Obesity-associated insulin resistance (IR) may develop in multiple organs, representing different aetiologies towards cardiometabolic diseases. This study aimed to identify distinct plasma lipid ...profiles in overweight/obese individuals who show muscle-IR and/or liver-IR.
Baseline data of the European multicenter DiOGenes project were used (n = 640; 401 women, nondiabetic BMI: 27-45 kg/m
). Muscle insulin sensitivity index (MISI) and hepatic insulin resistance index (HIRI) were derived from a 5-point oral glucose tolerance test. The 140 plasma lipids were quantified by liquid chromatography-mass spectrometry. Linear mixed models were used to evaluate associations between MISI, HIRI and plasma lipids.
MISI was comparable between sexes while HIRI and triacylglycerol (TAG) levels were lower in women than in men. MISI was associated with higher lysophosphatidylcholine (LPC) levels (standardized (std)β = 0.126; FDR-p = 0.032). Sex interactions were observed for associations between HIRI, TAG and diacylglycerol (DAG) lipid classes. In women, but not in men, HIRI was associated with higher levels of TAG (44 out of 55 species) and both DAG species (stdβ: 0.139-0.313; FDR-p < 0.05), a lower odd-chain/even-chain TAG ratio (stdβ = -0.182; FDR-p = 0.005) and a lower very-long-chain/long-chain TAG ratio (stdβ = -0.156; FDR-p = 0.037).
In overweight/obese individuals, muscle insulin sensitivity is associated with higher plasma LPC concentrations. Women have less hepatic IR and lower TAG than men. Nevertheless, hepatic IR is associated with higher plasma TAG and DAG concentrations and a lower abundance of odd-chain and very-long-chain TAG in women, but not in men. This suggests a more pronounced worsening of plasma lipid profile in women with the progression of hepatic IR.
An enhanced innate immune response is suggested in subjects with chronic multisite musculoskeletal pain.
Dysregulation of the immune system may play a role in chronic pain, although study findings ...are inconsistent. This cross-sectional study examined whether basal inflammatory markers and the innate immune response are associated with the presence and severity of chronic multisite musculoskeletal pain. Data were used on 1632 subjects of the Netherlands Study of Depression and Anxiety. The Chronic Pain Grade questionnaire was used to determine the presence and severity of chronic multisite musculoskeletal pain. Subjects were categorized in a chronic multisite musculoskeletal pain group (n=754) and a control group (n=878). Blood levels of the basal inflammatory markers C-reactive protein, interleukin-6, and tumor necrosis factor-alpha were determined. To obtain a measure of the innate immune response, 13 inflammatory markers were assessed after lipopolysaccharide (LPS) stimulation in a subsample (n=707). Subjects with chronic multisite musculoskeletal pain showed elevated levels of basal inflammatory markers compared with controls, but statistical significance was lost after adjustment for lifestyle and disease variables. For some LPS-stimulated inflammatory markers, we did find elevated levels in subjects with chronic multisite musculoskeletal pain both before and after adjustment for covariates. Pain severity was not associated with inflammation within chronic pain subjects. An enhanced innate immune response in chronic multisite musculoskeletal pain may be examined as a potential biomarker for the onset or perpetuation of chronic pain.
Obesity-related insulin resistance (IR) may develop in multiple organs, representing various etiologies for cardiometabolic diseases. We identified abdominal subcutaneous adipose tissue (ScAT) ...transcriptome profiles in liver or muscle IR by means of RNA sequencing in overweight or obese participants of the Diet, Obesity, and Genes (DiOGenes) (NCT00390637, ClinicalTrials.gov) cohort (
= 368). Tissue-specific IR phenotypes were derived from a 5-point oral glucose tolerance test. Hepatic and muscle IR were characterized by distinct abdominal ScAT transcriptome profiles. Genes related to extracellular remodeling were upregulated in individuals with primarily hepatic IR, while genes related to inflammation were upregulated in individuals with primarily muscle IR. In line with this, in two independent cohorts, the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) (
= 325) and the Maastricht Study (
= 685), an increased systemic low-grade inflammation profile was specifically related to muscle IR but not to liver IR. We propose that increased ScAT inflammatory gene expression may translate into an increased systemic inflammatory profile, linking ScAT inflammation to the muscle IR phenotype. These distinct IR phenotypes may provide leads for more personalized prevention of cardiometabolic diseases.
Inconsistent findings have been reported on the role of comorbid alcohol use disorders as risk factors for a persistent course of depressive and anxiety disorders.
To determine whether the course of ...depressive and/or anxiety disorders is conditional on the type (abuse or dependence) or severity of comorbid alcohol use disorders.
In a large sample of participants with current depression and/or anxiety (n = 1369) we examined whether the presence and severity of DSM-IV alcohol abuse or alcohol dependence predicted the 2-year course of depressive and/or anxiety disorders.
The persistence of depressive and/or anxiety disorders at the 2-year follow-up was significantly higher in those with remitted or current alcohol dependence (persistence 62% and 67% respectively), but not in those with remitted or current alcohol abuse (persistence 51% and 46% respectively), compared with no lifetime alcohol use disorder (persistence 53%). Severe (meeting six or seven diagnostic criteria) but not moderate (meeting three to five criteria) current dependence was a significant predictor as 95% of those in the former group still had a depressive and/or anxiety disorder at follow-up. This association remained significant after adjustment for severity of depression and anxiety, psychosocial factors and treatment factors.
Alcohol dependence, especially severe current dependence, is a risk factor for an unfavourable course of depressive and/or anxiety disorders, whereas alcohol abuse is not.
