Impact of adiponectin and ghrelin on incident glucose intolerance and on weight change

Objectives Adiponectin and ghrelin are associated with adiposity and type 2 diabetes in several studies. We sought to prospectively determine the interaction of adiponectin and ghrelin in the development of adiposity and hyperglycaemia. Design Prospective observational study. Participants 393 community‐dwelling Afro‐Jamaicans (mean age 47 ± 13 years; BMI 27·3 ± 6·3 kg/m²; 63% women) without glucose intolerance at baseline. Measurements Anthropometry, fasting plasma glucose, 2‐h plasma glucose, insulin resistance (HOMA‐IR), adiponectin and ghrelin concentrations were measured at baseline and 4·1 ± 0·9 years later. Multivariate analyses were used to explore the associations of HOMA‐IR, adiponectin and ghrelin with weight change and glycaemia. Results The mean weight change was 2·6 ± 5·5 kg. There were 114 incident cases of impaired glucose tolerance (IGT) and 35 cases of diabetes mellitus. Adiponectin was positively correlated with age and female sex (P‐values < 0·01). After adjusting for age and sex, adiponectin and ghrelin were significantly correlated with weight at baseline and follow‐up. However, they were not associated with weight change even after further adjustment for baseline weight. Adiponectin, but not ghrelin, was associated with 2‐h glucose concentrations at follow‐up even after adjusting for age, sex, HOMA‐IR and BMI (P = 0·04). In the fully adjusted logistic regression model, adiponectin predicted incident IGT (OR 0·93; 95% CI: 0·87–0·99) and attenuated the effect of BMI on incident IGT. Conclusions These longitudinal data show that adiponectin and ghrelin may not be causally involved in the development of obesity. However, adiponectin is independently associated with decreased risk of incident IGT.     

Acute hyperinsulinaemia and hyperlipidaemia modify circulating adiponectin and its oligomers

Objective Obesity and insulin resistance are associated with low adiponectin levels, although adiponectin is exclusively expressed in white adipose tissue. The mechanism beyond that paradox is not entirely clear, although insulin itself may reduce circulating adiponectin levels. However, obesity is also associated with hyperlipidaemia and the effects of free fatty acids (FFAs) and triglycerides (TG) on circulating adiponectin levels have not yet been investigated. Materials and methods We analysed the effect of an acute and euglycaemic elevation of insulin on adiponectin oligomers in 23 healthy individuals. In a subgroup including 11 healthy men, FFAs and TG were acutely elevated by infusion of heparin/lipids over 120 min. Again the effect on circulating adiponectin and its oligomers was investigated. Adiponectin was determined by ELISA, oligomers were detected by nondenaturating Western blot. Results Acute hyperinsulinaemia resulted in a significant reduction of total adiponectin to 7·74 ± 0·98 µg/ml (P = 0·004). High molecular weight (HMW) adiponectin did not change (0·80 ± 0·12 to 0·81 ± 0·14 µg/ml; P = 0·887), whereas MMW adiponectin decreased from 4·30 ± 0·51 to 3·78 ± 0·48 µg/ml (P = 0·005) and LMW adiponectin from 3·63 ± 0·42 to 3·15 ± 0·46 µg/ml (P = 0·048). Interestingly, heparin/lipid infusion also reduced circulating adiponectin levels (P = 0·001), which was primarily the result of reduced MMW adiponectin (P = 0·004), whereas LMW and HMW were not significantly affected. Conclusions The presented data suggest that both, hyperinsulinaemia and hyperlipidaemia, may contribute to low adiponectin levels in states of obesity.     

Serum resistin is positively correlated with the accumulation of metabolic syndrome factors in type 2 diabetes

Objective Resistin, secreted from adipocytes, causes insulin resistance in rodents. We reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at ?420 increases type 2 diabetes (T2DM) susceptibility by enhancing promoter activity. We also showed that serum resistin was positively correlated with G at SNP‐420, the duration of T2DM, and HbA1c in T2DM. The aim of this study was to determine the relation between serum resistin and factors related to the metabolic syndrome (MetS) in T2DM. Design, patients and measurements We analysed 238 Japanese T2DM subjects (124 males and 114 females, age 60·2 ± 11·3 years, body mass index (BMI) 24·1 ± 3·9) whose overnight fasting sera were available. Serum resistin was measured using ELISA. Results Serum resistin was higher in subjects with either obesity (P = 0·041), low HDL (P = 0·004), high triglycerides (TG) (P = 0·019), hypertension (HT) (P = 0·001) or atherosclerosis (P = 0·012). Simple regression analysis revealed that serum resistin was correlated with lower HDL, TG and high‐sensitivity C‐reactive protein (hsCRP). Multiple regression analysis (or logistic regression analysis for HT), adjusted for age, gender, BMI and the duration of T2DM, revealed that serum resistin was correlated with lower HDL (P = 0·008), TG (P = 0·041), HT (P = 0·031) and hsCRP (P = 0·004). Serum resistin was positively correlated with the number of MetS factors, independent of age, gender and the duration of T2DM (P < 0·001). Adjustment by either thiazolidinedione (TZD) treatment or hsCRP had no effects on these findings. Conclusions Serum resistin was positively correlated with the accumulation of MetS factors in T2DM.     

