Mechanisms of insulin resistance in South Asians (MIRSA): the roles of skeletal muscle microvasculature and mitochondrial metabolism

2型糖尿病是一个主要的公共卫生问题，预计到2035年，全球糖尿病病例将从目前的约4亿增加到约6亿。不同种族患糖尿病的风险并不一致，南亚裔(印度、巴基斯坦、孟加拉国、斯里兰卡)血统的人占世界人口的近四分之一，他们的发病率是欧洲白人的2-4倍。南亚人患糖尿病的时间也比欧洲白人早5-10年，而且体重较轻。到70岁时，30-40%的南亚人患有糖尿病。影响2型糖尿病风险的一个关键因素是肌肉对胰岛素做出适当反应以从血液中吸收葡萄糖(糖)的能力降低。这被称为胰岛素抵抗。越来越多的证据表明，与欧洲白人相比，较低的健康水平和肌肉燃烧脂肪的能力会导致南亚人的胰岛素抵抗和更高的糖尿病风险，但运动能在多大程度上改善这一点尚不清楚。目前这项建议的主要目的是确定南亚成年人通过运动训练干预可以在多大程度上改善胰岛素抵抗，并确定导致这种改善的具体肌肉变化。目前的建议是一项随机对照试验，44名患糖尿病风险增加的南亚成年人将被随机分配到为期12周的运动训练干预或12周的日常生活方式(对照)中。我们将使用被称为正常血糖高胰岛素钳夹的金标准方法来评估干预对胰岛素抵抗的影响，该方法衡量胰岛素激素使葡萄糖从血液中被清除的程度。我们还将使用最先进的技术来确定运动训练如何改善南亚人的胰岛素抵抗，方法是测量运动干预对以下方面的影响：肌肉燃烧肌肉内细胞器内称为线粒体的脂肪的能力，对肌肉结构内的小血管(称为微血管系统)的数量，以及这些小血管的放松能力。这一知识将有助于优化南亚人基于生活方式的糖尿病预防干预措施，并有助于确定潜在的新治疗方法。

Type 2 diabetes is a major public health problem with worldwide cases projected to rise from ~400 million, currently, to ~600 million by 2035. The risk of diabetes is not consistent across different ethnic groups with people of South Asian (Indian, Pakistani, Bangladeshi, Sri Lankan) origin, who make up nearly a quarter of the world's population, having 2-4 fold higher rates than white Europeans. South Asians also develop diabetes 5-10 years earlier and at lower body weights than white Europeans. By the age of 70, 30-40% of South Asians have diabetes. A key factor influencing risk of type 2 diabetes is a reduction in the ability of muscle to respond appropriately to insulin to take up glucose (sugar) from the blood. This is termed insulin resistance. There is growing evidence that lower levels of fitness and capacity of muscle to burn fat (compared with white Europeans) contributes to South Asians' insulin resistance and higher diabetes risk, but the extent to which this can be improved by exercise is unclear. The main aim of the current proposal, which combines expertise from world-leading groups across three UK Universities, is to determine the extent to which insulin resistance can be improved by an exercise training intervention in South Asian adults, and to identify specific changes in muscle which are responsible for this improvement.The current proposal is a randomised controlled trial in which 44 South Asian adults at increased risk of diabetes will be randomly assigned to either a 12-week exercise training intervention or 12-weeks of usual lifestyle (control). We will assess the effects of the intervention on insulin resistance, using the gold-standard method, called a euglycaemic hyperinsulinaemic clamp, which measures how well the hormone insulin enables glucose to be removed from the blood. We will also use state-of-the-art techniques to identify how exercise training improves insulin resistance in South Asians by measuring effects of the exercise intervention on: the ability of muscle to burn fat within organelles within muscle called mitochondria, on the number of small blood vessels within the muscle structure (called the microvasculature), and the ability of these small blood vessels to relax. This knowledge will help to optimise lifestyle-based diabetes prevention interventions in South Asians, as well as helping to identify potential new treatment approaches.