Association between Serum Leptin Concentrations and Insulin Resistance: A Population-Based Study from China

Background

Insulin resistance contributes to the cardio-metabolic risk. The effect of leptin in obese and overweight population on insulin resistance was seldom reported.

Methods

A total of 1234 subjects (572 men and 662 women) aged ≥18 y was sampled by the procedure. Adiposity measures included BMI, waist circumference, hip circumference, WHR, upper arm circumference, triceps skinfold and body fat percentage. Serum leptin concentrations were measured by an ELISA method. The homeostasis model (HOMA-IR) was applied to estimate insulin resistance.

Results

In men, BMI was the variable which was most strongly correlated with leptin, whereas triceps skinfold was most sensitive for women. More importantly, serum leptin levels among insulin resistant subjects were almost double compared to the subjects who had normal insulin sensitivity at the same level of adiposity in both men and women, after controlling for potential confounders. In addition, HOMA-IR increased significantly across leptin quintiles after adjustment for age, BMI, total energy intake, physical activity and smoking status in both men and women (p for trend <0.0001).

Conclusions

There was a significant association between HOMA-IR and serum leptin concentrations in Chinese men and women, independently of adiposity levels. This may suggest that serum leptin concentration is an important predictor of insulin resistance and other metabolic risks irrespective of obesity levels. Furthermore, leptin levels may be used to identify the cardio-metabolic risk in obese and overweight population.     

Insulin Dynamics in Young Women with Polycystic Ovary Syndrome and Normal Glucose Tolerance across Categories of Body Mass Index

Background

Evidence favours insulin resistance and compensatory hyperinsulinemia as the predominant, perhaps primary, defects in polycystic ovary syndrome (PCOS). The aim of the present study was to evaluate insulin metabolism in young women with PCOS but normal glucose tolerance as compared with age, body mass index and insulin resistance-matched controls to answer the question whether women with PCOS hypersecrete insulin in comparison to appropriately insulin resistance-matched controls.

Research Design and Methods

Sixty-nine cases were divided according to their body mass index (BMI) in normal-weight (N = 29), overweight (N = 24) and obese patients (N = 16). Controls were 479 healthy women (age 16–49 y). Whole body Insulin Sensitivity (WBISI), fasting, and total insulin secretion were estimated following an oral glucose tolerance test (C-peptide deconvolution method).

Results

Across classes of BMI, PCOS patients had greater insulin resistance than matched controls (p<0.0001 for all the comparisons), but they showed higher fasting and total insulin secretion than their age, BMI and insulin resistance-matched peers (p<0.0001 for all the comparisons).

Conclusion

Women with PCOS show higher insulin resistance but also larger insulin secretion to maintain normal glucose homeostasis than age-, BMI- and insulin resistance-matched controls.     

Role of Muscle c-Jun NH2-Terminal Kinase 1 in Obesity-Induced Insulin Resistance

Obesity caused by feeding of a high-fat diet (HFD) is associated with an increased activation of c-Jun NH₂-terminal kinase 1 (JNK1). Activated JNK1 is implicated in the mechanism of obesity-induced insulin resistance and the development of metabolic syndrome and type 2 diabetes. Significantly, Jnk1^−/− mice are protected against HFD-induced obesity and insulin resistance. Here we show that an ablation of the Jnk1 gene in skeletal muscle does not influence HFD-induced obesity. However, muscle-specific JNK1-deficient (M^KO) mice exhibit improved insulin sensitivity compared with control wild-type (M^WT) mice. Thus, insulin-stimulated AKT activation is suppressed in muscle, liver, and adipose tissue of HFD-fed M^WT mice but is suppressed only in the liver and adipose tissue of M^KO mice. These data demonstrate that JNK1 in muscle contributes to peripheral insulin resistance in response to diet-induced obesity.Obesity is a major risk factor for the development of insulin resistance, hyperglycemia, and metabolic syndrome that can lead to β-cell dysfunction and type 2 diabetes (8). The prevalence of human obesity represents a serious health problem in the United States. It is therefore important that we obtain a detailed understanding of the molecular mechanism that accounts for obesity-induced insulin resistance. Recent progress has led to the identification of signal transduction pathways that may mediate the effects of obesity on insulin resistance (14, 23).c-Jun NH₂-terminal kinase 1 (JNK1) represents one signaling pathway that has been implicated in the pathogenesis of metabolic syndrome and type 2 diabetes (21). JNK1 is activated when mice are fed a high-fat diet (HFD) (7). Moreover, Jnk1^−/− mice are protected against HFD-induced insulin resistance (7). The mechanism of protection is mediated, in part, by the failure of Jnk1^−/− mice to develop HFD-induced obesity (7). However, JNK1 can regulate insulin resistance independently of obesity. Thus, mice with an adipose tissue-specific JNK1 deficiency develop normal diet-induced obesity but exhibit selective protection against HFD-induced insulin resistance in both the liver and adipose tissue (16). These data indicate that adipose tissue JNK1 plays a critical role during the development of HFD-induced insulin resistance.The liver plays a key role in the insulin-stimulated disposal of blood glucose during the postprandial state because of reduced gluconeogenesis and increased glycogen synthesis (17). However, glucose uptake by skeletal muscle also makes a major contribution to insulin-stimulated glucose disposal (17). Muscle may therefore be an important target of obesity-induced JNK1 signaling and the regulation of glucose homeostasis.The purpose of this study was to test the role of JNK1 in muscle. Our approach was to examine the effect of a muscle-specific ablation of the Jnk1 gene in mice. We found that HFD-fed control wild-type (M^WT) mice and muscle-specific JNK1-deficient (M^KO) mice became similarly obese. However, M^KO mice were selectively protected against HFD-induced insulin resistance. This analysis demonstrates that muscle JNK1 contributes to the effects of obesity on insulin resistance.     

