Mesenteric Fat Cryolipolysis to Reverse Insulin Resistance

肠系膜脂肪冷冻溶脂逆转胰岛素抵抗

• 批准号: 10603168
• 负责人: Rafi Mazor
• 金额: $ 30万
• 依托单位: B2M MEDICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10603168
• 关键词: Abdomen; Acute; Adipocytes; Adopted; Adult; Anatomy; Animal Model; Blood Vessels; Cardiovascular system; Cell Death; Cells; Central obesity; Chronic; Clinical; Clinical Research; Clinical Trials; Computer Analysis; Data; Deposition; Development; Device Designs; Device Safety; Devices; Diabetes Mellitus; Drainage procedure; Epidemic; Evaluation; Excision; Family suidae; Fatty acid glycerol esters; Feasibility Studies; Female; Financial Hardship; Finite Element Analysis; Freezing; Functional disorder; Gender; Glucose; Greater omentum; Health; Health Care Costs; Hepatic; High Fat Diet; High temperature of physical object; Human; Impairment; Incidence; Individual; Inflammation Mediators; Inflammatory; Insulin Resistance; Intestines; Laparotomy; Life Style; Lipids; Liquid substance; Literature; Liver; Measures; Mesentery; Metabolic; Metabolic syndrome; Methods; Modality; Modeling; Morbidity - disease rate; Needles; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Omentum; Operative Surgical Procedures; Patients; Phase; Prediabetes syndrome; Prevalence; Procedures; Property; Protocols documentation; Risk; Role; Safety; Shapes; Skin; Small Business Innovation Research Grant; Structure; Techniques; Technology; Temperature; Testing; Thick; Tissues; Translating; Translations; Unresectable; Validation; Visceral fat; Water; abdominal fat; adipokines; base; cell type; cold temperature; comorbidity; cytokine; diabetic patient; diabetogenic; diet-induced obesity; dietary; efficacy study; feasibility testing; first-in-human; in vivo; insulin sensitivity; male; minimally invasive; mortality; neurovascular; nonhuman primate; novel; novel strategies; porcine model; prototype; recruit; safety and feasibility; safety study; safety testing; side effect; subcutaneous; tool; treatment duration

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.

抽象的。胰岛素抵抗、II 型糖尿病、肥胖和代谢并发症的患病率 综合症正在上升。超过 1.2 亿美国成年人患有糖尿病或处于糖尿病前期。这承载着巨大的 经济负担，2019 年估计约为 $404B。内脏脂肪（但不是皮下脂肪），特别是 肠系膜脂肪被证明在胰岛素抵抗和糖尿病的病理生理学中具有重要作用。 与任何其他细胞类型相比，脂肪细胞对低温更敏感。脂肪在较高温度下凝固 温度高于水的冰点温度，形成促进细胞死亡的针状结构。 在 +100C 的温度下已经检测到低温诱导脂肪细胞死亡（冷冻脂肪分解）。这 相对较高的温度使冷冻溶脂成为一种有吸引力的诱导肠系膜脂肪量减少的方法 一种减少内脏肥胖患者胰岛素抵抗和糖尿病的新治疗方式。 我们的目标是测试一种新方法和设备的可行性和安全性，以减少机器人的质量 使用低温治疗肠系膜脂肪，作为逆转胰岛素抵抗和发病率的新治疗选择 糖尿病。 假设：肠系膜脂肪过多是导致胰岛素抵抗、糖尿病、 和代谢综合征。寒冷的温度传递到肠系膜脂肪会促进脂肪细胞损失 不损伤周围组织，也没有任何明显的副作用。肠系膜脂肪会减少 对胰岛素抵抗、糖尿病进展和代谢综合征有有益的影响。来测试我们的 假设，我们提出以下具体目标： 1A。利用基于有限元分析 (FEA) 的计算传热方法来模拟脂肪 不同设备温度、形状、材料和处理持续时间的热循环。 1B.验证急性 用于体内慢性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并对 1A 中计算的组织温度进行体内验证将是 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 阻力（目标 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是治疗胰岛素抵抗的一种安全有效的方法。该设备已开发出来，并且 获得的结果将为优化设备设计以及利用的安全性和有效性研究铺平道路 设想的方案最终将转化为人体试验。