Liver fat and sex hormone binding globulin affect insulin resistance in perimenopausal women: The Study of Women Across the Nation (SWAN)

Liver fat is recognized as a separate and important contributor to metabolic disease development. The liver is an insulin responsive tissue that contributes significantly to both whole body insulin sensitivity and availability of sex steroids through the production of sex hormone binding globulin (SHBG). Our objective was to describe the relationship between ectopic liver fat, insulin resistance, and hormonal profile in perimenopausal women. The Study of Women Across the Nation (SWAN) is a cross sectional multiethnic population of women recruited from multiple geographic areas during their perimenopausal years for longitudinal evaluation. A subset of women from SWAN (n=208) were evaluated from the Pittsburgh site as part of the SWAN-Heart study. Women had computed tomography scans to quantify visceral and subcutaneous adipose tissue, and liver fat. Adiposity measures, blood pressure, and menopausal stage, based on cycle irregularity, were recorded. Blood samples were collected and measured for hormonal and metabolic endpoints. We found in this overweight but healthy cohort that liver fat and SHBG were unaffected by menopausal stage or race. Both endpoints remained significantly associated with insulin after adjustment for adiposity. SHBG and liver fat had interactive effects on measured insulin concentration. Other sex hormones were not significantly associated with metabolic endpoints. Only liver fat accounted for differences in insulin across increasing SHBG quartiles, suggesting ectopic liver fat modifies SHBG. Both higher liver fat and lower SHBG have consequences for insulin sensitivity and the role of liver fat in modifying SHBG should be explored.Master of Public Healt

Type-2-diabetes alters CSF but not plasma metabolomic and AD risk profiles in vervet monkeys

Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a twofold to fourfold increased risk for developing Alzheimer's disease (AD), however, the exact mechanisms linking the two diseases are unknown. In both conditions, the majority of pathophysiological changes, including glucose and insulin dysregulation, insulin resistance, and AD-related changes in Aβ and tau, occur decades before the onset of clinical symptoms and diagnosis. In this study, we investigated the relationship between metabolic biomarkers associated with T2D and amyloid pathology including Aβ levels, from cerebrospinal fluid (CSF) and fasting plasma of healthy, pre-diabetic (PreD), and T2D vervet monkeys (Chlorocebus aethiops sabaeus). Consistent with the human disease, T2D monkeys have increased plasma and CSF glucose levels as they transition from normoglycemia to PreD and diabetic states. Although plasma levels of acylcarnitines and amino acids remained largely unchanged, peripheral hyperglycemia correlated with decreased CSF acylcarnitines and CSF amino acids, including branched chain amino acid (BCAA) concentrations, suggesting profound changes in cerebral metabolism coincident with systemic glucose dysregulation. Moreover, CSF Aβ 40 and CSF Aβ 42 levels decreased in T2D monkeys, a phenomenon observed in the human course of AD which coincides with increased amyloid deposition within the brain. In agreement with previous studies in mice, CSF Aβ 40 and CSF Aβ 42 were highly correlated with CSF glucose levels, suggesting that glucose levels in the brain are associated with changes in Aβ metabolism. Interestingly, CSF Aβ 40 and CSF Aβ 42 levels were also highly correlated with plasma but not CSF lactate levels, suggesting that plasma lactate might serve as a potential biomarker of disease progression in AD. Moreover, CSF glucose and plasma lactate levels were correlated with CSF amino acid and acylcarnitine levels, demonstrating alterations in cerebral metabolism occurring with the onset of T2D. Together, these data suggest that peripheral metabolic changes associated with the development of T2D produce alterations in brain metabolism that lead to early changes in the amyloid cascade, similar to those observed in pre-symptomatic AD

Dietary Cholesterol Promotes Adipocyte Hypertrophy and Adipose Tissue Inflammation in Visceral, But Not Subcutaneous, Fat in Monkeys

Objective—Excessive caloric intake is associated with obesity and adipose tissue dysfunction. However, the role of dietary cholesterol in this process is unknown. The aim of this study was to determine whether increasing dietary cholesterol intake alters adipose tissue cholesterol content, adipocyte size, and endocrine function in nonhuman primates. Approach and Results—Age-matched, male African Green monkeys (n=5 per group) were assigned to one of three diets containing 0.002 (Lo), 0.2 (Med) or 0.4 (Hi) mg cholesterol/Kcal. After 10 weeks of diet feeding, animals were euthanized for adipose tissue, liver, and plasma collection. With increasing dietary cholesterol, free cholesterol (FC) content and adipocyte size increased in a step-wise manner in visceral, but not subcutaneous fat, with a significant association between visceral adipocyte size and FC content (r2=0.298; n=15; p=0.035). In visceral fat, dietary cholesterol intake was associated with: 1) increased pro-inflammatory gene expression and macrophage recruitment, 2) decreased expression of genes involved in cholesterol biosynthesis and lipoprotein uptake, and 3) increased expression of proteins involved in FC efflux. Conclusions—Increasing dietary cholesterol selectively increases visceral fat adipocyte size, FC and macrophage content, and proinflammatory gene expression in nonhuman primates

Ongoing β-Cell Turnover in Adult Nonhuman Primates Is Not Adaptively Increased in Streptozotocin-Induced Diabetes

