Correlates of health-related quality of life in overweight and obese adults with type 2 diabetes

Objective: This paper describes and examines conceptually relevant correlates of health‐related quality of life (HRQL) in overweight or obese persons with type 2 diabetes. Research Design and Procedures: The investigation was a cross‐sectional study of 5145 overweight or obese adults with type 2 diabetes between the ages of 45 and 74 years. Analyses examined the relationship that demographic characteristics, disease burden, and cardiovascular fitness had with HRQL: the Short Form 36 (SF‐36) and the Beck Depression Inventory (BDI) II. Results: Means for the SF‐36 physical component summary (PCS) scores, the mental component summary scores, and the BDI‐II were as follows: 47.0, 54.0, and 5.7. Less desirable PCS scores were related to several comorbidities, insulin use, physical complaints, a high BMI, low metabolic equivalent (MET) capacity, and lower education. Interactions between categories of obesity and MET capacity revealed that greater BMI was related to lower PCS scores when individuals had lower MET capacities yet was absent for those individuals who had higher MET capacities. In addition, although greater BMI was associated with more severe depressive symptomatology, this association was the most dramatic for those with class III obesity who had low MET capacity. Discussion: Although participants in Look AHEAD had a favorable profile on the SF‐36 and the BDI‐II at baseline, lower PCS scores were related to disease severity and the presence of other comorbidities. More important, although the temporal ordering of associations cannot be determined in a cross‐sectional design, the interactions between obesity class and MET capacity suggest that the adverse effect of BMI on PCS and BDI‐II scores may be buffered by higher MET capacities.     

One-year changes in symptoms of depression and weight in overweight/obese individuals with type 2 diabetes in the Look AHEAD study

Depressed individuals are frequently excluded from weight loss trials because of fears that weight reduction may precipitate mood disorders, as well as concerns that depressed participants will not lose weight satisfactorily. The present study examined participants in the Look AHEAD study to determine whether moderate weight loss would be associated with incident symptoms of depression and suicidal ideation, and whether symptoms of depression at baseline would limit weight loss at 1 year. Overweight/obese adults with type 2 diabetes (n = 5,145) were randomly assigned to an Intensive Lifestyle Intervention (ILI) or a usual care group, Diabetes Support and Education (DSE). Of these, 5,129 participants completed the Beck Depression Inventory (BDI) and had their weight measured at baseline and 1 year. Potentially significant symptoms of depression were defined by a BDI score ≥10. Participants in ILI lost 8.6 ± 6.9% of initial weight at 1 year, compared to 0.7 ± 4.8% for DSE (P < 0.001, effect size = 1.33), and had a reduction of 1.4 ± 4.7 points on the BDI, compared to 0.4 ± 4.5 for DSE (P < 0.001, effect size = 0.23). At 1 year, the incidence of potentially significant symptoms of depression was significantly lower in the ILI than DSE group (6.3% vs. 9.6%) (relative risk (RR) = 0.66, 95% confidence interval (CI) = 0.5, 0.8; P < 0.001). In the ILI group, participants with and without symptoms of depression lost 7.8 ± 6.7% and 8.7 ± 6.9%, respectively, a difference not considered clinically meaningful. Intentional weight loss was not associated with the precipitation of symptoms of depression, but instead appeared to protect against this occurrence. Mild (or greater) symptoms of depression at baseline did not prevent overweight/obese individuals with type 2 diabetes from achieving significant weight loss.     

Moderate weight loss improves heart rate variability in overweight and obese adults with type 2 diabetes

The objective of this study was to determine the effects of weight loss on heart rate variability (HRV) and its association with traditional cardiovascular disease risk factors in overweight and obese patients with type 2 diabetes. Forty five patients [body mass index (BMI) 35.4 ± 0.7 kg/m2; age 56.5 ± 1.1 yr] with type 2 diabetes followed an energy-restricted diet (6-7 MJ/day) for 16 wk. Body weight, blood pressure, glucose, insulin, insulin resistance [homeostasis model assessment index 2 (HOMA2)], glycosylated hemoglobin (HbA1c), total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides, resting HR, and HRV were measured before and after the intervention period. Mean reduction in body weight was 11.1 ± 1.0 kg (10%), with significant reductions in blood pressure (-10%), total cholesterol (-15.9%), LDL (-17.7%), HDL (-7.5%), triglycerides (-21.2%), glucose (-23.4%), insulin (-37.6%), HOMA2 (-40.1%), and HbA1c (-14.5%) (P ≤ 0.05 for all variables). There were increases in several HRV components, including total power (1,370 ± 280 to 2,045 ± 280 ms2), low-frequency power (345 ± 70 to 600 ± 108 ms2), SD of normal to normal intervals (SDNN; 35.0 ± 2.5 to 43.0 ± 2.7 s), and square root of the mean squared differences of successive normal to normal intervals (RMSSD; 23.0 ± 3.5 to 32.0 ± 3.1 s), and a decrease in HR (69.0 ± 1.3 to 60.0 ± 1.2 beats/min) (P ≤ 0.03 for all variables). Changes in HR, SDNN, total power, and low-frequency power correlated with change in BMI (P < 0.05). In addition to improvements in traditional cardiovascular and metabolic risk factors, weight loss improves HRV in overweight and obese patients with type 2 diabetes.     

