Modeling Pathogenesis of Type 2 Diabetes

在以前的报告中，我们已经描述了我们的T2D发病机制模型。它建立在Topp等人(J.Theor.比奥尔。2000年；206(4)：605-19)，该研究假设血糖适度但持续的上升通过增加复制或减少凋亡的方式，通过增加β细胞质量来调节负反馈，从而增加胰岛素的分泌。然而，如果这种增加不能发生或不足以恢复正常的葡萄糖稳态，葡萄糖的进一步增加就会使其上升到对β细胞产生毒性的水平。不是负反馈(稳态)，而是正反馈(反稳态)，这会导致β细胞质量和T2D的灾难性损失。除了定量改进以更准确地反映在人类和啮齿动物中测量到的T2D进展动态，我们还包括对β细胞功能的调节，除了质量之外，还有两种不同的形式。数据显示，这种变化比质量变化更快、更广泛，特别是对人类来说，他们的β细胞复制在青春期后非常缓慢。 该模型捕捉到了T2D进展的许多关键特征，包括在长期逐渐恶化(阈值行为)后血糖控制突然恶化，以及这样一个事实，即预防通常比逆转容易得多，但激进的干预，如减肥手术和极端热量限制，可以逆转既定的疾病。 该模型已进一步扩展到跟踪空腹和餐后血糖，而不仅仅是平均每日血糖，这一点很重要，因为不同的人在血糖的哪个方面首先偏离正常水平有所不同。此外，该模型可以在多年进展过程中的任何时间点暂停，以模拟口服(OGTT)和静脉注射(IVGTT)的葡萄糖耐量试验。我们还使用该模型研究了高胰岛素导致胰岛素抵抗的假设，而不是我们在模型中假设的相反情况。尽管有强有力的证据表明，高胰岛素血症确实会导致胰岛素抵抗，但模型模拟表明，这充其量在糖尿病的发展中只起到了很小的作用。 我们继续支持Anne Sumner博士(NIDDK)在非洲开发T2D和T2D风险筛查方法的长期项目，在非洲，使用标准方法存在许多挑战。我们为萨姆纳博士领导的一项研究做出了贡献，该研究将居住在美国的非洲移民视为一个利益群体，同时也是生活在非洲的非洲人的可接近的代理人。非洲的糖尿病引起了人们的极大关注，因为它正以世界上最高的速度增长，并影响到生活在快速工业化城市的肥胖人口和生活在城市以外的瘦弱人口。这项研究旨在通过检测糖耐量异常(ABN1-GT)的患病率来评估胰岛素抵抗或β细胞衰竭是否是导致2型糖尿病的主要损害。异常糖耐量(ABN1-GT)的定义是，在有或没有胰岛素抵抗的OGTT期间，空腹或两小时血糖过高，定义为松田指数的最低四分位数。在没有胰岛素抵抗的情况下，ABN1-GT被认为是由β细胞衰竭引起的。38%的Abnl-GT患者被发现存在胰岛素抵抗，这表明这是非洲人中不太常见的途径。他们也有更高的身体质量指数(BMI)和易患心血管疾病的血脂谱，包括低高密度脂蛋白胆固醇，高甘油三酯，以及较小的低密度脂蛋白和高密度脂蛋白颗粒，这将表明更有必要针对血脂异常进行干预。该著作已发表于《参考文献》。#1. 虽然最初被设计为从正常糖耐量到糖尿病前期再到糖尿病进展的纵向模型，但我们发现，通过对OGTTS的数据进行拟合，该模型可以应用于评估过程中任何阶段的胰岛素抵抗和β细胞功能。我们发现，这些估计与其他广泛使用、但更具侵入性和成本更高的方法的估计结果具有很好的相关性和一致性。一种是频繁采样的静脉葡萄糖耐量试验，它需要20多个葡萄糖和胰岛素样本，然后使用Bergman-Cobelli最小模型(MINMOD)进行分析。另一种是高胰岛素、正血糖钳夹，在胰岛素输注的同时，注入葡萄糖以将葡萄糖维持在固定水平。这在技术上具有挑战性，需要长达四个小时的时间。对于大规模的临床研究，OGTTS更容易实施，成本效益更高，因此我们的模型具有提高此类研究价值的潜力。我们还发现，倾向性指数，即β细胞功能与胰岛素抵抗的比率，可以从我们的模型计算出来，而不需要测量胰岛素，进一步有利于大规模的临床研究。一篇论文正在准备中。 心血管疾病是肥胖和血糖-胰岛素调节受损的主要并发症。对于肥胖、胰岛素抵抗、肥胖和胰岛素抵抗的年轻人来说，这已经是一个亚临床层面的问题。我们的合作者Stephanie Chung和Sheela Magge试图通过评估好的(高密度脂蛋白)和坏的(低密度脂蛋白)胆固醇浓度以及脂肪颗粒大小的分布来确定胰岛素抵抗和高血糖在155名肥胖青年中的作用，这些肥胖青年被归类为胰岛素敏感型、胰岛素抵抗或糖耐量异常。根据MINMOD和我们的模型的测量，与动脉粥样硬化相关的特征与胰岛素抵抗有关，但与糖耐量异常无关。这部著作已在参考文献中发表。#2.

