P. G. McTernan

Serum high molecular weight complex of adiponectin correlates better with glucose tolerance than total serum adiponectin in Indo-Asian males

Aims/hypothesisIt is well established that total systemic adiponectin is reduced in type 2 diabetic subjects. To date most studies have been concerned with the singular full-length protein or proteolytically cleaved globular domain. It is, however, apparent that the native protein circulates in serum as a lower molecular weight hexamer and as larger multimeric structures of high molecular weight (HMW). In this study we address the clinical significance of each form of the protein with respect to glucose tolerance.MethodsSerum was obtained from 34 Indo-Asian male subjects (BMI 26.5±3.1; age 52.15±10.14 years) who had undertaken a 2-h oral glucose tolerance test. An aliquot of serum was fractionated using velocity sedimentation followed by reducing SDS-PAGE. Western blots were probed for adiponectin, and HMW adiponectin as a percentage of total adiponectin (percentage of higher molecular weight adiponectin [SA] index) was calculated from densitometry readings. Total adiponectin was measured using ELISA; leptin, insulin and IL-6 were determined using ELISA.ResultsAnalysis of the cohort demonstrated that total adiponectin (r=0.625, p=0.0001), fasting insulin (r=−0.354, p=0.040) and age (r=0.567, p=0.0001) correlated with SA. SA showed a tighter, inverse correlation with 2-h glucose levels (r=−0.58, p=0.0003) than total adiponectin (r=−0.38, p=0.0001).Conclusions/interpretationThis study demonstrates the importance of the SA index as a better determinant of glucose intolerance than measurements of total adiponectin. Our findings suggest that HMW adiponectin is the active form of the protein.

Epicardial Adipose Tissue as a Source of Nuclear Factor-κB and c-Jun N-Terminal Kinase Mediated Inflammation in Patients with Coronary Artery Disease

CONTEXTnVisceral adipose tissue (AT) is known to confer a significantly higher risk of type 2 diabetes and cardiovascular disease. Epicardial AT has been shown to be related to cardiovascular disease and myocardial function through unidentified mechanisms. Epicardial AT expresses an inflammatory profile of proteins; however, the mechanisms responsible are yet to be elucidated.nnnOBJECTIVESnThe objectives of the study were to: 1) examine key mediators of the nuclear factor-kappaB (NFkappaB) and c-Jun N-terminal kinase (JNK) pathways in paired epicardial and gluteofemoral (thigh) AT from coronary artery disease (CAD) and control patients and 2) investigate circulating endotoxin levels in CAD and control subjects.nnnDESIGNnSerums and AT biopsies (epicardial and thigh) were obtained from CAD (n = 16) and non-CAD (n = 18) patients. Inflammation was assessed in tissue and serum samples through Western blot, real-time PCR, ELISAs, and activity studies.nnnRESULTSnWestern blotting showed epicardial AT had significantly higher NFkappaB, inhibitory-kappaB kinase (IKK)-gamma, IKKbeta, and JNK-1 and -2 compared with thigh AT. Epicardial mRNA data showed strong correlations between CD-68 and toll-like receptor-2, toll-like receptor-4, and TNF-alpha. Circulating endotoxin was elevated in patients with CAD compared with matched controls [CAD: 6.80 +/- 0.28 endotoxin unit(EU)/ml vs. controls: 5.52 +/- 0.57 EU/ml; P<0.05].nnnCONCLUSIONnEpicardial AT from patients with CAD shows increased NFkappaB, IKKbeta, and JNK expression compared with both CAD thigh AT and non-CAD epicardial AT, suggesting a depot-specific as well as a disease-linked response to inflammation. These studies implicate both NFkappaB and JNK pathways in the inflammatory profile of epicardial AT and highlight the role of the macrophage in the inflammation within this tissue.

Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells

Aims/hypothesisDamage persists in HUVECs exposed to a constant high glucose concentration long after glucose normalisation, a phenomenon termed ‘metabolic memory’. Evaluation of the effects of exposure of HUVECs to oscillating high glucose on the induction of markers of oxidative stress and DNA damage (phospho-γ-histone H2AX and PKCδ) and onset of metabolic memory, and the possible role of the tumour suppressor transcriptional factor p53 is of pivotal interest.MethodsHUVECs were incubated for 3xa0weeks in 5 or 25xa0mmol/l glucose or oscillating glucose (24xa0h in 5xa0mmol/l glucose followed by 24xa0h in 25xa0mmol/l glucose) or for 1xa0week in constant 5xa0mmol/l glucose after being exposed for 2xa0weeks to continuous 25xa0mmol/l high glucose or oscillating glucose. Transcriptional activity of p53 was also evaluated in the first 24xa0h after high glucose exposure.ResultsHigh constant glucose upregulated phospho-γ-histone H2AX and protein kinase C (PKC)δ compared with control. Oscillating glucose was even more effective than both normal and constant high glucose. Both constant and oscillating glucose resulted in a memory effect, which was more pronounced in the oscillating condition. Transcriptional activity of p53 peaked 6xa0h after glucose exposure, showing a predicted oscillatory behaviour.Conclusions/interpretationExposure to oscillating glucose was more deleterious than constant high glucose and induced a metabolic memory after glucose normalisation. Hyperactivation of p53 during glucose oscillation might be due to the absence of consistent feedback inhibition during each glucose spike and might account for the worse outcome of this condition.

Serum resistin is associated with C-reactive protein and LDL- cholesterol in type 2 diabetes and coronary artery disease in a Saudi population

AimsResistin is an adipocyte-derived factor implicated in obesity-associated type 2 diabetes (T2DM). This study examines the association between human serum resistin, T2DM and coronary heart disease.MethodsOne hundred and fourteen Saudi Arabian patients (male: female ratio 46:68; age 51.4 (mean ± SD)11.7 years; median and range: 45.59 (11.7) years and BMI: 27.1 (mean ± SD) 8.1 Kgm2 median and range: 30.3 (6.3) were studied. Serum resistin and C-reactive protein (CRP), a marker of inflammation CRP levels, were measured in all subjects. (35 patients had type 2 diabetes mellitus (T2DM); 22 patients had coronary heart disease (CHD).ResultsSerum resistin levels were 1.2-fold higher in type 2 diabetes and 1.3-fold higher in CHD than in controls (p = 0.01). In addition, CRP was significantly increased in both T2DM and CHD patients (p = 0.007 and p = 0.002 respectively). The use of regression analysis also determined that serum resistin correlated with CRP levels (p = 0.04, R2 0.045).ConclusionThe findings from this study further implicate resistin as a circulating protein associated with T2DM and CHD. In addition this study also demonstrates an association between resistin and CRP, a marker of inflammation in type 2 diabetic patients.

DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue

Context:u2002 Dipeptidyl peptidase IV (DPP‐IV) inactivates the incretin hormone glucagon‐like peptide. It can also affect the orexigenic hormone neuropeptide Y (NPY1–36) which is truncated by DPP‐IV to NPY3–36, as a consequence NPY’s affinity changes from receptor Y1, which mediates the antilipolytic function of NPY, to other NPY receptors. Little is known whether DPP‐IV inhibitors for the treatment of type 2 diabetic (T2DM) patients could influence these pathways.

Relationship of serum adiponectin and resistin to glucose intolerance and fat topography in south-Asians