OBJECTIVE: \u3b2-Cell turnover and its potential to permit \u3b2-cell regeneration in adult primates are unknown. Our aims were 1) to measure \u3b2-cell turnover in adult nonhuman primates; 2) to establish the relative contribution of \u3b2-cell replication and formation of new \u3b2-cells from other precursors (defined thus as \u3b2-cell neogenesis); and 3) to establish whether there is an adaptive increase in \u3b2-cell formation (attempted regeneration) in streptozotocin (STZ)-induced diabetes in adult nonhuman primates. RESEARCH DESIGN AND METHODS: Adult (aged 7 years) vervet monkeys were administered STZ (45-55 mg/kg, n = 7) or saline (n = 9). Pancreas was obtained from each animal twice, first by open surgical biopsy and then by euthanasia. \u3b2-Cell turnover was evaluated by applying a mathematic model to measured replication and apoptosis rates. RESULTS: \u3b2-Cell turnover is present in adult nonhuman primates (3.3 \ub1 0.9 mg/month), mostly (~80%) derived from \u3b2-cell neogenesis. \u3b2-Cell formation was minimal in STZ-induced diabetes. Despite marked hyperglycemia, \u3b2-cell apoptosis was not increased in monkeys administered STZ. CONCLUSIONS: There is ongoing \u3b2-cell turnover in adult nonhuman primates that cannot be accounted for by \u3b2-cell replication. There is no evidence of \u3b2-cell regeneration in monkeys administered STZ. Hyperglycemia does not induce \u3b2-cell apoptosis in nonhuman primates in vivo

Wellbeing intervention for chronic kidney disease (WICKD): a randomised controlled trial study protocol

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were madeBackground Incidence of end stage kidney disease (ESKD) for Indigenous Australians is especially high in remote and very remote areas of Australia (18 and 20 times the rate of comparable non-Indigenous people). Relocating away from family and country for treatment, adjusting to life with a chronic condition and time lost to dialysis cause grief and sadness which have immense impact on quality of life and challenges treatment adherence. We describe the first randomised controlled trial to address both chronic disease and mental health in Indigenous people with ESKD, which is the first to test the effectiveness of a culturally adapted e-mental health intervention in this population. It builds on an existing program of mental health research with demonstrated efficacy – the Aboriginal and Islander Mental Health Initiative (AIMhi) – to test the newly developed electronic motivational care planning (MCP) therapy – the AIMhi Stay Strong App. Methods This is a 3-arm, waitlist, single-blind randomised controlled trial testing the efficacy of the Stay Strong App in improving psychological distress, depressive symptoms, quality of life and treatment adherence among Indigenous clients undergoing haemodialysis for ESKD in Alice Springs and Darwin with follow up over two periods of 3 months (total of 6 months observation). The study compares the efficacy of MCP using the AIMhi Stay Strong App with two control groups (control app intervention and treatment as usual) on participant-reported psychological distress (the primary outcome) using the Kessler Distress Scale (K10); depressive symptoms using the adapted Patient Health Questionnaire (PHQ-9); quality of life using the EuroQoL instrument (EQ5D) and adherence to dialysis treatment planning through file audit. Participants are randomised to receive MCP either at baseline (early treatment) or after 3 months (delayed treatment). The study also examines the cost effectiveness of this therapy in this setting through examination of health care service utilisation across groups during the first 3 months. Discussion This project will contribute much needed evidence on the efficacy of an electronic wellbeing intervention for Indigenous people with ESKD – a group in which distress is likely to be unacceptably high, yet relatively untreated

17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex.

In genetically heterogeneous mice produced by the CByB6F1 x C3D2F1 cross, the non-feminizing estrogen, 17-α-estradiol (17aE2), extended median male lifespan by 19% (p \u3c 0.0001, log-rank test) and 11% (p = 0.007) when fed at 14.4 ppm starting at 16 and 20 months, respectively. 90th percentile lifespans were extended 7% (p = 0.004, Wang-Allison test) and 5% (p = 0.17). Body weights were reduced about 20% after starting the 17aE2 diets. Four other interventions were tested in males and females: nicotinamide riboside, candesartan cilexetil, geranylgeranylacetone, and MIF098. Despite some data suggesting that nicotinamide riboside would be effective, neither it nor the other three increased lifespans significantly at the doses tested. The 17aE2 results confirm and extend our original reports, with very similar results when started at 16 months compared with mice started at 10 months of age in a prior study. The consistently large lifespan benefit in males, even when treatment is started late in life, may provide information on sex-specific aspects of aging

The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

<i>Lactobacillus acidophilus</i> DDS-1 Modulates the Gut Microbial Co-Occurrence Networks in Aging Mice

Age-related alterations in the gut microbiome composition and its impacts on the host’s health have been well-described; however, detailed analyses of the gut microbial structure defining ecological microbe–microbe interactions are limited. One of the ways to determine these interactions is by understanding microbial co-occurrence patterns. We previously showed promising abilities of Lactobacillus acidophilus DDS-1 on the aging gut microbiome and immune system. However, the potential of the DDS-1 strain to modulate microbial co-occurrence patterns is unknown. Hence, we aimed to investigate the ability of L. acidophilus DDS-1 to modulate the fecal-, mucosal-, and cecal-related microbial co-occurrence networks in young and aging C57BL/6J mice. Our Kendall’s tau correlation measures of co-occurrence revealed age-related changes in the gut microbiome, which were characterized by a reduced number of nodes and associations across sample types when compared to younger mice. After four-week supplementation, L. acidophilus DDS-1 differentially modulated the overall microbial community structure in fecal and mucosal samples as compared to cecal samples. Beneficial bacteria such as Lactobacillus, Oscillospira, and Akkermansia acted as connectors in aging networks in response to L. acidophilus DDS-1 supplementation. Our findings provided the first evidence of the DDS-1-induced gut microbial ecological interactions, revealing the complex structure of microbial ecosystems with age