Brock A. Beamer

Sleep-disordered breathing, glucose intolerance, and insulin resistance

Sleep-disordered breathing (SDB) is a common condition with prevalence estimates of 2-4% in the general population. Epidemiological data suggest that SDB is an independent risk factor for cardiovascular disease. Glucose intolerance and insulin resistance are also well-recognized risk factors for the development of cardiovascular disease. A number of recent clinic-based studies suggest that, independent of obesity, SDB may adversely affect glucose tolerance and insulin sensitivity. The purpose of this study was to systematically review the evidence for the link between SDB, glucose intolerance, and insulin resistance. A MEDLINE search for SDB and metabolic disorders was performed and 24 articles that met the inclusion criteria were identified. Population-based studies indicate that habitual snoring is independently associated with glucose intolerance and insulin resistance. Studies that have used objective measures of SDB (e.g. polysomnography) provide further support for an independent link between SDB, glucose intolerance, and insulin resistance. However, studies on the treatment of SDB with continuous positive airway pressure (CPAP) have yielded inconsistent results and overall do not reveal an improvement in the metabolic disturbance after treatment. Although population-based prospective data on the metabolic implications of SDB are still lacking, current data point to an independent association between SDB and impaired glucose homeostasis. Potential mediators of this association include altered adrenergic function, the direct effects of hypoxemia on glucose regulation, and release of proinflammatory cytokines that affect metabolism.

Alterations in Glucose Disposal in Sleep-disordered Breathing

RATIONALE It is well established that sleep-disordered breathing (SDB) is independently associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. However, data on whether SDB alters in vivo kinetics of glucose and insulin are lacking. OBJECTIVES The primary goal of this study was to use the frequently sampled intravenous glucose tolerance test (FSIVGTT) in subjects with and without SDB to model the in vivo kinetics of glucose and insulin. Minimal model analysis of the FSIVGTT data was used to derive parameters of insulin sensitivity, glucose effectiveness (a measure of the ability of glucose to mediate its own disposal), and pancreatic beta-cell function. RESULTS A total of 118 nondiabetic subjects underwent polysomnography, the FSIVGTT, and body composition measurements including determination of percent body fat. Compared with normal subjects (apnea-hypopnea index < 5 events/h), those with mild, moderate, and severe SDB displayed a 26.7, 36.5 and 43.7% reduction in insulin sensitivity, respectively, independent of age, sex, race, and percent body fat. The disposition index, an integrated measure of pancreatic beta-cell function, was also reduced in patients with moderate to severe SDB. The decrease in insulin sensitivity and the disposition index were correlated with the average degree of oxyhemoglobin desaturation. In contrast, glucose effectiveness was negatively correlated with the frequency of respiratory event-related arousals. CONCLUSIONS The results of this study suggest that, independent of adiposity, SDB is associated with impairments in insulin sensitivity, glucose effectiveness, and pancreatic beta-cell function. Collectively, these defects may increase the risk of glucose intolerance and type 2 diabetes mellitus in SDB.

Admixture Mapping of White Cell Count: Genetic Locus Responsible for Lower White Blood Cell Count in the Health ABC and Jackson Heart Studies

White blood cell count (WBC) is an important clinical marker that varies among different ethnic groups. African Americans are known to have a lower WBC than European Americans. We surveyed the entire genome for loci underlying this difference in WBC by using admixture mapping. We analyzed data from African American participants in the Health, Aging, and Body Composition Study and the Jackson Heart Study. Participants of both studies were genotyped across >or= 1322 single nucleotide polymorphisms that were pre-selected to be informative for African versus European ancestry and span the entire genome. We used these markers to estimate genetic ancestry in each chromosomal region and then tested the association between WBC and genetic ancestry at each locus. We found a locus on chromosome 1q strongly associated with WBC (p < 10(-12)). The strongest association was with a marker known to affect the expression of the Duffy blood group antigen. Participants who had both copies of the common West African allele had a mean WBC of 4.9 (SD 1.3); participants who had both common European alleles had a mean WBC of 7.1 (SD 1.3). This variant explained approximately 20% of population variation in WBC. We used admixture mapping, a novel method for conducting genetic-association studies, to find a region that was significantly associated with WBC on chromosome 1q. Additional studies are needed to determine the biological mechanism for this effect and its clinical implications.

