What and when is diabetes? A devil's advocate perspective on contemporary controversies in diabetes criteria and classification (2018)

In a world of such incredible scientific progress in so many areas of human health, it may come as a shock to many, or at least a major surprise, that the question “What and when is diabetes?” is asked. This question raises a number of issues, and not just the more recent one of the relative utility of whether blood glucose or HbA1c is a better reflection of glucose tolerance status. The joint issue of classification and criteria has serious implications not only for the management and prevention of diabetes, but also for biomedical research, particularly genomic studies where discrete categories need to be phenotypically “pure.” This “purity” is almost impossible in type 2 diabetes mellitus (T2DM), where the actual determinants for cut-off points for diabetes, and indeed for impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), remain a subject of debate.1 Traditionally, the threshold for the development of microvascular complications, like retinopathy, has been used as the marker for developing the diagnostic criteria for diabetes, but this may not be the best marker to target. In 1989, almost 30 years ago, one of us (PZ) raised issues arising as to the appropriate classification of diabetes.2 It was argued that what we call T2DM is not a single or discrete entity, but part of a non-communicable disease (NCD) syndrome or risk factor complex. This argument was not new then and has continued with vigor uninterrupted until today, along with the argument regarding appropriate diagnostic criteria.1-3 Numerous attempts, particularly by World Health Organization (WHO) and the American Diabetes Association (ADA), have been made to get satisfactory answers on classification. These have been reviewed in detail elsewhere.1 Over the years, there have been several other attempts to reactivate debate1 and, very recently, the international media ran a provocative headline “Diabetes is actually five separate diseases, research suggests.”4 That headline referred to a publication from Ahlqvist et al.5 in which the authors stratified patients into five subgroups with differing disease progression and risk of diabetes complications. Ahlqvist et al.5 suggested this innovative approach may eventually help tailor and target prompt treatment for the people with diabetes who would benefit most. Indeed, such an approach may also be useful for choosing subjects most likely to respond to different interventions for the prevention of T2DM. However neat a concept, given the heterogeneity of T2DM, the concept may be too simplistic. The original attempts to classify diabetes were helped by the important observation of Himsworth in 1936,6 who noted that there appeared to be two forms of diabetes, insulin sensitive and insulin insensitive. Some 15 years later, this was validated by Bornstein and Lawrence,7 who, arguably, were the first to use a bioassay for insulin to describe the two discrete entities predicted by Himsworth, the conditions we now recognize as type 1 diabetes mellitus (T1DM) and T2DM. The main complexity, and that addressed in this Commentary, relates to T2DM (Himsworth's insulin-sensitive form), its classification, the much-debated diagnostic criteria and their appropriate use and value. Over the