Association of type 2 diabetes susceptibility loci with one-year weight loss in the look AHEAD clinical trial

The importance of lifestyle intervention for the prevention and treatment of type 2 diabetes (T2D) has been underscored by the limited benefit of pharmacologic therapies. We sought to determine whether genetic variants that contribute to T2D risk modify the response of weight and waist circumference to an intensive lifestyle intervention (ILI) in patients with obesity and T2D. Look AHEAD (Action for Health in Diabetes) is a randomized clinical trial comparing an ILI with a control condition on the risk of cardiovascular disease in overweight adults with T2D. We analyzed 28 single-nucleotide polymorphisms (SNPs) at/near 17 T2D-susceptibility genes in 3,903 consented participants. We genetically characterized the cohort by assessing whether T2D-susceptibility loci were overrepresented compared with a nondiabetic community-based cohort (N = 1,016). We evaluated the association of individual variants and a composite genetic risk score (GRS) with anthropometric traits at baseline and after 1-year of intervention. Look AHEAD subjects carried more T2D-susceptibility alleles than the control population. At baseline, TCF7L2 risk alleles and the highest GRS were associated with lower BMI and waist circumference. Nominally significant genotype-by-intervention interactions were detected for 1-year change in waist circumference with JAZF1, MTNR1B, and IRS1, and BMI with JAZF1. Highest GRS was associated with a greater reduction in waist circumference at year 1, although the variance in change attributable to the GRS was small. This study shows that the genetic burden associated with T2D risk does not undermine the effect of lifestyle intervention and suggests the existence of additional genomic regions, distinct from the T2D-susceptibility loci, which may enhance or mitigate weight loss.     

Potential interaction of brain natriuretic peptide with hyperadiponectinemia in preeclampsia

Adiponectin was reported recently to have roles in the pathophysiology of preeclampsia. Moreover, elevation of adiponectin and brain natriuretic peptide (BNP) has been observed in preeclampsia. We examined the possible links between adiponectin and BNP in the pathophysiology of preeclampsia. We performed a cross-sectional study in 56 preeclampsia patients and 56 controls matched for gestational age and body mass index. The BNP, leptin, and adiponectin levels were measured by ELISA, and their mRNA expressions were evaluated in omental adipose tissue by real-time PCR. The effects of BNP on adiponectin and leptin mRNA expression and secretion were investigated in primary cultures of adipocytes from obese and normal-weight women. The BNP, adiponectin, and leptin levels were significantly higher in preeclampsia patients compared with controls. The adiponectin level was increased significantly in normal-weight preeclampsia patients compared with overweight preeclampsia patients. Adiponectin mRNA expression was increased significantly in adipose tissues of preeclampsia patients compared with controls and was also increased significantly in normal-weight preeclampsia patients compared with overweight preeclampsia patients, whereas leptin was not. BNP and adiponectin showed significant positive correlations in both normal-weight and overweight preeclampsia patients. BNP had a significantly weaker effect on adiponectin in overweight compared with normal-weight preeclampsia patients. Moreover, BNP had a weaker effect on adiponectin production in adipocytes from overweight women compared with adipocytes from normal-weight women using primary culture of human adipocytes. These data suggested that BNP may play a role in hyperadiponectinemia of preeclampsia patients. The weaker effect of BNP on adiponectin production may participate in the pathophysiology of overweight preeclampsia patients.     

