The Role of Hyaluronan and CD44 in the Pathogenesis of Type 2 Diabetes

慢性2型糖尿病(T2 DM)通常以进行性β细胞衰竭为特征，导致血糖控制不良、胰岛素依赖和更严重的糖尿病并发症。虽然高血糖和炎症与这种β细胞死亡有关，但其潜在机制尚不清楚。全基因组关联研究表明，CD44是与T2 DM发病密切相关的一个分子，它是一种细胞表面蛋白多糖，介导细胞和细胞外基质之间的相互作用。我们已经确定了CD44及其主要配体透明质酸(HA)在与T2 DM相关的β细胞衰竭中的新作用。我们最近报道，T2 DM患者的高血糖和炎性细胞因子引起CD44和HA的系统性升高。与此一致，胰岛HA和CD44水平在非糖尿病受试者中可以忽略不计，但在患有T2 DM的身体供者中大量存在。在这种疾病的db/db小鼠模型中也有类似的发现。此外，用β细胞毒素链脲佐菌素治疗小鼠可提高β细胞产生HA和CD44的能力。这些数据表明，作为对损伤的急性反应，胰岛HA和CD44表达上调，它们在T2 DM中的长期表达可能是致病的。我们的初步数据强烈表明HA和CD44与β细胞衰竭有关，这是T2 DM的特征。用4-甲基伞形酮(4-MU)治疗db/db小鼠，4-甲基伞形酮(4-MU)是一种HA合成的口服抑制剂，可以清除这些动物的胰岛HA沉积并促进胰岛素的产生。类似地，CD44-/-.db/db小鼠即使是病态肥胖，也不会失去β细胞团或患上糖尿病。此外，4-MU处理和CD44缺失对小剂量链脲佐菌素均有保护作用。综上所述，这些数据表明，HA和CD44在β细胞衰竭中起决定性作用。与此一致，我们已经确定了HA和CD44在成纤维细胞生长因子21(FGF21)反应中的作用，成纤维细胞生长因子21是β细胞功能和动态平衡的关键调节因子。β-表达CD44的细胞对成纤维细胞生长因子21介导的成纤维细胞生长因子受体1信号反应较差，尤其是在HA存在的情况下。然而，T2 DM中β细胞衰竭的潜在机制及其贡献尚不清楚。根据我们令人兴奋的初步数据，我们假设CD44通过抑制FGF21反应来驱动T2 DM的β细胞衰竭。此外，我们建议已经批准的药物4-MU可以被重新用于预防T2 DM的β细胞衰竭。为了验证这一假设，在目标1中，我们将定义CD44在T2 DM的β细胞丢失中的作用。在目标2中，我们将确定CD44介导的β细胞FGF21反应的相关机制。最后，在目标3中，我们将开发针对HA/CD44的疗法来保护人类β细胞团。总之，这些目标有可能揭示T2 DM发展的基本新途径，并引入新的治疗方法来改善T2 DM的血糖控制。

PChronic Type 2 Diabetes Mellitus (T2DM) is often characterized by progressive β-cell failure, leading to poor glycemic control, insulin dependence, and more severe diabetic complications. While hyperglycemia and inflammation are implicated in this β-cell demise, the underlying mechanisms are unclear. One molecule strongly implicated in T2DM pathogenesis by genome-wide association studies is CD44, a cell-surface proteoglycan that mediates interactions between cells and the extracellular matrix. We have identified a novel role for CD44 and its primary ligand hyaluronan (HA) in the β-cell failure associated with T2DM. We recently reported that both CD44 and HA are increased systemically in response to hyperglycemia and inflammatory cytokines in T2DM. Consistent with this, islet HA and CD44 levels are negligible in non-diabetic subjects but abundant in human cadaveric donors with T2DM. Similar findings are present in the db/db mouse model of the disease. Further, treatment of mice with the β-cell toxin streptozotocin enhances β-cell production of both HA and CD44. These data suggest that islet HA and CD44 are upregulated as an acute response to injury and that their prolonged expression in T2DM may be pathogenic. Our preliminary data strongly implicate HA and CD44 in the β-cell failure that characterizes T2DM. Treatment of db/db mice with 4-methylumbelliferone (4-MU), an oral inhibitor of HA synthesis, clears islet HA deposits and promotes insulin production in these animals. Similarly, CD44-/-.db/db mice do not lose β-cell mass or develop diabetes despite being morbidly obese. Moreover, both 4-MU treatment and deletion of CD44 are protective against low-dose streptozotocin. Together, these data point to decisive roles for HA and CD44 in β-cell failure. Consistent with this, we have identified a role for HA and CD44 in responses to fibroblast growth factor 21 (FGF21), a key regulator of β-cell function and homeostasis. β-cells that express CD44 are less responsive to FGF21-mediated FGF receptor 1 (FGFR1) signaling, particularly in the presence of HA. However, the underlying mechanisms and their contribution to β-cell failure in T2DM are unknown. In light of our exciting preliminary data, we hypothesize that CD44 drives β-cell failure in T2DM via inhibition of FGF21 responses. Further, we propose that 4-MU, already an approved drug, could be repurposed to prevent β-cell failure in T2DM. To test this hypothesis, in Aim 1 we will define the role of CD44 in β-cell loss in T2DM. In Aim 2: we will then define the mechanisms involved in CD44-mediated effects on β-cell FGF21 responses. Finally, in Aim 3 we will develop therapies that target HA/CD44 to preserve human β-cell mass. Together, these Aims have the potential to reveal fundamental new pathways underlying the development of T2DM and to introduce novel treatments that will improve glycemic control in T2DM.