subsequent six decades, there were been numerous attempts, particularly by the WHO and the National Diabetes Data Group (NDDG), to come to grips with a useful classification.1 The classification should not only be of descriptive value, but also one that could be useful for individualizing treatment regimens given that T2DM is highly heterogeneous and there is an urgent need to provide a format that helps determine individual specific therapeutic needs. Those attempts and the background discussion are detailed elsewhere,1 but in 1965 the WHO held its first Expert Committee meeting on diabetes.8 This was one of the first attempts to establish consensus on the classification of diabetes, but even so no global uniformity resulted. The contemporary classification of diabetes started with, and is still based largely on, that developed in 1979 by the NDDG9 and the second WHO Expert Committee in 1980.10 The first major revision of the 1980 WHO classification was published in 1999,11 and this generated a new international classification and revised criteria. Subsequently, there have been several attempts, including that by Ahlqvist et al.,5 to provide a more contemporary classification more attuned to clinical needs rather than the current focus on T1DM and T2DM. Schwartz et al.12 have recommended that there should be a re-evaluation of classification for informing both research programs and patient care. Their view was that the current classification presents challenges to the diagnosis and treatment of people with diabetes, due, in part, to the conflicting definitions of T1DM, T2DM, and the “newer” entity of latent autoimmune diabetes in adults (LADA), an entity that we first characterized.13 In their view, available classifications lack a foundation that readily incorporates advances in the understanding of diabetes and its treatment.12 Schwartz et al.12 propose a novel approach and alternative classification based on a β-cell-centric classification that would avoid the inherent and unintended confusions of the current system. It is certain the overall issue for a globally acceptable, all-embracing classification is still some way from resolution! The diagnostic criteria for diabetes and associated states of glucose intolerance provides a similar dilemma.1, 3 We recently reviewed in more detail the various attempts to achieve consensus on criteria, particularly between the WHO and ADA.1 The failures for international agreement have produced global confusion, with the use of different criteria making it impossibly difficult to compare data for both scientific and public health scenarios. The report of the first WHO Expert Committee was one of the first attempts at international consensus.8 The main diagnostic recommendation was a 2-h venous blood glucose of 130 mg/% (7.2 mmol/L) after a 50-g oral glucose load. The acceptance and effect of this decision was negligible and, despite a number of alternative diagnostic criteria being proposed in ensuing years, no semblance of uniformity existed until 1980. Diagnostic criteria for states of glucose intolerance (diabetes and IGT) began with, and are still based largely on, those developed in 1979 by the NDDG9 and WHO in 1980.10 Preceded by an ADA attempt,14 a major revision of the 1980 WHO criteria occurred in 1999.11 The fasting plasma glucose (FPG) threshold for diabetes was lowered from 7.8 