Interaction between brain natriuretic peptide and atrial natriuretic peptide in caecal circular smooth muscle cells

Guinea pig caecal circular smooth muscle cells were used to determine whether brain natriuretic peptide (BNP) can inhibit the contractile response produced by cholecystokinin-octapeptide (CCK-8). In addition, we examined the effect of an inhibitor of cAMP-dependent protein kinase, an inhibitor of particulate or soluble guanylate cyclase, an atrial natriuretic peptide (ANP) antagonist (ANP 1-11), and selective receptor protection on the BNP-induced relaxation of these muscle cells. The effect of BNP on cAMP formation was also examined. BNP inhibited the contractile response produced by CCK-8 in a dose-response manner, with an IC50 value of 8.5 nM, and stimulated the production of cAMP. The inhibitor of cAMP-dependent protein kinase and the inhibitor of soluble guanylate cyclase significantly inhibited the relaxation produced by BNP. In contrast, the inhibitor of particulate guanylate cyclase did not have any significant effect on the relaxation produced by BNP. ANP 1-11 significantly but partially inhibited the relaxation produced by BNP. The muscle cells where CCK-8 and ANP binding sites were protected completely preserved the inhibitory response to ANP, but partially preserved the inhibitory response to BNP. The muscle cells where CCK-8 and BNP binding sites were protected completely preserved the inhibitory response to both ANP and BNP. This study demonstrates that BNP induces relaxation of these muscle cells via both ANP binding sites coupled to soluble guanylate cyclase and distinct BNP binding sites coupled to adenylate cyclase.     

Lifestyle intervention and/or statins for the reduction of C‐reactive protein in type 2 diabetes: From the look AHEAD study

Objective:

Cardiovascular risk remains high despite statin use. Overweight/obese diabetic persons usually have normal/low LDL‐cholesterol but high C‐reactive protein (CRP) levels. We aimed to examine the effects of intensive lifestyle intervention for weight loss (ILI) on CRP levels in overweight/obese diabetic individuals by statin use.

Design and Methods:

Look AHEAD was a randomized trial in overweight/obese type 2 diabetic individuals testing whether ILI would reduce cardiovascular mortality, when compared to usual care. CRP changes in 1,431 participants with biomarker levels, who remained on or off statin treatment for 1 year, were evaluated.

Results:

The reduction in CRP levels with ILI at 1 year in men and women on statins was ?44.9 and ?42.3%, respectively, compared to ?13.7 and ?21.0% for those on statins and usual care (P < 0.0001). At 1 year, median CRP levels were: 1.8 mg L^?1 in participants randomized to ILI on statin therapy; 2.6 mg L^?1 for those on statins randomized to usual care and 2.9 mg L^?1 for participants not on statins but randomized to ILI. Weight loss was associated with 1‐year CRP reduction (P < 0.0001) in statin and nonstatin users.

Conclusions:

Our findings suggest that in overweight/obese diabetic persons, ILI and statin therapy may have substantial additive anti‐inflammatory benefits.

     

Molecular regulation of the brain natriuretic peptide gene

After brain natriuretic peptide (BNP) was isolated in 1988, rapid progress was made in cloning its cDNA and gene, facilitating studies of tissue-specific expression and molecular regulation of gene expression. This review focuses on the molecular determinants of regulation of the rat and human BNP genes, including signaling pathways that impact on changes in gene expression and cis regulatory elements responsive to these signaling pathways. For both rat and human genes, elements in the proximal promoter (-124 to -80), including GATA, MCAT, and AP-1-like, have been shown to contribute to basal and inducible regulation. More distal elements in the human BNP gene respond to calcium signals (an NF-AT site at -927), thyroid hormone (a thyroid-responsive element at -1000), and mechanical stretch (shear stress-responsive elements at -652 and -162). Understanding how BNP is regulated by signaling molecules that are activated in the hypertrophied and ischemic heart should be useful in understanding the underlying pathology. This may lead to therapeutic strategies that prevent hypertrophy while allowing for the beneficial effects of BNP production.     

Evaluation of atrial natriuretic peptide and brain natriuretic peptide in atrial granules of rats with experimental congestive heart failure.

