Interleukin 12 disruption provides beta cell and microvessel protection in type 2diabetes

摘要/摘要 β细胞衰竭、微血管内皮细胞功能障碍、纤维化和钙化具有重要的临床意义。 2型糖尿病(T2D)患者的问题，因为他们会导致心肌梗死、中风、外周 动脉疾病、视网膜病变、肾病、心肌病和伤口愈合延迟。然而， 在T2D中导致这些病理的有害机制还没有完全被了解。当前 T2D的治疗既不能阻止或逆转β细胞衰竭、内皮细胞功能障碍，也不能逆转组织 并发症。因此，迫切需要确定基于机制的、可治疗的靶点。 改善β细胞和微血管功能，减少纤维化和钙化，限制 T2D多组织器官异常。T2D患者细胞因子和脂肪因子分泌增加， 它会影响β细胞和微血管的功能和结构。具体地说，支持的水平- 炎性细胞因子白介素12(IL-12)在青少年和成人T2D患者中升高。然而，它 目前尚不清楚抑制IL-12是否保护了β细胞和微血管功能，从而降低了 多个器官的纤维化和钙化。此外，增加IL-12的机制可能 因为这些病理都是未知的。前提是，给非肥胖小鼠注射IL-12会导致 糖尿病、肝脏毒性和纤维化、肾脏损害和动脉粥样硬化，支持IL-1的有害作用。 12例为糖尿病，并伴有多组织器官损害。我们假设T2D中IL-12的升高 小鼠造成β细胞功能障碍、高血糖、胰岛素抵抗、微血管内皮细胞 炎症、内质网(ER)应激导致的功能障碍、纤维化和钙化， 和自噬机制。为了验证这一假设，我们提出了以下目标：目标1：IL-12 导致T2D中的β细胞和内皮细胞功能障碍、纤维化和钙化。我们将评估 IL-12基因缺失或中和IL-12能否消除IL-12诱导的T2D病理改变 12抗体；目的#2：IL-12诱导T2D胰岛炎症。我们将检查基因是否 在T2D小鼠中缺失IL-12或中和IL-12抗体可以减轻胰岛的炎症， 进而改善β细胞和内皮细胞功能，减少纤维化和钙化； 目的#3：IL-12诱导的β细胞和内皮细胞功能障碍、纤维化和钙化 T2D中的内质网应激机制。我们将在贝塔细胞和内皮细胞中阐明这一机制。 由此，IL-12导致T2D中的β细胞和内皮细胞功能障碍、纤维化和钙化；目标4： IL-12诱导的β细胞和内皮细胞功能障碍、纤维化和钙化是由 T2D中的自噬机制。我们将在β细胞和内皮细胞中阐明这一机制 由此，IL-12导致T2D中的β细胞和内皮细胞功能障碍、纤维化和钙化。

SUMMARY/ABSTRACT Beta cell failure, microvascular endothelial cell dysfunction, fibrosis, and calcification are clinically significant problems in type 2 diabetic (T2D) patients because they cause myocardial infarction, stroke, peripheral artery disease, retinopathy, nephropathy, cardiomyopathy, and wound healing delay. However, the detrimental mechanisms responsible for these pathologies in T2D are not completely understood. Current therapies for T2D neither halt nor reverse beta cell failure, endothelial cell dysfunction, nor the tissue complications. Therefore, there is a critical need for the identification of mechanism-based, treatable targets to improve beta cell and microvascular function, to reduce fibrosis and calcification, and to limit the abnormalities of multiple tissues and organs in T2D. Cytokine and adipokine secretion is increased in T2D, which affects beta cell and microvascular function and structure. Specifically, the level of the pro- inflammatory cytokine interleukin-12 (IL-12) is increased in adolescent and adult T2D patients. However, it is unknown whether the inhibition of IL-12 protects beta cell and microvascular function, thereby reducing fibrosis and calcification in multiple organs. Furthermore, the mechanism by which increased IL-12 might cause these pathologies is unknown. The premise is that IL-12 administration to non-obese mice leads to diabetes, liver toxicity and fibrosis, kidney damage, and atherosclerosis, supporting a detrimental role of IL- 12 in diabetes, and multiple tissues and organs damage. We hypothesize that increased IL-12 in T2D mice causes beta cell dysfunction, hyperglycemia, insulin resistance, microvascular endothelial cell dysfunction, fibrosis, and calcification through inflammation, endoplasmic reticulum (ER) stress, and autophagy mechanisms. To test the hypothesis, we proposed the following aims: Aim #1: IL-12 causes beta cell and endothelial cell dysfunction, fibrosis, and calcification in T2D. We will assess whether IL-12-induced pathology in T2D can be abrogated using genetic deletion of IL-12 or neutralizing IL- 12 antibody; Aim #2: IL-12 induces pancreatic islet inflammation in T2D. We will examine if genetic deletion of IL-12 or neutralizing IL-12 antibody in T2D mice attenuates the inflammation in pancreatic islets, and subsequently improves beta cell and endothelial cell function, and reduces fibrosis and calcification; Aim #3: IL-12 induced beta and endothelial cell dysfunction, fibrosis, and calcification are dictated by an ER stress mechanism in T2D. We will illustrate the mechanisms in beta cells and endothelial cells whereby IL-12 leads to beta cell and endothelial cell dysfunction, fibrosis and calcification in T2D; Aim #4: IL-12 induced beta cell and endothelial cell dysfunction, fibrosis, and calcification are driven by an autophagy mechanism in T2D. We will elucidate the mechanisms in beta cells and endothelial cells whereby IL-12 leads to beta cell and endothelial cell dysfunction, fibrosis, and calcification in T2D.