Bone Microarchitecture in Men and Women with Diabetes: The Importance of Cortical Porosity.

High-resolution peripheral quantitative computed tomography (HR-pQCT) captures novel aspects of bone geometry, volumetric bone mineral density and offers the ability to measure bone microarchitecture, but data relating measures obtained from this technique to diabetic status are inconsistent in women and lacking in men. Here, we report an analysis from the Hertfordshire Cohort Study, where we were able to study associations between bone microarchitecture from HR-pQCT of distal radius and distal tibia in 332 participants (177 men and 155 women) aged 72.1-81.4 years with or without diabetes mellitus (DM); n = 29 (18 men and 11 women) and n = 303, respectively. Statistical analyses were performed separately for women and men. The mean (SD) age of participants was 76.4 (2.6) and 76.1 (2.5) years in women and men, respectively. Participants with DM differed significantly in terms of weight in both women (70.4 ± 12.3 vs. 80.3 ± 18.3 kg; p = 0.015) and men (81.7 ± 11.4 vs. 92.8 ± 16.3 kg; p < 0.001) but no differences were found in height, smoking status, alcohol intake, social class and physical activity among women or men. Analyses in women revealed that cortical pore volume (Ct.Po.V) was higher in participants with DM and close to statistical significance for cortical porosity (Ct.Po) (ß = 0.76 [0.12, 1.41] z-score, p = 0.020 and ß = 0.62 [-0.02, 1.27] z-score, p = 0.059, respectively) at the distal radius. Adjustment for weight did not materially affect the relationship described for Ct.Po.V (ß = 0.74 [0.09, 1.39], p = 0.027) and Ct.Po (ß = 0.65 [-0.01, 1.30], p = 0.053) at the distal radius. After adjustment for weight, analyses in men revealed that Ct.Po and Ct.Po.V were higher in participants with DM (ß = 0.57 [0.09, 1.06] z-score, p = 0.021 and ß = 0.48 [0.01, 0.95] z-score, p = 0.044, respectively) at the distal tibia. Analyses of distal radial and tibial trabecular bone parameters according to diabetic status revealed no significant differences among men or women after adjustment for weight. We found higher cortical porosity and cortical pore volume at the distal tibia in men with DM and higher cortical pore volume at the distal radius in women with a non-significant tendency for higher cortical porosity. The results of our study suggest that deficits in cortical bone exist both in older men and women with DM.

Processed meat consumption and lung function: modification by antioxidants and smoking.

Unhealthy dietary patterns are associated with poor lung function. It is not known whether this is due to low consumption of antioxidant-rich fruit and vegetables, or is a consequence of higher intakes of harmful dietary constituents, such as processed meat. We examined the individual and combined associations of processed meat, fruit and vegetable consumption and dietary total antioxidant capacity (TAC) with lung function among 1551 males and 1391 females in the UK in the Hertfordshire Cohort Study. Diet was assessed using a food frequency questionnaire. After controlling for confounders, processed meat consumption was negatively associated with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio in males and females, while fruit and vegetable consumption and dietary TAC were positively associated with FEV1 and FVC, but not FEV1/FVC ratio. In males, the negative association between processed meat consumption and FEV1 was more marked in those who had low fruit and vegetable consumption (p=0.035 for interaction), and low dietary TAC (p=0.025 for interaction). The deficit in FEV1/FVC associated with processed meat consumption was larger in males who smoked (p=0.022 for interaction). Higher processed meat consumption is associated with poorer lung function, especially in males who have lower fruit and vegetable consumption or dietary TAC, and among current smokers.

Clustering of lifestyle risk factors and poor physical function in older adults: the Hertfordshire cohort study.

OBJECTIVES: To examine the relationship between number of lifestyle risk factors (out of low physical activity, poor diet, obesity, smoking) and physical function in older community-dwelling men and women. DESIGN: Cross-sectional study, Hertfordshire, United Kingdom. PARTICIPANTS: Men (n = 1,682) and women (n = 1,540) aged 59 to 73. MEASUREMENTS: Physical activity was assessed using an administered questionnaire with a score from 0 to 100; low activity was defined as a score of 50 or less. Diet was assessed using a food frequency questionnaire; diet quality was assessed according to a score for a principal component analysis-defined "healthy" dietary pattern. Poor diet was categorized as a dietary pattern score in the lowest quarter of the distribution. Obesity was defined as a body mass index of 30.0 kg/m(2) or more. Physical function was assessed according to self-report (SF-36); poor function was defined as a score in lowest quarter of the distribution. A subgroup of participants had objective assessments of physical function (Timed Up-and-Go Test, timed 3-m walk, chair rises, one-legged standing balance). RESULTS: There was a graded increase in prevalence of poor self-reported physical function in men and women with increasing number of risk factors (men, adjusted odds ratio (AOR) for 3 or 4 risk factors vs none = 3.79, 95% confidence interval (CI) = 2.31-6.21; women, AOR = 5.37, 95% CI = 2.66-10.84). With the exception of balance, the objective assessments also showed graded relationships with number of risk factors, such that more risk factors was associated with poorer physical function. CONCLUSION: These modifiable lifestyle risk factors are linked to marked differences in risk of poorer physical function in older adults. Efforts to encourage healthy lifestyles have the potential to improve physical function and to promote healthier ageing.

Muscle size, strength, and physical performance and their associations with bone structure in the Hertfordshire Cohort Study.

