Pathogenesis of the Metabolic Syndrome
代谢综合征的发病机制
基本信息
- 批准号:8048752
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-10-01 至 2014-09-30
- 项目状态:已结题
- 来源:
- 关键词:1,2-diacylglycerol2,4-thiazolidinedioneAbdomenActivity CyclesAddressAdipose tissueAffectAfrican AmericanAmino AcidsBiological MarkersBiopsyBlood CirculationBody CompositionBody Weight decreasedCarbohydratesCarboxylic AcidsCardiovascular DiseasesCeramidesComplexDEXADataDefectDevelopmentDietDiglyceridesDiseaseEnergy MetabolismEuglycemic ClampingEuropeanFatty AcidsGenerationsGlucoseGlucose ClampGoalsGrantHealth Care CostsHeart DiseasesHormonesHourHumanHuman VolunteersHydroxyl RadicalHyperinsulinismIndirect CalorimetryIndividualInflammatoryInsulinInsulin ReceptorInsulin ResistanceLinkLipid PeroxidationLipid PeroxidesLipidsMeasuresMediatingMedicineMetabolicMetabolic syndromeMetabolismMitochondriaMolecularMuscleNADH dehydrogenase (ubiquinone)NF-kappa BNMR SpectroscopyNon-Insulin-Dependent Diabetes MellitusNutrientOxidative StressPathogenesisPathway interactionsPatientsPatternPhosphorylationPhysiologicalPioglitazonePlasmaPopulationPrediabetes syndromeProcessProtein-Serine-Threonine KinasesProteinsReactive Oxygen SpeciesResearchResearch DesignResolutionRespirationRestRodentRoleSerineSignal TransductionSkeletal MuscleStressTechnologyTestingThiazolidinedionesTissuesTranslational ResearchTriglyceridesUrineVeteransacylcarnitineadiponectinbasecytokinedesensitizationdiabeticglucose metabolismimprovedinsulin sensitivityinsulin signalingintervention effectlipid metabolismlong chain fatty acidmetabolomicsnon-diabeticnovelnovel diagnosticsorganic acidoxidationpreventrespiratoryresponsetheoriesweight maintenance
项目摘要
DESCRIPTION (provided by applicant):
The spectrum of cardiometabolic disease encompasses the Metabolic Syndrome, Pre-diabetes, Type 2 Diabetes (T2DM), and cardiovascular disease, and these diseases are responsible for a huge burden of patient suffering and health care costs among veterans and the US population in general. Insulin resistance at the level of skeletal muscle is central to the underlying pathogenesis of all these disease manifestations. Regarding the mechanism of insulin resistance, the conventional hypothesis is that oxidation of long-chain fatty acids (LCFA) is impaired while availability is increased, and this results in the accumulation of intramyocellular lipid (IMCL) and metabolites of LCFAs such as diacylglycerol, LCFA-CoAs, and ceramides. These latter compounds activate various serine kinases, such as PKC or IKK2 (in association with activation of NF-:B), which then phosphorylate insulin receptor substrate (IRS) molecules resulting in impaired insulin signal transduction. However, our preliminary data point to an alternative or complementary pathophysiological process. The first clue was that IMCL was completely independent of insulin sensitivity in African Americans, while oxidative stress related to lipid peroxidation in muscle was predictive of insulin resistance in both European- and African-Americans. The second clue was provided by metabolomic studies of plasma obtained from normal controls and insulin-resistant patients with T2DM. The metabolomic profile in T2DM was consistent with incomplete oxidation of long-chain fatty acids (LCFA) as evidenced by accumulation of medium chain acylcarnitines, rather than increased LCFAs and accumulation as IMCL triglyceride, together with decreased tri-carboxylic acid (TCA) cycle activity and diminished anaplerosis. Given these observations, we wish to test a novel hypothesis that the abnormal metabolome is the result of intrinsic mitochondrial defects that both impair FA oxidation and generate reactive oxygen species (ROS). Activation of serine kinases is then mediated either directly by medium-chain acylcarnitines and/or by peroxidized lipids generated by mitochondrial ROS that activate inflammatory pathways (e.g., NG-:B). In this proposal, we will test these hypotheses in humans. Normoglycemic insulin sensitive and insulin resistant subjects, and patients with T2DM will be metabolically characterized by hyperinsulinemic clamps, body composition, IMCL, energy expenditure and substrate oxidation rates, and will be studied before and after perturbations that alter insulin sensitivity including short-term very low calorie diet, after stabilization following 10% weight loss, and insulin-sensitizing thiazolidinedione treatment. Metabolomic profiles will be assessed for acylcarnitines, fatty acids, organic acids, amino acids, and LCFA-CoAs in plasma, urine, and in biopsied muscle tissue. In addition, mitochondria isolated from muscle will be functionally studied for substrate oxidation capacity using high resolution respirometry, reactive oxygen species generation, and activity of individual respiratory complexes. Oxidative stress will be measured in muscle by hydroxyl-nonenal and protein carbonyls. The effect of oxidative stress and/or metabolomic analytes to activate inflammatory pathways in muscle leading to serine phosphorylation and desensitization of IRS and insulin signaling will be examined. These studies represent a state-of-the-art application of new metabolomics technologies, combined with molecular studies of mitochondrial function and insulin signaling, in human muscle, and will test new hypotheses regarding the link between abnormal lipid metabolism and insulin resistance. These data will predictably identify new diagnostic biomarkers for insulin resistance and T2DM, and advance our understanding of molecular mechanisms underlying human insulin resistance.
PUBLIC HEALTH RELEVANCE:
Most patients with Type 2 Diabetes, Pre-Diabetes, Metabolic Syndrome, and heart disease are insulin resistant due to an inability of insulin to move glucose from bloodstream into skeletal muscle. These interrelated diseases cause a huge burden of suffering and health care costs. Improved ways to treat and prevent these diseases will require a better understanding of the molecular causes of insulin resistance. Therefore, based on preliminary data, will test a new theory for how abnormal fat metabolism leads to abnormal glucose metabolism. Our studies will involve human patients before and after diet-induced weight loss and a medicine that makes muscle more insulin sensitive. These studies represent a state-of-the-art application of new metabolomics technologies, combined with molecular studies of mitochondrial function and insulin action, in human muscle. These data will predictably identify new diagnostic biomarkers for insulin resistance and T2DM, and advance our understanding of molecular mechanisms underlying human insulin resistance.
描述(由申请人提供):
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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W Timothy GARVEY其他文献
W Timothy GARVEY的其他文献
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{{ truncateString('W Timothy GARVEY', 18)}}的其他基金
Depletion of pancreatic lipid improves beta-cell function in early type 2 diabetes
胰腺脂质的消耗可改善早期 2 型糖尿病的 β 细胞功能
- 批准号:
9902431 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Depletion of pancreatic lipid improves beta-cell function in early type 2 diabetes
胰腺脂质的消耗可改善早期 2 型糖尿病的 β 细胞功能
- 批准号:
10379925 - 财政年份:2018
- 资助金额:
-- - 项目类别: