Signaling mechanisms and mouse models for insulin-mediated pseudoacromegaly

胰岛素通过其降低血糖的能力作为代谢调节剂具有重要的作用。然而，胰岛素也是一个很强的促有丝分裂(生长)因子。因此，大多数单基因胰岛素抵抗综合征都与矮小有关。我们的研究小组发现了一名患有极其罕见的胰岛素抵抗综合征的患者，该综合症与生长过度和身材高大有关。这种综合征，胰岛素介导性假性肢端肥大症(IMPA)，以胰岛素水平极高、身材高大、肢端肥大症、肥胖和多毛症为特征。外显子组测序显示，该先证者携带成纤维细胞生长因子受体1(FGFR1)和β-Klotho(KLB)两个罕见的、潜在有害的变异，这两个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所必需的跨膜辅助因子，导致固有的酪氨酸激酶活性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对胰岛素的敏感性。FGF21还通过下调肝脏STAT5和IGF-1以及上调IGF-1结合蛋白1而导致生长激素抵抗。因此，对FGF21的抵抗可以解释该患者严重的胰岛素抵抗和身高。FGF21水平升高与肥胖、脂肪肝、致动脉粥样硬化性血脂谱和骨密度降低有关。药理应用FGF21可以抵抗高脂饮食导致的体重增加，改善葡萄糖耐量以及肝脏和外周胰岛素敏感性(不会引发低血糖)，并使高胰岛素血症和高甘油三酯血症正常化。有趣的是，在胰岛素抵抗和瘦素抵抗状态下，对FGF21的抵抗类似于循环中胰岛素和瘦素的高浓度。我们假设，FGFR1和KLb的这些变体一起是致病的，导致FGF21耐药状态。这可以解释这个先证者严重的胰岛素抵抗、高个子和多毛症。在这个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；以及2)表征携带IMPA突变的FGFR1和KLB突变小鼠的生理和代谢。这些目的共同作为一种功能基因组学方法来确定一种新的胰岛素抵抗综合征的机制。此外，这些研究将提高我们对FGF21生物学在人类中的理解。这与常见的胰岛素抵抗障碍，如2型糖尿病和代谢综合征有额外的相关性。

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.