There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease.
To investigate associations between plasma metabolites and kidney function in people ...with type 2 diabetes (T2D).
3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts.
Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing.
In total, 125 metabolites were significantly associated (PFDR = 1.5×10-32 - 0.046; β = -11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 0.05). Albeit some metabolites were associated with UACR levels (P < 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (PTyr = 0.003; PHDLrelated < 0.05), but not after.
This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation.
Although several cross-sectional studies have linked obesity and depression, less is known about their longitudinal association and about the relative influence of obesity subtypes. We prospectively ...examined whether obesity (specifically, abdominal) increased the risk of onset of depression in a population-based sample of older persons.
Participants were 2,547 nondepressed, well-functioning white and black persons, aged 70-79 years, enrolled in the Health, Aging, and Body Composition Study, an ongoing prospective community-based cohort study. Baseline measurements were conducted between April 1997 and June 1998. Overall obesity was assessed by body mass index (BMI) and percent body fat (measured by dual energy x-ray absorptiometry), whereas abdominal obesity measures included waist circumference, sagittal diameter, and visceral fat (measured by computer tomography). Onset of significant depressive symptoms was defined as a Center for Epidemiologic Studies Depression 10-item score > or = 10 at any annual follow-up over 5 years and/or new antidepressant medication use. Persistent depression was defined as depression at 2 consecutive follow-up visits.
Over 5 years, significant depressive symptoms emerged in 23.7% of initially nondepressed persons. In men, both overall (BMI: hazard ratio HR per SD increase = 1.20; 95% CI, 1.03-1.40) and abdominal obesity (visceral fat: HR per SD increase = 1.19; 95% CI, 1.07-1.33) predicted onset of depressive symptoms after adjustment for sociodemographics. When BMI and visceral fat were adjusted for each other, only visceral fat was significantly associated with depression onset (HR = 1.18; 95% CI, 1.04-1.34). Stronger associations were found for persistent depressive symptoms. No associations were found in women.
This study shows that obesity, in particular visceral fat, increases the risk of onset of significant depressive symptoms in men. These results suggest that specific mechanisms might relate visceral fat to the onset of depression.
Summary Introduction Depression has been hypothesized to be associated with metabolic abnormalities which increase the risk of cardiovascular disease (CVD) and diabetes. Such a link could be due to ...increased HPA-axis activity. This study investigates the cross-sectional relationship between depression, urinary cortisol and metabolic syndrome in an older population. Methods Data are from 867 participants of the InChianti Study, aged ⩾65 years. Depressive symptoms were assessed using the CES-D scale; cortisol levels were determined in 24-h urine samples. Metabolic syndrome was defined as three or more of the following: abdominal obesity, high triglycerides, low HDL cholesterol, high blood pressure, and high fasting glucose. Results Clinically relevant depressed mood (CES-D⩾20) was present in 20.6% of the sample, and 24.5% had the metabolic syndrome. After adjustment for sociodemographics and health indicators, depression score (per SD increase: OR=1.20, 95% CI=1.02–1.41) and urinary cortisol level (per SD increase: OR=1.23, 95% CI=1.01–1.51) were significantly associated with presence of metabolic syndrome. There was, however, a significant interaction ( p = 0.003 ) between depressed mood and urinary cortisol in the probability of having metabolic syndrome. The odds of metabolic syndrome in persons with both depressed mood and urinary cortisol excretion in the highest tertile was 1.84 (95% CI=1.02–3.34) compared to persons with neither condition. Discussion This study suggests a synergistic relationship between depression, cortisol and metabolic syndrome. Hypercortisolemic depression may constitute a specific risk group for the metabolic syndrome.
Context: Stress is suggested to lead to metabolic dysregulations as clustered in the metabolic syndrome, but the underlying biological mechanisms are not yet well understood.
Objective: We examined ...the relationship between two main str systems, the autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, with the metabolic syndrome and its components.
Design: The design was baseline data (yr 2004–2007) of a prospective cohort: the Netherlands Study of Depression and Anxiety (NESDA).
Setting: The study comprised general community, primary care, and specialized mental health care.
Participants: This study included 1883 participants aged 18–65 yr.
Main Outcome Measures: Autonomic nervous system measures included heart rate, respiratory sinus arrhythmia (RSA; high RSA reflecting high parasympathetic activity), and preejection period (PEP; high PEP reflecting low sympathetic activity). HPA axis measures included the cortisol awakening response, evening cortisol, and a 0.5 mg dexamethasone suppression test as measured in saliva. Metabolic syndrome was based on the updated Adult Treatment Panel III criteria and included high waist circumference, serum triglycerides, blood pressure, serum glucose, and low high-density lipoprotein cholesterol.
Results: RSA and PEP were both independently negatively associated with the presence of the metabolic syndrome, the number of metabolic dysregulations as well as all individual components except high-density lipoprotein cholesterol (all P < 0.02). Heart rate was positively related to the metabolic syndrome, the number of metabolic dysregulations, and all individual components (all P < 0.001). HPA axis measures were not related to metabolic syndrome or its components.
Conclusion: Our findings suggest that increased sympathetic and decreased parasympathetic nervous system activity is associated with metabolic syndrome, whereas HPA axis activity is not.
Persons with metabolic syndrome and metabolic dysregulations exhibit diminished cardiac vagal control and increased sympathetic activity, whereas they display normal cortisol levels.
Objective:Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between ...common genomewide variation and lifetime suicide attempts.
Method:The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort.
Results:Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety.
Conclusions:The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation.
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