The Pro115Gln and Pro12Ala PPAR gamma gene mutations in obesity and type 2 diabetes

OBJECTIVE: Peroxisome-proliferator-activated receptors γ (PPAR γ), is a key regulator of adipocyte differentiation and energy balance. Two naturally occurring mutations in the PPAR γ gene, Pro115Gln and Pro12Ala, have recently been shown to impair the function of the PPARγ2 isoform of the receptor and to be associated with obesity or diabetes- related phenotypes in different populations.SUBJECTS: We studied the occurrence and possible associations of the Pro115Gln and Pro12Ala in the PPAR γ2 gene with several clinical and metabolic phenotypes in three independent large populations of non-obese non-diabetic, type 2 diabetic, and morbidly obese French Caucasians.RESULTS: The Pro115Gln mutation was not found in any of the 1069 subjects screened including 626 obese patients. The frequency of the Pro12Ala mutation was similar in all groups (0.08, 0.11,0.09) and was not associated with BMI or any of the clinical parameters tested.CONCLUSIONS: We conclude that the Pro115Gln mutation is not a frequent cause of morbid obesity in Caucasians and that the Pro12Ala mutation is not associated with clinically significant changes in these populations.

The Pro12Ala variant of peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) is associated with measures of obesity in Mexican Americans

Peroxisome proliferator-activated receptors (PPAR) are transcription factors that regulate adipocyte differentiation and gene expression. We tested the hypothesis that the Pro12Ala variant of PPAR-γ2 is associated with obesity and type 2 diabetes-related traits in 921 subjects from the San Antonio Family Heart Study. Subjects with at least one Ala allele (n=210) had significantly higher body mass index (P=0.015) and waist circumference (P=0.028) and significantly higher levels of serum leptin (P=0.022) than those without the allele. Further studies will determine whether the Pro12Ala variant itself, or other genetic variation at PPAR-γ, is responsible for this association with measures of obesity in Mexican Americans.

Simple Biologically Informed Inflammatory Index of Two Serum Cytokines Predicts 10 Year All-Cause Mortality in Older Adults

BACKGROUND Individual measurements of inflammation have been utilized to assess adverse outcomes risk in older adults with varying degrees of success. This study was designed to identify biologically informed, aggregate measures of inflammation for optimal risk assessment and to inform further biological study of inflammatory pathways. METHODS In total, 15 nuclear factor-kappa B-mediated pathway markers of inflammation were first measured in baseline serum samples of 1,155 older participants in the InCHIANTI population. Of these, C-reactive protein, interleukin-1-receptor antagonist, interleukin-6, interleukin-18, and soluble tumor necrosis factor-α receptor-1 were independent predictors of 5-year mortality. These five inflammatory markers were measured in baseline serum samples of 5,600 Cardiovascular Health Study participants. A weighted summary score, the first principal component summary score, and an inflammation index score were developed from these five log-transformed inflammatory markers, and their prediction of 10-year all-cause mortality was evaluated in Cardiovascular Health Study and then validated in InCHIANTI. RESULTS The inflammation index score that included interleukin-6 and soluble tumor necrosis factor-α receptor-1 was the best predictor of 10-year all-cause mortality in Cardiovascular Health Study, after adjusting for age, sex, education, race, smoking, and body mass index (hazards ratio = 1.62; 95% CI: 1.54, 1.70) compared with all other single and combined measures. The inflammation index score was also the best predictor of mortality in the InCHIANTI validation study (hazards ratio 1.33; 95% CI: 1.17-1.52). Stratification by sex and CVD status further strengthened the association of inflammation index score with mortality. CONCLUSION A simple additive index of serum interleukin-6 and soluble tumor necrosis factor-α receptor-1 best captures the effect of chronic inflammation on mortality in older adults among the 15 biomarkers measured.

Heterogeneity in Rate of Decline in Grip, Hip, and Knee Strength and the Risk of All-Cause Mortality: The Women’s Health and Aging Study II

OBJECTIVES: To assess the relationship between rate of change in muscle strength and all‐cause mortality.

