Physiology - Research Publications
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ItemCeramides Contained in LDL Are Elevated in Type 2 Diabetes and Promote Inflammation and Skeletal Muscle Insulin Resistance(AMER DIABETES ASSOC, 2013-02)Dysregulated lipid metabolism and inflammation are linked to the development of insulin resistance in obesity, and the intracellular accumulation of the sphingolipid ceramide has been implicated in these processes. Here, we explored the role of circulating ceramide on the pathogenesis of insulin resistance. Ceramide transported in LDL is elevated in the plasma of obese patients with type 2 diabetes and correlated with insulin resistance but not with the degree of obesity. Treating cultured myotubes with LDL containing ceramide promoted ceramide accrual in cells and was accompanied by reduced insulin-stimulated glucose uptake, Akt phosphorylation, and GLUT4 translocation compared with LDL deficient in ceramide. LDL-ceramide induced a proinflammatory response in cultured macrophages via toll-like receptor-dependent and -independent mechanisms. Finally, infusing LDL-ceramide into lean mice reduced insulin-stimulated glucose uptake, and this was due to impaired insulin action specifically in skeletal muscle. These newly identified roles of LDL-ceramide suggest that strategies aimed at reducing hepatic ceramide production or reducing ceramide packaging into lipoproteins may improve skeletal muscle insulin action.
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ItemSugar- and Intense-Sweetened Drinks in Australia: A Systematic Review on Cardiometabolic Risk(MDPI, 2017-10)Sugar-sweetened beverages (SSBs) are consumed globally, and have been associated with adverse health outcomes, including weight gain, high blood pressure, type 2 diabetes (T2D), and cardiovascular disease (CVD). There is global variation in beverage formulation in terms of glucose and fructose concentration, which may pose unique health risks linked to glycemic control for Australian consumers. However, previous systematic reviews have overlooked Australian-based literature. A systematic review was performed to synthesise evidence for the associations between consumption of SSBs and intense-sweetened beverages with clinical cardiometabolic risk factors in the Australian population. Articles were sourced from Global Health, Health Source: Nursing/Academic Edition, Medline, and Culmative Index to Nursing and Allied Health Literature. To be eligible for review, studies had to report on the consumption of sugar-sweetened (including fruit juice and fruit drinks) and/or intense-sweetened beverages, and at least one clinical cardiometabolic risk factor. Eighteen studies were included in this review. Research has mostly focused on the relationship between SSB consumption and adiposity-related outcomes. No studies have examined indices of glycaemic control (glucose/insulin), and the evidence for the health impact of intense-sweetened drinks is limited. In addition, studies have primarily been of cross-sectional design, and have examined children and adolescents, as opposed to adult populations. In the Australian population, there is modest but consistent evidence that SSB consumption has adverse associations with weight, but there is insufficient data to assess relationships with cardiometabolic outcomes.
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ItemMicroRNA-194 Modulates Glucose Metabolism and Its Skeletal Muscle Expression Is Reduced in Diabetes(PUBLIC LIBRARY SCIENCE, 2016-05-10)BACKGROUND: The regulation of microRNAs (miRNAs) at different stages of the progression of type 2 diabetes mellitus (T2DM) and their role in glucose homeostasis was investigated. METHODS: Microarrays were used to assess miRNA expression in skeletal muscle biopsies taken from healthy individuals and patients with pre-diabetes or T2DM, and insulin resistant offspring of rat dams fed a high fat diet during pregnancy. RESULTS: Twenty-three miRNAs were differentially expressed in patients with T2DM, and 7 in the insulin resistant rat offspring compared to their controls. Among these, only one miRNA was similarly regulated: miR-194 expression was significantly reduced by 25 to 50% in both the rat model and in human with pre-diabetes and established diabetes. Knockdown of miR-194 in L6 skeletal muscle cells induced an increase in basal and insulin-stimulated glucose uptake and glycogen synthesis. This occurred in conjunction with an increased glycolysis, indicated by elevated lactate production. Moreover, oxidative capacity was also increased as we found an enhanced glucose oxidation in presence of the mitochondrial uncoupler FCCP. When miR-194 was down-regulated in vitro, western blot analysis showed an increased phosphorylation of AKT and GSK3β in response to insulin, and an increase in expression of proteins controlling mitochondrial oxidative phosphorylation. CONCLUSIONS: Type 2 diabetes mellitus is associated with regulation of several miRNAs in skeletal muscle. Interestingly, miR-194 was a unique miRNA that appeared regulated across different stages of the disease progression, from the early stages of insulin resistance to the development of T2DM. We have shown miR-194 is involved in multiple aspects of skeletal muscle glucose metabolism from uptake, through to glycolysis, glycogenesis and glucose oxidation, potentially via mechanisms involving AKT, GSK3 and oxidative phosphorylation. MiR-194 could be down-regulated in patients with early features of diabetes as an adaptive response to facilitate tissue glucose uptake and metabolism in the face of insulin resistance.
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ItemStatin action favors normalization of the plasma lipidome in the atherogenic mixed dyslipidemia of MetS: potential relevance to statin-associated dysglycemia(ELSEVIER, 2015-12)The impact of statin treatment on the abnormal plasma lipidome of mixed dyslipidemic patients with metabolic syndrome (MetS), a group at increased risk of developing diabetes, was evaluated. Insulin-resistant hypertriglyceridemic hypertensive obese males (n = 12) displaying MetS were treated with pitavastatin (4 mg/day) for 180 days; healthy normolipidemic age-matched nonobese males (n = 12) acted as controls. Statin treatment substantially normalized triglyceride (-41%), remnant cholesterol (-55%), and LDL-cholesterol (-39%), with minor effect on HDL-cholesterol (+4%). Lipidomic analysis, normalized to nonHDL-cholesterol in order to probe statin-induced differences in molecular composition independently of reduction in plasma cholesterol, revealed increment in 132 of 138 lipid species that were subnormal at baseline and significantly shifted toward the control group on statin treatment. Increment in alkyl- and alkenylphospholipids (plasmalogens) was prominent, and consistent with significant statin-induced increase in plasma polyunsaturated fatty acid levels. Comparison of the statin-mediated lipidomic changes in MetS with the abnormal plasma lipidomic profile characteristic of prediabetes and T2D in the Australian Diabetes, Obesity, and Lifestyle Study and San Antonio Family Heart Study cohorts by hypergeometric analysis revealed a significant shift toward the lipid profile of controls, indicative of a marked trend toward a normolipidemic phenotype. Pitavastatin attenuated the abnormal plasma lipidome of MetS patients typical of prediabetes and T2D.
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ItemSex-Specific Associations in Nutrition and Activity-Related Risk Factors for Chronic Disease: Australian Evidence from Childhood to Emerging Adulthood.(MDPI AG, 2018-01-26)Global assessments of burden of disease suggests there are sex differences in risk factors for chronic disease, including overweight/obesity, dietary patterns and habitual physical activity. Given that prevention efforts aim to target such factors to reduce disease risk, the age at which sex differences may occur is of particular interest. Early life to young adulthood is the optimal time for intervention, with lifestyle habits typically forming during this period. This study aimed to identify the sex differences in risk factors for chronic disease during childhood (5-9 years), adolescence (10-17 years) and emerging adulthood (18-25 years) in a large population-representative Australian sample. Among children in this study (n = 739), no sex-related differences were observed. Among adolescents (n = 1304), females were more likely than males to meet daily fruit and vegetable recommendations (12.9% vs. 7.5%; OR = 1.84, 95% CI = 1.16, 2.93, p < 0.05). Among emerging adults (n = 909), females were less likely to be overweight/obese (30.1% vs. 39.8%; OR = 0.65, 95% CI = 0.44, 0.95, p < 0.05) and more likely to meet physical activity recommendations (52.1% vs. 42.3%; OR = 1.44, 95% CI = 1.01, 2.06, p < 0.05). These findings suggest that sex differences for risk factors of chronic disease occur during adolescence and emerging adulthood, although the differences are not consistent across age periods. From adolescence onwards, it appears that females exhibit lower risk factors than males and a life span approach to risk factor monitoring is warranted.