Pre-gravid physical activity and reduced risk of glucose intolerance in pregnancy: the role of insulin sensitivity

Objective Pre‐gravid physical activity has been associated with a reduced risk of gestational diabetes mellitus (GDM), although neither the types of exercise nor the physiologic mechanisms underlying this protective effect have been well‐studied. Thus, we sought to study the relationships between types of pre‐gravid physical activity and metabolic parameters in pregnancy, including glucose tolerance, insulin sensitivity and β‐cell function. Design/patients/measurements A total of 851 women underwent a glucose challenge test (GCT) and a 3‐h oral glucose tolerance test (OGTT) in late pregnancy, yielding four glucose tolerance groups: (i) GDM; (ii) gestational impaired glucose tolerance (GIGT); (iii) abnormal GCT with normal glucose tolerance on OGTT (abnormal GCT NGT); and (iv) normal GCT with NGT on OGTT (normal GCT NGT). Pre‐gravid physical activity was assessed using the Baecke questionnaire, which measures (i) total physical activity and (ii) its three component domains: work, nonsport leisure‐time, and vigorous/sports activity. Results Glucose tolerance status improved across increasing quartiles of pre‐gravid total physical activity (P = 0·0244). Whereas neither work nor nonsport leisure‐time activity differed between glucose tolerance groups, pre‐gravid vigorous/sports activity was significantly higher in women with normal GCT NGT compared to women with (i) abnormal GCT NGT (P = 0·0018) (ii) GIGT (P = 0·0025), and (iii) GDM (P = 0·0044). In particular, vigorous/sports activity correlated with insulin sensitivity (measured by IS_OGTT) (r = 0·21, P < 0·0001). Furthermore, on multiple linear regression analysis, pre‐gravid vigorous/sports activity emerged as a significant independent predictor of IS_OGTT in pregnancy (t = 4·97, P < 0·0001). Conclusions Pre‐gravid vigorous/sports activity is associated with a reduced risk of glucose intolerance in pregnancy, an effect likely mediated by enhanced insulin sensitivity.     

Serum total and high molecular weight adiponectin levels are correlated with the severity of diabetic retinopathy and nephropathy

Objective Adiponectin is secreted specifically from adipocytes, and improves insulin sensitivity. Of its isoforms, the high molecular weight (HMW) complex is thought to be the most active. The aim of this study was to determine the relationship between serum total or HMW adiponectin and diabetic microangiopathy. Design, patients and measurements We analysed 198 Japanese patients with type 2 diabetes mellitus (T2DM) whose fasting serum samples were available. Serum total adiponectin and HMW adiponectin were measured using an enzyme‐linked immunosorbent assay (ELISA). Results Serum total adiponectin was found to have increased in the advanced stages of diabetic retinopathy (mean ± SE, none, 6·9 ± 0·3; simple, 8·3 ± 1·0; preproliferative, 8·4 ± 0·8; proliferative, 12 ± 1·1 mg/l; anova P = 0·0004) and nephropathy (stage I, 7·0 ± 0·3; II, 7·7 ± 0·5; III, 9·5 ± 0·9; IV, 16 ± 4·5 mg/l, P < 0·0001). Similarly, serum HMW adiponectin had increased in the advanced stages of retinopathy (3·7 ± 0·2, 4·6 ± 0·5, 4·6 ± 0·6 and 6·9 ± 0·8 mg/l, respectively, P = 0·0005) and nephropathy (3·7 ± 0·2, 4·3 ± 0·4, 5·3 ± 0·7 and 7·9 ± 2·2 mg/l, respectively, P = 0·0007). Neither serum total nor HMW adiponectin was correlated with neuropathy. The HMW/total adiponectin ratio was not correlated with microangiopathy. Multiple regression analysis revealed that serum total and HMW adiponectin were independent factors for retinopathy stage (P = 0·0055 and P = 0·0027, respectively) and nephropathy stage (P = 0·0003 and P = 0·0018, respectively), when adjusted for age, gender, body mass index (BMI) and the duration of T2DM. This correlation remained significant when serum creatinine (or estimated glomerular filtration rate) and hypertension were added as independent variables. Treatment with thiazolidinediones (TZDs) did not affect these findings. Conclusions Serum total adiponectin and HMW adiponectin were found to be positively correlated with the severity of retinopathy and nephropathy but not with neuropathy in T2DM.     

