Loss of the Exocrine Pancreas Improves Glucose Tolerance and Insulin Secretion
外分泌胰腺的丧失可改善葡萄糖耐量和胰岛素分泌
基本信息
- 批准号:10675473
- 负责人:
- 金额:$ 16.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAcetic AcidsAcinar CellAcinus organ componentAdultAdverse effectsAffectAnabolismAnimalsAttentionBeta CellBiphasic PatternCause of DeathCell membraneCell physiologyCellular biologyCharacteristicsClosure by clampCoculture TechniquesCommunicationCytoplasmic GranulesDataDefectDevelopmentDiabetes MellitusDiagnosisDiphtheria ToxinDuct (organ) structureEconomic BurdenElastasesEndothelial CellsEnzymesExcisionExocrine pancreasExocytosisFinancial HardshipFundingGenetic ModelsGenetic TranscriptionGlucoseGlucose tolerance testGoalsHealthHigh Fat DietHumanHyperglycemiaHypoglycemiaImageIn SituInfusion proceduresInstitutionInsulinIntercellular FluidInterventionIslets of LangerhansMediatingModelingMolecularMorbidity - disease rateMusNon-Insulin-Dependent Diabetes MellitusObesityOperative Surgical ProceduresPancreasPancreatic Ductal AdenocarcinomaPancreatic ductPancreatic enzymePathway interactionsPatientsPeptide HydrolasesPhasePhenotypePhysiologicalPhysiologyPrediabetes syndromePreparationPrevalenceReportingResearchResearch PersonnelResourcesReverse Transcriptase Polymerase Chain ReactionRodentSerine Proteinase InhibitorsSignal TransductionStreptozocinSupervisionSurgical ModelsTestingTissuesTranslationsTransplantationUnited StatesUniversitiesViralViral GenesWorkallotransplantblood glucose regulationcancer celldesigndiphtheria toxin receptoreconomic costgene therapyglucose toleranceimpaired glucose toleranceimprovedin vivoinsulin granuleinsulin secretioninsulin sensitivityisletknock-downmortalitymouse modelnegative affectnerve supplynonhuman primatenovel therapeuticsperipheral bloodpromoterradiological imagingresponseselective expressionsmall hairpin RNAtherapeutic targettraffickingtranscriptome sequencingtumor
项目摘要
Abstract
Type 2 diabetes (T2D) is a major health problem in the US and worldwide, causing high morbidity and mortality.
According to the CDC, in 2017, ~32.5 million had T2D, and an estimated 88 million adults in the United States
had prediabetes. Diabetes is the seventh leading cause of death and has become the number one biomedical
financial burden in the US, with an estimated national economic cost of $327 billion in 2017. Currently, there is
no radical cure for T2D.
Studies have demonstrated that glucose induces insulin secretion in a biphasic pattern: an initial first-phase,
which develops rapidly but lasts only a few minutes, followed by a nadir, then a sustained second-phase. Loss
of first-phase insulin secretion and reduced second-phase secretion are characteristic features of T2D. It is well
known that a decrease in the first-phase insulin secretion is the earliest and detrimental defect detected in
impaired glucose tolerance (prediabetes) and T2D. Although studies have highlighted the existence of two intra-
pancreatic axes of communication between the endocrine and exocrine pancreas (the insular–acinar axis and
the acinar–insular axis), little attention has been paid to any direct effect of the exocrine pancreas on β-cell
function. We recently designed a surgical mouse model wherein a pancreatic ductal infusion of 1% acetic acid
(AcA) led to complete ablation of the exocrine pancreas, but importantly with complete sparing of the islets. This
model allows us to study β-cell function in-situ in the pancreas, with the islets retaining their native innervation
and vasculature, but in the absence of the exocrine pancreas. We also established a genetic model that uses
the diphtheria toxin receptor selectively expressed in acinar cells via the elastase promoter to quickly ablate
acinar cells using diphtheria toxin. Our preliminary data in mice, and now in non-human primates, show a
significant improvement in glucose tolerance and first-phase insulin secretion to supranormal levels following
exocrine pancreas ablation. Observing a similar phenotype with both acinar-only ablation in the genetic model
and global exocrine (acini and ducts) ablation in the surgical model supports our hypothesis that it is the acinar
cells that are specifically detrimental to the β-cells.
This proposal aims to understand the improvements in the physiology of glucose homeostasis in this model by
performing the hyperglycemic clamp. It also aims to test the potential translatability of this study by examining
the effect of exocrine pancreas loss in a mouse model of obesity-induced hyperglycemia and identifying the
underlying causes of the improved insulin secretion following the loss of the exocrine tissue. Also, an important
aim of this study is to try to identify the acinar-secreted factor that has an adverse effect on β-cell function.
Successful completion of this project will provide the basis for the ultimate objective of this study of generating a
therapeutic target for T2D that can physiologically increase insulin secretion, particularly the first-phase, without
causing hypoglycemia.
摘要
项目成果
期刊论文数量(0)
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Mohamed Saleh其他文献
Mohamed Saleh的其他文献
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{{ truncateString('Mohamed Saleh', 18)}}的其他基金
Loss of the Exocrine Pancreas Improves Glucose Tolerance and Insulin Secretion
外分泌胰腺的丧失可改善葡萄糖耐量和胰岛素分泌
- 批准号:
10449695 - 财政年份:2022
- 资助金额:
$ 16.32万 - 项目类别:
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