Variation in plasma leptin-like immunoreactivity in free-living European starlings (Sturnus vulgaris)

Leptin, a protein hormone secreted by fat cells, is best known for its role as an adiposity signal; however, leptin has diverse physiological roles ranging from regulation of feeding behavior and body weight, to effects on reproduction and immune function. Although leptin has been extensively studied in mammals, the identification and function of leptin in birds remains controversial, and studies have focused on captive or domesticated species. Here, we describe changes in plasma leptin-like immunoreactivity during the reproductive and non-reproductive seasons in free-living female European starlings (Sturnus vulgaris). Plasma leptin-like immunoreactivity was high during egg-laying (27.8 ± 2.4 ng/mL) and clutch completion (23.8 ± 1.6 ng/mL), decreased during incubation (13.0 ± 1.6 ng/mL) and chick-rearing (12.0 ± 1.3 ng/mL), but was elevated again in non-breeders in November (23.7 ± 1.1 ng/mL). Although there was marked and consistent variation in total body mass and body composition with breeding stage and season in this population, plasma leptin-like immunoreactivity did not parallel changes in body mass or body composition. These data suggest that the strong positive relationship between plasma leptin-like immunoreactivity and body mass reported for captive birds and mammals does not hold for free-living birds. Rather, among free-living female European starlings, variation in plasma leptin-like immunoreactivity is associated with breeding stage or seasonal variation per se, and we discuss possible mechanisms underlying this variation, focusing on ovarian function and egg production.     

Diet quality is associated with circulating C-reactive protein but not irisin levels in humans

Objective

Adherence to a healthy diet has been shown to decrease the incidence of obesity and associated comorbidities. C-reactive protein (CRP) is an established inflammatory marker and irisin was recently identified as a molecule which may play a role in energy regulation and obesity but whether diet alters irisin levels remains unknown. We aimed to investigate the association between circulating irisin, leptin, and CRP levels and dietary quantity and quality using the Alternate Healthy Eating Index (AHEI) and the Alternate Mediterranean Diet Score (aMED).

Materials/Methods

The study evaluated dietary data and biomarker levels of 151 participants between 2009 and 2011 (71 male vs. 80 female, over 35 years old, obese 43.7%). AHEI and aMED scores were calculated based on data derived from self-administered 110-item food-frequency questionnaires estimating usual nutrient intake over the past year. Cross-sectional associations between dietary quantity, quality, body composition by bioelectric impedance, and biomarker levels including irisin, leptin, and CRP after fasting were assessed.

Results

CRP, but not irisin, was negatively correlated with AHEI (r = − 0.34) and aMED (r = − 0.31). Irisin was positively correlated with BMI (r = 0.22), fat mass (r = 0.21), waist circumference (r = 0.24), waist–hip ratio (r = 0.20), leptin (r = 0.32), and CRP (r = 0.25). Participants with the highest AHEI scores tended to have 11.6% lower concentrations of irisin (P for trend = 0.09), but they were not significant after adjustment for potential confounders. Better diet quality was associated with lower CRP concentrations (P for trend = 0.02) in multivariate model. Percentage of energy from carbohydrate was inversely associated with CRP.

Conclusions

Unlike CRP, irisin is not associated with dietary quality or quantity.     

The levels of plasma growth arrest-specific protein 6 is associated with insulin sensitivity and inflammation in women

Aims

Vitamin K-dependent growth arrest-specific protein 6 (Gas6) and its receptors of the TAM (TYRO-3/Axl/Mer) family are ubiquitously expressed in immune, cardiovascular, and reproductive systems. They play pivotal roles of regulating tissue homeostasis via anti-inflammatory effects. Recent studies show that the Gas6/TAM system is involved in glucose tolerance-related metabolic disorders. Our aim was to investigate the link between Gas6 protein, insulin sensitivity and inflammatory cytokines in men and women.

Methods

A total of 278 adults (126 men and 152 women) were recruited in this study. Plasma Gas6 concentration and various biochemical, proinflammatory and endothelial markers were measured. Insulin sensitivity was estimated by homeostasis model assessment.

Results

Waist, fasting and 2 h post-load glucose, and glycated hemoglobin (HbA_1C) were significantly lower in women than in men. Age, high-density lipoprotein cholesterol, and highly-sensitive C-reactive protein levels were significantly higher in women than in men. Plasma Gas6 levels were negatively correlated with waist (r = −0.187, P = 0.022), HOMA-IR (r = −0.171, P = 0.035), interleukin 6 (r = −0.362, P < 0.001), and E-selectin (r = −0.216, P = 0.008), while they were positively correlated with insulin sensitivity (QUICKI) (r = 0.168, P = 0.039) in women, but not in men. Stepwise multiple regression analysis showed that TNF-α was independently correlated with plasma Gas6 levels in both the sexes (P < 0.001).

Conclusion

Plasma Gas6 is associated with obesity, insulin sensitivity, inflammation, and endothelial dysfunction in women and may be a general marker of inflammatory conditions in women.     

Effects of KATP channel openers diazoxide and pinacidil in coronary-perfused atria and ventricles from failing and non-failing human hearts

This study compared the effects of ATP-regulated potassium channel (K_ATP) openers, diazoxide and pinacidil, on diseased and normal human atria and ventricles. We optically mapped the endocardium of coronary-perfused right (n = 11) or left (n = 2) posterior atrial-ventricular free wall preparations from human hearts with congestive heart failure (CHF, n = 8) and non-failing human hearts without (NF, n = 3) or with (INF, n = 2) infarction. We also analyzed the mRNA expression of the K_ATP targets K_ir6.1, K_ir6.2, SUR1, and SUR2 in the left atria and ventricles of NF (n = 8) and CHF (n = 4) hearts. In both CHF and INF hearts, diazoxide significantly decreased action potential durations (APDs) in atria (by − 21 ± 3% and − 27 ± 13%, p < 0.01) and ventricles (by − 28 ± 7% and − 28 ± 4%, p < 0.01). Diazoxide did not change APD (0 ± 5%) in NF atria. Pinacidil significantly decreased APDs in both atria (− 46 to −80%, p < 0.01) and ventricles (− 65 to − 93%, p < 0.01) in all hearts studied. The effect of pinacidil on APD was significantly higher than that of diazoxide in both atria and ventricles of all groups (p < 0.05). During pinacidil perfusion, burst pacing induced flutter/fibrillation in all atrial and ventricular preparations with dominant frequencies of 14.4 ± 6.1 Hz and 17.5 ± 5.1 Hz, respectively. Glibenclamide (10 μM) terminated these arrhythmias and restored APDs to control values. Relative mRNA expression levels of K_ATP targets were correlated to functional observations. Remodeling in response to CHF and/or previous infarct potentiated diazoxide-induced APD shortening. The activation of atrial and ventricular K_ATP channels enhances arrhythmogenicity, suggesting that such activation may contribute to reentrant arrhythmias in ischemic hearts.     

Inhibition of leukotriene C4 action reduces oxidative stress and apoptosis in cardiomyocytes and impedes remodeling after myocardial injury

Tissue damage leads to release of pro-inflammatory mediators. Among these, leukotriene C₄ (LTC₄) is a powerful, intracellularly induced mediator of inflammation, which requires inside-out transport of LTC₄. We investigated whether release of LTC₄via the multidrug resistance related protein 1 (MRP1) induces apoptosis in cardiomyocytes in vitro and in vivo. Methods and results: Incubation of cultured embryonic cardiomyocytes (eCM) with recombined LTC₄ caused enhanced rates of reactive oxygen species (ROS) release measured via L012-luminescence method and apoptosis. Pharmacologic LTC₄ receptor blockade antagonized this effect in vitro. To evaluate the relevance of MRP1 mediated LTC₄ release after myocardial injury in vivo, MRP1^−/− mice and FVB wildtype mice (WT) received cryoinjury of the left ventricle. Fourteen days after injury, left-ventricular ejection fraction (EF), end-diastolic volume (EDV), and akinetic myocardial mass (AMM) were quantified via echocardiography. MRP1^−/− mice demonstrated increased EF (MRP1^−/−: 39 ± 3%, WT: 29 ± 4%) and reduced AMM (MRP1^−/−: 13 ± 2% WT: 16 ± 4%), indicating reduced post-infarction remodeling. Mechanistically, LTC₄ serum concentrations and levels of cellular apoptosis were increased in myocardial cryosections of FVB WT mice as compared to MRP1^−/− mice. To identify key targets for pharmacological inhibition of LTC₄ actions, WT mice were treated with the specific Cys-LT1-receptor blocker Montelukast or the MRP1-Inhibitor MK571. Treatment of WT mice resulted in significant increase of EF (WT_Montelukast: 40 ± 5%, WT_MK571: 39 ± 3%, WT_vehicle: 33 ± 3% and decrease of AMM (WT_Montelukast: 12 ± 1%, WT_MK571: 10 ± 3%, WT_vehicle: 15 ± 5%) compared to untreated WT mice. Conclusion: Inhibition of leukotriene C₄ reduces levels of oxidative stress and apoptosis and demonstrates beneficial effects on myocardial remodeling after left ventricular injury.     