Sarcopenia is associated with a greater fracture risk. This relationship was originally thought to be explained by an increased risk of falls in sarcopenic individuals. However, in addition, there is growing evidence of a functional muscle-bone unit in which bone health may be directly influenced by muscle function. Because a definition of sarcopenia encompasses muscle size, strength, and physical performance, we investigated relationships for each of these with bone size, bone density, and bone strength to interrogate these hypotheses further in participants from the Hertfordshire Cohort Study. A total of 313 men and 318 women underwent baseline assessment of health and detailed anthropometric measurements. Muscle strength was measured by grip strength, and physical performance was determined by gait speed. Peripheral quantitative computed tomography (pQCT) examination of the calf and forearm was performed to assess muscle cross-sectional area (mCSA) at the 66% level and bone structure (radius 4% and 66% levels; tibia 4% and 38% levels). Muscle size was positively associated with bone size (distal radius total bone area ß = 17.5 mm2 /SD [12.0, 22.9]) and strength (strength strain index (ß = 23.3 mm3 /SD [18.2, 28.4]) amongst women (p < 0.001). These associations were also seen in men and were maintained after adjustment for age, height, weight-adjusted-for-height, limb-length-adjusted-for-height, social class, smoking status, alcohol consumption, calcium intake, physical activity, diabetes mellitus, and in women, years since menopause and estrogen replacement therapy. Although grip strength showed similar associations with bone size and strength in both sexes, these were substantially attenuated after similar adjustment. Consistent relationships between gait speed and bone structure were not seen. We conclude that although muscle size and grip strength are associated with bone size and strength, relationships between gait speed and bone structure and strength were not apparent in this cohort, supporting a role for the muscle-bone unit.

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans.

OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.

A study of relationships between single nucleotide polymorphisms from the growth hormone-insulin-like growth factor axis and bone mass: the Hertfordshire cohort study.

OBJECTIVE: We sought evidence of association of candidate single nucleotide polymorphisms (SNP) within the growth hormone-insulin-like growth factor 1 (IGF1) axis, largely selected on the basis of functional data available at the time of our study, with adult bone mass. METHODS: Four hundred ninety-eight men and 468 women aged 59-71 years were recruited. A lifestyle questionnaire was administered, and bone mineral content (BMC) and bone mineral density (BMD) were measured at the lumbar spine and femoral neck. Two hundred fifty-four men and 271 women had repeat bone densitometry 4 years later. DNA was obtained from whole blood samples using standard extraction techniques. Single nucleotide variants in the growth hormone releasing hormone gene (GHRH, G/A 223 Phe75Leu, rs4988492), growth hormone releasing hormone receptor gene (GHRHR, G/A 217, Ala57Thr, rs4988496), the growth hormone secretagogue receptor gene (GHSR, T/C, Gly57Gly, rs495225), and the growth hormone receptor gene (GHR, T/G, noncoding, rs2940944) were analyzed. RESULTS: In both sexes, allelic variation in the gene encoding GHRH was associated with BMC and BMD at the proximal femur and lumbar spine, with results generally stronger in women. In women, the mean BMC lumbar spine within the GHRH 11 genotype was 56.9 g, while that of the GHRH 12 genotype was 68.4 g [p < 0.001, fully adjusted for age, body mass index, cigarette and alcohol consumption, dietary calcium intake, physical activity, years since menopause, and hormone replacement therapy (HRT) use]; corresponding figures for BMD lumbar spine (GHRH 11 genotype) were 0.96 g/cm(2) versus 1.10 g/cm(2) (p < 0.001 fully adjusted). CONCLUSION: We have demonstrated a relationship between allelic variation in the gene encoding GHRH and bone density; we welcome attempts at replication in other populations.

Growth in early life predicts bone strength in late adulthood: the Hertfordshire Cohort Study.

Infant growth is a determinant of adult bone mass, and poor childhood growth is a risk factor for adult hip fracture. Peripheral quantitative computed tomography (pQCT) allows non-invasive assessment of bone strength. We utilised this technology to examine relationships between growth in early life and bone strength. We studied 313 men and 318 women born in Hertfordshire between 1931 and 1939 who were still resident there in adult life, for whom detailed early life records were available. Lifestyle factors were evaluated by questionnaire, anthropometric measurements made, and peripheral QCT examination of the radius and tibia performed (Stratec 4500). Birthweight and conditional weight at 1 year were strongly related to radial and tibial length in both sexes (p<0.001) and to measures of bone strength [fracture load X, fracture load Y, polar strength strain index (SSI)] at both the radius and tibia. These relationships were robust to adjustment for age, body mass index (BMI), social class, cigarette and alcohol consumption, physical activity, dietary calcium intake, HRT use, and menopausal status in women. Among men, BMI was strongly positively associated with radial (r=0.46, p=0.001) and tibial (r=0.24, p=0.006) trabecular bone mineral density (BMD). Current smoking was associated with lower cortical (radius: p=0.0002; tibia: p=0.08) and trabecular BMD (radius: p=0.08; tibia: p=0.04) in males. Similar trends of BMD with these anthropometric and lifestyle variables were seen in women but they were non-significant. Current HRT use was associated with greater female cortical (radius: p=0.0002; tibia: p=0.001) and trabecular (radius: p=0.008; tibia: p=0.04) BMD. Current HRT use was also associated with greater radial strength (polar SSI: p=0.006; fracture load X: p=0.005; fracture load Y: p=0.02) in women. Women who had sustained any fracture since the age of 45 years had lower radial total (p=0.0001), cortical (p<0.005) and trabecular (p=0.0002) BMD, poorer forearm bone strength [polar SSI (p=0.006), fracture load X and Y (p=0.02)], and lower tibial total (p<0.001), cortical (p=0.008), and trabecular (p=0.0001) BMD. We have shown that growth in early life is associated with bone size and strength in a UK population aged 65-73 years. Lifestyle factors were associated with volumetric bone density in this population.