O’Brien, Peter C.

OBJECTIVE Reductions in insulin sensitivity in conjunction with muscle mitochondrial dysfunction have been reported to occur in many conditions including aging. The objective was to determine whether insulin resistance and mitochondrial dysfunction are directly related to chronological age or are related to age-related changes in body composition. RESEARCH DESIGN AND METHODS Twelve young lean, 12 young obese, 12 elderly lean, and 12 elderly obese sedentary adults were studied. Insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp, and skeletal muscle mitochondrial ATP production rates (MAPRs) were measured in freshly isolated mitochondria obtained from vastus lateralis biopsy samples using the luciferase reaction. RESULTS Obese participants, independent of age, had reduced insulin sensitivity based on lower rates of glucose infusion during a hyperinsulinemic-euglycemic clamp. In contrast, age had no independent effect on insulin sensitivity. However, the elderly participants had lower muscle MAPRs than the young participants, independent of obesity. Elderly participants also had higher levels inflammatory cytokines and total adiponectin. In addition, higher muscle MAPRs were also noted in men than in women, whereas glucose infusion rates were higher in women. CONCLUSIONS The results demonstrate that age-related reductions in insulin sensitivity are likely due to an age-related increase in adiposity rather than a consequence of advanced chronological age. The results also indicate that an age-related decrease in muscle mitochondrial function is neither related to adiposity nor insulin sensitivity. Of interest, a higher mitochondrial ATP production capacity was noted in the men, whereas the women were more insulin sensitive, demonstrating further dissociation between insulin sensitivity and muscle mitochondrial function.

Context: Aging, low dehydroepiandrosterone (DHEA), and testosterone are associated with increased adiposity and metabolic risk. Treatment with these hormones may improve these abnormalities. Objective: The objective of the study was to determine effects of aging, DHEA, or testosterone replacement on adiposity, meal fat partitioning, and postabsorptive lipolysis. Design: This was a cross-sectional, 2-yr, double-blind, randomized, placebo-controlled trial. Setting: The study was conducted in the general community. Patients: Elderly women and men (≥60 yr) with low DHEA sulfate (women and men) and bioavailable testosterone (men) concentrations and young adults. Interventions: Thirty elderly women each received 50 mg DHEA or placebo daily for 2 yr. Thirty elderly men received 75 mg DHEA, 29 received 5 mg testosterone (patch), and 32 received placebo daily for 2 yr. Thirty young women and 32 young men served as controls. Main Outcome Measures: In vivo measures of meal fat storage into sc fat, postabsorptive lipolysis, and regional adiposity at baseline and after treatment. Results: At baseline, the elderly had more body fat, greater systemic lipolysis (women, P = 0.0003; men, P < 0.0001) adjusted for resting energy expenditure, greater meal fat oxidation (women, P = 0.026; men, P = 0.0025), and less meal fat storage in sc fat (women, P = 0.0139; men, P= 0.0006). Although testosterone treatment increased meal fat storage into upper- vs. lower-body fat in elderly men, neither hormone affected regional adiposity, meal fat oxidation, or systemic lipolysis. Conclusions: Aging, in the context of low DHEA sulfate (women and men) and bioavailable testosterone (men) concentrations, is associated with changes in meal fat partitioning and postabsorptive lipolysis that are not corrected by DHEA and only partly corrected by testosterone replacement. DHEA or testosterone treatment of hormone-deficient elderly does not normalize adipose tissue lipolysis, but testosterone restores a “youthful” meal fat storage pattern in elderly men.

We investigated age and sex effects and determined whether androgen replacement in elderly individuals (≥60 yr) could augment protein synthesis. Thirty young men and 32 young women (18‐31 yr) were studied once, whereas 87 elderly men were studied before and after 1 yr of treatment with 5 mg/day testosterone (T), 75 mg/day dehydroepiandrosterone (DHEA), or placebo (P);and 57 elderly women were studied before and after 1 yr of treatment with 50 mg/day DHEA or P. [ 15 N]Phenylalanine and [ 2 H 4 ]tyrosine tracers were infused, with measurements in plasma and vastus lateralis muscle. Whole‐body protein synthesis per fat‐free mass and muscle protein fractional synthesis rate (FSR) were lower in elderly than in young individuals (P< 0.001), not significantly affected by hormone treatments, and higher in women than in men (P<0.0001), with no sex × age interaction. In regression analyses, peak O 2 consumption (VO 2peak ), resting energy expenditure (REE), and sex were independently associated with muscle FSR, as were VO 2peak , REE, and interactions of sex with insulin‐like growth factor‐II and insulin for whole‐body protein synthesis. Women maintain higher protein synthesis than men across the lifespan as rates decline in both sexes, and neither full replacement of DHEA (in elderly men and women) nor partial replacement of bioavailable T (in elderly men) is able to amend the age‐related declines.— Henderson, G. C., Dhatariya, K., Ford, G. C., Klaus, K. A., Basu, R., Rizza, R. A., Jensen, M. D., Khosla, S., O'Brien, P., Nair, K. S. Higher muscle protein synthesis in women than men across the lifespan, and failure of androgen administration to amend age‐related decrements. FASEB J. 23, 631–641 (2009)

Background and Purpose — We sought to determine pedigree availability for a concordant sibling pair study of genetic risk factors in ischemic stroke. Methods — Probands with confirmed ischemic stroke were prospectively enrolled. Family histories were obtained by systematic interview. A study neurologist prospectively assigned stroke subtype. Results — Of 310 probands (median age, 75 years; range, 26 to 97 years; 48% women), 75% had at least 1 living sibling; 10%, at least 1 concordant living sibling; 2%, at least 1 concordant sibling living in the same city; and 7%, at least 1 concordant living and 1 discordant living sibling. Likelihood of having a concordant sibling increased significantly with proband age, even after adjustment for sibship size ( P =0.002). Positive family history of stroke was not related to either proband stroke subtype or risk factor profile. Conclusions — Approximately 10 probands were screened to find 1 potentially concordant living sibling. A concordant sibling pair study should be multicentered and enable enrollment of siblings from diverse geographic areas.