Oxidative stress and systemic inflammation as modifiers of cardiac autonomic responses to particulate air pollution

Background

The role of oxidative stress and systemic inflammation on the association between personal exposures to ambient fine particulate matter ≤ 2.5 μm in diameter (PM_2.5) and cardiac autonomic dysfunction, indicated by reduction in heart rate variability (HRV), has not been examined.

Methods

We performed a repeated measures study on community adults in a densely populated inner city neighborhood in Boston, Massachusetts. Continuous ambulatory electrocardiogram (ECG) monitoring and personal exposure to PM_2.5 were measured for up to two consecutive days. Peripheral blood and spot urine samples were collected at 12-hour intervals for the measurements of markers of inflammation including C-reactive protein (CRP), fibrinogen, white blood cell (WBC) and platelet counts as well as for the analysis of urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage.

Results

After adjusting for confounders, we found a pronounced decrease in nighttime standard deviation of normal-to normal intervals (SDNN): an interquartile range (IQR) increase in PM_2.5 (13.6 μg/m³) was associated with an 8.4% decrease in SDNN (95% CI: − 11.3 to − 5.5). Compared with the lower eightieth percentile, significantly greater PM_2.5 associated nighttime SDNN reductions were observed among subjects in the upper twentieth percentile of 8-OHdG by − 25.3%, CRP by − 24.9%, fibrinogen by − 28.7%, WBC by − 23.4%, and platelet counts by − 24.0% (all P < 0.0001; all P_interaction < 0.01).

Conclusions

These data suggest that oxidative stress and systemic inflammation exacerbate the adverse effects of PM_2.5 on the cardiac autonomic function even at ambient levels of exposure.     

Does Vitamin D Modulate Asymmetric Dimethylarginine and C-Reactive Protein Concentrations?

Background

Vitamin D deficiency is associated with significant increases in the incidence of cardiovascular risk factors and mortality. However, the mechanisms underlying this association remain unclear. The current study evaluated the possible relationships among vitamin D status, endothelial dysfunction, and inflammation.

Methods

Plasma concentrations of 25-hydroxyvitamin D₃ were determined by radioimmunoassay in a normal population cohort (n = 253) aged 51 to 77 years (mean 63.4 ± 6 years). Asymmetric dimethylarginine, a marker/mediator of endothelial dysfunction, was assayed by high-performance liquid chromatography. High-sensitivity C-reactive protein levels were used as a marker of inflammatory activation.

Results

On univariate analyses, low 25-hydroxyvitamin D₃ levels were inversely correlated with asymmetric dimethylarginine concentrations, high-sensitivity C-reactive protein levels, and body mass index. Seasonal fluctuations in 25-hydroxyvitamin D₃ levels were associated with reciprocal asymmetric dimethylarginine concentration fluctuations. Hypertension and treatment with an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker also were associated with low 25-hydroxyvitamin D₃ levels. On multiple linear analysis, both asymmetric dimethylarginine (β = −0.19, P = .003) and high-sensitivity C-reactive protein (β = −0.14, P = .03) concentrations were inversely correlated with plasma 25-hydroxyvitamin D₃ concentrations; other significant correlates were male gender (β = 0.19, P = .003), calcium levels (β = 0.14, P = .03), and use of angiotensin-converting enzyme inhibitor (β = −0.17, P = .007).

Conclusion

Low 25-hydroxyvitamin D₃ levels are associated with markers of endothelial dysfunction and inflammatory activation, representing potential mechanisms for incremental coronary risk.     