to 7.0 mmol/L. In addition, impaired fasting glucose (IFG), a new category of abnormal glucose metabolism with an FPG of 6.1–6.9 mmol/L, was introduced. Furthermore, the ADA report,14 but not the WHO report,11 recommended that FPG rather than the oral glucose tolerance test (OGTT) be used as the diagnostic test of choice for both clinical and epidemiologic purposes. This latter recommendation, albeit seemingly a practical decision, was misguided and pivotal in initiating considerable confusion. Indeed, it resulted in many countries, researchers, and the WHO STEPS program using FPG as the standard procedure for diagnosing diabetes despite FPG underestimating diabetes prevalence by as much as 30%.1 To add to the confusion, in 2003 the ADA Expert Committee had recommended that the threshold for IFG be lowered from 6.1 to 5.6 mmol/L.15 This proposal was rejected by a joint WHO and International Diabetes Federation consultation, and they retained 6.1 mmol/L as the IFG threshold.16 Just to further confuse the issue of diabetes diagnosis, the suggested use of HbA1c emerged as a more practical means to diagnose diabetes and other forms of glucose intolerance.17 However, it is clear from several studies that correlation between HbA1c and the OGTT diagnosis of diabetes is not necessarily synchronous.1 It is still uncertain which test is better, glucose or HbA1c, but the latter is more convenient, showing less day-to-day variation and not requiring fasting. An International Expert Committee convened by the ADA in 2009 had recommended the use of HbA1c for diagnosis, with the criterion of HbA1c ≥6.5% as diagnostic of diabetes,18 and 2 years later the WHO followed.11 There are a number of qualifications and HbA1c use requires stringent quality assurance tests,17 and there may be differences between different ethnic groups. However, in 2010, the ADA recommended that people with HbA1c of 5.7%–6.4% were also at increased risk of diabetes and should be considered as “prediabetes.”19 The effect of this decision was to generate yet another round of controversy. For example, the UK introduced HbA1c 6.0%–6.4% as the risk category in its national screening program but, with a lack of evidence to support the ADA decision, the WHO did not follow.17 Consequently, there is now a range of criteria and methods to diagnose diabetes, including FPG ≥7.0 mmol/L, the 75-g OGTT, 2-h plasma glucose ≥11.1 mmol/L, and HbA1c ≥6.5%. Therefore, it should not come as a surprise to anyone that these various tests do not all identify the same individuals as having diabetes.19 In addition, these different criteria result in large variations in the estimated prevalence of undiagnosed diabetes. Cowie et al.20 also showed in a US population that the prevalence of previously undiagnosed diabetes mellitus was 2.5% by FPG, 4.9% by 2-h plasma glucose, and 1.6% by HbA1c. Only 1.2% of subjects met all three criteria.20 If the diagnosis of diabetes represents a formidable task, the situation surrounding “prediabetes” provides even greater challenges.1 Using the ADA definition,1 if one or more of FPG, 2-h plasma glucose or HbA1c are measured, there are at least 18 possible combinations that can designate a person as “prediabetes”! In contrast, the WHO criteria for intermediate hyperglycemia are a 2-h plasma glucose after a 75-g OGTT of 7.8–11.0 mmol/L (IGT) or FPG 6.1–6.9 mmol/L with 2-h plasma glucose <7.8 mmol/L (IFG).18 The result is that the ADA definition diagnoses much larger numbers of people with prediabetes. So, although the criteria for diabetes are testing, those for people at elevated risk of developing T2DM who are designated as having “intermediate hyperglycemia” by the WHO17 or “prediabetes” by the ADA19 are even more confusing. As mentioned earlier, the ADA determined that people with HbA1c levels ≥5.7%–6.5% should be considered as a high-risk category (prediabetes). The WHO, having rejected this suggestion, retained FPG and 2-h plasma glucose as the only criteria for intermediate hyperglycemia. The WHO criteria for intermediate hyperglycemia has only three possible combinations: IFG, IGT, or IGT and IFG.17 The extent to which these many combinations overlap is unclear, but emerging evidence now suggests that the phenotype and possibly the cause of hyperglycemia in people with isolated IFG differs from that in people with IGT.21 This raises questions for designing interventions for prevention of T2DM in people at high risk of T2DM, especially those with isolated IFG. Prevention of diabetes in these subjects may be less effective (S. Thirunavukkarasu et al. unpublised observation, 2018). Just like the situation for diabetes, the disparities in the interpretation of criteria for prediabetes clearly cause difficulty in comparisons of prevalence between different countries and in defining who may best benefit from intervention. It is obvious from the above discussions that despite major advances in the genetics, pathophysiology, and treatment of diabetes, there are still major problems related to classification and diagnosis. Careful longitudinal studies relating both glycemia and HbA1c to outcomes are still needed so that those with highest risk can be identified. Similarly, more in-depth studies are needed to improve current classification, which inevitably affects treatment and even basic research strategies. There are some other practical issues regarding the diagnosis of diabetes that have been described in more detail elsewhere,1 including the correct conditions and method for measurement of plasma glucose and the different methodologies for measuring HbA1c and the limitations of its use.17 Reliable data on the burden posed by major types of diabetes mellitus are needed for many reasons beyond just raising and maintaining awareness of diabetes. These include meeting national and local needs for planning purposes to identify current and future healthcare priorities, to estimate direct and indirect economic and societal costs of the disease, and to allocate appropriate healthcare resources and expenditures for health care delivery. None declared. 在众多人类健康领域取得惊人科学进步的今天, 人们可能会对仍然存在“什么是糖尿病, 何时诊断糖尿病?”的问题感到震惊, 或者至少感到非常诧异。这个问题包含了多个方面, 而不仅仅是最近提出的血糖或HbA1c是否能更好地反映葡萄糖耐量状态的相对效用问题。 分类和标准问题不仅对糖尿病的管理和预防有重大的含义, 而且对生物医学研究, 特别是基因组研究具有重大影响, 其中的独立类别需要在表型上是“纯粹”的。这种“纯度”在2型糖尿病(T2DM)中几乎不可能, 其中糖尿病以及空腹血糖受损(impaired fasting glucose,IFG)和葡萄糖耐量减退(impaired glucose tolerance,IGT)的临界点的实际决定因素仍然是争论的主题。传统上, 发生微血管并发症(如视网膜病变)的阈值可被当作制定糖尿病诊断标准的标志物, 但这可能不是最佳的目标标志物。 大约30年前的1989年, 我们中的一个人(PZ)提出了对糖尿病进行适当分类的问题2。有人认为我们所谓的T2DM不是单一或独立的实体, 而是非传染性疾病综合征或风险因素复合体的一部分。这个争论并不新颖, 并且一直持续不断地争论至今, 同时伴有关于适当诊断标准的争论1-3。 人们已经做出了许多尝试, 特别是世界卫生组织(WHO)和美国糖尿病协会(ADA),试图在分类方面获得令人满意的答案。在其他文章中已经对此进行了详细综述1。 多年来, 还有其他一些尝试重新启动辩论1,最近, 国际媒体发起了一个很抓眼球的标题:“研究表明, 糖尿病实际上是5种独立的疾病4”。