Large Volume Visceral Fat Removal to Reverse Insulin Resistance in Type 2 Diabetes

摘要 过多的内脏脂肪（VF）与胰岛素抵抗和随后的2型胰岛素抵抗的发展密切相关 人类的T2 DM和啮齿动物脂肪切除术研究已经证明了这种关系是因果关系。 在近3000万受T2 DM影响的美国成年人中，疾病发作通常继发于体重 增益，过度VF被认为是主要驱动因素。生活方式的改变（饮食和锻炼）是第一道防线。 体重管理和疾病预防的治疗，但这些努力并没有被证明是有效的， 长期的通过大容量吸脂手术去除皮下脂肪已被探索作为一种替代方法 方法，但绝大多数这些研究都未能始终如一地证明改善， 代谢结果。因此，应优先确定清除退伍军人库的目标， 显着改善人类的代谢和整体健康。然而，由于大量的血管化和 由于VF内部和周围还有其他脆弱的结构，目前还没有可行的方法来执行该手术。 针对网膜的研究结果喜忧参半，可能是因为这个仓库只占 对于肥胖人中总VF质量的一部分（~10%）。因此，另外靶向肠系膜和肠系膜， 大多数VF所在的肾脏区域可能需要手术治疗T2 DM。为此我们 开发并商业化了一种用于去除白内障以及皮下脂肪库的技术， 我们将其称为组织液化技术™（TLT）。我们的方法是一种独特的专利方法， 将低水平的热能和机械能作为温热、低压和脉冲盐水流输送， 这导致易感的非结缔组织经历从固体到液体的相变， 结缔组织保护的血管和神经不受伤害。初步数据证明了我们的能力 成功地定位并清除猪和狒狒体内的VF深库。因此，这一具体目标 一项建议是确定狒狒中大体积VF清除以逆转胰岛素的可行性和有效性 阻力这将通过手术从所有三个VF储库中去除大量脂肪来确定 （约75%的网膜、肾周、肠系膜脂肪），7只超重和胰岛素抵抗狒狒中存在TLT，以及 使用“金标准”技术确定对代谢结果的影响，包括高胰岛素血症， 正葡萄糖钳夹、DXA、MRI、MRS和一系列广泛的血浆代谢物， 9个月随访。我们选择研究胰岛素抵抗狒狒，因为它们是一个经过充分验证的模型， 在我们的初步研究中，TLT已被证明可以轻松快速地消除狒狒（和人类）VF 问题研究我们的期望是，动物将表现出异常的恢复，没有并发症， 改善胰岛素敏感性，无VF储库的显著再生长或对肝脏和骨骼的不良影响 肌肉.总之，我们的技术是外科脂肪去除的重要一步，如果证明成功， 在这里，可能代表了T2 DM和其他疾病中胰岛素抵抗的革命性治疗选择。

Abstract Excess visceral fat (VF) has been strongly linked with development of insulin resistance and subsequent type 2 diabetes (T2DM) in humans, and rodent lipectomy studies have demonstrated that this relationship is causal. Among the nearly 30 million US adults affected by T2DM, disease onset typically appears secondary to weight gain, with excess VF considered to be a major driver. Lifestyle changes (diet and exercise) are the first line of treatment for weight management and disease prevention, but such efforts have not proven effective over the long-term. Surgically removing subcutaneous fat by large volume liposuction has been explored as an alternative approach, but the vast majority of these studies have failed to consistently demonstrate improvement in metabolic outcomes. Therefore, targeting the VF depots for removal should be prioritized in order to rapidly and significantly improve metabolic and overall health in humans. However, due to the heavy vascularization and other delicate structures within and around VF, there are currently no feasible methods to perform this procedure. Studies targeting the omentum have been conducted with mixed results, likely because this depot only accounts for a fraction of total VF mass (~10%) in an obese human. Thus, additionally targeting the mesentery and peri- renal areas, where most VF is harbored, may be required to surgically treat T2DM. To this end, we have developed and commercialized a technology in use for removal of cataracts as well as subcutaneous fat depots, which we refer to as Tissue Liquefaction Technology™ (TLT). Our method is a unique, patented approach that delivers low levels of thermal and mechanical energy as a stream of warmed, low-pressurized, and pulsed saline, which causes susceptible non-connective tissues to undergo a phase transition from solid to liquid, while connective tissue-protected blood vessels and nerves are unharmed. Preliminary data demonstrate our ability to successfully target and remove these deep VF depots in pigs and baboons. Thus, the Specific Aim of this proposal is to determine feasibility and efficacy of large-volume VF removal in the baboon to reverse insulin resistance. This will be determined by surgically removing significant quantities of fat from all three VF depots (~75% of omentum, peri-renal, mesenteric fat) with TLT in 7 overweight and insulin resistant baboons, and determining effects on metabolic outcomes using `gold standard' techniques, including hyperinsulinemic- euglycemic clamps, DXA, MRI, MRS and a broad array of plasma metabolites at pre-determined intervals over 9 mo follow up. We have chosen to study insulin resistant baboons, since they are a well-validated model of human metabolism, and TLT has proven to easily and rapidly liquefy baboon (and human) VF in our preliminary studies. Our expectation is that animals will demonstrate exceptional recoveries, free of complications, have improved insulin sensitivity, without significant regrowth of VF depots or adverse effects on liver and skeletal muscle. In summary, our technology is a significant step forward for surgical fat removal, and if proven successful here, may represent a revolutionary treatment option for insulin resistance in T2DM and other conditions.