Objective: To evaluate the diagnostic for classification of newly diagnosed diabetes patients and assess the application of the screening tests recommended by the 2022 Chinese Expert Consensus on Diabetes Classification. Methods: Retrospective case series study. The data from the electronic medical record system of patients with new-onset diabetes mellitus (within 1 year of disease onset) who attending the Diabetes Specialist Outpatient Clinic at the Second Xiangya Hospital of Central South University from January 1, 2018 to December 31, 2021 were collected for the analysis. Based on the consensus, patients were categorized according their age of onset, body mass index (BMI), and suspicion of type 1 diabetes mellitus (T1DM). The chi-square statistic was used to compare key classifier indicators, including C-peptide, islet autoantibodies, and genetic markers, in the subgroups. The diagnosis in suspected T1DM patients was also evaluated. The screening strategy recommended in the consensus was further assessed using a logistic regression model and the area under the receiver-operating curve (AUC). Results: A total of 3 384 patients with new-onset diabetes were included. The average age of disease onset was (46.3±13.9) years, and 61.0% (2 065/3 384) of the patients were male. The proportions of patients who completed C-peptide and glutamic acid decarboxylase antibody (GADA) tests were 36.6% (1 238/3 384) and 37.5% (1 269/3 384), respectively. There were no significant differences in C-peptide test results among the subgroups (all P>0.05). In contrast, the GADA detection rate was higher in patients with young age of onset (<30 years old), in those who were non-obese (BMI<24 kg/m2), and in those clinically suspected of T1DM (all P<0.05). According to the diagnostic pathway proposed by the consensus, only 57.4% (1 941/3 384) of patients could be subtyped. For a definitive diagnosis, the remaining patients needed completion of C-peptide, islet autoantibody, genetic testing, or follow-up. Furthermore, among patients with clinical features of suspected T1DM, the antibody positivity rate was higher than in non-suspected T1DM patients [24.5% (154/628) vs. 7.1% (46/646), P<0.001]. When the clinical features of suspected T1DM defined in the consensus were taken as independent variables and antibody positivity was considered the outcome variable in the logistic regression model, young onset, non-obese onset, and ketosis onset could enter the model. Based on AUC analysis, the accuracy of the diagnostic model was 0.77 (95%CI 0.73-0.81), suggesting that the clinical features of suspected T1DM in the consensus have good clinical diagnostic value for this patient subgroup. Conclusions: There was a significant discrepancy between the clinical practice of diabetes classification and the process recommended by the consensus, which was specifically reflected in the low proportions of both subtyping indicator testing and definitively subtyped diabetes patients. Attention should be pay to the classification diagnosis process proposed in the consensus and the clinical detection rate of key diabetes subtyping indicators such as C-peptide and islet autoantibodies for diabetes classification should be improved. Noteworthy, the screening strategy for T1DM proposed by the consensus showed good clinical application value.
目的： 以2022年发布的《糖尿病分型诊断中国专家共识》（以下简称共识）为依据，评估新发糖尿病患者分型诊断情况及共识推荐的分型诊断路径的应用情况。 方法： 回顾性病例系列研究。收集2018年1月1日至2021年12月31日在中南大学湘雅二医院糖尿病专科门诊就诊的新发糖尿病（病程1年内）患者的电子病历资料。以共识为依据，以起病年龄、体重指数（BMI）、是否疑诊1型糖尿病（T1DM）对患者进行分层分析。采用χ2检验比较各分层组间糖尿病患者分型关键指标（C肽、胰岛自身抗体、基因）的检测及其糖尿病分型情况，并评估疑诊T1DM患者的分型诊断情况。通过logistic回归及受试者工作特征曲线下面积（AUC）对共识中所推荐的分型诊断路径进行评价。 结果： 共纳入3 384例新发糖尿病患者，起病年龄为（46.3±13.9）岁，男性占61.0%（2 065/3 384），完成C肽和谷氨酸脱羧酶抗体（GADA）检测者分别占36.6%（1 238/3 384）和37.5%（1 269/3 384）。以年龄分层时，C肽检测率在各组患者中差异有统计学意义（P<0.001），但在以BMI分层及是否疑诊T1DM分层时各组间C肽检测率差异均无统计学意义（均P>0.05）；而GADA检测率在年轻起病（<30岁）、非肥胖体型（BMI<24 kg/m2）及临床疑诊为T1DM患者中较高（均P<0.05）。依据共识的诊断路径，仅57.4%（1 941/3 384）患者可以明确分型诊断，其余患者需要在完善C肽、胰岛自身抗体、基因检测或C肽随访后才能明确诊断。在具有疑诊 T1DM临床特征的患者中，抗体阳性率高于非疑诊T1DM患者［24.5%（154/628）比7.1%（46/646），P<0.001］。将共识中疑诊T1DM临床特征作为自变量，抗体阳性作为结局变量纳入logistic回归模型，发现年轻起病、非肥胖起病、酮症起病这3个特征可进入模型，诊断模型的AUC可达0.77（95%CI 0.73~0.81），提示共识中疑诊T1DM临床特征对T1DM患者有较好的临床诊断价值。 结论： 新发糖尿病分型诊断的临床实践与共识的建议流程有较大差距，体现在糖尿病分型诊断相关指标检测比例较低，同时可以明确分型诊断的患者比例较低。应重视共识中提出的分型诊断流程，提高C肽、胰岛自身抗体等糖尿病分型关键指标的临床检测率。此外，共识提出的疑诊T1DM的临床特征有较好的临床应用价值。.