The natriuretic peptides are believed to play an important role in the pathophysiology of congestive heart failure (CHF). We utilized a quantitative cytomorphometric method, using double immunocytochemical labeling, to assess the characteristics of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in atrial granules in an experimental model of rats with CHF induced by aortocaval fistula. Rats with CHF were further divided into decompensated (sodium-retaining) and compensated (sodium-excreting) subgroups and compared with a sham-operated control group. A total of 947 granules in myocytes in the right atrium were analyzed, using electron microscopy and a computerized analysis system. Decompensated CHF was associated with alterations in the modal nature of granule content packing, as depicted by moving bin analysis, and in the granule density of both peptides. In control rats, the mean density of gold particles attached to both peptides was 347.0 +/- 103.6 and 306.3 +/- 89.9 gold particles/microm2 for ANP and BNP, respectively. Similar mean density was revealed in the compensated rats (390.6 +/- 81.0 and 351.3 +/- 62.1 gold particles/microm2 for ANP and BNP, respectively). However, in rats with decompensated CHF, a significant decrease in the mean density of gold particles was observed (141.6 +/- 67.3 and 158.0 +/- 71.2 gold particles/microm2 for ANP and BNP, respectively; p<0.05 compared with compensated rats, for both ANP and BNP). The ANP:BNP ratio did not differ between groups. These findings indicate that the development of decompensated CHF in rats with aortocaval fistula is associated with a marked decrease in the density of both peptides in atrial granules, as well as in alterations in the quantal nature of granule formation. The data further suggest that both peptides, ANP and BNP, may be regulated in the atrium by a common secretory mechanism in CHF.     

Use of complementary and alternative therapies by overweight and obese adults

Objective: Obesity is associated with higher health‐care costs due, in part, to higher use of traditional health care. Few data are available on the relationship between obesity and the use of complementary and alternative medicine (CAM). Methods and Procedures: We analyzed data on CAM use from the 2002 National Health Interview Survey (NHIS) Alternative Medicine Supplement (n = 31,044). We compared the use of CAM overall, within the past 12 months, between normal weight (BMI from 18 to <25), overweight (from 25 to <30), mildly obese (from 30 to <35), moderately obese (from 35 to <40), and extremely obese (>40) adults. For the primary analysis, our multivariable model was adjusted for sociodemographic factors, insurance status, medical conditions, and health behaviors. We performed additional analyses to explore the association of BMI and the use of seven CAM modalities. Results: We found that adults with obesity have lower prevalence of use of yoga therapy, and similar prevalence of use of several CAM modalities, including relaxation techniques, natural herbs, massage, chiropractic medicine, tai chi, and acupuncture, compared to normal‐weight individuals. After adjustment for sociodemographic factors, insurance status, medical conditions, and health behaviors, adults with obesity were generally less likely to use most individual CAM modalities, although the magnitude of these differences were quite modest in many cases. Discussion: Even though adults with obesity have a greater illness burden and higher utilization of traditional medical care, adults with higher BMIs were no more likely to use each of the individual CAM therapies studied. Additional research is needed to improve our understanding of CAM use by adults with obesity.     

Confronting and coping with weight stigma: an investigation of overweight and obese adults

Objective: This study examined experiences of weight stigmatization, sources of stigma, coping strategies, psychological functioning, and eating behaviors in a sample of 2671 overweight and obese adults. Research Methods and Procedures: The total sample was partitioned into two subsamples for investigation. Sample I was comprised of 2449 adult women, and Sample II was a matched sample of adult men and women (N = 222) that was disaggregated to investigate gender differences. Both samples completed an online battery of self‐report questionnaires measuring frequency of weight stigmatization and coping responses to deal with bias, the most common sources of the bias, symptoms of depression, self‐esteem, attitudes about weight and obesity, and binge eating behaviors. Results: Experiences of weight stigmatization, in many forms and across multiple occasions, was common in both samples. A variety of coping strategies were used in response. More frequent exposure to stigma was related to more attempts to cope and higher BMI. Physicians and family members were the most frequent sources of weight bias reported. No gender differences were observed in types or frequency of stigmatization. Frequency of stigmatization was not related to current psychological functioning, although coping responses were associated with emotional well‐being. Discussion: These findings raise questions about the relationship between stigma and psychological functioning and have important implications for obesity treatment and stigma reduction intervention efforts, both of which are discussed.     

Effects of brain natriuretic peptide on pituitary-adrenal activation in rats

The aim of this study was to characterize the effects of brain natriuretic peptide (BNP) on the hypothalamo-pituitary-adrenal (HPA) responses to different stress paradigms (ether stress, electric shock and restraint). Rats were subjected to the stressful stimuli after intracerebroventricular administration of BNP (32.5 ng-6.5 microg) and plasma corticosterone was used as an indicator of the HPA activation. BNP did not modify the basal secretion, but inhibited the stress-induced rise in plasma corticosterone in a dose-dependent manner. BNP proved most effective in decreasing the corticosterone response to ether stress and attenuated the electric shock and restraint-induced HPA activation to a lesser extent. These results confirm the view that BNP takes part in the regulation of the HPA system.     

