A Variant in the Betacellulin Gene and Insulin Secretion

描述(由申请人提供)： 2型糖尿病是一种多基因、异质性疾病，其特征是同时存在β细胞功能障碍和胰岛素抵抗。尽管人类常见的2型糖尿病存在明显的遗传成分，但几乎没有发现易感基因。母公司K23拨款的目的是通过对几个候选基因变异进行良好控制的前瞻性临床研究，阐明胰岛素分泌的遗传基础。R03的目的是通过研究我的团队最近发现的Betacellin基因中的一个新的基因变体来扩展这些研究。这种变异与2型糖尿病有关，并可能影响胰岛素的分泌。拟议的研究将有助于阐明这种新的β-纤维素变异体在胰岛素分泌中的作用。此外，尽管人们一致认为2型糖尿病是一种多基因疾病，但很少有研究涉及基因-基因相互作用。为了验证我们的假设，我们建议前瞻性地招募携带Betacellin变体的非糖尿病受试者，单独招募，并与其他变体(Beta2/Neurod Ala45Thr，IRS2 GIy1057Asp，b3AR Trp64Arg)联合使用，并使用胰岛素修改的频繁采样静脉葡萄糖耐量试验、胰岛素振荡研究和胰岛素原水平来表征胰岛素的分泌。通过阐明β细胞蛋白基因变异单独以及与其他变异一起对胰岛素分泌的影响，我们将对α细胞功能障碍的潜在分子机制和2型糖尿病的多基因性质提供重要的见解。反过来，这将导致新的预防策略和新的分子靶点的设计和有效的治疗剂。

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus is a polygenic, heterogeneous disorder characterized by the presence of both beta cell dysfunction and insulin resistance. Although a clear genetic component exists for the common forms of human type 2 diabetes, few susceptibility genes have been identified. The purpose of the parent K23 grant is to elucidate the genetic underpinnings of insulin secretion through well-controlled prospective clinical studies of several candidate gene variants. The purpose of this R03 is to extend these studies by investigating a new gene variant in the betacellulin gene that my group has recently identified. This variant associates with type 2 diabetes and may affect insulin secretion. The proposed studies will help to clarify this new betacellulin variant's role in insulin secretion. Furthermore, despite the concurrences that type 2 diabetes is a polygenic disorder, few studies have been performed which address gene-gene interactions. To test our hypotheses, we propose to prospectively recruit non-diabetic subjects with the betacellulin variant, individually and in combination with other variants (BETA2/NeuroD Ala45Thr, IRS2 GIy1057Asp, b3AR Trp64Arg) and characterize insulin secretion using the insulin-modified frequently sampled intravenous glucose tolerance test, insulin oscillation studies, and proinsulin levels. By elucidating the effects of the betacellulin gene variant, individually and in combination with these other variants on insulin secretion, we will provide critical insight into the underlying molecular mechanisms of a-cell dysfunction and the polygenic nature of type 2 diabetes. In turn, this will lead to new preventative strategies and new molecular targets for the design and effective therapeutic agents.