Breast size and risk of type 2 diabetes mellitus

Background

Elevated waist circumference and body mass index (BMI), both traditional measures of obesity, are accepted risk factors for type 2 diabetes mellitus. Girls who are obese experience earlier onset of puberty and possibly greater breast development. We sought to evaluate whether a woman''s breast size in late adolescence is associated with an increased risk of type 2 diabetes mellitus in adulthood.

Methods

In conjunction with the ongoing Nurses'' Health Study II, which began to study risk factors for breast cancer among women in 1989, we conducted a prospective cohort study involving 92 106 of the participants. We assessed the risk of type 2 diabetes mellitus in relation to self-reported bra cup sizes, categorized as ≤ A, B, C and ≥ D cups, among participants at age 20.

Results

The mean age of participants at baseline was 38.1 years. A total of 1844 new cases of type 2 diabetes mellitus arose at a mean age of 44.9 years during 886 443 person-years of follow-up. Relative to bra cup size ≤ A, the respective age-adjusted hazard ratios (and 95% confidence intervals [CIs]) were 2.30 (1.99–2.66) for B cup, 4.32 (3.71–5.04) for C cup and 4.99 (4.12–6.05) for ≥ D cup. Upon further adjustments for age at menarche, parity, physical activity, smoking status, diet, multivitamin use, family history of diabetes mellitus, BMI at age 18 and current BMI, the corresponding hazard ratios (and 95% CIs) were 1.37 (1.18–1.59) for B cup, 1.80 (1.53- 2.11) for C cup and 1.64 (1.34–2.01) for ≥ D cup. The addition of waist circumference to this model minimally changed the hazard ratios (and 95% CIs): 1.32 (1.14–1.53) for B cup, 1.71 (1.46–2.01) for C cup and 1.58 (1.29–1.94) for ≥ D cup.

Interpretation

A large bra cup size at age 20 may be a predictor of type 2 diabetes mellitus in middle-aged women. Whether this relation is independent of traditional indicators of obesity remains to be determined.Obesity is an established risk factor for type 2 diabetes mellitus.^1,2 Affected individuals show signs of insulin resistance and hyperinsulinemia, a process that may begin in childhood.^3,4 Pre-adolescent obesity is also an important predictor of age of onset of breast development in young women, and of breast size after puberty.^5,6 Premature onset of puberty is preceded by childhood insulin resistance, hyperinsulinemia and hyperandrogenemia,⁷ which may persist after puberty⁸ and continue into early adulthood.⁹Although an elevated body mass index (BMI)^10,11 and central adiposity¹² are established risk factors for insulin resistance and the onset of type 2 diabetes mellitus, little is known about the contribution of extra-abdominal adipose tissue, including breast tissue, about 60% of which is fatty tissue, to this process.^13,14 We hypothesized that a woman''s breast size in late adolescence reflects her predisposition to insulin resistance and type 2 diabetes mellitus that is both additive to, and independent of, BMI. We explored this hypothesis in conjunction with the Nurses'' Health Study II by relating bra cup size, a proxy for breast size, to the onset of type 2 diabetes mellitus.     

Serum Liver Fatty Acid Binding Protein Levels Correlate Positively with Obesity and Insulin Resistance in Chinese Young Adults

Background

Liver fatty acid–binding protein (FABP1) plays an inconclusive role in adiposity. We investigated the association of serum FABP1 levels with obesity and insulin resistance in Chinese young people under 30 years old.