Serum concentrations of leptin, adiponectin and resistin, and their relationship with cardiovascular disease in patients with end-stage renal disease

Background and Objective High levels of some adipocytokines have been reported in patients with chronic renal failure, but little information is available on adipocytokine concentrations in uraemic patients under different modalities of therapy. Our aims were (1) to quantify the serum concentrations of leptin, adiponectin and resistin in uraemic patients on peritoneal dialysis (PD) and haemodialysis (HD), in comparison with patients on conservative management, and (2) to study the relationships between adipocytokine levels and previous atherosclerotic vascular disease. Patients and Measurements We studied 82 dialysis patients treated by PD (n = 44, 23 males and 21 females, mean age 54·4 ± 1·8 years) or HD (n = 38, 22 males and 16 females, age 60·8 ± 1·6 years). A group of 19 uraemic patients on conservative management served as the control. Serum concentrations of leptin, adiponectin and resistin were measured in all subjects. Information on vascular disease (cerebral vascular, peripheral vascular and heart disease) was obtained from a detailed medical history. Results PD patients showed significantly higher serum leptin concentrations [median (interquartile range), 28·7 (13·0–71·9) µg/l] than those found in patients on HD [9·7 (4·7–31·9) µg/l, P < 0·01] or in conservative management [5·9 (4·3–38·6) µg/l, P < 0·05]. Adiponectin concentrations were similar in the three groups of patients (mean ± SEM, 48·0 ± 4·5 mg/l in PD, 57·7 ± 4·4 mg/l in HD, and 44·4 ± 7·0 mg/l in controls, NS). Patients treated by both PD and HD exhibited resistin concentrations significantly higher than those found in controls (26·3 ± 0·99 and 27·5 ± 1·4 µg/l, respectively, vs. 17·3 ± 1·0 µg/l, P < 0·001). Leptin concentrations were positively correlated with body mass index (BMI) (r = 0·287, P < 0·01) and adiponectin levels were negatively related to BMI (r = ?0·416, P < 0·001) and the homeostatic model assessment (HOMA‐R) index (r =?0·216, P < 0·05). Leptin, adiponectin and resistin levels in patients with previous vascular events were similar to those found in patients without these complications. Logistic regression analysis did not demonstrate any relationship between serum adipocytokine concentrations and the presence of vascular disease of any type. A significant relationship between resistin and heart disease [odds ratio (OR) 1·80 (1·03–3·15), P = 0·039] was found when analysing subgroups of patients. Conclusions These data suggest that leptin levels are higher in PD patients, and resistin levels are higher in PD and HD patients in relation to patients on conservative management, whereas adiponectin concentrations are similar in the three groups. These results do not support the presence of a clinically relevant relationship between adipocytokines and previous episodes of vascular disease in the whole population or in patients classified in subgroups, with the only exception of a relationship between resistin levels and heart disease.     

Resistin gene variation is associated with systemic inflammation but not plasma adipokine levels, metabolic syndrome or coronary atherosclerosis in nondiabetic Caucasians

Objective Resistin causes insulin resistance and diabetes in mice whereas in humans it is linked to inflammation and atherosclerosis. Few human genetic studies of resistin in inflammation and atherosclerosis have been performed. We hypothesized that the –420C>G putative gain‐of‐function resistin variant would be associated with inflammatory markers and atherosclerosis but not with metabolic syndrome or adipokines in humans. Design and methods We examined the association of three resistin polymorphisms, –852A>G, –420C>G and +157C>T, and related haplotypes with plasma resistin, cytokines, C‐reactive protein (CRP), adipokines, plasma lipoproteins, metabolic syndrome and coronary artery calcification (CAC) in nondiabetic Caucasians (n = 851). Results Resistin levels were higher, dose‐dependently, with the –420G allele (CC 5·9 ± 2·7 ng/ml, GC 6·5 ± 4·0 ng/ml and GG 7·2 ± 4·8 ng/ml, trend P = 0·04) after age and gender adjustment [fold higher for GC + GG vs. CC; 1·07 (1·00–1·15), P < 0·05)]. The –852A>G single nucleotide polymorphism (SNP) was associated with higher soluble tumour necrosis factor‐receptor 2 (sol‐TNFR2) levels in fully adjusted models [1·06 (95% CI 1·01–1·11), P = 0·01)]. The estimated resistin haplotype (GGT) was associated with sol‐TNFR2 (P = 0·04) and the AGT haplotype was related to CRP (P = 0·04) in the fully adjusted models. Resistin SNPs and haplotypes were not associated with body mass index (BMI), fasting glucose, insulin resistance, metabolic syndrome, adipokines or CAC scores. Conclusions Despite modest associations with plasma resistin and inflammatory biomarkers, resistin 5′ variants were not associated with metabolic parameters or coronary calcification. This suggests that resistin is an inflammatory cytokine in humans but has little influence on adiposity, metabolic syndrome or atherosclerosis.     

