Proximal correlates of metabolic phenotypes during 'at-risk' and 'case' stages of the metabolic disease continuum.

OBJECTIVE: To examine the social and behavioural correlates of metabolic phenotypes during 'at-risk' and 'case' stages of the metabolic disease continuum. DESIGN: Cross-sectional study of a random population sample. PARTICIPANTS: A total of 718 community-dwelling adults (57% female), aged 18-92 years from a regional South Australian city. MEASUREMENTS: Total body fat and lean mass and abdominal fat mass were assessed by dual energy x-ray absorptiometry. Fasting venous blood was collected in the morning for assessment of glycated haemoglobin, plasma glucose, serum triglycerides, cholesterol lipoproteins and insulin. Seated blood pressure (BP) was measured. Physical activity and smoking, alcohol and diet (96-item food frequency), sleep duration and frequency of sleep disordered breathing (SDB) symptoms, and family history of cardiometabolic disease, education, lifetime occupation and household income were assessed by questionnaire. Current medications were determined by clinical inventory. RESULTS: 36.5% were pharmacologically managed for a metabolic risk factor or had known diabetes ('cases'), otherwise were classified as the 'at-risk' population. In both 'at-risk' and 'cases', four major metabolic phenotypes were identified using principal components analysis that explained over 77% of the metabolic variance between people: fat mass/insulinemia (FMI); BP; lipidaemia/lean mass (LLM) and glycaemia (GLY). The BP phenotype was uncorrelated with other phenotypes in 'cases', whereas all phenotypes were inter-correlated in the 'at-risk'. Over and above other socioeconomic and behavioural factors, medications were the dominant correlates of all phenotypes in 'cases' and SDB symptom frequency was most strongly associated with FMI, LLM and GLY phenotypes in the 'at-risk'. CONCLUSION: Previous research has shown FMI, LLM and GLY phenotypes to be most strongly predictive of diabetes development. Reducing SDB symptom frequency and optimising the duration of sleep may be important concomitant interventions to standard diabetes risk reduction interventions. Prospective studies are required to examine this hypothesis.

Testosterone modulates gene expression pathways regulating nutrient accumulation, glucose metabolism and protein turnover in mouse skeletal muscle.

Testosterone regulates energy metabolism and skeletal muscle mass in males, but the molecular mechanisms are not fully understood. This study investigated the response of skeletal muscle to castration and testosterone replacement in 8-week-old male mice. Using microarray analyses of mRNA levels in gastrocnemius muscle, 91 genes were found to be negatively regulated by testosterone and 68 genes were positively regulated. The mRNA levels of the insulin signalling suppressor molecule Grb10 and the glycogen synthesis inhibitors, protein phosphatase inhibitor-1 and phosphorylase kinase-γ, were negatively regulated by testosterone. The insulin-sensitive glucose and amino acid transporters, Glut3 and SAT2, the lipodystrophy gene, Lpin1 and protein targeting to glycogen were positively regulated. These changes would be expected to increase nutrient availability and sensing within skeletal muscle, increase metabolic rate and carbohydrate utilization and promote glycogen accumulation. The observed positive regulation of atrogin-1 (Fbxo32) by testosterone could be explained by the phosphorylation of Akt and Foxo3a, as determined by Western blotting. Testosterone prevented the castration-induced increase in interleukin-1α, the decrease in interferon-γ and the atrophy of the levator ani muscle, which were all correlated with testosterone-regulated gene expression. These findings identify specific mechanisms by which testosterone may regulate skeletal muscle glucose and protein metabolism.

Testosterone, aging and quality of life.

Testosterone levels decline over the lifespan. Many symptoms of hypogonadism are similar to age-related changes in older males. A small number of studies have suggested that some of these symptoms may be reversed by testosterone. Among them, one trial has suggested that decline in bioavailable testosterone may be related to the development of functional decline. Testosterone replacement during rehabilitation may improve functional outcomes and plays an important role in the maintenance of sexual related quality of life. The overall improvement in well-being and/or health-related quality of life in older males needs to be determined with large placebo-controlled trials. This is particularly important in view of the substantial placebo effect on aging symptomatology.

Frailty and the aging male.

Frailty occurs in aging males for a variety of reasons. It is less common in males than females. Diseases which are particularly associated with frailty are diabetes mellitus, atherosclerosis, anemia and chronic obstructive pulmonary disease. Insulin resistance syndrome plays a pathogenetic role in the "fat-frail" syndrome. Sarcopenia occurs predominantly because of hormone deficiency and cytokine excess. Pain and anorexia are also associated with frailty. Stem cell research represents a potential promise for the treatment of frailty.

Defining 'relative' androgen deficiency in aging men: how should testosterone be measured and what are the relationships between androgen levels and physical, sexual and emotional health?

In men, bioavailable and free testosterone levels decline by about 1.0 and 1.2% per year, respectively, after the age of 40. The definition of clinically relevant androgen deficiency in the aging male remains uncertain. Clinical features common to both aging and androgen deficiency include decreased muscle mass and strength, and increased fatigue, increased fat mass, loss of libido, erectile dysfunction, impaired cognitive function and depression. It is, however, difficult to separate the effect on plasma testosterone of concomitant disease, compared with the effects of a decrease in testosterone levels alone. Testosterone supplementation has been shown to be effective in improving many of the clinical features of androgen deficiency in the older male, and is safe, at least in the short term. The maximum benefit occurs in those men with the lowest testosterone levels.