In previous reports we have described our model for T2D pathogenesis. It builds on the foundational model of Topp et al (J. Theor. Biol. 2000; 206(4):605-19), which posited that moderate but persistent increases in blood sugar mediate negative feedback to increase insulin secretion by increasing beta-cell mass, either by increased replication or reduced apoptosis. However, if that increase fails to occur or is inadequate to restore normal glucose homeostasis, further increases in glucose raise it to a level where it becomes toxic to beta cells. Instead of negative feedback (homeostasis), there is then positive feedback (anti-homeostasis), which causes a catastrophic loss of beta-cell mass and T2D. In addition to quantitative refinements to more accurately reflect the measured dynamics of T2D progression in humans and rodents, we included regulation of beta-cell function, in two distinct forms, in addition to mass. Data show that such changes are more rapid and more extensive than changes in mass, especially for humans, for whom beta-cell replication is very slow after adolescence. The model captures many key features of T2D progression, including the sudden deterioration of glucose control after a long period of gradual worsening (threshold behavior) and the fact that prevention is generally much easier than reversal, but drastic interventions, such as bariatric surgery and extreme caloric restriction can reverse established disease. The model has been further extended to track fasting and post-prandial glucose, rather than just average daily glucose, which is important because individuals differ in which aspect of glucose deviates first from normal. In addition, the model can be paused at any point during progression over years to simulate glucose tolerance tests, both oral (OGTT) and intravenous (IVGTT). We also used the model to investigate the hypothesis that high insulin causes insulin resistance rather than the other way around, as we assume in our model. Although there is strong evidence that hyperinsulinemia does contribute to insulin resistance, model simulations suggest that this plays at best a minor role in the development of diabetes. We continued to provide support to the long-term project of Dr. Anne Sumner (NIDDK) to develop methods of screening for T2D and T2D risk in Africa, where there are many challenges to using standard methods. We contributed to a study led by Dr. Sumner of African immigrants living in the US as a group of interest in their own right as well as an accessible proxy for Africans living in Africa. Diabetes in Africa is of great interest because it is growing at the highest rate of world regions and affects both obese populations living in rapidly industrializing cities and lean non-urban populations living. The study was designed to assess whether insulin resistance or beta-cell failure is the predominant impairment leading to type 2 diabetes by examining the prevalence of abnormal glucose tolerance (Abnl-GT), defined as having high fasting or high two-hour glucose during an OGTT with or without insulin resistance, defined as the lowest quartile of the Matsuda index. Abnl-GT in the absence of insulin resistance was assumed to result from beta-cell failure. 38% of the individuals with Abnl-GT were found to have insulin resistance, which suggests that this is the less common pathway among Africans. They also had higher body mass index (BMI) and lipid profiles that predispose to cardiovascular disease, including low HDL cholesterol, high triglycerides, and smaller LDL and HDL particles, which would indicate a greater need for interventions targeted at dyslipdemia. The work has been published in Ref. #1. Although originally designed as longitudinal model for the progression from normal glucose tolerance through pre-diabetes to diabetes, we have found that the model can be applied to assess insulin resistance and beta-cell function at any stage along the process by fitting data from OGTTs. We have found that the estimates correlate and agree reasonably well with those from other widely used, but more invasive and costly approaches. One is the frequently sampled intravenous glucose tolerance test, which requires more than 20 glucose and insulin samples, which are then analyzed using the Bergman-Cobelli Minimal Model (MINMOD). Another is the hyperinsulinemic, euglycemic clamp, in which glucose is infused to maintain glucose at a fixed level in the face of simultaneous insulin infusion. This is technically challenging and takes up to four hours. OGTTs are much easier to implement and more cost-effective for large-scale clinical studies, so our model thus has the potential to enhance the value of such studies. We have also found that the disposition index, defined as the ratio of beta-cell function to insulin resistance, can be calculated from our model without the need to measure insulin, further benefiting large-scale clinical studies. A paper is in preparation. Cardiovascular disease is a major complication of obesity and impaired glucose-insulin regulation. This is a problem at the sub-clinical level already for obese, insulin-resistant youth people with obesity and insulin resistance. Our collaborators Stephanie Chung and Sheela Magge sought to determine the contributions of insulin resistance and hyperglycemia in a cohort of 155 obese youth classified as insulin sensitive, insulin resistant, or abnormal glucose tolerant by assessing the concentrations of good (HDL) and bad (LDL) cholesterol along with the distribution of lipid particle sizes. Profiles linked to atherosclerosis were associated with insulin resistance, as measured by both MINMOD and our model, but not with glucose intolerance. The work has been published in ref. #2.