Signaling mechanisms and mouse models for insulin-mediated pseudoacromegaly

胰岛素通过其降低血糖的能力，具有重要的代谢调节作用。然而，胰岛素也是一种强大的有丝分裂（生长）因子。因此，大多数单基因胰岛素抵抗综合征与身材矮小有关。我们的研究小组已经确定了一个极其罕见的胰岛素抵抗综合征患者与过度生长和高个子。胰岛素介导的假性肢端肥大症（IMPA）的特点是胰岛素水平极高、身材高大、肢端肥大、肥胖和多毛。外显子组测序显示，该先显子在成纤维细胞生长因子受体1 （FGFR1）和β - klotho （KLB）中携带2种罕见的潜在有害变异，这两种变异都位于成纤维细胞生长因子21 （FGF21）信号通路中。KLB是FGF21结合和激活FGFR1所需的跨膜辅助因子，导致内在酪氨酸激酶活性的激活和随后的信号转导。FGF21是一种主要来源于肝脏的循环激素。FGF21是饥饿代谢反应的重要组成部分。它通过允许葡萄糖摄取和脂肪酸氧化来促进肌肉和脂肪组织的胰岛素敏感性。FGF21还通过下调肝脏STAT5和IGF-1以及上调IGF-1结合蛋白1参与生长激素抵抗。因此，对FGF21的抵抗可以解释该患者严重的胰岛素抵抗和高大的身材。FGF21水平升高与肥胖、脂肪肝、致动脉粥样硬化脂质谱和骨密度降低有关。FGF21的药理作用增强了对高脂肪饮食引起的体重增加的抵抗力，改善了葡萄糖耐量和肝脏和外周胰岛素敏感性（不引发低血糖），并使高胰岛素血症和高甘油三酯血症正常化。有趣的是，对FGF21的抵抗分别类似于胰岛素抵抗和瘦素抵抗状态下的高循环胰岛素和瘦素浓度。我们假设，FGFR1和KLB中的这些变异共同具有致病性，导致FGF21耐药状态。这可以解释这个先证者的严重胰岛素抵抗、身材高大和多毛症。在本R21提案中，我们将：1)确定IMPA相关的FGFR1和KLB变体是否共同损害FGF21信号传导；2)表征携带Fgfr1和Klb IMPA突变的小鼠的生理和代谢。总之，这些目标作为一种功能基因组方法来识别一种新型胰岛素抵抗综合征的机制。此外，这些研究将提高我们对人类FGF21生物学的理解。这对常见的胰岛素抵抗疾病，如2型糖尿病和代谢综合征具有额外的相关性。

Insulin has important effects as a metabolic regulator via its ability to lower blood glucose. However, insulin is also a strong mitogenic (growth) factor. Therefore, the majority of monogenic insulin resistance syndromes are associated with short stature. Our research group has identified a patient with an extremely rare insulin resistance syndrome associated with overgrowth and tall stature. This syndrome, insulin-mediated pseudoacromegaly (IMPA), is characterized by extremely high levels of insulin, tall stature, acromegalic features, obesity, and hirsutism. Exome sequencing revealed that this proband carries 2 rare, potentially deleterious variants in Fibroblast Growth Factor Receptor 1 (FGFR1) and beta-Klotho (KLB), both of which are in the Fibroblast Growth Factor 21 (FGF21) signaling pathway. KLB is a transmembrane co-factor that is required for FGF21 to bind to and activate FGFR1, resulting in activation of intrinsic tyrosine kinase activity and subsequent signal transduction. FGF21 is a predominantly liver-derived circulating hormone. FGF21 is an important part of the metabolic response to starvation. It promotes insulin sensitivity in muscle and adipose tissue by permitting glucose uptake and fatty acid oxidation. FGF21 also contributes to growth hormone resistance via downregulation of hepatic STAT5 and IGF-1 and upregulation of IGF-1 binding protein 1. Therefore, resistance to FGF21 could explain this patient’s severe insulin resistance and tall stature. Increased levels of FGF21 is associated with obesity, fatty liver, atherogenic lipid profiles, and reduced bone mineral density. Pharmacologic administration of FGF21 imparts resistance to high fat diet-induced weight gain, improves glucose tolerance and hepatic and peripheral insulin sensitivity (without triggering hypoglycemia), and normalizes hyperinsulinemia and hypertriglyceridemia. Interestingly, resistance to FGF21 is similar to high circulating insulin and leptin concentrations in insulin- and leptin-resistant states, respectively. We posit that, together, these variants in FGFR1 and KLB are pathogenic, leading to a FGF21 resistant state. This could explain this proband’s severe insulin resistance, tall stature, and hirsutism. In this R21 proposal we will: 1) Determine whether IMPA associated FGFR1 and KLB variants together impair FGF21 signaling; and 2) Characterize the physiology and metabolism of mice carrying IMPA mutations in Fgfr1 and Klb. Together these aims serve as a functional genomic approach towards identifying the mechanism of a novel insulin resistance syndrome. Additionally, these studies will improve our understanding of FGF21 biology in humans. This has additional relevance for common disorders of insulin resistance such as type 2 diabetes and metabolic syndrome.