Influence of ethnicity on IGF-I and procollagen III peptide (P-III-P) in elite athletes and its effect on the ability to detect GH abuse

Context A method based on the two GH dependent markers, IGF‐I and procollagen III peptide (P‐III‐P) has been proposed to detect exogenously administered GH. As previous studies involved predominantly white European elite athletes, it is necessary to validate the method in other ethnic groups. Objective To examine serum IGF‐I and P‐III‐P in elite athletes of different ethnicities within 2 h of competing at national or international events. Design Cross‐sectional observational study. Setting National and International sporting events. Subjects 1085 elite athletes of different ethnicities. Intervention Serum IGF‐I and P‐III‐P were measured and GH‐2000 discriminant function score was calculated. Effect of ethnicity was assessed. Results In men, IGF‐I was 21·7 ± 2·6% lower in Afro‐Caribbeans than white Europeans (P < 0·0001) but there were no differences between other ethnic groups. In women, IGF‐I was 14·2 ± 5·1% lower in Afro‐Caribbeans (P = 0·005) and 15·6 ± 7·0% higher in Orientals (P = 0·02) compared with white Europeans. P‐III‐P was 15·2 ± 3·5%, 26·6 ± 6·6% and 19·3 ± 5·8% lower in Afro‐Caribbean (P < 0·0001), Indo‐Asian (P < 0·0001) and Oriental men (P = 0·001), respectively, compared with white European men. In women, P‐III‐P was 15·7 ± 4·7% lower in Afro‐Caribbeans compared to white Europeans (P =0·0009) but there were no differences between other ethnicities. Despite these differences, most observations were below the upper 99% prediction limits derived from white European athletes. All GH‐2000 scores lay below the cut‐off limit proposed for doping. Conclusions The GH‐2000 detection method based on IGF‐I and P‐III‐P would be valid in all ethnic groups.     

Long-term GH treatment is not associated with disadvantageous changes of inflammatory markers and adipocytokines in children born small for gestational age

Context Low birth weight is associated with increased risks for adult cardiovascular disease (CVD) and diabetes mellitus type 2 (DM2). Adiponectin and resistin are hormones, considered, respectively, protective and disadvantageous regarding these risks. No data exist on the effect of long‐term GH treatment on these hormones and inflammatory markers in children born small for gestational age (SGA). Objective To describe longitudinal changes in inflammatory markers and adipocytokines during and after a long‐term dose–response GH study. Design Longitudinal dose–response study [group A: 1 mg/m² body surface area (BSA) (approximately 0·033 mg/kg/day) vs. group B: 2 mg/m² BSA (approximately 0·067 mg/kg/day)] and comparison with age‐related controls. Patients One hundred and three SGA children. Measurements We measured adiponectin, resistin, interleukin‐6 (IL‐6) and C‐reactive protein (CRP) levels at baseline, after 1 and 7 years of GH treatment and 6 months after discontinuation of GH. Results Adiponectin levels decreased over time, but remained comparable with controls. Resistin levels increased and remained lower or comparable with controls. There were no significant differences between the GH dosage groups. After the GH treatment was stopped, adiponectin was decreased in group B and resistin increased in group A. GH therapy did not affect IL‐6 and CRP levels at any time point. An increase in body mass index (BMI) standard deviation score (SDS) over time was associated with a decrease in adiponectin levels. None of the markers were associated with insulin sensitivity. Conclusions Long‐term GH treatment is not associated with disadvantageous changes in adiponectin, resistin, IL‐6 and CRP levels, neither during nor after GH treatment.     

Insulin, adiponectin, IGFBP-1 levels and body composition in small for gestational age born non-obese children during prepubertal ages

Background Being small for gestational age (SGA) at birth and postnatal growth pattern may have an impact on insulin resistance and body composition in later life. Adiponectin is a strong determinant of insulin sensitivity. Objective The aim of this study was to evaluate insulin resistance and adiponectin levels in SGA born children with catch‐up growth (CUG) in the absence of obesity in prepubertal ages and relations with body composition and insulin‐like growth factor binding protein (IGFBP)‐1. Methods Twenty‐four (15F, 9M) SGA born children with CUG but without obesity were evaluated at age 6·3 ± 0·5 years with respect to glucose, insulin, IGFBP‐1, leptin and adiponectin levels, and body composition by dual‐energy X‐ray absorptiometry (DEXA). Their data were compared to that of 62 (27F, 35M) appropriate for gestational age (AGA) children. Results SGA and AGA children had similar height standard deviation score (SDS) corrected for parental height and body mass index (BMI) SDS. Homeostasis model for insulin resistance (HOMA‐IR) was significantly high in SGA (0·7 ± 0·6) than in AGA children (0·4 ± 0·2) (P = 0·029). There were no significant differences in leptin, IGFBP‐1, adiponectin, and total and truncal fat between SGA and AGA children. However, being born SGA and having higher BMI in the upper half for the distribution in the sample, although within normal ranges, was associated with lower adiponectin levels (estimated means of log adiponectin levels 3·8 ± 0·3 vs. 4·4 ± 0·1 µg/ml, P = 0·040). Conclusions SGA children with CUG and with no obesity have higher insulin levels compared to AGA children. Both SGA birth and recent size seem to have an effect on serum adiponectin levels in childhood.     