Methodology and Principal Findings

Cross-sectional analysis including 200 obese and 172 normal-weight subjects matched for age and sex, anthropometric measurements were performed and serum FABP1 and biochemical characteristics were measured. Insulin resistance was determined by homeostasis model assessment of insulin resistance (HOMA-IR) and by the insulin sensitivity index (S_i) derived from Bergman’s minimal model. FABP1 levels in obese subjects were significantly higher than those in normal-weight subjects (p<0.001) and the significance remained after adjustment for age, gender, alanine and aspartate aminotransferases (p<0.001). Serum FABP1 levels were significantly correlated with many metabolic-related parameters, with BMI and triglycerides as the independent determinants. FABP1 levels remained an independent risk factor of insulin resistance assessed by binary S_i (OR = 1.868 per SD unit, 95% CI [1.035–3.373], p = 0.038) after adjustment for age, sex, BMI, waist circumference, systolic blood pressure, serum triacylglycerol, total cholesterol, HDL- and LDL-cholesterol,. FABP1 levels were also elevated with an increasing number of components of the metabolic syndrome (p for trend <0.001). Multiple regression modeling for the MetS and its components demonstrated that hypertriglyceridemia and low HDL-cholesterol were significantly correlated to serum FABP1 levels.

Conclusions and Significance

Serum FABP1 correlates positively with obesity and insulin resistance in Chinese young adults. Our data supports the fact that FABP1 might be an important mediator participating in fatty acid metabolism and energy balance.     

Associations of amylin with inflammatory markers and metabolic syndrome in apparently healthy Chinese

Background

Cellular and animal studies implicate multiple roles of amylin in regulating insulin action, glucose and lipid metabolisms. However, the role of amylin in obesity related metabolic disorders has not been thoroughly investigated in humans. Therefore, we aimed to evaluate the distribution of circulating amylin and its association with metabolic syndrome (MetS) and explore if this association is influenced by obesity, inflammatory markers or insulin resistance in apparently healthy Chinese.

Methods

A population-based sample of 1,011 Chinese men and women aged 35–54 years was employed to measure plasma amylin, inflammatory markers (C-reactive protein [CRP] and interleukin-6 [IL-6]), insulin, glucose and lipid profiles. MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian-Americans.

Results

Plasma amylin concentrations were higher in overweight/obese participants than normal-weight counterparts (P<0.001) without sex difference. Circulating amylin was positively associated with CRP, IL-6, BMI, waist circumference, blood pressure, fasting glucose, insulin, amylin/insulin ratio, HOMA-IR, LDL cholesterol and triglycerides, while negatively associated with HDL cholesterol (all P<0.001). After multiple adjustments, the risk of MetS was significantly higher (odds ratio 3.71; 95% confidence interval: 2.53 to 5.46) comparing the highest with the lowest amylin quartile. The association remained significant even further controlling for BMI, inflammatory markers, insulin or HOMA-IR.

Conclusions

Our study suggests that amylin is strongly associated with inflammatory markers and MetS. The amylin-MetS association is independent of established risk factors of MetS, including obesity, inflammatory markers and insulin resistance. The causal role of hyperamylinemia in the development of MetS needs to be confirmed prospectively.     

Association between Class III Obesity (BMI of 40–59 kg/m2) and Mortality: A Pooled Analysis of 20 Prospective Studies

Background

The prevalence of class III obesity (body mass index [BMI]≥40 kg/m²) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity.

Methods and Findings

In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19–83 y at baseline, classified as obese class III (BMI 40.0–59.9 kg/m²) compared with those classified as normal weight (BMI 18.5–24.9 kg/m²). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976–2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40–44.9, 45–49.9, 50–54.9, and 55–59.9 kg/m² was associated with an estimated 6.5 (95% CI: 5.7–7.3), 8.9 (95% CI: 7.4–10.4), 9.8 (95% CI: 7.4–12.2), and 13.7 (95% CI: 10.5–16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report.

Conclusions

Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight. Please see later in the article for the Editors'' Summary     

Deletion of Shp2 Tyrosine Phosphatase in Muscle Leads to Dilated Cardiomyopathy,Insulin Resistance,and Premature Death

