过度表达α2A-上腺素受体有助于2型糖尿病的发生
Anders H Rosengren1, Ramunas Jokubka, Damon Tojjar
1Lund University Diabetes Centre, Malmö, SE-20502 Malmö, Sweden.
Science (New York, N.Y.)
|December 8, 2009
概括
研究了与2型糖尿病相关的遗传变异. 过度表达α-2A上腺素受体会通过影响颗粒对接而损害胰岛素分泌,这种机制在老鼠和人类中都很重要.
科学领域:
- 遗传学 是一个遗传学.
- 内分泌学 在内分泌学.
- 分子生物学分子生物学
背景情况:
- 2型糖尿病与遗传变异有关,但机制尚不清楚.
- 戈托-卡基扎基老鼠作为研究糖尿病相关遗传因素的模型.
研究的目的:
- 阐明2型糖尿病中胰岛素分泌受损的基因机制.
- 为了确定参与β细胞功能障碍的特定基因和途径.
主要方法:
- 使用来自戈托-卡基扎基糖尿病模型的先天性老鼠菌株.
- 进行基因位点分析以确定与胰岛素分泌受损相关的区域.
- 研究了α2A-上腺素受体 (Adra2a) 的作用及其下游效应.
- 分析了人类ADRA2A基因多态性及其与糖尿病风险和胰岛素分泌的关联.
主要成果:
- 确定了一种1.4兆基基因组位点,与胰岛素颗粒对接受损和β细胞外细胞减少有关.
- 在这个位点内,Adra2a显著过度表达,调解胰岛素分泌的上腺抑制.
- 药理学对抗或基因沉默的α(2A) AR恢复了老鼠小岛的胰岛素分泌.
- 人类ADRA2A单核酸多态性与α2AAR过度表达,胰岛素分泌量减少和2型糖尿病风险增加有关.
- 来自风险等位基载体的人类小岛显示颗粒对接受损和葡萄糖刺激的胰岛素分泌,由α2AAR抗剂逆转.
结论:
- 由于遗传因素导致的α-2A上腺素受体的过度表达会通过影响胰岛素颗粒对接而损害胰岛素分泌.
- 阿尔法2A-上腺素受体通路代表了2型糖尿病的潜在治疗标.
- 在ADRA2A中的遗传变异通过在Goto-Kakizaki大鼠模型中观察到的机制,有助于人类的2型糖尿病风险.
相关概念视频
01:24Type II Diabetes II: Pathophysiology
PathophysiologyType 2 diabetes mellitus (T2DM ) is a chronic metabolic disorder characterized by insulin resistance and progressive pancreatic β-cell dysfunction, leading to impaired glucose homeostasis. It results from interactions among genetic predisposition, environmental factors, and metabolic stressors, such as overnutrition and a sedentary lifestyle.Insulin Resistance and Glucose DysregulationEarly T2DM involves insulin resistance in skeletal muscle, adipose tissue, and the liver.
01:26Type II Diabetes I: Introduction
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance, in which target tissues such as the liver, muscle, and adipose tissue respond poorly to insulin. It is also associated with inadequate compensatory insulin secretion, where pancreatic β-cells fail to produce sufficient insulin. Together, these abnormalities lead to persistent hyperglycemia.EtiologyT2DM develops through a complex interaction of genetic predisposition and environmental or...
01:31Adrenergic Receptors: ɑ Subtype
Adrenoceptors are classified into α and ꞵ classes based on their potencies to catecholamine agonists. α-adrenoceptors show the following order of catecholamine potency:
Adrenaline ≥ Noradrenaline >> Isoprenaline
α-adrenoceptors are further divided into α1 and α2-adrenoceptors.
α1-Adrenoceptors: These receptors are located postsynaptically on the effector organs and cause constriction of smooth muscle mediated by activation of phospholipase C—inositol-1,4,5-trisphosphate...
Adrenaline ≥ Noradrenaline >> Isoprenaline
α-adrenoceptors are further divided into α1 and α2-adrenoceptors.
α1-Adrenoceptors: These receptors are located postsynaptically on the effector organs and cause constriction of smooth muscle mediated by activation of phospholipase C—inositol-1,4,5-trisphosphate...
01:36Carbohydrate Metabolism
Carbohydrates are polymers composed of molecules containing atoms of carbon, hydrogen and oxygen. One gram of carbohydrate can provide four kilo-calories of energy, which makes it the most efficient instant energy source.
Starch accounts for approximately 60% of the carbohydrates consumed by humans. Since amylase enzymes cannot function in the stomach's acidic environment, starch can only be digested in the mouth and small intestine. Simple sugars are found naturally in milk and fruits in the...
Starch accounts for approximately 60% of the carbohydrates consumed by humans. Since amylase enzymes cannot function in the stomach's acidic environment, starch can only be digested in the mouth and small intestine. Simple sugars are found naturally in milk and fruits in the...
01:26Type I Diabetes II: Pathophysiology
Type 1 diabetes mellitus arises from an immune-mediated destruction of pancreatic β-cells, resulting in an absolute deficiency of insulin. This process develops in genetically susceptible individuals when autoimmunity, environmental exposures, and immunologic dysregulation converge to trigger a targeted attack on the insulin-producing cells of the pancreas. The β-cells are located within the islets of Langerhans and are essential for regulating blood glucose by facilitating cellular uptake of...
01:22Diabetes Mellitus: Type 2 and Gestational
Type 2 diabetes, characterized by insulin resistance, arises when the insulin receptors on cells lose responsiveness to insulin, diminishing the cell's capacity to take up glucose, resulting in elevated blood glucose levels. To receive a diagnosis of Type 2 diabetes, a series of blood glucose tests are necessary to assess whether the blood glucose falls within normal parameters. If the result is out of the normal range, a patient may be diagnosed as prediabetic or diabetic, depending on the...