Irisin levels correlate with energy expenditure in a subgroup of humans with energy expenditure greater than predicted by fat free mass

Objective

Obesity is a result of chronic overconsumption of calories relative to the amount of energy expended. While fat free mass can account for ~ 80% of the variance in energy expenditure, there is still considerable variability in energy requirements between individuals that cannot be explained. We hypothesized that responsiveness to the recently discovered myokine, irisin, which has been touted to increase energy expenditure via activation of brown adipocytes in rodents and possibly humans, may explain some of the variability in energy expenditure.

Materials/methods

Post-menopausal women (n = 17) spent 24-h in a whole room indirect calorimeter. During the study day, subjects remained sedentary and consumed meals tailored to their energy requirements. Plasma irisin, leptin and adiponectin were measured in samples taken from each subject.

Results

Our results suggest that in general, irisin levels do not correlate with 24-h energy expenditure, however, for a subpopulation irisin levels and energy expenditure are highly correlative.

Conclusion

Irisin may help explain some of the observed variability in individual energy requirements that cannot be accounted for by fat free mass. Therefore, interventions designed to increase irisin action may prove to be promising avenues for the treatment of obesity.     

Circulating fetuin-A levels are not affected by short and long-term energy deprivation and/or by leptin administration

Objective

Fetuin-A may mediate cross-talk between the liver and adipose tissue. We studied the physiologic regulation of fetuin-A and explored its potential regulation by leptin.

Design and Methods

Fetuin-A levels were measured in three interventional studies as well as in in vitro experiments. Study 1: 15 lean subjects received placebo or physiologic replacement-dose recombinant human leptin (metreleptin) following short term complete caloric deprivation to induce severe hypoleptinemia; Study 2: 7 women with relative leptin deficiency due to strenuous exercise or low weight received 3 months of metreleptin; Study 3: 17 women with relative leptin deficiency were randomized to receive metreleptin or placebo over 9 months. In study 4 human hepatoma Hep G2 cells were treated with leptin. Fetuin-A mRNA expression and secretion were measured.

Results

Complete caloric deprivation significantly decreased leptin but had no effect on fetuin-A levels. Normalizing leptin levels with metreleptin in hypoleptinemic subjects had no effect on circulating fetuin-A levels. Leptin treatment had no effect on fetuin-A mRNA expression and secretion in vitro.

Conclusions

Circulating fetuin-A levels are not affected by short and long-term energy deprivation. Furthermore, both in vivo and in vitro experiments confirm that fetuin-A is not regulated by leptin.     

Direct AT2 receptor stimulation is athero-protective and stabilizes plaque in Apolipoprotein E-deficient mice

Background

The angiotensin II type 2 receptor (AT₂R) has been suggested to have an athero-protective role, however no studies have investigated the effect of direct stimulation of this receptor in atherosclerosis. Thus this study aimed to determine the effect of direct AT₂R stimulation in setting of atherosclerosis, using the known AT₂R agonist, CGP42112.

Methods and results

Apolipoprotein E-deficient (ApoE^−/−) mice were fed a high fat (21%) diet for 16 weeks, with subcutaneous infusions of CGP42112 (1, 5 or 10 μg/kg/min) administered via osmotic mini-pumps in the final 4 weeks. CGP42112 treatment at all doses significantly improved endothelial function (p < 0.001) when compared to acetylcholine mediated-vasorelaxation in aorta taken from vehicle-treated ApoE^−/− mice. In aortic segments adjacent to those used for vascular reactivity studies, CGP42112 treatment at all doses concomitantly increased eNOS immunoreactivity and protein levels whilst superoxide (O₂⁻) production was significantly (p < 0.01) decreased compared to levels measured in aorta from vehicle-treated ApoE^−/− mice. Moreover, CGP42112 (1 μg/kg/min) treatment significantly attenuated (p < 0.05) atherosclerotic lesion progression (assessed as both lipid deposits and luminal encroachment in thoracic aorta and aortic arch) and significantly increased plaque stability in the brachiocephalic artery, a region normally prone to rupture. Both the vaso- and athero-protective effects of CGP42112 (1 μg/kg/min) were reversed with co-infusion of the AT₂R antagonist, PD123319, but not the MasR antagonist, A779.

Conclusion

For the first time we have shown that direct stimulation of the AT₂R improves endothelial function, reduces atherosclerotic lesion progression and mediates plaque stability with these effects at least partly due to restoration of nitric oxide bioavailability.     