The intracellular signaling mechanisms underlying the pathogenesis of cardiac diseases are not fully understood. We report here that selective deletion of Shp2, an SH2-containing cytoplasmic tyrosine phosphatase, in striated muscle results in severe dilated cardiomyopathy in mice, leading to heart failure and premature mortality. Development of cardiomyopathy in this mouse model is coupled with insulin resistance, glucose intolerance, and impaired glucose uptake in striated muscle cells. Shp2 deficiency leads to upregulation of leukemia inhibitory factor-stimulated phosphatidylinositol 3-kinase/Akt, Erk5, and Stat3 pathways in cardiomyocytes. Insulin resistance and impaired glucose uptake in Shp2-deficient mice are at least in part due to impaired protein kinase C-ζ/λ and AMP-kinase activities in striated muscle. Thus, we have generated a mouse line modeling human patients suffering from cardiomyopathy and insulin resistance. This study reinforces a concept that a compound disease with multiple cardiovascular and metabolic disturbances can be caused by a defect in a single molecule such as Shp2, which modulates multiple signaling pathways initiated by cytokines and hormones.Heart failure is a serious life-threatening health problem worldwide. Numerous studies have demonstrated a link between cardiac dysfunction and insulin resistance, as well as deficiency in glucose transport (9, 35, 48). In the absence of manifest diabetes, insulin resistance and minor degrees of glucose intolerance are thought to be associated with and contribute to the development of nonischemic cardiomyopathy or idiopathic dilated cardiomyopathy (35, 45). However, the molecular basis for this link is poorly understood.Muscle-specific gene knockout mice have presented unprecedented opportunities to decipher molecular signaling mechanisms underlying cardiomyopathic changes. Deletion of PTEN in cardiomyocytes mediated by Mck-Cre results in cardiac hypertrophy in mice (8). Dilated cardiomyopathy was also observed to various degrees in mice with conditional ablation of ErbB2 (HER2), β₁ integrin, and the gp130 cytokine receptor component in the heart or muscle (16, 34, 37). Interestingly, despite the development of cardiomyopathy, most of these mutant mice survive to adulthood with a normal life span, suggesting limitations in their modeling of human patients'' pathological processes. These mutant mouse models also show no correlation between cardiomyopathy and insulin resistance. In fact, although muscle-specific PTEN knockout mice develop cardiac hypertrophy (8), they are protected against insulin resistance and diabetes induced by high-fat diet due to enhanced insulin-stimulated glucose uptake in soleus muscle (43).Shp2 is a widely expressed cytoplasmic tyrosine phosphatase with two SH2 domains that has been implicated in signaling events downstream of receptors for growth factors, cytokines, and hormones (25, 32). In particular, Shp2 has been shown to participate in leptin and insulin signaling for the regulation of energy balance and metabolism (23, 28, 46). In recent experiments, several groups have identified germ line gain and loss-of-function mutations in the human gene PTPN11, encoding Shp2, in Noonan syndrome and LEOPARD (for lentigines, electrocardiogram abnormalities, ocular hypertelorism, pulmonic valvular stenosis, abnormalities of genitalia, retardation of growth, and deafness) syndrome patients, respectively (21, 42). Paradoxically, these mutations either constitutively activate or inactivate the phosphatase activity leading to heart diseases, among other disorders observed in Noonan or LEOPARD syndrome patients. Since the conventional Shp2 knockout mice are embryonic lethal (36), tissue-specific deletion of Shp2 will be required to determine a specific function for Shp2 in the cardiovascular system in vivo.We report here that striated muscle-specific Shp2 knockout (MSKO) mice develop a severe dilated cardiomyopathy, resulting in heart failure and premature death in mice. More importantly, development of cardiomyopathy is associated with insulin resistance, glucose intolerance, and impaired insulin-stimulated glucose uptake in striated muscle cells in this mouse model.     

Association between Lipid Ratios and Insulin Resistance in a Chinese Population

Aim

To explore the association of lipid ratios and triglyceride (TG) with insulin resistance (IR) in a Chinese population. We also provide the clinical utility of lipid ratios to identify men and women with IR.

Methods

This cross-sectional study included 614 men and 1055 women without diabetes. Insulin resistance was defined by homeostatic model assessment of IR > 2.69. Lipid ratios included the TG/ high density lipoprotein cholesterol (HDL-C), the total cholesterol (TC)/HDL-C and the low density lipoprotein cholesterol (LDL-C)/HDL –C. Logistic regression models and accurate estimates of the area under the receiver operating characteristic (AUROC) curves were obtained.

Results

In normal-weight men, none of lipid ratios nor TG was associated with IR. In overweight/obese men, normal-weight women and overweight/obese women, the TG/HDL-C, the TC/HDL-C and TG were significantly associated with IR, and the associations were independent of waist circumference. All of the AUROCs for the TG/HDL-C and TG were > 0.7. The AUROCs for TC/HDL-C ratio were 0.69–0.77. The optimal cut-offs for TG/HDL-C were 1.51 in men and 0.84 in women. The optimal cut-offs for TG were 1.78 mmol/L in men and 1.49 mmol/L in women, respectively. In men, the optimal cut-off for LDL-C/HDL-C is 3.80. In women, the optimal cut-off for LDL-C/HDL-C is 3.82.

Conclusion

The TG/HDL-C, the TC/HDL-C and TG are associated with IR in overweight/obese men, normal-weight and overweight/obese women. The LDL-C/HDL-C is only associated with IR in normal-weight women. The TG/HDL-C and TG might be used as surrogate markers for assessing IR.     

High Dietary Magnesium Intake Is Associated with Low Insulin Resistance in the Newfoundland Population

Background

Magnesium plays a role in glucose and insulin homeostasis and evidence suggests that magnesium intake is associated with insulin resistance (IR). However, data is inconsistent and most studies have not adequately controlled for critical confounding factors.

Objective

The study investigated the association between magnesium intake and IR in normal-weight (NW), overweight (OW) and obese (OB) along with pre- and post- menopausal women.