该标题引用了Ahlqvist等5的文章, 文中作者将患者分为5个亚组, 这些亚组的疾病进展和糖尿病并发症风险不尽相同。 Ahlqvist等5表示, 这种创新方法可能最终有助于为糖尿病患者提供及时的个体化治疗, 使他们得到最大的受益。实际上, 这种方法对于选择最有可能采取不同干预措施来预防T2DM的受试者也是有益的。然而, 考虑到T2DM的异质性, 这个概念可能过于简单化。 1936年Himsworth6的重要观察结果是对糖尿病进行分类的最初尝试, 他注意到糖尿病似乎有两种形式, 胰岛素敏感型和胰岛素不敏感型。大约15年后, 这一点得到了Bornstein和Lawrence7的验证, 他们有争议性地被认为首次使用胰岛素生物测定来描述Himsworth预测的两个独立实体, 也就是我们现在认为的1型糖尿病和2型糖尿病。本评论中所提到的主要复杂性与T2DM(Himsworth预测的胰岛素敏感性糖尿病)及其分类, 以及备受争议的诊断标准及其合理用途和意义有关。 在随后的60年中有过多次尝试, 尤其是世界卫生组织和国家糖尿病数据组(National Diabetes Data Group,NDDG),试图制定有用的分类方法1。分类不仅应该具有描述价值, 还应该能够用于制定个体化治疗方案, 因为T2DM具有高度异质性, 并且迫切需要提供有助于确定个体化特定治疗需求的模式。 对这些尝试及其背景已经在其他文章中进行了详细综述1,1965年世界卫生组织召开了第一次糖尿病专家委员会会议8。这是首次就糖尿病分类达成共识的尝试之一, 但即使如此, 仍未达成全球共识。糖尿病的当代分类始于1979年由NDDG9和1980年由第二届世界卫生组织专家委员会制定的分类方法, 并且仍然是目前的主要依据10。1999年出版了对1980年WHO分类的第一次重大修订11,并产生了新的国际分类和修订标准。 随后有几次尝试, 包括Ahlqvist等5的, 目的是提供更符合临床需求的更现代的分类, 而不仅仅是目前对T1DM和T2DM的关注。Schwartz等12建议应重新评估分类, 以便为研究计划和患者治疗提供信息。他们的观点是, 目前的分类对糖尿病患者的诊断和治疗提出了挑战, 部分原因在于T1DM、T2DM和“新”实体—成人潜伏性自身免疫性糖尿病(latent autoimmune diabetes in adults,LADA)之间的定义存在着互相矛盾。LADA是第一个有详细特点描述的疾病13。在他们看来, 现有分类缺乏将糖尿病及其治疗认识的进展纳入其中的基础12。Schwartz等12提出了一种新的方法和以β细胞为中心的替代分类, 可以避免当前系统固有的和非预期的混淆。可以肯定的是, 全球都可接受的、无所不包的分类问题仍然尚未解决! 糖尿病及相关的糖耐量异常诊断标准也处于类似的困境1,3。我们最近更详细地回顾了各种想对诊断标准达成共识的尝试, 特别是WHO和ADA之间的共识1。无法达成国际共识导致了全球性混淆, 使用不同标准导致难以对科学和公共卫生数据进行比较。 第一届世界卫生组织专家委员会报告是达成国际共识的首次尝试之一8。主要诊断建议是口服50 g葡萄糖后2小时的静脉血糖为130 mg/dL(7.2 mmol/L)。这一决定的被接受程度和效果几乎可以忽略不计, 尽管随后几年也提出了许多替代诊断标准, 但直到1980年才达成一致。 糖耐量异常(糖尿病和IGT)的诊断标准始于1979年由NDDG9和1980年由世界卫生组织10制定的标准, 并且目前仍然主要基于这些标准。在ADA尝试之前14,在1999年对1980年WHO标准进行了重大修订11。糖尿病的空腹血糖(FPG)阈值从7.8降至7.0 mmol/L. 此外, 引入了空腹血糖受损(IFG)的概念, 这是一种新型葡萄糖代谢异常,FPG为6.1-6.9 mmol/L。此外,ADA报告14但不是WHO报告11,建议将FPG而非口服葡萄糖耐量试验(OGTT)用作临床和流行病学首选的诊断试验。 后一项建议虽然看似是一项切实可行的决定, 但却具有误导性, 会引起很大的混淆。实际上, 它导致许多国家、研究人员和WHO STEPS项目使用FPG作为诊断糖尿病的标准程序, 但是FPG会低估高达30%的糖尿病患病率1。进一步增加了混淆的是,2003年ADA专家委员会建议将IFG阈值从6.1降低到5.6 mmol/L15。这个提案被WHO和国际糖尿病联合会的一次联合咨询拒绝, 他们保留了6.1 mmol/L的IFG阈值16。 进一步混淆了糖尿病诊断问题的是, 建议使用HbA1c作为诊断糖尿病和其他形式糖耐量异常的更实用的方法17。然而, 从几项研究中可以清楚地看出HbA1c与OGTT诊断糖尿病之间的相关性并不一定同步1。目前仍然不能确定哪种检测更好, 葡萄糖还是HbA1c,但是后者更方便, 显示的日间变化较小且不需要禁食。 ADA于2009年召集的国际专家委员会建议使用HbA1c进行诊断, 将HbA1c ≤ 6.5%作为糖尿病的诊断标准18,2年后WHO也使用了这个标准11。HbA1c的使用有许多限定条件, 并且需要严格的有质量保证的测试17,不同种族之间也可能存在差异。然而, 在2010年,ADA建议,HbA1c为5.7%-6.4%的人群糖尿病风险增加, 应被视为“糖尿病前期”19。这一决定又产生了新的争议。例如, 英国在其国家筛查计划中加入了HbA1c为6.0%-6.4%的风险类别, 但由于缺乏支持ADA决定的证据, 世界卫生组织没有使用这个标准17。 因此, 现在有一系列标准和方法来诊断糖尿病, 包括FPG ≤ 7.0 mmol/ L,75 g OGTT,2小时血糖≤ 11.1mmol/ L,HbA1c ≤ 6.5%。因此, 对于这些不同的测试并不都能发现糖尿病患者, 任何人都不会感到惊讶19。此外, 这些不同的标准导致未确诊糖尿病的估算患病率出现很大差异。Cowie等20在美国人群中的研究也表明, 之前未确诊的糖尿病患病率使用FPG方法为2.5%,使用2小时血糖为4.9%,使用HbA1c为1.6%。只有1.2%的受试者符合所有3项标准20。 如果糖尿病的诊断是一项艰巨的任务, 那么“糖尿病前期”的情况就是更大的挑战1。如果测量FPG、2小时血糖或HbA1c中的一种或多种, 使用ADA定义1会产生至少18种可能的组合, 可以将一个人诊断为“糖尿病前期”! 相比之下, 世界卫生组织的中间高血糖(intermediate hyperglycemia)标准是75 g OGTT后的2小时血糖为7.8-11.0 mmol/L(IGT)或FPG为6.1-6.9 mmol/ L,2小时血糖< 7.8 mmol/ L(IFG)18。结果是根据ADA定义诊断出的糖尿病前期患者更多。因此, 虽然糖尿病的诊断标准仍在测试之中, 但那些T2DM风险升高的患者, 根据WHO标准可诊断为“中间高血糖”17,根据ADA标准可诊断为“糖尿病前期”19,这更加令人困惑。 如前所述,ADA认为HbA1c水平≤ 5.7%-6.5%的人群应被视为高风险类别(糖尿病前期)。世界卫生组织拒绝了这一建议, 保留了FPG和2小时血糖作为诊断中间高血糖的唯一标准。WHO中间高血糖的标准只有3种可能的组合:IFG、IGT或IGT和IFG17。这些组合重叠的程度尚不清楚, 但现在新出现的证据表明, 在单纯IFG的患者中, 这种表型以及可能的高血糖病因与IGT患者不同21。这为设计在T2DM高风险患者中预防T2DM的干预措施提出了问题, 尤其是单纯IFG的患者。在这些受试者中预防糖尿病的效果可能较差(S.Thirunavukkarasu等, 未发表的观察性研究,2018)。 与糖尿病的情况一样, 对糖尿病前期诊断标准的解释差异显然会导致在不同国家之间难以比较患病率, 以及难以筛选从干预措施中受益最大的患者。 从上述讨论中可以明显看出, 尽管在遗传学、病理生理学和糖尿病治疗方面取得了重大进展, 但仍存在与分类和诊断相关的主要问题。仍然需要仔细研究血糖和HbA1c与转归的相关性,