Neutral lipid dysregulation of the pancreatic beta-cell
Neutral lipid dysregulation of the pancreatic beta-cell
批准号:
6517794
负责人:
VINCENT POITOUT
金额:
$26.25万
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
已结题
起止时间:
2001-06-01 至 2005-05-31
关键词:
acyl coA blood glucose diacylglycerols esterification fatty acid biosynthesis fatty acids gel mobility shift assay gene expression genetic promoter element genetic transcription genetic translation glucose metabolism hyperglycemia insulin insulin sensitivity /resistance laboratory rat messenger RNA noninsulin dependent diabetes mellitus northern blottings pancreatic islet function pancreatic islets posttranscriptional RNA processing proinsulin tissue /cell culture transfection
中文摘要
描述:(摘自申请者的描述)2型糖尿病的特征是慢性高血糖,通常与
血脂水平升高。这项提议的总体目标是
确定长期暴露在高脂肪水平下的机制
酸(FA)影响2型糖尿病患者的胰岛β细胞功能。
此前,我们已经证明,长期接触FA会损害胰岛素
只有在高糖存在的情况下才能表达基因,而这是
与中性脂肪合成增加有关。具体目标一:确定
沿着中性脂途径产生的代谢中间体(S)
胰岛素分泌和基因损伤的合成
在长期暴露于FA时的表达。分离的大鼠胰岛,HIT-T15,和
将培养1~7天的BetaHC-L3细胞置于增殖期
葡萄糖和FA的浓度。将使用药理工具来抑制
或刺激中性脂肪合成的每一步,以识别
沿着酯化途径产生的代谢中间体(S,
长链酰辅酶A、二酰甘油或三酰甘油)负责
甲醛对胰岛β细胞功能的损伤。具体目标二:评估是否
长期暴露于高浓度甲醛的血糖依赖性有害效应
对β细胞功能的影响是葡萄糖专一性的,以及这些机制是否
影响是转录的、转录后的或翻译的。β细胞
在下列情况下的实验中,将区分精疲力竭和真实毒性
二氮嗪将用于抑制胰岛素的释放。糖蛋白的葡萄糖特异性
PA的影响将通过使用非葡萄糖促分泌剂来研究
刺激胰岛素分泌和胰岛素基因表达。依赖葡萄糖的
FA对胰岛素原生物合成、胰岛素信使核糖核酸稳定性的影响
内源性胰岛素基因转录将被评估。甲醛对人体健康的影响
胰岛素启动子活性将在HIT-T15和BetaHC-13细胞中表征
并在原代胰岛中使用重组腺病毒进行了研究
系统。具体目标三:确定高脂肪饲料是否
高血糖Goto-Kakizaki(GK)大鼠胰岛素分泌受损
生物合成和胰岛素基因表达,以及这些影响是否
通过血糖水平的正常化来预防。GK或对照大鼠将被
喂高脂饮食6周后,胰岛素分泌、胰岛素原
将评估胰岛素的生物合成和胰岛素基因的表达。血糖
GK大鼠体内的血药浓度将通过给药使其正常化。
预防高脂饮食对胰岛β细胞有害影响的尝试
功能。这些实验将为我们提供对
2型糖尿病胰岛β细胞功能障碍的病理生理学研究
对这种疾病的治疗的影响。
英文摘要
DESCRIPTION: (Scanned from the applicant's description) Type 2 diabetes mellitus is characterized by chronic hyperglycemia and is often associated with
elevated plasma lipid levels. The overall objective of this proposal is to
ascertain the mechanisms whereby prolonged exposure to elevated levels of fatty
acids (FA) affects pancreatic beta-cell function in Type 2 diabetes.
Previously, we have demonstrated that prolonged exposure to FA impairs insulin
gene expression only in the presence of high glucose, and that this is
associated with increased neutral lipid synthesis. Specific Aim I: To identify
the metabolic intermediate(s) generated along the pathway of neutral lipid
synthesis responsible for the impairment of insulin secretion and gene
expression upon prolonged exposure to FA. Isolated rat islets, HIT-T15, and
betaHC-l3 cells will be cultured for 1 to 7 days in the presence of increasing
concentrations of glucose and FA. Pharmacological tools will be used to inhibit
or stimulate each step of neutral lipid synthesis, in order to identify the
metabolic intermediate(s) generated along the esterification pathway (i.e.,
long-chain Acyl-CoA, diacyiglycerols, or triacylglycerols) responsible for the
FA-induced impairment of beta-cell function. Specific Aim II: To assess whether
the glucose-dependent deleterious effects of prolonged exposure to elevated FA
on beta-cell function are glucose-specific, and whether the mechanisms of these
effects are transcriptional, post-transcriptional, or translational. beta-cell
exhaustion will be distinguished from bona fide toxicity in experiments where
diazoxide will be used to inhibit insulin release. The glucose-specificity of
PA effects will be investigated by using a non-glucose secretagogue to
stimulate insulin secretion and insulin gene expression. The glucose-dependent
effects of FA on proinsulin biosynthesis, insulin mRNA stability, and
endogenous insulin gene transcription will be assessed. The effects of FA on
insulin promoter activity will be characterized in HIT-Tl5 and betaHC-13 cells
and also investigated in primary islets using the recombinant adenovirus
system. Specific Aim III: To determine whether high-fat feeding in
hyperglycemic Goto-Kakizaki (GK) rats impairs insulin secretion, insulin
biosynthesis, and insulin gene expression, and whether these effects are
prevented by normalization of blood glucose levels. GK or control rats will be
fed a high-fat diet for 6 weeks, after which insulin secretion, proinsulin
biosynthesis, and insulin gene expression will be assessed. Blood glucose
levels will be normalized in GK rats by phloridzin administration, in an
attempt to prevent the deleterious effects of high-fat diet on beta-cell
function. These experiments will provide important insights into the
pathophysiology of beta-cell dysfunction of type 2 diabetes, and have clear
implications for the treatment of this disease.
期刊论文(0)
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会议论文
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海外基金