Design

A total of 2295 subjects (590 men and 1705 women) were recruited from the CODING study. Dietary magnesium intake was computed from the Willett Food Frequency Questionnaire (FFQ). Adiposity (NW, OW and OB) was classified by body fat percentage (%BF) measured by Dual-energy X-ray absorptiometry according to the Bray criteria. Multiple regression analyses were used to test adiposity-specific associations of dietary magnesium intake on insulin resistance adjusting for caloric intake, physical activity, medication use and menopausal status.

Results

Subjects with the highest intakes of dietary magnesium had the lowest levels of circulating insulin, HOMA-IR, and HOMA-ß and subjects with the lowest intake of dietary magnesium had the highest levels of these measures, suggesting a dose effect. Multiple regression analysis revealed a strong inverse association between dietary magnesium with IR. In addition, adiposity and menopausal status were found to be critical factors revealing that the association between dietary magnesium and IR was stronger in OW and OB along with Pre-menopausal women.

Conclusion

The results of this study indicate that higher dietary magnesium intake is strongly associated with the attenuation of insulin resistance and is more beneficial for overweight and obese individuals in the general population and pre-menopausal women. Moreover, the inverse correlation between insulin resistance and dietary magnesium intake is stronger when adjusting for %BF than BMI.     

Anti-tumour necrosis factor alpha therapy improves insulin sensitivity in normal-weight but not in obese patients with rheumatoid arthritis

Introduction

Insulin resistance (IR), a risk factor for the development of cardiovascular disease, is common among patients with rheumatoid arthritis (RA). Inflammation, and especially tumour necrosis factor alpha (TNFα), has been associated with IR, and the administration of anti-TNFα agents is suggested to improve insulin sensitivity. However obesity, a potent contributor to IR, may limit the beneficial effects of anti-TNFα medication on IR. The aim of this study is to compare the effects of anti-TNFα therapy on IR between normal-weight and obese patients with RA.

Methods

Patients who were normal-weight with IR (N+IR) or obese with IR (O+IR) and had embarked on anti-TNFα treatment, participated. Assessments included body mass index (BMI), insulin sensitivity (Homeostasis Model Assessment of insulin resistance, HOMA and the Quantitative Insulin sensitivity Check Index, QUICKI), and RA disease characteristics before and following six months of anti-TNFα treatment. Their results were compared to matched (for age, gender, BMI, disease duration and smoking status) normal-weight patients without IR (N-IR) and obese without IR (N-IR), respectively. In total, 32 patients were assessed for this study, with 8 in each group.

Results

Following six months of treatment, disease activity was significantly reduced in all groups (P < 0.05) to a similar extent (P for differences between groups > 0.05 in all cases). In the total population, changes in HOMA (mean reduction at 6 m = -0.2 ± 0.1; P = 0.088) and QUICKI (mean increase at 6 m = 0.03 ± 0.022; P = 0.092) after treatment were not statistically significant, though a trend towards improvement was observed. However, N+IR patients showed a significant decrease in HOMA (mean reduction at 6 m = -0.54 ± 0.2; P = 0.002) and increase in QUICKI (mean increase at 6 m = 0.046 ± 0.02; P = 0.011). These changes were significantly different compared to the other groups (P < 0.05 in all cases). Multivariable analyses showed that the change in Erythrocyte Sedimentation Rate (ESR), and the change in C-Reactive Protein (CRP) associated with the improvement in HOMA (ESR: F_1-7 = 5.143, P = 0.019; CRP: F_1-7 = 3.122, P = 0.022) and QUICKI (ESR: F_1-7 = 3.814, P = 0.021; CRP: F_1-7 = 2.67; P = 0.041) only in the N+IR group.

Conclusions

Anti-TNFα therapy, through controlling inflammation, seems to improve insulin sensitivity in normal-weight RA patients with insulin resistance, but is not sufficient to achieving the same beneficial effect in obese RA patients with insulin resistance.     

Short-Term Overfeeding Increases Circulating Adiponectin Independent of Obesity Status

Background

Adiponectin is an adipose tissue derived hormone which strengthens insulin sensitivity. However, there is little data available regarding the influence of a positive energy challenge (PEC) on circulating adiponectin and the role of obesity status on this response.

Objective

The purpose of this study was to investigate how circulating adiponectin will respond to a short-term PEC and whether or not this response will differ among normal-weight(NW), overweight(OW) and obese(OB).

Design

We examined adiponectin among 64 young men (19-29 yr) before and after a 7-day overfeeding (70% above normal energy requirements). The relationship between adiponectin and obesity related phenotypes including; weight, percent body fat (%BF), percent trunk fat (%TF), percent android fat (%AF), body mass index (BMI), total cholesterol, HDLc, LDLc, glucose, insulin, homeostatic model assessment insulin resistance (HOMA-IR) and β-cell function (HOMA-β) were analyzed before and after overfeeding.