In the recently published consensus statement on the treatment and management of type 1 diabetes issued by experts from the American (ADA) and European (EASD) diabetes societies, measurement of endogenous insulin secretion using fasting C-peptide is recommended as a diagnostic criterion. In contrast, our group recently suggested fasting C-peptide/glucose ratio (CGR) for the determination of endogenous insulin secretion. In addition, this ratio may turn out as a potential decision aid for pathophysiologically based differential therapy of diabetes. In this comment, the following points will be discussed: i) CGR as the basis of differential diagnosis of type 1 diabetes, ii) CGR as the basis of treatment decisions for or against insulin in diabetes, and iii) the ease of application of CGR in clinical practice. The use of CGR may complement the ADA/EASD recommendations and should provide a practical application in clinical practice.

A substantial proportion of patients with adult-onset diabetes share features of both type 1 diabetes (T1D) and type 2 diabetes (T2D). These individuals, at diagnosis, clinically resemble T2D patients by not requiring insulin treatment, yet they have immunogenetic markers associated with T1D. Such a slowly evolving form of autoimmune diabetes, described as latent autoimmune diabetes of adults (LADA), accounts for 2-12% of all patients with adult-onset diabetes, though they show considerable variability according to their demographics and mode of ascertainment. While therapeutic strategies aim for metabolic control and preservation of residual insulin secretory capacity, endotype heterogeneity within LADA implies a personalized approach to treatment. Faced with a paucity of large-scale clinical trials in LADA, an expert panel reviewed data and delineated one therapeutic approach. Building on the 2020 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus for T2D and heterogeneity within autoimmune diabetes, we propose \"deviations\" for LADA from those guidelines. Within LADA, C-peptide values, proxy for β-cell function, drive therapeutic decisions. Three broad categories of random C-peptide levels were introduced by the panel: 1) C-peptide levels <0.3 nmol/L: a multiple-insulin regimen recommended as for T1D; 2) C-peptide values ≥0.3 and ≤0.7 nmol/L: defined by the panel as a \"gray area\" in which a modified ADA/EASD algorithm for T2D is recommended; consider insulin in combination with other therapies to modulate β-cell failure and limit diabetic complications; 3) C-peptide values >0.7 nmol/L: suggests a modified ADA/EASD algorithm as for T2D but allowing for the potentially progressive nature of LADA by monitoring C-peptide to adjust treatment. The panel concluded by advising general screening for LADA in newly diagnosed non-insulin-requiring diabetes and, importantly, that large randomized clinical trials are warranted.

β-cell replacement therapy, available currently as pancreas or islet transplantation, has developed without a clear definition of graft functional and clinical outcomes. The International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplantation Association held a workshop to develop consensus for an International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplant Association Statement on the definition of function and failure of current and future forms of β-cell replacement therapy. There was consensus that β-cell replacement therapy could be considered as a treatment for β-cell failure, regardless of etiology and without requiring undetectable C-peptide, accompanied by glycemic instability with either problematic hypoglycemia or hyperglycemia. Glycemic control should be assessed at a minimum by glycated hemoglobin (HbA1c) and the occurrence of severe hypoglycemia. Optimal β-cell graft function is defined by near-normal glycemic control (HbA1c ≤6.5% [48 mmol/mol]) without severe hypoglycemia or requirement for insulin or other antihyperglycemic therapy, and with an increase over pretransplant measurement of C-peptide. Good β-cell graft function requires HbA1c less than 7.0% (53 mmol/mol) without severe hypoglycemia and with a significant (>50%) reduction in insulin requirements and restoration of clinically significant C-peptide production. Marginal β-cell graft function is defined by failure to achieve HbA1c less than 7.0% (53 mmol/mol), the occurrence of any severe hypoglycemia, or less than 50% reduction in insulin requirements when there is restoration of clinically significant C-peptide production documented by improvement in hypoglycemia awareness/severity, or glycemic variability/lability. A failed β-cell graft is defined by the absence of any evidence for clinically significant C-peptide production. Optimal and good function are considered successful clinical outcomes.

