Investigation of the Roles of Protein Kinase C epsilon in Insulin Secretion and Insulin Clearance

餐后血胰岛素水平的升高通常通过增加某些组织，特别是肌肉中葡萄糖的摄取和储存来降低血糖水平。2型糖尿病的部分特征是胰腺不能产生足够的胰岛素来应对血糖的升高。这种胰岛素分泌的丧失与脂肪可获得性的增加密切相关，尽管原因尚不清楚。我们最近发现，缺乏特定酶(蛋白激酶C epsilon)的小鼠在处理高脂肪饮食引起的血糖问题时不太容易受到影响。我们发现，这部分是由于胰岛素分泌的改善，也是因为肝脏分解胰岛素的速度较慢，从而增加了胰岛素对靶组织的利用率。这个项目的目的是研究发生在肝脏和胰腺中的这种酶有助于改善胰岛素作用的机制。首先，我们将检查肝细胞对胰岛素的摄取，以研究这种酶是如何控制这一过程的。其次，我们将确定酶的激活，一旦增加了对胰岛β细胞的脂肪供应，就会减少对葡萄糖的胰岛素分泌的机制。最后，将评估这两种酶作用在改善血糖水平控制方面的相对重要性。这项工作将有助于更好地理解脂肪供应过剩，从而导致肥胖在2型糖尿病的发展中发挥作用的机制，以便将它们作为开发新的、更有效的治疗疾病和预防其发病的靶点。

The rise in blood insulin levels after a meal normally reduces blood sugar levels by increasing glucose uptake and storage in certain tissues, especially muscle. Type 2 diabetes is characterized in part by a failure of the pancreas to produce adequate insulin in response to increases in blood sugar. This loss of insulin secretion has been strongly linked to increases in the availability of fat, although the reasons for this are not clear. We have recently found that mice lacking a specific enzyme (protein kinase C epsilon) are much less susceptible to the problems in dealing with blood sugar that are caused by a high fat diet. We showed that this is due partly to improved insulin secretion, and also to a slower breakdown of insulin by the liver, which increases its availability to target tissues. The aim of this project is to investigate the mechanisms occurring in the liver and in the pancreas by which this enzyme contributes to improved insulin action. Firstly, we will examine insulin uptake in liver cells, to investigate how the enzyme controls this process. Secondly, we will determine the mechanism through which the activation of the enzyme, upon increased fat supply to pancreatic beta-cells, reduces insulin secretion in response to glucose. Finally, will assess the relative importance of these two actions of the enzyme in improving the control of blood sugar levels. This work will lead to a better understanding of the mechanisms by which fat oversupply, and hence obesity, can play a role in the development of Type 2 diabetes, so that they can be targeted both for the development of new and more effective treatments for the disorder and for prevention of its onset.