ObjectivesSouth-Asians have lower adiponectin levels compared to Caucasians. It was not clear however, if this intrinsic feature is related to aspects of glucose metabolism. This study aims to determine the relationship between body fat distribution and adipocytokine in South-Asian subjects by measuring serum adipocytokines, adiposity, insulinemia, and glucose tolerance levels.MethodsIn this cross-sectional study, 150 South-Asians (80 males, 70 females) were included, 60 had NGT (Control group, Age 51.33 ± 11.5, BMI 27 ± 2.3), 60 had IGT (Age 57.7 ± 12.5, BMI 27.2 ± 2.7), 30 had type 2 DM (Age 49.5 ± 10.9, BMI 28 ± 1.7). Measures of adiposity, adipocytokines and other metabolic parameters were determined. Parameters were measured using the following: a) Plasma glucose by glucose oxidase method b) CRP by immunoturbidimetric method (Roche/Hitachi analyser) c) insulin by Medgenix INS-ELISA immunoenzymetric assay by Biosource (Belgium) d) Leptin, Adiponectin by radioimmunoassay kits by Linco Research (St. Charles MO) e) Resistin by immunoassay kits by Phoenix Pharmaceuticals INC (530 Harbor Boulevard, Belmont CA 94002, USA).ResultsAdiponectin concentrations were highest in NGT, decreased in IGT and lowest in DMT2, (both p < 0.01). Leptin was significantly higher in DMT2 than IGT and NGT p = 0.02 and 0.04 respectively. There was a significant positive relationships between log adiponectin and 2-hr insulin values, p = 0.028 and history of hypertensions and a ischemic heart disease p = 0.008 with R = 0.65. There was a significant inverse correlation between log adiponectin and resistin, p < 0.01.ConclusionResistin levels had an inverse correlation with adiponectin levels, indicating an inverse relationship between pro-inflammatory cytokines and adiponectin. Adiponectin levels were related to glucose tolerance.

Telomere length in relation to insulin resistance, inflammation and obesity among Arab youth.

Aim:u2002 The aim of this study was to determine the associations of telomere length to markers of obesity, insulin resistance and inflammation in Saudi children.

Effect of the orlistat on serum endotoxin lipopolysaccharide and adipocytokines in South Asian individuals with impaired glucose tolerance

Background:u2002 Orlistat has been shown to increase adiponectin and reduce progression to type 2 diabetes in obese Caucasians. Some effects of orlistat are thought to be independent of weight loss by altering gut flora and the production of endotoxin lipopolysaccharide (LPS). We studied the effect of dietary treatment with and without orlistat in South Asian individuals with impaired glucose tolerance (IGT) on adiponectin and inflammatory markers including LPS.

Impact of acute hyperglycaemia on endothelial function and retinal vascular reactivity in patients with Type 2 diabetes

Diabet. Med. 28, 450–454 (2011)

Effects of menopausal status on circulating calcitonin gene-related peptide and adipokines: implications for insulin resistance and cardiovascular risks.

Objectives To determine, first, the effects of menopausal status on circulating calcitonin gene-related peptide (CGRP) levels and, second, the correlation between circulating CGRP levels and biomarkers for cardiovascular disease. Methods Cross-sectional study of healthy premenopausal and postmenopausal women volunteers and women admitted for elective benign abdominal surgery in a district general hospital. All women were non-smokers, had no history of endocrinological problems and were not receiving any hormone therapy. Fasting blood samples (premenopausal (n = 45): follicle stimulating hormone (FSH) < 20 IU/l, estradiol (mean ± SEM) 440.33 ± 51.82 pmol/l; postmenopausal women (n = 28): FSH > 20 IU/l, estradiol 93.79 ± 17.40 pmol/l) were analyzed for CGRP, resistin, leptin, adiponectin, insulin and lipids using ELISA and immunoassays. Results Mean circulating CGRP levels were higher in the postmenopausal women compared with premenopausal women (pre: 41.79 ± 9.01 pg/ml, post: 138.14 ± 45.75 pg/ml; p = 0.047). Among women who were experiencing hot flushes, the postmenopausal women had significantly higher CGRP levels than the premenopausal women (pre: 21.98 ± 4.95 pg/ml, post: 171.08 ± 61.80 pg/ml; p = 0.028). Serum CGRP levels positively correlated with serum insulin levels (r = 0.652, p = 0.016) and HOMA index (r = 0.54, p < 0.001). Conclusion These data show that circulating CGRP levels are influenced by menopausal status and suggest additional mechanisms through which increased risk of hyperinsulinemia and cardiovascular disease may arise in postmenopausal women.