Results

Analysis of variance (ANOVA) and partial correlations were used to compute the effect of overfeeding on adiponectin and its association with adiposity measurements, respectively. Circulating Adiponectin levels significantly increased after the 7-day overfeeding in all three adiposity groups. Moreover, adiponectin at baseline was not significantly different among NW, OW and OB subjects defined by either %BF or BMI. Baseline adiponectin was negatively correlated with weight and BMI for the entire cohort and %TF, glucose, insulin and HOMA-IR in OB. However, after controlling for insulin resistance the correlation of adiponectin with weight, BMI and %TF were nullified.

Conclusion

Our study provides evidence that the protective response of adiponectin is preserved during a PEC regardless of adiposity. Baseline adiponectin level is not directly associated with obesity status and weight gain in response to short-term overfeeding. However, the significant increase of adiponectin in response to overfeeding indicates the physiological potential for adiponectin to attenuate insulin resistance during the development of obesity.     

Impact of Baseline BMI on Glycemic Control and Weight Change with Metformin Monotherapy in Chinese Type 2 Diabetes Patients: Phase IV Open-Label Trial

Background

Differences exist between treatment recommendations regarding the choice of metformin as first-line therapy for type 2 diabetes patients according to body mass index (BMI). This study compared the efficacy of metformin monotherapy among normal-weight, overweight, and obese patients with newly diagnosed type 2 diabetes.

Methods

In this prospective, multicenter, open-label study in China, patients aged 23–77 years were enrolled 1∶1:1 according to baseline BMI: normal-weight (BMI 18.5−23.9 kg/m²; n = 125); overweight (BMI 24.0−27.9 kg/m²; n = 122) or obese (BMI ≥28 kg/m²; n = 124). Extended-release metformin was administered for 16 weeks (500 mg/day, up-titrated weekly to a maximum 2,000 mg/day). The primary efficacy endpoint was the effect of baseline BMI on glycemic control with metformin monotherapy, measured as the change from baseline in glycosylated hemoglobin (HbA_1c) at week 16 compared among BMI groups using ANCOVA. Other endpoints included comparisons of metformin’s effects on fasting plasma glucose (FPG), lipid levels and body weight.

Results

Mean HbA_1c decreases at week 16, adjusted for baseline values, were –1.84%, –1.78% and –1.78% in normal-weight, overweight and obese patients, (P = 0.664); body weight decreased by 2.4%, 3.9% and 3.5%, respectively. FPG levels decreased similarly over time in all BMI groups (P = 0.461) and changes from baseline in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) did not differ significantly among BMI groups at week 16 (P = 0.143 and 0.451, respectively).

Conclusions

Baseline BMI had no impact on glycemic control, weight change or other efficacy measures with metformin monotherapy. These data suggest that normal-weight type 2 diabetes patients would derive the same benefits from first-line treatment with metformin as overweight and obese patients, and are not at increased risk of excess weight loss.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00778622","term_id":"NCT00778622"}}NCT00778622     

Whole-Body and Hepatic Insulin Resistance in Obese Children

Background

Insulin resistance may be assessed as whole body or hepatic.

Objective

To study factors associated with both types of insulin resistance.

Methods

Cross-sectional study of 182 obese children. Somatometric measurements were registered, and the following three adiposity indexes were compared: BMI, waist-to-height ratio and visceral adiposity. Whole-body insulin resistance was evaluated using HOMA-IR, with 2.5 as the cut-off point. Hepatic insulin resistance was considered for IGFBP-1 level quartiles 1 to 3 (<6.67 ng/ml). We determined metabolite and hormone levels and performed a liver ultrasound.

Results

The majority, 73.1%, of obese children had whole-body insulin resistance and hepatic insulin resistance, while 7% did not have either type. HOMA-IR was negatively associated with IGFBP-1 and positively associated with BMI, triglycerides, leptin and mother''s BMI. Girls had increased HOMA-IR. IGFBP-1 was negatively associated with waist-to-height ratio, age, leptin, HOMA-IR and IGF-I. We did not find HOMA-IR or IGFBP-1 associated with fatty liver.

Conclusion

In school-aged children, BMI is the best metric to predict whole-body insulin resistance, and waist-to-height ratio is the best predictor of hepatic insulin resistance, indicating that central obesity is important for hepatic insulin resistance. The reciprocal negative association of IGFBP-1 and HOMA-IR may represent a strong interaction of the physiological processes of both whole-body and hepatic insulin resistance.     

BMI and Risk of Serious Upper Body Injury Following Motor Vehicle Crashes: Concordance of Real-World and Computer-Simulated Observations

Background

Men tend to have more upper body mass and fat than women, a physical characteristic that may predispose them to severe motor vehicle crash (MVC) injuries, particularly in certain body regions. This study examined MVC-related regional body injury and its association with the presence of driver obesity using both real-world data and computer crash simulation.