High molecular weight adiponectin dominates in cord blood of newborns but is unaffected by pre-eclamptic pregnancies

Objective This study is the first to report high molecular weight (HMW) adiponectin in newborns from normal and pre‐eclamptic pregnancies (PE). Adiponectin is adversely related to Metabolic Syndrome‐linked diseases such as obesity, dyslipidaemia, insulin resistance and hypertension. It is abundant in human plasma where it circulates as several characteristic multimeric forms of which the HMW form is the most active. As children from PE‐pregnancies have a greater susceptibility to hypertensive disorders later in life, we hypothesized that adiponectin measured in cord blood could be a putative risk marker. Design and patients Cross‐sectional, hospital‐based study of newborns from mothers with pre‐eclampsia (30 cases and 62 controls). Venous cord blood samples were collected immediately after birth and were analysed for total adiponectin and HMW adiponectin. Measurements Total adiponectin and HMW adiponectin were measured by commercially available enzyme‐linked immunosorbent assay (ELISA) kits. Results The PE newborns showed a significantly lower gestational age (GA), total adiponectin and HMW adiponectin levels than the controls. No differences in adiponectin levels were found between case and control groups when correcting for GA. In combined groups, log (total adipo) = 0·40 + 0·027*GA; r = 0·43, P < 0·001. Furthermore, the HMW form is the dominant form of adiponectin: HMW adipo = –5·06 + 0·81*total adipo; r = 0·90, P < 0·001. Conclusions Adiponectin in cord blood from PE pregnancies may not be a tentative risk marker for Metabolic Syndrome‐linked diseases. HMW adiponectin is the dominant form of adiponectin in cord blood. Its role during pregnancy and postnatal life should be further explored.     

Adiponectin, skeletal muscle adiponectin receptor expression and insulin resistance following dexamethasone

Objective Skeletal muscle is a major site of adiponectin action and of glucocorticoid‐induced insulin resistance. Little human data exist however, regarding the impact of exogenous glucocorticoids on adiponectin receptors in skeletal muscle. Design and patients Twelve subjects with type 2 diabetes and 12 controls underwent blood sampling and muscle biopsy of vastus lateralis before and after 4 days of 4 mg dexamethasone. Measurements (i) Total and high molecular weight (HMW) plasma adiponectin, glucose and insulin; (ii) Skeletal muscle adiponectin receptor AdipoR1 and AdipoR2 mRNA levels by quantitative real time RT‐PCR. Results Baseline total adiponectin (8·0 ± 0·89 vs. 12·5 ± 1·46 µg/ml, P = 0·013), HMW adiponectin (2·8 ± 0·44 vs. 5·9 ± 1·04 µg/ml, P = 0·014) and AdipoR2 mRNA levels (mean ΔC_T 14·71 ± 0·35 vs. 13·37 ± 0·28, P = 0·017) were significantly lower in diabetic subjects. After dexamethasone, AdipoR2 mRNA fell in the controls but there was no change in the diabetic group, while there was a significant increase in total (P = 0·002) and HMW adiponectin (P < 0·001) across both groups. Total and HMW plasma adiponectin correlated with clinical and biochemical measures of insulin sensitivity. However following dexamethasone which increased insulin resistance, the relationship between adiponectin and the biochemical measures was lost. Conclusions Plasma adiponectin and skeletal muscle AdipoR2 mRNA expression are reduced in subjects with diabetes; both are likely to contribute to the observed insulin resistance. Dexamethasone inhibits AdipoR2 mRNA expression in nondiabetic subjects, while there is a small rise in plasma adiponectin levels. The close relationship between plasma adiponectin and biochemical measures of insulin sensitivity is lost in the setting of glucocorticoid‐induced insulin resistance.     

