Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, ON, Canada.
Diabetologia. 2021 Jun;64(6):1189-1200. doi: 10.1007/s00125-021-05403-9. Epub 2021 Mar 4.
Award programmes that acknowledge the remarkable accomplishments of long-term survivors with type 1 diabetes have naturally evolved into research programmes to determine the factors associated with survivorship and resistance to chronic complications. In this review, we present an overview of the methodological sources of selection bias inherent in survivorship research (selection of those with early-onset diabetes, incidence-prevalence bias and bias from losses to follow-up in cohort studies) and the breadth and depth of literature focusing on this special study population. We focus on the learnings from the study of longstanding type 1 diabetes on discoveries about the natural history of insulin production loss and microvascular complications, and mechanisms associated with them that may in future offer therapeutic targets. We detail descriptive findings about the prevalence of preserved insulin production and resistance to complications, and the putative mechanisms associated with such resistance. To date, findings imply that the following mechanisms exist: strategies to maintain or recover beta cells and their function; activation of specific glycolytic enzymes such as pyruvate kinase M2; modification of AGE production and processing; novel mechanisms for modification of renin-angiotensin-aldosterone system activation, in particular those that may normalise afferent rather than efferent renal arteriolar resistance; and activation and modification of processes such as retinol binding and DNA damage checkpoint proteins. Among the many clinical and public health insights, research into this special study population has identified putative mechanisms that may in future serve as therapeutic targets, knowledge that likely could not have been gained without studying long-term survivors.
奖励计划承认 1 型糖尿病长期幸存者的卓越成就，这些计划自然而然地演变成了研究计划，以确定与生存和抵抗慢性并发症相关的因素。在这篇综述中，我们概述了生存研究中固有的选择偏倚的方法学来源（选择那些早期发病的人、发病率-患病率偏倚以及队列研究中随访丢失的偏倚），以及关注这一特殊研究人群的文献的广度和深度。我们重点介绍了从长期 1 型糖尿病研究中获得的关于胰岛素产生损失和微血管并发症的自然史以及与之相关的机制的知识，这些知识将来可能提供治疗靶点。我们详细介绍了关于保留胰岛素产生和抵抗并发症的流行率的描述性发现，以及与这种抵抗相关的潜在机制。迄今为止，研究结果表明存在以下机制：维持或恢复β细胞及其功能的策略；激活特定的糖酵解酶，如丙酮酸激酶 M2；AGE 产生和处理的修饰；肾素-血管紧张素-醛固酮系统激活的新型修饰机制，特别是那些可能使传入而不是传出肾小动脉阻力正常化的机制；以及激活和修饰视黄醇结合和 DNA 损伤检查点蛋白等过程。在众多临床和公共卫生见解中，对这一特殊研究人群的研究确定了潜在的机制，这些机制将来可能成为治疗靶点，如果不研究长期幸存者，这些知识可能无法获得。
