Etiology of Impaired Counterregulation in Glucose Homeostasis: Exploring the Roles of Glucagon, Somatostatin, Cortisol, and Epinephrine through Mathematical Modeling of Oral Glucose Tolerance Tests
葡萄糖稳态反调节受损的病因学:通过口服葡萄糖耐量测试的数学模型探索胰高血糖素、生长抑素、皮质醇和肾上腺素的作用
基本信息
- 批准号:10351245
- 负责人:
- 金额:$ 12.58万
- 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:2022-02-16 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAcuteAlpha CellAnimalsApoptosisBehaviorBeta CellCarbohydratesChronicDataDevelopmentDiabetes MellitusDiseaseDisease ManagementDisease ProgressionDisease modelDropsEpidemicEpinephrineEtiologyEventFastingFunctional disorderGlucagonGluconeogenesisGlucoseGoalsHealthcare SystemsHomeostasisHormonesHourHydrocortisoneHyperglycemiaHypoglycemiaImpairmentIngestionInstructionInsulinInsulin ResistanceInvestigationLeadLiverLongitudinal StudiesMediatingModelingNatureNon-Insulin-Dependent Diabetes MellitusOGTTPathologyPatientsPersonsPlasmaPlayPolycystic Ovary SyndromePrediabetes syndromeReactive hypoglycemiaRecoveryRegulationRoleSignal TransductionSomatostatinSomatotropinSymptomsType 2 diabeticValidationaggressive therapybaseblood glucose regulationcell regenerationcounterregulationdata modelingdiabeticdiabetic patientendocrine pancreas developmentexperiencefallsfasting glucoseglucagon-like peptide 1glucose disposalglycogenolysisinhibitorinsightinsulin secretionmathematical modelresponse
项目摘要
PROPOSAL SUMMARY
Glucose homeostasis is tightly controlled in animals with plasma glucose levels maintained in a narrow range.
While insulin, secreted by the beta cell, regulates by promoting efficient glucose disposal and suppressing
glucose release from the liver when glucose levels rise, glucagon, secreted by the alpha cells, counterregulates
by facilitating glucose release from the liver through glycogenolysis and gluconeogenesis when levels fall.
Epinephrine, cortisol and growth hormone play supporting roles in glucose counterregulation. Impaired
counterregulatory responses can lead to hypoglycemia, a potentially fatal condition. Hypoglycemia is frequently
experienced by type 1 and late-stage type 2 diabetics, which limits the use of aggressive therapies in disease
management. The etiology of this impaired counterregulation is not well understood. On the other hand, alpha
cell dysfunction (impaired inhibition of glucagon secretion by glucose) leads to elevated fasting glucose levels
and diminished early suppression of glucagon after glucose challenge. This form of impairment exacerbates type
2 diabetes and may contribute to its development and progression. I propose to study both forms of impairment.
In oral glucose tolerance tests, diminished early suppression of glucagon followed by greater late glucagon
suppression is observed in type 2 diabetics. This leads to worsened hyperglycemia followed by hypoglycemia.
If the mechanism behind persistent glucagon suppression and delayed recovery is fully elucidated, it would be
possible to protect against hypoglycemic events. I propose to explore the different mechanisms of somatostatin
and GLP-1 mediated regulation of glucagon secretion by extending the parsimonious model of glucose-insulin-
glucagon dynamics I developed. Reactive Hypoglycemia (RHG) occurs a few hours after ingesting a
carbohydrate rich meal. Plasma glucose levels drop below 55 mg/dl and the patient displays neuroglycopenic
symptoms which are relieved by glucose ingestion. There is currently no definitive explanation for this behavior.
I will extend the glucose-insulin-glucagon minimal model I developed to include the other hormones and validate
the model with data from OGTT studies of patients with RHG. I will also investigate the role of insulin in
potentiating RHG. An overarching question in type 2 diabetes pathophysiology is the nature of disease
progression from normal through prediabetic to overt diabetic state. The critical role of alpha cell dysfunction in
disease development and progression has not yet been studied. I will interface the glucose-insulin-glucagon
model I developed with existing disease progression models. This will identify the role of alpha cell dysfunction
and glucagon action in development and acceleration of type 2 diabetes. I will study the etiology of hypoglycemia
in aims 1 and 2 and the impact of alpha cell dysfunction in type 2 diabetes through longitudinal modeling of
disease progression in aim 3.
建议总结
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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Vijaya Subramanian其他文献
Vijaya Subramanian的其他文献
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{{ truncateString('Vijaya Subramanian', 18)}}的其他基金
Etiology of Impaired Counterregulation in Glucose Homeostasis: Exploring the Roles of Glucagon, Somatostatin, Cortisol, and Epinephrine through Mathematical Modeling of Oral Glucose Tolerance Tests
葡萄糖稳态反调节受损的病因学:通过口服葡萄糖耐量测试的数学模型探索胰高血糖素、生长抑素、皮质醇和肾上腺素的作用
- 批准号:
10574564 - 财政年份:2022
- 资助金额:
$ 12.58万 - 项目类别:
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