Inflammatory markers and visceral fat are inversely associated with maximal oxygen consumption in women with polycystic ovary syndrome (PCOS)

Background We investigated whether several different inflammatory markers including C‐reactive protein (CRP) and fibrinogen and white blood cells (WBCs) count, are associated with maximal oxygen consumption (VO_2max) in women with polycystic ovary syndrome (PCOS). Methods In PCOS women (n = 124, 24·1 ± 4·5 year‐old) VO_2max was measured during symptom‐limited cardiopulmonary exercise test. Abdominal fat distribution was determined by ultrasound. Physical activity level was assessed by a standardized questionnaire. CRP was measured by immunoassays, fibrinogen by the Clauss method, and WBCs count with a Coulter counter. Results Pearson's analysis showed a significant correlation between VO_2max and logCRP (r = –0·437, P < 0·001), fibrinogen (r = –0·479, P < 0·001), and WBCs count (r = –0·438, P < 0·001). Multivariable logistic regression model showed that age (β = –0·127, P = 0·005), AUC_INS (β = –0·335, P < 0·001), HDL‐C (β = 0·390, P < 0·001), physical activity score (β = 0·238, P = 0·002), visceral fat (β =–0·184), P = 0·023), FAI (β = –0·291, P = 0·028); CRP (β = –0·216, P = 0·011), fibrinogen (β = –0·113, P = 0·008) and WBCs count (β = –0·177, P < 0·001) were significantly associated with VO_2max. Conclusions Acute‐phase reactants, such as CRP and fibrinogen, and WBCs count were independently and inversely associated with a direct measure of cardiorespiratory fitness (VO_2max) in women with PCOS, even after adjustment for physical activity level and other potential confounding factors. These findings add to the growing body of evidence linking inflammation to cardiorespiratory fitness in PCOS women.     

Adiponectin is an indicator of insulin resistance in non-obese prepubertal children born large for gestational age (LGA) and is affected by birth weight

Background and objective Being born as large for gestational age (LGA) has an increased risk of developing insulin resistance. Hypoadiponectinaemia is associated with insulin resistance. The aim of this study was to evaluate adiponectin levels and insulin resistance in association with body composition in LGA born non‐obese children at prepubertal ages. Patients and methods Thirty‐five (17 female and 18 male) LGA born non‐obese children (mean age 4·8 ± 0·3 years) were evaluated with respect to glucose, insulin, IGFBP‐1, leptin, adiponectin levels and body composition by DEXA. Their data were compared to that of non‐obese 49 (20 female, 29 male) appropriate for gestational age (AGA) children (mean age 3·8 ± 0·1 year). Results LGA children, who had similar body mass index standard deviation scores (BMI SDS) as AGA children, had significantly higher insulin (P = 0·043) and statistically borderline significant homeostasis model assessment‐insulin resistance (HOMA‐IR) levels (P = 0·054) than those of AGA children. Adiponectin levels were significantly lower in LGA than AGA children (P = 0·004) even after controlling for age, sex and BMI (P = 0·016). IGFBP‐1, leptin levels and body composition did not show a difference. When the LGA group was divided into subgroups according to birth weight, the analysis revealed that after controlling for BMI, being an LGA and having a higher birth weight in the upper half were associated with lower adiponectin levels (estimated marginal means of logarithmic adiponectin levels 2·6 ± 0·2 vs. 2·1 ± 0·2 µg/ml, P = 0·042). Conclusion LGA children have higher insulin and lower adiponectin levels than AGA children in spite of similar BMI. Adiponectin is a better indicator of insulin resistance in LGA children at prepubertal ages and is affected by birth weight.     

Visfatin, low-grade inflammation and body mass index (BMI)

Objective Visfatin is an adipokine with revealing roles in inflammatory mechanisms but its implication in inflammation related to excessive adiposity/obesity is not studied yet. Our aim was to investigate the relations of visfatin with inflammation markers and body mass index (BMI) in the peripheral blood mononuclear cells (PBMCs), a type of cells closely related to inflammatory mechanisms. Design Cross‐sectional study, quantification of visfatin, TNF‐α, IL‐6 mRNA in PBMCs. Patients Eighty‐three supposed healthy individuals from the STANISLAS cohort, belonging in three BMI categories: BMI < 25 kg/m² (lean), 25 kg/m² ≤ BMI < 30 kg/m² (overweight) or BMI ≥ 30 kg/m² (obese). Measurements We measured visfatin gene expression (by real‐time quantitative PCR), in relation to gene expression of the pro‐inflammatory cytokines TNF‐α, IL‐6 in PBMCs and to anthropometric parameters (weight, BMI, waist : hip ratio), blood pressure, lipid profile, glucose and inflammatory markers (C‐reactive protein, lymphocyte count). Results Visfatin expression in PBMCs was significantly associated with BMI in a negative way (r = –0·21, P = 0·05). Global anova analysis test for lean and over‐weight/obese individuals showed a negative significant association between visfatin expression in PBMCs and BMI both for men and women (P = 0·05 and P = 0·01, respectively) and these associations remained significant after separating subjects in three groups (lean, overweight, obese) for men and women (P = 0·02 and P = 0·05, respectively). Correlation analysis between levels of expression of visfatin and TNF‐α showed a significant positive linear association (r² = 0·27, P < 0·0001). Conclusion These findings reveal a probable new role of visfatin in inflammation reflected in PBMCs, in the context of obesity.     

Relationship between ghrelin and the metabolic syndrome in the elderly: a longitudinal population-based study

Context Ghrelin regulates energy homeostasis and may contribute to the development of the metabolic syndrome (MS) in the elderly. Objective To study the relationship between ghrelin and the MS, IGF‐I and life style factors over a 2‐year follow‐up. Design Longitudinal population‐based study, starting from 2002; 2 years follow‐up. Participants Three hundred and thirteen (153 men/160 women) individuals living independently older than 70 years. Results MS was found in 54·9% of men and 61% of women. In the 229 subjects available at follow‐up, ghrelin was higher in men than in women at basal (P = 0·002) and 2‐year follow‐up (P = 0·004). Ghrelin decreased over time in both genders (P < 0·01). Ghrelin was lower in individuals showing MS compared to non‐MS (P = 0·08), but this difference was more evident at 2‐year follow‐up (P = 0·016), mostly due to men with MS (P = 0·002) and even after adjustment for BMI, gender and age. Individuals with MS had an OR of 1·67 (95% CI: 1·0–2·78) for low ghrelin (< first tertile); when adjusting by BMI, gender and age, only high triglycerides with OR 1·8 (1·0–3·3), remained statistically significant among the MS components. IGF‐I showed a positive correlation with ghrelin only in individuals without MS (r_s 0·403, P < 0·001) with no gender differences; this relationship was not found in MS (r_s 0·120, P = 0·129). A positive association of ghrelin was found with academic level, alcohol consumption and smoking. Conclusions Ghrelin is higher in old men in comparison to women and decreases over time with a steeper decline in subjects with MS; moreover, in these subjects ghrelin/IGF‐I correlation is lost.     

Concentrations of the acute phase reactants high-sensitive C-reactive protein and YKL-40 and of interleukin-6 before and after treatment in patients with acromegaly and growth hormone deficiency

Background Acromegaly is accompanied by increased cardiovascular mortality and a cluster of proatherogenic risk factors. In the general population, ischaemic heart disease (IHD) is associated with elevated levels of inflammatory markers. The acute phase reactant (APR) C‐reactive protein (CRP) has been reported to be reduced in acromegaly and increase after treatment, suggesting that excess of GH/IGF‐I could have anti‐inflammatory effects. This is in accordance with results obtained in patients with growth hormone deficiency (GHD), where increased levels of CRP have been reported. Objective To investigate the hypothesis that the GH/IGF‐I system is a suppressive regulator of inflammatory processes. Subjects and methods Twenty‐one acromegalic patients and 19 GH‐deficient patients were studied. The two APRs CRP and YKL‐40 and the proinflammatory cytokine interleukin‐6 (IL‐6) were measured before and after treatment and in healthy matched controls. Results In acromegalic patients, serum concentrations of high‐sensitive CRP (hsCRP) and YKL‐40 were reduced compared to controls (P < 0·001) and increased (P < 0·001) after treatment, together with IL‐6 (P = 0·021), to levels comparable with controls. Pretreatment serum YKL‐40 and IL‐6 showed a significant inverse correlation with IGF‐I and GH. In GH‐deficient patients, hsCRP and YKL‐40 were elevated compared to controls (P = 0·001 and P = 0·048). During treatment, levels of both APRs showed a trend towards a decrease (P = 0·087 and P = 0·060), and after treatment, levels of YKL‐40 no longer differed from that of controls. Serum IL‐6 was not different from controls and did not change during GH treatment. Conclusion The results point to the possibility of a relationship between GH disturbances and inflammatory processes.     

High plasma C-reactive protein (CRP) is related to low paraoxonase-I (PON-I) activity independently of high leptin and low adiponectin in type 2 diabetes mellitus