Methods and Findings

Real-world data were from the 2001 to 2005 National Automotive Sampling System Crashworthiness Data System. A total of 10,941 drivers who were aged 18 years or older involved in frontal collision crashes were eligible for the study. Sex-specific logistic regression models were developed to analyze the associations between MVC injury and the presence of driver obesity. In order to confirm the findings from real-world data, computer models of obese subjects were constructed and crash simulations were performed. According to real-world data, obese men had a substantially higher risk of injury, especially serious injury, to the upper body regions including head, face, thorax, and spine than normal weight men (all p<0.05). A U-shaped relation was found between body mass index (BMI) and serious injury in the abdominal region for both men and women (p<0.05 for both BMI and BMI²). In the high-BMI range, men were more likely to be seriously injured than were women for all body regions except the extremities and abdominal region (all p<0.05 for interaction between BMI and sex). The findings from the computer simulation were generally consistent with the real-world results in the present study.

Conclusions

Obese men endured a much higher risk of injury to upper body regions during MVCs. This higher risk may be attributed to differences in body shape, fat distribution, and center of gravity between obese and normal-weight subjects, and between men and women. Please see later in the article for the Editors'' Summary     

Serum Acylated Ghrelin Concentrations in Response to Short-Term Overfeeding in Normal Weight,Overweight, and Obese Men

Background

Ghrelin, an orexigenic gut hormone secreted primarily from the stomach, is involved in energy homeostasis. However, little data is available regarding its response to energy surplus and the development of human obesity.

Objective

The present study investigated the response of circulating acylated ghrelin to a 7-day positive energy challenge.

Design

A total of 68 healthy young men were overfed 70% more calories than required, for 1-week. Subjects were classified based on percent body fat (measured by dual-energy X-ray absorptiometry) as normal weight, overweight, and obese. Serum acylated ghrelin concentration was measured before and after the positive energy challenge. Additionally, the relationship between acylated ghrelin and obesity-related phenotypes including weight, body mass index, percent body fat, cholesterol, HDL-c, LDL-c, glucose, insulin and homeostasis model assessment of insulin resistance and β-cell function at baseline and change due to overfeeding, were assessed.

Results

Contrary to our expectations, serum acylated ghrelin was significantly increased in response to overfeeding and the increase was independent of obesity status. There was no significant difference in fasting acylated ghrelin between normal weight, overweight, and obese men at baseline. Acylated ghrelin was negatively correlated with weight and BMI for normal weight and with BMI in overweight men. Also ghrelin was correlated with change in weight and BMI in overweight (negative relationship) and obese (positive relationship) groups.

Conclusion

Our results showed that circulating acylated ghrelin was increased after a 7-day positive energy challenge regardless of adiposity status. However, acylated ghrelin was correlated with change in weight and BMI in opposing directions, in overweight and obese subjects respectively, thus dependent on obesity status.     

Metabolic Abnormalities Are Common among South American Hispanics Subjects with Normal Weight or Excess Body Weight: The CRONICAS Cohort Study

Objective

We aimed to characterize metabolic status by body mass index (BMI) status.

Methods

The CRONICAS longitudinal study was performed in an age-and-sex stratified random sample of participants aged 35 years or older in four Peruvian settings: Lima (Peru’s capital, costal urban, highly urbanized), urban and rural Puno (both high-altitude), and Tumbes (costal semirural). Data from the baseline study, conducted in 2010, was used. Individuals were classified by BMI as normal weight (18.5–24.9 kg/m²), overweight (25.0–29.9 kg/m²), and obese (≥30 kg/m²), and as metabolically healthy (0–1 metabolic abnormality) or metabolically unhealthy (≥2 abnormalities). Abnormalities included individual components of the metabolic syndrome, high-sensitivity C-reactive protein, and insulin resistance.

Results

A total of 3088 (age 55.6±12.6 years, 51.3% females) had all measurements. Of these, 890 (28.8%), 1361 (44.1%) and 837 (27.1%) were normal weight, overweight and obese, respectively. Overall, 19.0% of normal weight in contrast to 54.9% of overweight and 77.7% of obese individuals had ≥3 risk factors (p<0.001). Among normal weight individuals, 43.1% were metabolically unhealthy, and age ≥65 years, female, and highest socioeconomic groups were more likely to have this pattern. In contrast, only 16.4% of overweight and 3.9% of obese individuals were metabolically healthy and, compared to Lima, the rural and urban sites in Puno were more likely to have a metabolically healthier profile.

Conclusions

Most Peruvians with overweight and obesity have additional risk factors for cardiovascular disease, as well as a majority of those with a healthy weight. Prevention programs aimed at individuals with a normal BMI, and those who are overweight and obese, are urgently needed, such as screening for elevated fasting cholesterol and glucose.     

