Test of catestatin (CST) and its mimetic as a new therapy for type 2 diabetes (T2D)
儿茶素 (CST) 及其模拟物作为 2 型糖尿病 (T2D) 新疗法的测试
基本信息
- 批准号:10823055
- 负责人:
- 金额:$ 30.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-25 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAgonistAmericanAmino AcidsAngioneurotic EdemaAnimal ExperimentsAnimalsAnti-Inflammatory AgentsAntidiabetic DrugsAntihypertensive AgentsBiological AvailabilityBiologyBlood GlucoseCOVID-19Cardiovascular systemChromogranin AClinical ResearchCombined Modality TherapyDataDiabetes MellitusDiabetic mouseDipeptidyl PeptidasesDiseaseDoseDrug KineticsDrug or chemical Tissue DistributionDrug resistanceEatingEffectivenessEvaluationFastingGLP-I receptorGluconeogenesisGluconeogenesis InhibitionGlucoseGlycogenesis InductionGlycogenolysis InductionGoalsGrantHalf-LifeHepaticHourHypoglycemiaImpairmentIndividualInfectionInfiltrationInflammationInflammatoryInsulinInsulin ResistanceIntraperitoneal InjectionsInvestigationKnockout MiceLDL Cholesterol LipoproteinsLaboratoriesLife StyleLiverMacrophageMarketingMedicineMetforminMusNon-Insulin-Dependent Diabetes MellitusObese MiceObesityOralOral AdministrationOrganOutsourcingOverweightPancreatitisPathway interactionsPeptidesPersonsPharmaceutical PreparationsPharmacy SchoolsPhasePhase I Clinical TrialsPhysiologicalPlasmaPopulationPositioning AttributePrediabetes syndromePredispositionPropertyScientistSensitivity and SpecificitySignal PathwaySmall Business Innovation Research GrantSodiumStructural BiologistSulfonylurea CompoundsTestingTherapeuticThiazolidinedionesToxic effectToxicity TestsWorkabsorptionanalogcell growth regulationchronic infectioncohortcost effective treatmentcytokinediabetes mellitus therapydiabeticdiabetic patientdiet-induced obesityefficacy testingexperimental studyfasting glucosegastrointestinalglucagon-like peptide 1glucose metabolismglucose productionglucose toleranceglycogenesisimprovedin vivoinhibitorinsulin secretioninsulin sensitivitymimeticsnovel therapeuticspandemic diseasepharmacologicpolyureapreventprogramsprohormoneresponseside effectsymportertherapeutic effectiveness
项目摘要
Over 130 million Americans are either diabetic or pre-diabetic. A significant fraction of them is obese or
overweight. There are seven classes of diabetic therapies against type II diabetes available including insulin
therapy. But all these drugs are associated with some side effects including the danger of hypoglycemia.
Therefore, more options to treat T2D are needed. We found that Catestatin (CST) and its analog, retro-inverso
(RI)-CST have anti-diabetic properties. CST is a Chromogranin A-derived peptide that improves insulin sensitivity
and reduces blood glucose levels in diet-induced obese (DIO) mouse model of diabetes by acting on multiple
pathways including anti-inflammatory and glucose metabolism. Its anti-inflammatory activity prevents the
infiltration of pro-inflammatory macrophages in the liver. It inhibits gluconeogenesis and glycogenolysis but
induces glycogenesis. Also notable is that CST and RI-CST can be administered orally, and plasma CST appears
within 15 min with a half-life of around 7 hrs. These remarkable properties position CST and RI-CST as highly
potential diabetes therapies which we plan to investigate in this proposal. We further plan to investigate the
therapeutic potential of CST and its mimic RI-CST as combination therapies. All currently used diabetes therapy
is associated with side effects which include gastrointestinal, cardiovascular, pancreatitis, polyurea,
angioedema, and LDL cholesterol. We hypothesize that toxic side effects of currently used diabetes medicine
will be minimized if their doses can be lowered which can be accomplished by the addition of CST. Indeed, our
preliminary results confirm our hypothesis where we found two-fold lower amounts of TZD are more effective
when used in combination with CST than the regular dose of TZD alone. We propose two aims: in Aim 1, we
plan to investigate the absorption and tissue distribution of RI-CST and determine the toxicity of both CST and
RI-CST in mice. In aim 2, we plan to investigate the effectiveness of both mono and combination therapy of CST
and RI-CST.
超过1.3亿美国人患有糖尿病或糖尿病前期。他们中有很大一部分是肥胖或
项目成果
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