Objectives In type 2 diabetes mellitus, circulating C‐reactive protein (CRP) is increased, whereas the high density lipoprotein (HDL)‐associated, anti‐oxidative and anti‐inflammatory enzyme, paraoxonase‐I, is decreased. Both high CRP and low paraoxonase‐I activity may predict cardiovascular disease. It is unknown whether lower paraoxonase‐I activity contributes to higher CRP levels in diabetes. In type 2 diabetic and control subjects, we determined the relationship of CRP with paraoxonase‐I when taking account of plasma levels of pro‐ and anti‐inflammatory adipokines. Design and patients In 81 type 2 diabetic patients and 89 control subjects, plasma high‐sensitive CRP, serum paraoxonase‐I activity (arylesterase activity, assayed as the rate of hydrolysis of phenyl acetate into phenol), plasma leptin, adiponectin, resistin and lipids were determined. Results Body mass index (BMI), waist, insulin resistance, triglycerides, CRP, leptin and resistin levels were higher (P < 0·05 to P < 0·001), whereas HDL cholesterol, paraoxonase‐I activity and adiponectin levels were lower (P = 0·02 to P < 0·001) in diabetic compared to control subjects. Multiple linear regression analysis demonstrated that, after controlling for age and gender, CRP was inversely related to paraoxonase‐I activity (β = –0·15, P = 0·028) and adiponectin (β = –0·18, P = 0·009), and positively to leptin (β = 0·33, P < 0·001) and BMI (β = 0·22, P = 0·007), independently of the diabetic state (or of fasting glucose or HbA1c), insulin resistance and lipids (P > 0·20 for all). Conclusions low paraoxonase‐I activity is related to higher CRP, independently of adipokines, as well as of obesity and lipids. Low paraoxonase‐I activity in type 2 diabetes mellitus may contribute to increased cardiovascular risk via an effect on enhanced systemic low‐grade inflammation.     

Substance P is increased in patients with sickle cell disease and associated with haemolysis and hydroxycarbamide use

Sickle cell disease (SCD) pain transitions from acute to chronic for unknown reasons. Chronic elevation of the pain neurotransmitter substance P (SP) sensitizes pain nociceptors. We evaluated SP levels in controls and SCD patients during baseline and acute pain and investigated associations between SP and age, gender, pain history, haemolysis and hydroxycarbamide (also termed hydroxyurea) use. Plasma SP levels were measured using enzyme‐linked immunosorbent assay. Independent samples t‐test compared SP levels between: (i) SCD baseline and controls, and (ii) SCD baseline and acute pain. Multivariate linear regression determined associations between SP and age, gender, pain history and hydroxycarbamide use. Spearman correlation determined an association between SP and haemolysis. We enrolled 35 African American controls, 25 SCD baseline and 12 SCD pain patients. SCD patients were 7‐19 years old. Mean ± standard deviation SP level (pg/ml) in SCD baseline was higher than controls (32·4 ± 11·6 vs. 22·9 ± 7·6, P = 0·0009). SP in SCD pain was higher than baseline (78·1 ± 43·4 vs. 32·4 ± 11·6, P = 0·004). Haemolysis correlated with increased SP: Hb (r = ?0·7, P = 0·0002), reticulocyte count (r = 0·61, P = 0·0016), bilirubin (r = 0·68, P = 0·0216), lactate dehydrogenase (r = 0·62, P = 0·0332), aspartate aminotransferase (r = 0·68, P = 0·003). Patients taking hydroxycarbamide had increased SP (β = 29·2, P = 0·007). SP could be a mediator of or marker for pain sensitization in SCD and a biomarker and/or target for novel pain treatment.     

Associations of inflammatory factors with glycaemic status among middle-aged and older Chinese people

Objective Low‐grade chronic inflammation is associated with risk for type 2 diabetes. We investigated the associations between inflammatory factors and glycaemic status in a middle‐aged and older Chinese population. Design A population‐based cross‐sectional study of 3289 residents aged 50–70 years from Beijing and Shanghai. Measurements C‐reactive protein (CRP), interleukin‐6 (IL‐6) and soluble tumour necrosis factor α‐receptor two (sTNFR2) were assayed. Results Comparing the highest with the lowest quartile of CRP, the odds ratio (OR) of diabetes was significantly higher in women [3·66 (95% CI 2·23–6·03)] than in men [1·51 (0·95–2·41)] (P for interaction = 0·004), while the increased OR for impaired fasting glucose (IFG) was only observed in women [OR 2·03 (1·44–2·84)] (P for interaction = 0·022), after adjustment for age, geographic location, education, lifestyle factors, family history of diabetes, and use of antibiotics, aspirin and lipid‐lowering drugs. The multiple‐adjusted OR of IL‐6 for diabetes was also higher in women [2·95 (1·78–4·90)] than in men [2·23 (1·39–3·59)] (P for interaction = 0·045). sTNFR2 was not associated with diabetes but inversely associated with IFG in men [OR 0·59 (0·41–0·85)] and women [OR 0·78 (0·56–1·09)] (P for interaction = 0·13). In addition, CRP was significantly associated with increased HbA_1c in both genders within euglycaemia after multiple adjustments. Conclusions Inflammatory markers are closely associated with diabetes and IFG in Chinese people. These associations appear to be stronger in women than in men. Furthermore, plasma CRP is positively associated with HbA_1c even in euglycaemic individuals.