Factors associated with growth patterns from birth to 18 months in a Beninese cohort of children

The aim of this study was to analyze factors influencing the growth pattern of children from birth to 18 months. A longitudinal prospective study was conducted in three maternity wards in Southern Benin. Inclusion took place between June 2007 and July 2008; children were followed-up until 18 months of age. Height-for-age and weight-for-height Z-scores were computed using the newborn's anthropometric measurements taken at delivery, every month up to 6 months and then quarterly. Infant and young child feeding (IYCF) practices and malarial morbidity were recorded. Gestational age was estimated using the Ballard method; William's sex-specific reference curve of birth weight-for-gestational-age was used to determine intrauterine growth retardation (IUGR). Analyses were performed on 520 children using a linear mixed model. Low birth weight (coef = −0.43; p = 0.002), IUGR (coef = −0.49; p < 0.001), maternal short stature (coef = −0.25; p = 0.001) and maternal low weight status (coef = −0.19; p = 0.006) were significantly associated with growth impairment. Only LBW (coef = −0.28; p = 0.05) and maternal low weight status (coef = −0.23; p = 0.004) were associated with wasting. A good IYCF score was positively associated with weight gain (coef = 0.14; p < 0.001) whereas we found a paradoxical association with length (coef = −0.18; p < 0.001). Malaria morbidity was not associated with growth. LBW, IUGR and maternal low weight status and height were important determinants of children's growth. These results reinforce and justify continuing public health initiatives to fight IUGR and LBW and break the intergenerational cycle of malnutrition.     

Expression of leptin-like peptide (LLP) mRNA in channel catfish (Ictalurus punctatus) is induced by exposure to Edwardsiella ictaluri but is independent of energy status

Leptin is a key pleiotropic cytokine involved in regulation of energy homeostasis and immunity in mammals. In channel catfish, the presence of a partial messenger RNA sequence that encodes a leptin-like peptide (LLP) has been identified and investigated. The objectives of the present studies were to clone and characterize full-length catfish LLP gene, examine tissue expression of LLP mRNA, and determine effects of prolonged fasting and exposure to Edwardsiella ictaluri (E. ictaluri), the bacteria that causes enteric septicemia in catfish, on LLP mRNA expression. Full-length catfish LLP gene was sequenced by genome walking and by 5′- and 3′-RACE. Catfish LLP gene contained three exons with the coding region located in exons 2 and 3. The amino acid sequence of the channel catfish LLP shared very low sequence similarities with leptin of other fish species or the mammalian leptin (24-49%). Using real-time polymerase chain reaction, LLP mRNA expression was detected in various tissues including brain, stomach, spleen, heart, liver, and trunk kidney and was especially high in the liver and trunk kidney. Expression of LLP mRNA in liver and brain was similar between fish that were fasted for 30 days and those that received feed daily for 30 days (P > 0.10). Expression of LLP mRNA was increased in liver, spleen, and trunk kidney within 48 h post-exposure to E. ictaluri compared to unexposed fish (P < 0.05). Based on the results of the current studies, amino acid sequence of catfish LLP is highly dissimilar to mammalian and fish leptin. Unlike in most mammals, catfish LLP expression is independent of energy status. However, the expression of catfish LLP is increased after exposure to pathogenic bacteria, which is similar to mammals. Further investigations are required to clearly define the biological function and regulation of catfish LLP.     

Impaired platelet function reduces myocardial infarct size in Galphaq knock-out mice in vivo

Platelet aggregation and secretion play a crucial role in acute coronary syndromes. In Gα_q knock-out mice (Gα_q(−/−)) platelet function is eliminated in terms of aggregation and secretion of cytokines. We investigated whether restricted platelet aggregation and secretion reduces myocardial infarct size in vivo. Thirty minute regional myocardial ischemia was followed by 24 h reperfusion (I/R) in vivo. Infarct size was determined by counterstaining. Left ventricular function was measured by ultrasound. Infarct size to area at risk ratio was significantly smaller in Gα_q(−/−) mice (5.6 ± 1.6%) compared to wild-type (WT) mice (27.2 ± 3.0%, p < 0.01). Fractional shortening was improved in Gα_q(−/−) mice compared to WT (42.2 ± 1.4% versus 30.5 ± 1.4%, respectively, p < 0.01). WT mice, transplanted with Gα_q(−/−) bone marrow showed a significant reduction in infarct size compared to control (7.8 ± 2.2% versus 18.4 ± 2.7%, respectively, p < 0.01). Platelets of Gα_q(−/−) mice had an impaired aggregation and secretion phenotype. In the in vivo model of ischemia and reperfusion, beyond impaired platelet aggregation, platelet secretion plays an additional role in myocardial infarct extension. Blocking platelet aggregation in combination with secretion might be a promising supplementary therapeutic strategy in acute myocardial infarction.     

Immunologic and mass-spectrometric estimates of SHBG concentrations in healthy women

Objective

Sex-hormone binding globulin (SHBG) concentrations across the adult female lifespan are not well defined. To address this knowledge gap, SHBG was quantified by both immunological and criterion methods, viz, mass spectrometry (MS).

Methods

Setting: Center for Translational Science Activities (CTSA). Participants: Healthy nonpregnant women (N = 120) ages 21 to 79 years. Outcomes: SHBG, testosterone (T), estradiol (E₂) and estrone (E₁) each determined by MS. Uni- and multivariate regression of SHBG concentrations on age, body mass index (BMI), total and visceral abdominal fat (TAF, AVF), albumin, glucose, insulin, sex steroids, selected cytokines, blood pressure, and lipids.

Results

By univariate regression, MS-estimated SHBG correlated negatively with BMI, TAF, AVF, insulin, free T and bioavailable T (bio T) (each P ≤ 10^− 4), but not with blood pressure or lipids. By stepwise multivariate regression analysis, free and total T (both positive) and bio T (negative) were correlated with SHBG in all 4 assays (each P < 10^− 15, R² ≥ 0.481). In addition, TAF and BMI were negatively associated with SHBG (P ≤ 0.0066) in 2 SHBG assays, and estrone and IL-8 with SHBG weakly (P ≤ 0.035) in one SHBG assay each. When nonsignificant cytokines were excluded, SHBG was jointly associated with AVF, total T and HDL (P < 10^− 9, R² = 0.358).

Conclusion

According to MS, three metabolic factors, T, AVF and HDL, together explain more than one-third of the interindividual variation in SHBG levels. We speculate that these measures reflect insulin action.     

Plasma 15-F2t-isoprostane in idiopathic pulmonary arterial hypertension

Background

15-F_2t-isoprostane (15-F_2t-IsoP), a prostaglandin F₂-like compound, is widely recognized as a biomarker of chronic heart failure. This study investigated the potential role and prognostic significance of plasma 15-F_2t-IsoP in patients with idiopathic pulmonary arterial hypertension (IPAH).

Methods

Plasma 15-F_2t-IsoP concentrations were determined in 80 consecutive IPAH patients at the time of their first right heart catheterization, and monitored for 30 ± 12 months. The expression of 15-F_2t-IsoP protein in autopsy lung samples was determined by immunohistochemical staining.

Results

Plasma 15-F_2t-IsoP concentrations were significantly increased in patients with IPAH compared with healthy controls (91 pg/ml vs. 30 pg/ml, respectively; P < 0.001). Patients with baseline 15-F_2t-IsoP concentrations ≥ 97 pg/ml had a significantly lower survival rate than those with lower baseline concentrations (P < 0.001). During follow-up, 15-F_2t-IsoP concentrations in survivors decreased, whereas concentrations in non-surviving patients increased further (P < 0.05). Elevated concentrations of 15-F_2t-IsoP were correlated with a severity of WHO functional class, lower 6-minute walking distance and mixed venous oxygen saturation, higher mean right atrial pressure and brain natriuretic peptide. Multivariate analysis revealed that the plasma 15-F_2t-IsoP concentration was an independent factor associated with mortality. Histological studies showed that the expression of 15-F_2t-IsoP was up-regulated in remodeled pulmonary vessels.

Conclusions

An elevated plasma 15-F_2t-IsoP concentration and a further increase during follow-up may be a risk factor for higher mortality in patients with IPAH.     

Eight weeks of treatment with long-acting GLP-1 analog taspoglutide improves postprandial insulin secretion and sensitivity in metformin-treated patients with type 2 diabetes

Objective

Loss of pancreatic function is pivotal to the deterioration of fasting and postprandial glycemic control in type 2 diabetes (T2D). We evaluated the effects of a long-acting, human glucagon-like peptide-1 analog, taspoglutide, added to metformin, on pancreatic function and peripheral insulin sensitivity.

