Risk of prevalent and incident dementia associated with insulin-like growth factor and insulin-like growth factor-binding protein 3.

Insulin-like growth factor 1 (IGF-1) influences cell proliferation and survival. In the extracellular environment, IGF-1 circulates bound to proteins (IGF-binding proteins; IGFBP), some of which have physiological effects that seem independent of IGF-1, including the brain (for example, IGFBP-3). We completed a systematic review of the association between dementia and IGF-1 and IGFBP-3, and a cross-sectional and longitudinal study designed to investigate if lower plasma concentration of these proteins increased the risk of prevalent and incident dementia. A total of 3967 men aged 71-89 years joined the study, of whom 535 (13.5%) showed evidence of prevalent cognitive impairment. The plasma concentrations of IGF-1 and IGFBP-3 were similar for men with and without cognitive impairment. The 3432 men free of cognitive impairment were then followed for up to 13 years. During this time 571 (16.6%) developed dementia. The plasma concentration of IGF-1 had no association with incident dementia. The doubling of the plasma concentration of IGFBP-3 decreased the hazard ratio of dementia by 23% (95% confidence interval=5-37%). The results were not affected by age, body mass index and history of smoking, diabetes, hypertension, coronary heart disease or stroke. If these findings are confirmed by others, the plasma concentration of IGFBP-3 could be used to improve the accuracy of predictive models of dementia and as a potential new factor to assist in the development of prevention and treatment strategies.

Serum bicarbonate concentration and the risk of cardiovascular disease and death in type 2 diabetes: the Fremantle Diabetes Study.

BACKGROUND: Serum bicarbonate is associated with mortality, heart failure (HF) and progression of renal failure in studies of healthy people and patients with chronic kidney disease, but the significance of these observations in unselected patients with diabetes in the general population is unknown. The aim of this study was to determine whether serum bicarbonate was associated with mortality and cardiovascular disease risk in type 2 diabetes. METHODS: Baseline serum bicarbonate was available for 1283 well-characterized community-based patients (mean ± SD age 64.1 ± 11.3 years, 48.7 % males) from the longitudinal observational Fremantle Diabetes Study followed for a mean of 12 years. Associations between serum bicarbonate and mortality, coronary heart disease (CHD) and incident HF were analysed using Cox proportional hazards regression. RESULTS: Serum bicarbonate was independently and negatively associated with incident CHD. For each 1 mmol/L increase in bicarbonate, the hazard ratio for CHD was 0.95 (95 % confidence interval 0.92-0.99) after adjustment for age as time scale, age at baseline, sex, English fluency, diabetes duration, loge(serum triglycerides), loge(urinary albumin: creatinine ratio), peripheral sensory neuropathy and peripheral arterial disease. There were no independent associations between serum bicarbonate and all-cause mortality [0.98 (0.95-1.004)] or incident HF [0.99 (0.95-1.03)]. CONCLUSIONS: Serum bicarbonate was a significant independent predictor of incident CHD but not death or HF in community-based patients with type 2 diabetes. This supports intervention trials of bicarbonate replacement in type 2 patients at risk of CHD and who have a low serum bicarbonate concentration.

Associations of insulin-like growth factor-I and its binding proteins and testosterone with frailty in older men.

OBJECTIVE: Ageing is associated with frailty and decreased anabolic hormones, insulin-like growth factor-I (IGF-I) and testosterone. We hypothesized that components of the IGF-I system, in conjunction with testosterone, modulate frailty risk in the elderly. We examined associations between IGF-I, its binding proteins IGFBP1 and IGFBP3 and testosterone with frailty in men. DESIGN: Observational study of 3 447 community-dwelling men aged 70-89 years assessed in 2001-04, with 1 654 reassessed in 2008-09. METHODS: Baseline total IGF-I, IGFBP1, IGFBP3 and testosterone were assayed. Frailty was assessed using the FRAIL scale, comprising 5 domains: fatigue; difficulty climbing stairs; difficulty walking >100 m; >5 illnesses; weight loss >5%. Men with ≥ 3 domains were considered frail. RESULTS: At baseline, 527 men (15·3%) were frail. Frail men had lower IGFBP3 (3 630 ng/ml vs not frail: 3 800 ng/ml, P < 0·001) and comparable IGFBP1 (23·5 vs 21·5 ng/ml, P = 0·09). In multivariate analyses, higher IGFBP1 was associated with increased prevalence of frailty (highest vs lowest quartile Q4:Q1, adjusted odds ratio [OR] = 1·39, 95% CI = 1·03-1·88). New-onset frailty arose in 260 (17·5%) of 1 484 men. Lower baseline IGF-I predicted new-onset frailty (Q1:Q4 OR = 1·48, 95% CI = 1·00-2·20) as did higher IGFBP1 (Q4:Q1 OR = 1·59, 95% CI = 1·01-2·50). Men with both IGF-I and free testosterone in Q1 had greater odds of prevalent frailty (OR = 2·13, 95% CI = 1·54-2·95). CONCLUSIONS: Older men with higher IGFBP1 level, or both lower IGF-I and testosterone, are more likely to be frail, while those with lower IGF-I and higher IGFBP1 are more likely to become frail. Components of the IGF-I system may be biomarkers or independent predictors of frailty.

A five-year prospective study of bone mineral density in men and women with diabetes: the Fremantle Diabetes Study.

To examine longitudinally the effect of diabetes on bone structure and metabolism, we measured bone mineral density (BMD) and turnover markers in 26 type 1 (mean age 49 years) and 27 type 2 (mean age 65 years) diabetic patients without known osteoporosis from a community-based sample at baseline and 5 years later. In the 17 type 1 men, BMD fell at the femoral neck (0.804 ± 0.145 vs. 0.769 ± 0.129 g/cm(2); P = 0.003) with no change at lumbar spine or forearm. In the 11 type 2 women, BMD decreased at all sites except spine (femoral neck 0.779 ± 0.119 vs. 0.742 ± 0.090 g/cm(2); P = 0.019). BMD did not fall at any site in type 1 women or type 2 men. There was an increase in serum alkaline phosphatase and trend to higher serum beta carboxyl-terminal type I collagen telopeptide concentrations in the type 1 patients, and a decrease in free testosterone in the type 1 men. These data show that the rate of demineralization at the femoral neck in type 1 men is similar to that in older post-menopausal type 2 women. Changes in biochemical markers suggest that, in type 1 men, there is ineffective bone formation associated with accelerated bone resorption and lower sex steroid bioavailability. These findings may have implications for the clinical management of young male adults with diabetes.