OBJECTIVE—Assessing clinimetric performance of diabetic sensorimotor polyneuropathy (DSPN) end points in single and multicenter trials. RESEARCH DESIGN AND METHODS—Assessed were placebo-treated patients with DSPN in the Viatris and Eli Lilly trials and an epidemiologic cohort. RESULTS—Test reproducibility in clinical trial cohorts (rI ∼ 0.7–0.85) approached that in the epidemiologic cohort (rI ∼ 0.85–0.95). Associations between pairs of end points explained &lt;10% of the variability of data (sometimes 15–35%), being higher in the epidemiologic cohort and the Viatris trial than in the Lilly trial. Most end points did not show monotonic worsening over 4 years. However, sural nerve amplitude and peroneal motor conduction velocity did. A nerve conduction score (Σ 5 NC nds [5 attributes of nerve conduction expressed as normal deviates]) did not show monotonic worsening in established DSPN. In the epidemiologic cohort followed for 9.5 years, monotonic worsening of small magnitude occurred for sural amplitude, vibration detection threshold, and especially for composite quantitative sensation. CONCLUSIONS—The main reason why it is difficult to demonstrate monotonic worsening of neuropathic end points appears to be a very slow worsening of DSPN, a placebo effect for symptoms and signs, and measurement noise. Demonstrating disease progression in controlled trials of DSPN is more likely when 1) patients with developing rather than established DSPN are selected, 2) type 1 diabetic patients are preferentially recruited, 3) patients are selected who cannot or will not achieve ideal glycemic control, 4) end points chosen are known to show monotonic worsening, and 5) a restricted number of centers and expert examiners (trained, certified, using standard approaches, and reference values and interactive surveillance of tests) are used.

Alzheimer disease and type 2 diabetes are characterized by increased prevalence with aging, a genetic predisposition, and comparable pathological features in the islet and brain (amyloid derived from amyloid β protein in the brain in Alzheimer disease and islet amyloid derived from islet amyloid polypeptide in the pancreas in type 2 diabetes). Evidence is growing to link precursors of amyloid deposition in the brain and pancreas with the pathogenesis of Alzheimer disease and type 2 diabetes, respectively. Given these similarities, we questioned whether there may be a common underlying mechanism predisposing to islet and cerebral amyloid. To address this, we first examined the prevalence of type 2 diabetes in a community-based controlled study, the Mayo Clinic Alzheimer Disease Patient Registry (ADPR), which follows patients with Alzheimer disease versus control subjects without Alzheimer disease. In addition to this clinical study, we performed a pathological study of autopsy cases from this same community to determine whether there is an increased prevalence of islet amyloid in patients with Alzheimer disease and increased prevalence of cerebral amyloid in patients with type 2 diabetes. Patients who were enrolled in the ADPR (Alzheimer disease n = 100, non-Alzheimer disease control subjects n = 138) were classified according to fasting glucose concentration (FPG) as nondiabetic (FPG &lt;110 mg/dl), impaired fasting glucose (IFG, FPG 110–125 mg/dl), and type 2 diabetes (FPG &gt;126 mg/dl). The mean slope of FPG over 10 years in each case was also compared between Alzheimer disease and non-Alzheimer disease control subjects. Pancreas and brain were examined from autopsy specimens obtained from 105 humans (first, 28 cases of Alzheimer disease disease vs. 21 non-Alzheimer disease control subjects and, second, 35 subjects with type 2 diabetes vs. 21 non-type 2 diabetes control subjects) for the presence of islet and brain amyloid. Both type 2 diabetes (35% vs. 18%; P &lt; 0.05) and IFG (46% vs. 24%; P &lt; 0.01) were more prevalent in Alzheimer disease versus non-Alzheimer disease control subjects, so 81% of cases of Alzheimer disease had either type 2 diabetes or IFG. The slope of increase of FPG with age over 10 years was also greater in Alzheimer disease than non-Alzheimer disease control subjects (P &lt; 0.01). Islet amyloid was more frequent (P &lt; 0.05) and extensive (P &lt; 0.05) in patients with Alzheimer disease than in non-Alzheimer disease control subjects. However, diffuse and neuritic plaques were not more common in type 2 diabetes than in control subjects. In cases of type 2 diabetes when they were present, the duration of type 2 diabetes correlated with the density of diffuse (P &lt; 0.001) and neuritic plaques (P &lt; 0.01). In this community cohort from southeast Minnesota, type 2 diabetes and IFG are more common in patients with Alzheimer disease than in control subjects, as is the pathological hallmark of type 2 diabetes, islet amyloid. However, there was no increase in brain plaque formation in cases of type 2 diabetes, although when it was present, it correlated in extent with duration of diabetes. These data support the hypothesis that patients with Alzheimer disease are more vulnerable to type 2 diabetes and the possibility of linkage between the processes responsible for loss of brain cells and β-cells in these diseases.