Mesenteric Fat Cryolipolysis to Reverse Insulin Resistance

抽象的。胰岛素抵抗、II型糖尿病、肥胖症和代谢性疾病共病的患病率 综合症正在上升。超过1.2亿美国成年人患有糖尿病或糖尿病前期。这是一个巨大的 财务负担，2019年估计约为4040亿美元。内脏脂肪（但不是皮下脂肪）， 肠系膜脂肪显示在胰岛素抵抗和糖尿病的病理生理学中具有主要作用。 脂肪细胞对低温比任何其他类型的细胞更敏感。脂肪凝固在一个更高的 温度高于水的冻结温度，形成针状结构，促进细胞死亡。 在+100 ℃的温度下已经检测到低温（冷冻溶脂）诱导脂肪细胞死亡。这 相对较高的温度使冷冻溶脂成为诱导肠系膜脂肪质量损失的有吸引力的方法， 一种新的治疗方式，以减少胰岛素抵抗和糖尿病患者的内脏肥胖。 我们的目标是测试一种新的方法和设备的可行性和安全性，以减少质量的 肠系膜脂肪利用低温，作为一种新的治疗选择，以扭转胰岛素抵抗和发病率 糖尿病 假设：过多的肠系膜脂肪是胰岛素抵抗、糖尿病、 和代谢综合征。低温输送到肠系膜脂肪将促进脂肪细胞损失 而不损伤周围组织并且没有任何显著的副作用。肠系膜脂肪的减少 对胰岛素抵抗、糖尿病进展和代谢综合征具有有益作用。来测试我们 根据这一假设，我们提出以下具体目标： 1A.利用基于有限元分析（FEA）的计算传热方法对脂肪进行建模 不同器械温度、形状、材料和治疗持续时间的热循环。1B.验证急性 用于体内长期安全性和可行性研究的安全性和热循环（目标2）。 2.在Ossabaw猪胰岛素抵抗模型中，评价肠系膜脂肪的安全性和可行性 冷冻溶脂对胰岛素抵抗进展的影响。 里程碑：成功模拟内脏脂肪的热循环将被视为第一个里程碑。 构建冷冻溶脂原型装置和在1A中计算的组织温度的体内验证将是 第二个里程碑术后7天无并发症生存将被视为第三个 里程碑成功安全地减少肠系膜脂肪量并逆转胰岛素的进展 第二个里程碑（Aim 2）将是第四个里程碑。这些研究的成功完成将表明， 肠系膜脂肪冷冻溶脂术是治疗胰岛素抵抗的一种安全有效的方法。该设备开发，并 所获得的结果将为最佳器械设计以及安全性和有效性研究铺平道路， 设想的方案最终将在人体试验中转化。

Abstract. The prevalence of insulin resistance, type II diabetes, obesity and co-morbidities of the metabolic syndrome is rising. More than 120M US adults are living with diabetes or are pre-diabetics. This carries a huge financial burden, which was estimated at ~$404B in 2019. Visceral fat (but not subcutaneous) and specifically the mesenteric fat, was shown to have a major role in the pathophysiology of insulin resistance and diabetes. Fat cells are more sensitive to low temperatures compared to any other cell type. Fat solidifies at a higher temperature than the freezing temperature of water, forming needle like structures that promote cell death. Induction of fat cell death by low temperatures (cryolipolysis) is already detected at a temperature of +100C. This relatively high temperature is making cryolipolysis an attractive approach to induce mesenteric fat mass loss as a new treatment modality to reduce Insulin resistance and diabetes in patients with visceral obesity. Our objective is to test the feasibility and safety of a novel approach and device to reduce the mass of the mesenteric fat using cold temperatures, as a new treatment option to reverse insulin resistance and the incidence of diabetes. Hypothesis: excessive mesenteric fat is a major contributor to the progression of insulin resistance, diabetes, and the metabolic syndrome. Cold temperatures delivered into the mesenteric fat will promote fat cells loss without injuring surrounding tissues and without any significant side effects. The decrease in mesenteric fat will have beneficial effects on insulin resistance, diabetes progression, and the metabolic syndrome. To test our hypothesis, we propose the following Specific Aims: 1A. To utilize computational heat transfer methods based on Finite Element Analysis (FEA) to model fat thermal cycle for different device temperatures, shapes, materials, and treatment duration. 1B. To validate acute safety and thermal cycle to be used in in-vivo chronic safety and feasibility studies (Aim 2). 2. In the Ossabaw pig model of insulin resistance, to evaluate the safety and feasibility of mesenteric fat cryolipolysis on insulin resistance progression. Milestones: Successfully modeling the thermal cycle in visceral fat will be considered as a first milestone. Building a cryolipolysis prototype device and in vivo validation of tissue temperatures calculated in 1A will be the second milestone. Seven days post-procedure survival without complications will be considered as the third milestone. Successfully and safely reducing the mesenteric fat mass and reversing the progression of insulin resistance (Aim 2) will be the fourth milestone. The successful completion of these studies will show that cryolipolysis of mesenteric fat is a safe and effective way to treat insulin resistance. The device developed, and the results obtained, will pave the way for optimal device design and safety and efficacy studies utilizing envisioned protocols to be eventually translated in human trials.