The Association between Hematological Parameters and Insulin Resistance Is Modified by Body Mass Index – Results from the North-East Italy MoMa Population Study

Objective

Increments in red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Ht) levels are reportedly associated with higher insulin resistance (IR). Obesity may cause IR, but underlying factors remain incompletely defined, and interactions between obesity, hematological parameters and IR are incompletely understood. We therefore determined whether: 1) BMI and obesity per se are independently associated with higher RBC, hemoglobin and hematocrit; 2) hematological parameters independently predict insulin resistance in obese individuals.

Design and Methods

We investigated the associations between BMI, hematological parameters and insulin resistance as reflected by homeostasis model assessment (HOMA) in a general population cohort from the North-East Italy MoMa epidemiological study (M/F = 865/971, age = 49±1).

Results

In all subjects, age-, sex- and smoking-adjusted hematological parameters were positively associated with BMI in linear regression (P<0.05), but not after adjustment for HOMA or waist circumference (WC) and potential metabolic confounders. No associations were found between hematological parameters and BMI in lean, overweight or obese subgroups. Associations between hematological parameters and HOMA were conversely independent of BMI in all subjects and in lean and overweight subgroups (P<0.01), but not in obese subjects alone.

Conclusions

In a North-East Italy general population cohort, obesity per se is not independently associated with altered RBC, Hb and Ht, and the association between BMI and hematological parameters is mediated by their associations with abdominal fat and insulin resistance markers. High hematological parameters could contribute to identify insulin resistance in non-obese individual, but they do not appear to be reliable insulin resistance biomarkers in obese subjects.     

Adiposity and dietary intake in cardiovascular risk in an obese population from a Mediterranean area

The aim of the study was to determine the particular relevance of android fat distribution and dietary intake in cardiovascular risk in an obese Mediterranean population with high intake of monounsaturated fatty acids (MUFA) and to compare the findings with those from normal-weight subjects. For the study, 193 subjects aged 25-60 were selected: 118 obese (BMI > or = 27 kg/m2), and 75 normal-weight (BMI < 25 kg/m2). Cardiovascular risk factors including hypertension, dyslipidaemia, glucose intolerance and insulin resistance were assessed. Nutrient intake and body fat distribution were determined. Results show that MUFA were highly consumed in the total population (21% of total energy). The obese population was normolipidemic and normoinsulinemic. However, cardiovascular risk factors (CVRF) were significantly higher than in normal-weight (P < 0.05). Obese subjects derived a greater percentage of their energy intake from total fat and lower from carbohydrates and saturated fats (P < 0.05). BMI and waist-hip ratio positively correlated with fat percentage of total energy intake and with MUFA (g/100 g fatty acids) in men, indicating that the excess of fat intake in obesity is due to a larger consumption of olive oil. CVRF were significantly and positively associated to waist circumference and WHR, both in obese and in normal-weight subjects. In conclusion, not only obesity but also android fat in normal-weight subjects are important factors in cardiovascular disease even in the Mediterranean population, with a high intake of MUFA, where these factors seem to be more relevant to cardiovascular risk than dietary composition.     

The Severity of Nocturnal Hypoxia but Not Abdominal Adiposity Is Associated with Insulin Resistance in Non-Obese Men with Sleep Apnea

Background

Beyond obesity, sleep apnea syndrome is frequently associated with excess abdominal adiposity that could contribute to the deteriorated cardiometabolic risk profile of apneic patients.

Methods

The present study addressed the respective contribution of the severity of sleep apnea syndrome and excess abdominal adiposity to the cardiometabolic risk profile of 38 non obese men with polysomnography-diagnosed sleep apnea syndrome (apnea-hypopnea index >15 events/hour). These otherwise healthy men performed a 75g-oral glucose tolerance test (OGTT) with plasma lipid/inflammatory and redox profiles. Twenty-one apneic men with high-waist circumference (>94 cm) were compared to 17 apneic men with low-waist circumference.

Results

Apneic men with high-waist circumference had higher AUC glucose and AUC insulin than apneic men with low-waist circumference. Accordingly, apneic men with high-waist circumference had higher hepatic insulin resistance as reflected by higher HOMA-resistance index, and lower global insulin sensitivity as reflected by lower insulin sensitivity index of Matsuda (derived from OGTT). The sleep structure and the apnea-hypopnea index were not different between the two groups. However, apneic men with high-waist circumference presented with lower mean nocturnal oxyhemoglobin (SpO₂). In the 38 men, waist circumference and mean nocturnal SpO₂ were inversely correlated (r = −0.43, p = 0.011) and were both associated with plasma glucose/insulin homeostasis indices: the higher the waist circumference, the lower the mean nocturnal SpO₂, the lower the insulin-sensitivity. Finally, in multivariable regression model, mean nocturnal SpO₂ and not waist circumference was associated with insulin-resistance.

Conclusion

Thus, excess abdominal adiposity in non obese apneic men was associated with a deteriorated insulin-sensitivity that could be driven by a more severe nocturnal hypoxemia.