Materials/methods

We studied 80 T2D patients inadequately controlled [glycosylated hemoglobin (HbA_1c), 7.0%–9.5%] receiving stable metformin for ≥ 12 weeks. They were a subset of participants to a phase 2 trial that received also a 240-min mixed-meal tolerance test (MTT) at baseline and study end. Patients received once weekly (QW) sc injection of taspoglutide 5, 10, or 20 mg (n = 21, 19, or 19), or placebo (n = 21), plus metformin, for 8 weeks. We measured postprandial plasma glucose (PPG) and insulin profiles, insulin secretion rate (ISR), oral glucose insulin sensitivity (OGIS) index; β-cell glucose sensitivity, glucagon/glucose and insulin/glucagon ratios, and insulin sensitivity-to-insulin resistance (or disposition) index.

Results

After 8 weeks of treatment, taspoglutide 5, 10, and 20 mg QW doses vs. placebo improved mean PPG_{0–240 min} (relative change from baseline: − 22.1%, − 25.9%, and − 22.9% vs. − 8.1%; P < 0.005) and mean postprandial ISR_{0–240 min} (+ 14%, + 18%, and + 23% vs. + 1%; P < 0.005 vs dose). Taspoglutide at 20 mg QW dose also resulted in improvements from baseline in OGIS, β-cell glucose sensitivity, glucagon/glucose and insulin/glucagon ratios and the disposition index during the MTT.

Conclusion

Taspoglutide QW significantly improved pancreatic function in patients with T2D treated with metformin.     

A preliminary study on pro- and anti-inflammatory cytokine profiles in Plasmodium vivax malaria patients from central zone of India

The aim of this preliminary study was to investigate the plasma cytokine profiles in a group of patients suffering from Plasmodium vivax malaria during the peak of its transmission season. Plasma samples of 173 P. vivax patients and 34 healthy individuals were analyzed for IFN-γ, TNF-α, IL-10 and IP-10 levels by ELISA. Levels of both pro- and anti-inflammatory cytokines were significantly higher in P. vivax patients compared to controls. Children with P. vivax infection had significantly higher levels of IFN-γ than adults (P = 0.017). Asexual parasitaemia versus TNF-α (r = −0.31, P = 0.01), IL-10 (r = −0.30, P = 0.015) and gametocytaemia versus IFN-γ (r = −0.26; P = 0.034) levels showed significant negative correlation in children compared to adults. The median concentrations of IFN-γ (P = 0.001), IL-10 (P = 0.032) and IP-10 (P ≤ 0.05) were higher in children reported with chills and rigors, whereas in adults only IFN-γ levels was higher (P < 0.0001). The median plasma concentrations of IFN- γ (P = 0.02), IL-10 (P < 0.0001) and IP-10 (P = 0.068) were higher in patients with mild anaemia compared to non-anaemic patients. The results indicated that both pro- and anti-inflammatory cytokine responses are associated with clinical signs of mild anaemia and paroxysm during symptomatic P. vivax malaria in Central India.     

Aerobic and resistance training effects compared to aerobic training alone in obese type 2 diabetic patients on diet treatment

Aims

The study was designed to compare a combined aerobic and resistance training (ART) with an aerobic training (AT) over hemodynamic, glucose metabolism and endothelial factors, adipokines and pro-inflammatory marker release in a population of obese type 2 diabetic patients.

Methods

Forty-seven patients were randomly assigned to aerobic (27 patients) or aerobic plus resistance (20 patients) exercise trainings, on the top of a diet regime. Anthropometric, metabolic, hormonal and inflammatory variables were measured at hospitalization and discharge.

Results

Both exercise programs equally improved body weight and fructosamine levels however ART only partially decreased HOMA index compared with AT (ART: −25% vs AT: −54%, p < 0.01). Mean blood pressure (AT: −3.6 mmHg vs ART: +0.6 mmHg, p < 0.05) and endothelin-1 (ET-1) incremental areas during walking test (AT: −11% vs ART: +30%, p < 0.001) decreased after AT while increased after ART. Adiponectin levels increased by 54% after AT while decreased by 13% after ART (p < 0.0001) and matrix metalloproteinase-2 (MMP-2), tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractan protein-1 (MCP-1) levels significantly decreased in AT while increased in ART group.

Conclusions

Compared with AT, ART similarly enhanced body weight loss but exerted less positive effects on insulin sensitivity and endothelial factors, adipokines and pro-inflammatory marker release.     