Polymorphisms in the Mitochondrial DNA Control Region and Frailty in Older Adults

Background Mitochondria contribute to the dynamics of cellular metabolism, the production of reactive oxygen species, and apoptotic pathways. Consequently, mitochondrial function has been hypothesized to influence functional decline and vulnerability to disease in later life. Mitochondrial genetic variation may contribute to altered susceptibility to the frailty syndrome in older adults. Methodology/Principal Findings To assess potential mitochondrial genetic contributions to the likelihood of frailty, mitochondrial DNA (mtDNA) variation was compared in frail and non-frail older adults. Associations of selected SNPs with a muscle strength phenotype were also explored. Participants were selected from the Cardiovascular Health Study (CHS), a population-based observational study (1989–1990, 1992–1993). At baseline, frailty was identified as the presence of three or more of five indicators (weakness, slowness, shrinking, low physical activity, and exhaustion). mtDNA variation was assessed in a pilot study, including 315 individuals selected as extremes of the frailty phenotype, using an oligonucleotide sequencing microarray based on the Revised Cambridge Reference Sequence. Three mtDNA SNPs were statistically significantly associated with frailty across all pilot participants or in sex-stratified comparisons: mt146, mt204, and mt228. In addition to pilot participants, 4,459 additional men and women with frailty classifications, and an overlapping subset of 4,453 individuals with grip strength measurements, were included in the study population genotyped at mt204 and mt228. In the study population, the mt204 C allele was associated with greater likelihood of frailty (adjusted odds ratio = 2.04, 95% CI = 1.07–3.60, p = 0.020) and lower grip strength (adjusted coefficient = −2.04, 95% CI = −3.33– −0.74, p = 0.002). Conclusions This study supports a role for mitochondrial genetic variation in the frailty syndrome and later life muscle strength, demonstrating the importance of the mitochondrial genome in complex geriatric phenotypes.

Prediction of Risk of Falling, Physical Disability, and Frailty by Rate of Decline in Grip Strength: The Women's Health and Aging Study

Bishop); Division of General Internal Medicine, Department of Medicine, Mount Sinai School of Medicine, New York (Dr Federman); and Division of General Internal Medicine, Department of Medicine, University of California, San Francisco, San Francisco Veterans Affairs Hospital, San Francisco (Dr Keyhani). Correspondence: Dr Bishop, Department of Public Health, Weill Cornell Medical College, 402 E 67th St, Room LA218, New York, NY 10021 (tlfernan@med.cornell.edu). Author Contributions: Study concept and design: Bishop, Federman, and Keyhani. Analysis and interpretation of data: Bishop and Federman. Drafting of the manuscript: Bishop. Critical revision of the manuscript for important intellectual content: Federman and Keyhani. Statistical analysis: Bishop. Study supervision: Federman and Keyhani. Financial Disclosure: None reported. Funding/Support: This specific project was not grant supported. Drs Federman and Keyhani are supported by grants from the National Institute on Aging; the National Heart, Lung, and Blood Institute; and the Veterans Administration Health Services Research and Development Service. Online-Only Material: The eTable is available at http: //www.archinternmed.com.

IL-6 gene variation is not associated with increased serum levels of IL-6, muscle, weakness, or frailty in older women.

Elevated levels of the inflammatory cytokine IL-6 are associated with the development of disability, frailty, and mortality in older adults. These outcomes are likely mediated through inflammatory activity that alters hormones, skeletal muscle, and the immune system. Polymorphic variants in the IL-6 gene influence IL-6 expression. We hypothesized that IL-6 alleles associate with increased serum of IL-6, decreased muscle strength, and frailty, and tested this in the Womens Health and Aging cohorts. We genotyped 463 participants age 70-79, and identified three common IL-6 haplotype blocks for the Caucasian (n=363) and African American (n=100) subsets. Using linear and logistic regression, and adjusting for age, BMI, race, and osteoarthritis, we identified no significant or clinically meaningful relationship between any single IL-6 single nucleotide polymorphism (SNP) or any IL-6 haplotype and serum IL-6 level, grip, knee, or hip strength, or frailty. Given that the promoter SNP (rs1800795) has been reported to influence IL-6 levels and health outcomes, we performed a similar association study in the In Chianti population (n=266) and confirmed lack of association. These results suggest that IL-6 gene variation may not be an important factor in the determination of elevated IL-6 levels and related phenotypes found in older women.