occur in more than 50% of all patients on chronic therapy with aspirin or clopidogrel. Postulated mechanisms of aspirin and clopidogrel resistance include alterations in genetic, pharmacokinetic, and platelet properties. There is a dearth of information in regard to their clinical significance, methods to test them, and strategies to treat them. Further research is necessary in these areas to identify these patients and treat them appropriately.     

Baseline cholesterol is associated with the response to antiviral therapy in chronic hepatitis C

Background: Hepatitis C virus (HCV) partially interacts with low‐density lipoprotein (LDL) receptors, suggesting a role for lipids in regulating HCV clearance. Our aim was to study if baseline lipids can discriminate responders from non‐responders among patients with HCV infection. Methods: A total of 109 HCV patients were studied. Laboratory measurements included serum lipids, aminotransferases and viral load, as well as HCV genotype determinations. Results: Responders (n = 53) had significantly higher serum baseline levels of total cholesterol, LDL cholesterol and apolipoprotein B compared to non‐responders (n = 56). Multivariate logistic regression analysis showed that a 10 mg/dL increase in total cholesterol was associated with 3.02 higher odds of responding to treatment (95% CI 1.74–5.32, P < 0.001), while a 10 mg/dL increase in apolipoprotein B levels was associated with 1.81 higher odds of responding to treatment (95% CI 1.37–2.54, P < 0.001), after adjustment for age, sex, body mass index (BMI), smoking habits, baseline viral load, liver histology and administration of pegylated interferon. An inverse association between BMI and response to treatment was also evident (adjusted odds ratio 0.73, 95% CI 0.55–0.96; P = 0.03). Conclusion: Baseline serum total cholesterol levels and BMI could be helpful in discriminating responders to antiviral therapy among patients with HCV infection.     

Recurrent late drug-eluting stent thrombosis upon discontinuation of antiplatelet therapy

Stent thrombosis is a rare but serious complication of percutaneous coronary intervention. Stent thrombosis usually occurs early after stent implantation but can occasionally occur late, especially when drug-eluting stents are used. We report a case of recurrent late paclitaxel-eluting stent thrombosis (8 and 21 months after initial stent implantation) upon discontinuation of dual antiplatelet therapy.     

Paradoxical thrombosis, part 2: anticoagulant and antiplatelet therapy

Arterial thrombosis is the leading causes of morbidity and mortality worldwide, whereas venous thrombosis is the most common preventable cause of hospital death. In either case, venous and arterial thrombosis should be considered autonomous entities, with only minor overlaps in terms of risk factors, predisposing conditions and pathogenesis. Besides the widespread perception of embolization originating from low-pressure venous system and triggering ischemic stroke or peripheral arterial occlusion, "paradoxical" thrombosis might also develop or occur within clinical or biological circumstances where the blood should be less predisposed to clot, and wherein this risk is mostly unpredictable or overlooked. In this article we review epidemiological evidence and potential pathogenetic mechanisms of paradoxical thrombosis developing during antithrombotic therapy with vitamin K antagonists and heparin (i.e. heparin-induced thrombocytopenia), or antiplatelet agents such as aspirin, glycoprotein IIb/IIIa inhibitors or clopidogrel, and mostly attributable to direct effect of the agent.     

Obesity is associated with impaired insulin-mediated potassium uptake

The ability of insulin to promote extrarenal potassium uptake and to stimulate glucose uptake was examined in eight obese and ten normal weight control subjects. Insulin was infused at three rates to produced plasma insulin concentrations of approximately 100, 1,900, and 19,000 microU/mL. Insulin-mediated potassium, as well as glucose uptake, was diminished during the lowest dose insulin clamp study (100 microU/mL) but could be normalized at pharmacologic plasma insulin concentrations. These results indicate that obese subjects are resistant to the ability of insulin to stimulate potassium uptake by extrarenal tissues. Impaired potassium uptake at physiologic plasma insulin levels, with normalization at supraphysiologic insulin concentrations, is most consistent with a decrease in the number of insulin receptors on insulin target tissues.     

Sarcopenia is associated to an impaired autonomic heart rate modulation in community-dwelling old adults

PurposeThe aims of this study were to compare the autonomic heart control parameters from sarcopenic and non-sarcopenic community-dwelling elders.MethodsThis is a cross-sectional study including 76 community-dwelling old adults, which was clinically stratified as sarcopenic or non-sarcopenic, according to the current recommendations. They were submitted to 5-min recordings of successive RR intervals. The analysis of the RR intervals variability was carried out in time (mean RR, RMSSD, pNN50, SDNN and triangular index) and frequency domains (LFnu, HFnu and LF/HF ratio), and with nonlinear methods (SD1, SD2, and D₂). The parameters of autonomic heart rate modulation (AHRM) were adjusted for potential confounders: sex, diabetes, beta-blockers use, cardiovascular disease, body mass index and physical activity level, smoking habit. Normality of the data was tested by Kolmogorov-Smirnov test and, since most variables did not exhibit a normal distribution the Mann-Whitney test was used to compare the parameters of AHRM. The significance level was set as p ≤ 0.05 and all statistical procedures were performed with SPSS^®.ResultsAdjusted parameters of AHRM obtained from time domain and nonlinear methods were significantly different between sarcopenic and non-sarcopenic elders (p < 0.05), while parameters obtained from frequency domain analysis did not were different between groups (p > 0.05).ConclusionSarcopenic old adults exhibited lower parasympathetic-associated modulation, suggesting a poor cardioprotection associated to this condition.