Comparison of IFCC-calibrated HbA1c from laboratory and point of care testing systems

Objective

WHO, IDF and ADA recommend HbA_1c ≥6.5% (48 mmol/mol) for diagnosis of diabetes with pre-diabetes 6.0% (42 mmol/mol) [WHO] or 5.7% (39 mmol/mol) [ADA] to 6.4% (47 mmol/mol). We have compared HbA_1c from several methods for research relating glycaemic markers.

Research design and methods

HbA_1c was measured in EDTA blood from 128 patients with diabetes on IE HPLC analysers (Bio-Rad Variant II NU, Menarini HA8160 and Tosoh G8), point of care systems, POCT, (A1cNow+ disposable cartridges and DCA 2000^®+ analyser), affinity chromatography (Primus Ultra2) and the IFCC secondary reference method (Menarini HA8160 calibrated using IFCC SRM protocol).

Results

Median (IQ range) on IFCC SRM was 7.5% (6.8–8.4) (58(51–68) mmol/mol) HbA_1c with minimum 5.3%(34 mmol/mol)/maximum 11.9%(107 mmol/mol). There were positive offsets between IFCC SRM and Bio-Rad Variant II NU, mean difference (1SD), +0.33%(0.17) (+3.6(1.9) mmol/mol), r² = 0.984, p < 0.001 and Tosoh G8, +0.22%(0.20) (2.4(2.2) mmol/mol), r² = 0.976, p < 0.001 with a very small negative difference −0.04%(0.11) (−0.4(1.2) mmol/mol), r² = 0.992, p < 0.001 for Menarini HA8160. POCT methods were less precise with negative offsets for DCA 2000^®+ analyser −0.13%(0.28) (−1.4(3.1) mmol/mol), r² = 0.955, p < 0.001 and A1cNow+ cartridges −0.70%(0.67) (−7.7(7.3) mmol/mol), r² = 0.699, p < 0.001 (n = 113). Positive biases for Tosoh and Bio-Rad (compared with IFCC SRM) have been eliminated by subsequent revision of calibration.

Conclusions

Small differences observed between IFCC-calibrated and NGSP certified methods across a wide HbA_1c range were confirmed by quality control and external quality assurance. As these offsets affect estimates of diabetes prevalence, the analyser (and calibrator) employed should be considered when evaluating diagnostic data.     

Effects of prediabetes and diabetes on left ventricular and coronary microvascular functions

Background

Coronary flow reserve (CFR) provides independent prognostic information in diabetic patients with known or suspected coronary artery disease. However, there have been no substantial data to evaluate CFR in prediabetics. Accordingly, we aimed to evaluate CFR in subjects with prediabetes using second harmonic transthoracic Doppler echocardiography.

Methods and Results

We measured CFR of 65 subjects with prediabetes, 45 patients with overt type 2 diabetes, and 43 sex and age matched normoglycemic healthy subjects with normal glucose tolerance. Ages, gender, existence of hypertension or hypercholesterolemia, smoking status were similar among the groups. CFR was significantly lower in diabetics (2.15 ± 0.39) than in prediabetics (2.39 ± 0.45) and controls (2.75 ± 0.35); in addition, it was significantly lower in prediabetics than controls. Only 2 (5%) of control subjects had abnormal CFR (< 2) but 11 (17%) prediabetic subjects and 19 (42%) diabetic patients had abnormal CFR. We found that only age (β = − 0.31, P < 0.01) and presence of the diabetes (β = − 0.57, P < 0.01) were significant predictors of lower CFR in a multivariable model that adjusted for other variables. CFR was significantly and inversely correlated with age (r = − 0.15, P = 0.04), fasting glucose level (r = − 0.27, P = 0.001), postprandial glucose level (r = 0.43, P < 0.001), hemoglobin A1C level (r = − 0.34, P < 0.001), LDL cholesterol level (r = 0.22, P = 0.009), mitral A velocity (r = − 0.27, P = 0.001) and Tei index (r = − 0.19, P = 0.02), whereas mitral E/A ratio, mitral Em (r = 0.18, P = 0.02), mitral Em/Am ratio (r = 0.23, P = 0.004) were significantly and positively correlated with CFR.

Conclusion

CFR is impaired in subjects with prediabetics, but this impairment is not as severe as that in diabetics.