Uncoordinated regulation of atrial natriuretic factor and brain natriuretic peptide in lipopolysaccharide-treated rats

We investigated the expression and secretion of the natriuretic peptides (NPs) ANF and BNP in lipopolysaccharide (LPS)-induced sepsis and its association with cytokines and other biologically active substances. LPS treatment increased plasma levels of ANF and BNP. The latter increase was larger than the increase in plasma ANF. LPS also increased cardiac content and gene expression of BNP but not of ANF. LPS treatment significantly increased gene expression cytokines, chemokines and proteases, which significantly correlated with BNP gene expression. SB203580, a p38 MAP kinase inhibitor, inhibited the elevation of BNP in plasma. The present work suggests that during inflammation, BNP gene expression and secretion is uniquely related to changes in gene expression in the absence of hemodynamic changes and hence differentiates ANF and BNP as biomarkers of cardiac disease.     

Atrial and brain natriuretic peptide in adrenal steroidogenesis.

We elucidated the role of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in human and bovine adrenocortical steroidogenesis. The urinary volume, sodium excretion and cyclic GMP (cGMP) excretion and plasma cGMP were markedly increased by the synthetic alpha-human ANP (alpha-hANP) infusion in healthy volunteers. Plasma arginine vasopressin (AVP) and aldosterone levels were significantly suppressed. Both ANP and BNP inhibited aldosterone, 19-OH-androstenedione, cortisol and DHEA secretion dose-dependently and increased the accumulation of intracellular cGMP in cultured human and bovine adrenal cells. alpha-hANP significantly suppressed P450scc-mRNA in cultured bovine adrenal cells stimulated by ACTH. Autoradiography and affinity labeling of [125I]hANP, and Scatchard plot demonstrated a specific ANP receptor in bovine and human adrenal glands. Purified ANP receptor from bovine adrenal glands identified two distinct types of ANP receptors, one is biologically active, the other is silent. A specific BNP receptor was also identified on the human and bovine adrenocortical cell membranes. The binding sites were displaced by unlabelled ANP as well as BNP. BNP showed an effect possibly via a receptor which may be shared with ANP. The mean basal plasma alpha-hANP level was 25 +/- 5 pg/ml in young men. We confirmed the presence of ANP and BNP in bovine and porcine adrenal medulla. Plasma or medullary ANP or BNP may directly modulate the adrenocortical steroidogenesis. We demonstrated that the lack of inhibitory effect of alpha-hANP on cultured aldosterone-producing adenoma (APA) cells was due to the decrease of ANP-specific receptor, which caused the loss of suppression of aldosterone and an increase in intracellular cGMP.     

Detection of oxytocin,atrial natriuretic peptide,and brain natriuretic peptide using novel imprinted polymers produced with amphiphilic monomers

The cystine‐bridged cyclic peptide hormones (CBCPHs) represent signature structural feature as well as unique biological activity. In this study, three CBCPHs have been identified and characterized, namely, oxytocin, atrial natriuretic peptides (ANPs), and brain natriuretic peptides (BNPs). Because research has shown that ANPs and BNPs are powerful diagnostic biomarkers for heart disease, a highly laudable endeavor would be to develop a novel sensor for detecting ANP or BNP levels. Therefore, an amphiphilic monomer Acr‐His‐NHNH‐Fmoc was synthesized to form molecularly imprinted polymers (MIPs) for targeted CBCPH detection. First, oxytocin, a cardiovascular hormone and a CBCPH, was used as a template to fabricate MIPs on quartz crystal microbalance (QCM) chips. On the other hand, fabricated selected ANP segment or BNP segment as an epitope is able to construct epitope‐mediated MIPs (EMIPs) for ANP or BNP. The developed oxytocin or ANP sensor reached a detection limitation of 0.1nM with the dissociation constants being 30pM for oxytocin and 20pM for ANP. Moreover, BNP sensor achieved a detection limitation of 2.89pM with an even lower K_d value as 2pM. Compared with the performance of EMIPs, the imprinted films showed high affinity and selectivity in special binding to CBCPHs. The developed MIPs‐QCM biosensors thus provide an improved sensing platform using an amphiphilic monomer and may be useful for applications toward cyclotides, cystine knot motifs, or insulin‐like peptides.