BACKGROUND: Differentiating between type 1 and type 2 diabetes is fundamental to ensuring appropriate management of patients, but can be challenging, especially when treating with insulin. The 2010 UK Practical Classification Guidelines for Diabetes were developed to help make the differentiation.
OBJECTIVE: To assess diagnostic accuracy of the UK guidelines against \'gold standard\' definitions of type 1 and type 2 diabetes based on measured C-peptide levels.
METHODS: In total, 601 adults with insulin-treated diabetes and diabetes duration ≥5 years were recruited in Devon, Northamptonshire, and Leicestershire.
METHODS: Baseline information and home urine sample were collected. Urinary C-peptide creatinine ratio (UCPCR) measures endogenous insulin production. Gold standard type 1 diabetes was defined as continuous insulin treatment within 3 years of diagnosis and absolute insulin deficiency (UCPCR<0.2 nmol/mmol ≥5 years post-diagnosis); all others classed as having type 2 diabetes. Diagnostic performance of the clinical criteria was assessed and other criteria explored using receiver operating characteristic (ROC) curves.
RESULTS: UK guidelines correctly classified 86% of participants. Most misclassifications occurred in patients classed as having type 1 diabetes who had significant endogenous insulin levels (57 out of 601; 9%); most in those diagnosed ≥35 years and treated with insulin from diagnosis, where 37 out of 66 (56%) were misclassified. Time to insulin and age at diagnosis performed best in predicting long-term endogenous insulin production (ROC AUC = 0.904 and 0.871); BMI was a less strong predictor of diabetes type (AUC = 0.824).
CONCLUSIONS: Current UK guidelines provide a pragmatic clinical approach to classification reflecting long-term endogenous insulin production; caution is needed in older patients commencing insulin from diagnosis, where misclassification rates are increased.

Pre-clinical efficacy and complication data required to justify a porcine islet transplantation clinical trial have been considered. To be relevant to clinical islet transplantation, pre-clinical data should be obtained in a pig-to-diabetic non-human primate (NHP) model. In view of the difficulties of maintaining immunosuppressed NHPs for long periods of time, flexibility must be allowed with regard to the following recommendations. A pre-clinical trial would be deemed a success if five of eight consecutive experiments in NHPs with proven diabetes meet the following guidelines. 1. The fasting and non-fasting blood glucose levels have been maintained in the NHP at approximately <150 mg/dl (>8.3 mmol/l) and <200 mg/dl (11.1 mmol/l), respectively, throughout a 6-month follow-up period (preferably with observations in one or two NHPs extending to 12 months). 2. After the transplantation of adult or fetal/neonatal pig islets, no or greatly reduced exogenous insulin has been required after the development of a state of normoglycemia (that may take approximately the first 4 weeks for adult and 12 weeks for fetal/neonatal islets, respectively), except under exceptional, temporary circumstances. 3. Sequential intravenous glucose tolerance tests [at 1, 3, 6 (and 12) months post-transplantation] or arginine stimulation tests have indicated a significant response to glucose in the form of porcine C-peptide in the absence of a significant response of NHP C-peptide. 4. Histologic study of the native pancreas (if present) after necropsy indicates no or minimal insulin-positive beta cells, and histologic examination of the liver or other site of islet transplantation indicates multiple viable insulin-positive cells. 5. Numerous or serious life-threatening complications have not been associated with the transplantation procedure, immunosuppressive regimen, tolerance-inducing regimen, or encapsulation of the islets. Pre-clinical trials in which the recipient NHPs do not require continuing immunosuppressive therapy (e.g., when encapsulated islets have been transplanted) may possibly be considered acceptable as a basis for a clinical trial with slightly less stringent requirements with regard to points (1) and (2), but would be expected to provide evidence that points (3), (4), and (5) had been achieved.

Biogenesis of the regulated secretory pathway in the pancreatic beta-cell involves packaging of products, notably proinsulin, into immature secretory granules derived from the trans-Golgi network. Proinsulin is converted to insulin and C-peptide as granules mature. Secretory proteins not entering granules are conveyed by transport intermediates directly to the plasma membrane for constitutive secretion. One of the co-authors, Peter Arvan, has proposed that in addition, small vesicles bud from granules to traffic to the endosomal system. From there, some proteins are secreted by a (post-granular) constitutive-like pathway. He argues that retention in granules is facilitated by condensation, rendering soluble products (notably C-peptide and proinsulin) more available for constitutive-like secretion. Thus he argues that prohormone conversion is potentially important in secretory granule biogenesis. The other co-author, Philippe Halban, argues that the post-granular secretory pathway is not of physiological relevance in primary beta-cells, and contests the importance of proinsulin conversion for retention in granules. Both, however, agree that trafficking from granules to endosomes is important, purging granules of unwanted newly synthesized proteins and allowing their traffic to other destinations. In this Traffic Interchange, the two co-authors attempt to reconcile their differences, leading to a common vision of proinsulin trafficking in primary and transformed cells.

In recent years the physiological role of the proinsulin C-peptide has received increasing attention, focusing on the potential therapeutic value of C-peptide replacement in preventing and ameliorating type 1 diabetic complications. In order to consolidate these new data and to identify the immediate directions of C-peptide research and its clinical usefulness, an International Symposium was held in Detroit, Michigan, on October 20-21, 2000, under the auspices of the Wayne State University/Morris Hood Jr. Comprehensive Diabetes Center. In this communication, we review the cellular, physiological and clinical effects of C-peptide replacement in animal models and in patients with type 1 diabetes. Finally, recommendations are presented as to the most urgent studies that should be pursued to further establish the biological action of C-peptide and its therapeutic value.