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ItemFasting Plasma Glucose, Self-Appraised Diet Quality and Depressive Symptoms: A US-Representative Cross-Sectional Study.(MDPI AG, 2017-12-07)Depression and type 2 diabetes (T2D) contribute significantly to global burden of disease and often co-occur. Underpinning type 2 diabetes is poor glycaemic control and glucose is also an obligatory substrate for brain metabolism, with potential implications for cognition, motivation and mood. This research aimed to examine the relationships between fasting plasma glucose and depressive symptoms in a large, population representative sample of US adults, controlling for other demographic and lifestyle behavioural risk factors. Using the 2013-2014 National Health and Nutrition Examination Survey (NHANES) data, this study first investigated the relationship between fasting plasma glucose and mental disorders at a population-level, accounting for demographic, health behavioural and weight-related factors known to co-occur with both type 2 diabetes and mental disorders. Depressive symptoms were derived from the 9-item Patient Health Questionnaire. Fasting plasma glucose was obtained through medical examination and demographic (age, household income, sex) and health characteristics (perceived diet quality, daily time sedentary) were self-reported. Body mass index was calculated from objectively measured height and weight. In the univariate model, higher fasting plasma glucose was associated with greater depressive symptoms among females (b = 0.24, 95% CI = 0.05, 0.43, p < 0.05), but not males. In the final fully adjusted model, the relationship between fasting plasma glucose and depressive symptoms was non-significant for both males and females. Of all independent variables, self-appraised diet quality was strongly and significantly associated with depressive symptoms and this remained significant when individuals with diabetes were excluded. Although diet quality was self-reported based on individuals' perceptions, these findings are consistent with a role for poor diet in the relationship between fasting plasma glucose and depressive symptoms.
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ItemEpiMetal: an open-source graphical web browser tool for easy statistical analyses in epidemiology and metabolomics(OXFORD UNIV PRESS, 2020-08)MOTIVATION: An intuitive graphical interface that allows statistical analyses and visualizations of extensive data without any knowledge of dedicated statistical software or programming. IMPLEMENTATION: EpiMetal is a single-page web application written in JavaScript, to be used via a modern desktop web browser. GENERAL FEATURES: Standard epidemiological analyses and self-organizing maps for data-driven metabolic profiling are included. Multiple extensive datasets with an arbitrary number of continuous and category variables can be integrated with the software. Any snapshot of the analyses can be saved and shared with others via a www-link. We demonstrate the usage of EpiMetal using pilot data with over 500 quantitative molecular measures for each sample as well as in two large-scale epidemiological cohorts (N >10 000). AVAILABILITY: The software usage exemplar and the pilot data are open access online at [http://EpiMetal.computationalmedicine.fi]. MIT licensed source code is available at the Github repository at [https://github.com/amergin/epimetal].
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ItemPlasma Docosahexaenoic Acid and Eicosapentaenoic Acid Concentrations Are Positively Associated with Brown Adipose Tissue Activity in Humans(MDPI, 2020-10)Brown adipose tissue (BAT) activation is a possible therapeutic strategy to increase energy expenditure and improve metabolic homeostasis in obesity. Recent studies have revealed novel interactions between BAT and circulating lipid species-in particular, the non-esterified fatty acid (NEFA) and oxylipin lipid classes. This study aimed to identify individual lipid species that may be associated with cold-stimulated BAT activity in humans. A panel of 44 NEFA and 41 oxylipin species were measured using mass-spectrometry-based lipidomics in the plasma of fourteen healthy male participants before and after 90 min of mild cold exposure. Lipid measures were correlated with BAT activity measured via 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT), along with norepinephrine (NE) concentration (a surrogate marker of sympathetic activity). The study identified a significant increase in total NEFA concentration following cold exposure that was positively associated with NE concentration change. Individually, 33 NEFA and 11 oxylipin species increased significantly in response to cold exposure. The concentration of the omega-3 NEFA, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) at baseline was significantly associated with BAT activity, and the cold-induced change in 18 NEFA species was significantly associated with BAT activity. No significant associations were identified between BAT activity and oxylipins.
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ItemSedentary Behavior and Public Health: Integrating the Evidence and Identifying Potential Solutions(ANNUAL REVIEWS, 2020)In developed and developing countries, social, economic, and environmental transitions have led to physical inactivity and large amounts of time spent sitting. Research is now unraveling the adverse public health consequences of too much sitting. We describe improvements in device-based measurement that are providing new insights into sedentary behavior and health. We consider the implications of research linking evidence from epidemiology and behavioral science with mechanistic insights into the underlying biology of sitting time. Such evidence has led to new sedentary behavior guidelines and initiatives. We highlight ways that this emerging knowledge base can inform public health strategy: First, we consider epidemiologic and experimental evidence on the health consequences of sedentary behavior; second, we describe solutions-focused research from initiatives in workplaces and schools. To inform a broad public health strategy, researchers need to pursue evidence-informed collaborations with occupational health, education, and other sectors.