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型糖尿病的发展密切相关。 人类糖尿病(T2 DM)和啮齿动物脂肪切除的研究表明，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，疾病的发病通常似乎次于体重 收益，过量的VF被认为是一个主要的驱动因素。改变生活方式(饮食和锻炼)是 体重控制和疾病预防的治疗，但这些努力在过去几年中并未被证明有效 长期的。通过大容量吸脂手术去除皮下脂肪已经被探索为一种替代方案 方法，但这些研究中的绝大多数未能始终如一地证明 代谢结果。因此，应优先考虑移除VF仓库的目标，以便快速和 显著改善人类的新陈代谢和整体健康。然而，由于严重的血管化和 由于VF内部和周围的其他微妙结构，目前还没有可行的方法来实施这一程序。 针对大网膜的研究结果喜忧参半，可能是因为这个仓库只占了 肥胖者的VF总质量的一小部分(~10%)。因此，额外针对肠系膜和周围- 大多数室性心动过速的肾区可能需要手术治疗T2 DM。为此，我们有 开发并商业化了一项用于摘除白内障和皮下脂肪库的技术， 我们称之为组织液化技术(TLT)(™)。我们的方法是一种独特的专利方法 以加热、低压和脉冲生理盐水的形式提供低水平的热能和机械能， 这会导致易感的非结缔组织经历从固体到液体的相变，而 结缔组织保护的血管和神经未受损伤。初步数据表明我们有能力 为了成功地瞄准并清除这些猪和狒狒体内的深VF仓库。因此，这一行动的具体目的是 建议确定在狒狒体内大量去除室颤以逆转胰岛素的可行性和有效性。 抵抗。这将通过手术从所有三个VF储存库中移除大量脂肪来确定 (~75%的大网膜、肾周、肠系膜脂肪)和TLT，在7只超重和胰岛素抵抗的狒狒中，以及 使用“黄金标准”技术确定对代谢结果的影响，包括高胰岛素血症- 正常血糖钳，DXA，MRI，MRS和一系列血浆代谢物在预定的时间间隔 9个月随访。我们选择对抵抗胰岛素的狒狒进行研究，因为它们是一个经过充分验证的 人的新陈代谢，TLT已被证明在我们的初步研究中可以轻松、快速地液化狒狒(和人类)VF 学习。我们的期望是，动物将表现出非凡的恢复能力，没有并发症， 改善胰岛素敏感性，不会明显再生VF库，也不会对肝脏和骨骼产生不良影响 肌肉。总而言之，我们的技术是外科脂肪去除方面向前迈出的重要一步，如果证明成功的话， 在这里，它可能代表着T2 DM和其他条件下胰岛素抵抗的一种革命性治疗选择。

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.