Modeling Pathogenesis of Type 2 Diabetes

在以前的报告中，我们已经描述了我们的T2 D发病机制模型。 它建立在Topp等人（J. Theor. Biol. 2000; 206（4）：605-19），其假定血糖的适度但持续增加介导负反馈以通过增加β细胞质量（通过增加复制或减少凋亡）来增加胰岛素分泌。 然而，如果这种增加未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会使其升高到对β细胞有毒的水平。 而不是负反馈（稳态），然后有正反馈（反稳态），这会导致β细胞质量和T2 D的灾难性损失。 除了定量改进以更准确地反映人类和啮齿动物中T2 D进展的测量动态外，我们还包括β细胞功能的调节，除了质量外，还包括两种不同形式。 数据显示，这种变化比质量的变化更迅速、更广泛，特别是对人类来说，青春期后β细胞的复制非常缓慢。 该模型捕捉了T2 D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，以及预防通常比逆转容易得多的事实，但激烈的干预措施，如减肥手术和极端热量限制可以逆转已建立的疾病。 该模型已被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，这很重要，因为个体在血糖首先偏离正常的方面存在差异。 此外，该模型可以在多年进展期间的任何时间点暂停，以模拟口服（OGTT）和静脉内（IVGTT）的葡萄糖耐量试验。 我们还使用该模型来研究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。 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，这在糖尿病的发展中充其量只发挥次要作用。 我们继续为Anne Sumner博士（NIDDK）的长期项目提供支持，以开发非洲T2 D和T2 D风险筛查方法，在那里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，该研究将生活在美国的非洲移民视为一个对自身利益感兴趣的群体，也是生活在非洲的非洲人的一个可访问的代理人。非洲的糖尿病是非常令人感兴趣的，因为它以世界地区最高的速度增长，并影响生活在快速工业化城市的肥胖人口和生活在非城市的瘦人口。 这项研究是 设计用于通过检查异常葡萄糖耐量（Abnl-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，异常葡萄糖耐量（Abnl-GT）定义为在OGTT期间具有高空腹或高两小时葡萄糖，有或没有胰岛素抵抗，定义为Matsuda指数的最低四分位数。 假定在不存在胰岛素抗性的情况下Abnl-GT是由β细胞衰竭引起的。 38%的Abnl-GT患者被发现患有胰岛素抵抗，这表明这是非洲人中不太常见的途径。 他们也有较高的体重指数（BMI）和血脂谱，易患心血管疾病，包括低HDL胆固醇，高甘油三酯，和较小的LDL和HDL颗粒，这将表明更需要针对血脂异常的干预措施。 这篇文章发表在Ref.#1。 虽然最初设计为从正常葡萄糖耐量到糖尿病前期进展的纵向模型，但我们发现该模型可通过拟合来自OGTT的数据来应用于评估该过程沿着任何阶段的胰岛素抵抗和β细胞功能。 我们发现，这些估计值与其他广泛使用但更具侵入性和成本更高的方法的估计值相关并相当一致。 一种是频繁采样的静脉葡萄糖耐量试验，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、正葡萄糖钳夹，其中在同时胰岛素输注的情况下输注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。 OGTT对于大规模临床研究来说更容易实施，更具成本效益，因此我们的模型有可能提高此类研究的价值。 我们还发现，处置指数（定义为β细胞功能与胰岛素抵抗的比率）可以从我们的模型中计算出来，而无需测量胰岛素，进一步有利于大规模临床研究。 正在编写一份文件。 心血管疾病是肥胖和葡萄糖-胰岛素调节受损的主要并发症。对于肥胖和胰岛素抵抗的肥胖、胰岛素抵抗的年轻人来说，这已经是一个亚临床水平的问题。 我们的合作者Stephanie Chung和Sheela Magge试图通过评估好（HDL）和坏（LDL）胆固醇的浓度沿着脂质颗粒大小的分布来确定155名肥胖青年（分类为胰岛素敏感，胰岛素抵抗或异常葡萄糖耐受）中胰岛素抵抗和高血糖的贡献。 MINMOD和我们的模型测量的动脉粥样硬化相关的特征与胰岛素抵抗相关，但与葡萄糖耐受不良无关。 这篇文章发表在参考文献#2中。

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.