C-peptide and autoimmune markers in diabetes

Autoimmune markers such as islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA) and islet antigen-2 antibodies (IA-2A) are found in high frequencies among type 1 patients and especially among younger patients. Presence of these autoantibodies confirms the destructive process of the beta cells associated with immune-mediated type 1 diabetes. Type 2 diabetes is characterised by peripheral insulin resistance and a relative deficiency in insulin production. However, when autoimmune markers are analysed these are found in about 10% of patients clinically classified as type 2 diabetes, indicating that the frequency of type 1 diabetes is underestimated. GADA is the most frequent marker both among patients clinically classified as type 1 and type 2. GADA is also highly predictive for insulin treatment in patients not classified as type 1 diabetes. C-peptide is the best marker of the endogenous insulin production. Sampling of C-peptide is preferably done in the non-fasting condition since these values differentiate better between autoimmune and non-autoimmune diabetes. The presence of autoimmune markers at diagnosis predicts a course of further deteriorating beta cell function, whereas absence of autoimmune markers predicts stable beta cell function for the first two years in adults. Presence of GADA and in particular in high levels are prognostic for a low beta cell function within the next few years after diagnosis. Positivity only for ICA indicates a more preserved beta cell function for the first three years compared to positivity for other autoimmune markers.     

Crucial points at diagnosis. Type 2 diabetes or slow type 1 diabetes

Two major types of diabetes have been recognized since the late 1930s. However, in recent times there have been major changes in classification and understanding of these types, including improved knowledge of maturity-onset diabetes in the young, with the identification of mutations relating to impaired insulin secretion and the recognition of slow-onset type 1 diabetes in adults now designated as latent autoimmune diabetes in adults (LADA). A major problem area in diabetes classification concerns cases of slowly progressive forms of type 1 and type 2 diabetes, particularly in adults aged 25-50 years. This is a more contemporary problem because cases of type 2 diabetes are presenting at an increasingly younger age. In the landmark U.K. Prospective Diabetes Study of type 2 diabetes, islet cell antibodies (ICAs) and antibodies to glutamic acid decarboxylase (anti-GAD) were measured at diagnosis in 3,672 patients. The overall proportion with ICAs was 6%, and anti-GADs was 10%. These subjects clearly had type 1 diabetes or LADA by both phenotypic and genotypic features. The presence of auto antibodies correlated particularly with a younger age and phenotypic features consistent with type 1 diabetes (e.g., early age at diagnosis, lower BMI, and reduced beta-cell function). Overall, of patients requiring insulin by 6 years, 38% were anti-GAD+ at baseline compared with 5.3% of those not on insulin at 6 years. Antibodies to GAD indicate an underlying autoimmune process and have a high positive predictive value for type 1 diabetes and future insulin dependency in adults.     

Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients

A direct association of islet-autoreactive T cells with β cell destruction in human pancreatic islets from type 1 diabetes (T1D) patients has never been demonstrated, and little is known about disease progression after diagnosis. Frozen pancreas samples were obtained from 45 cadaveric T1D donors with disease durations ranging from 1 wk to >50 yr, 14 nondiabetic controls, 5 nondiabetics with islet autoantibodies, 2 cases of gestational diabetes, and 6 T2D patients. Sections were systematically analyzed for the presence of insulin-sufficient β cells, CD8(+) insulitic lesions, and HLA class I hyperexpression. Finally, consecutive sections from HLA-A2-expressing individuals were probed for CD8 T cell reactivity against six defined islet autoantigens associated with T1D by in situ tetramer staining. Both single and multiple CD8 T cell autoreactivities were detected within individual islets in a subset of patients up to 8 yr after clinical diagnosis. Pathological features such as HLA class I hyperexpression and insulitis were specific for T1D and persisted in a small portion of the patients with longstanding disease. Insulitic lesions consistently presented in a multifocal pattern with varying degrees of infiltration and β cell loss across affected organs. Our observations provide the first direct proof for islet autoreactivity within human islets and underscore the heterogeneous and chronic disease course.     

Latent Autoimmune Diabetes of Adults (LADA) Is Likely to Represent a Mixed Population of Autoimmune (Type 1) and Nonautoimmune (Type 2) Diabetes

Latent autoimmune diabetes of adults (LADA) is typically defined as a new diabetes diagnosis after 35 years of age, presenting with clinical features of type 2 diabetes, in whom a type 1 diabetes–associated islet autoantibody is detected. Identifying autoimmune diabetes is important since the prognosis and optimal therapy differ. However, the existing LADA definition identifies a group with clinical and genetic features intermediate between typical type 1 and type 2 diabetes. It is unclear whether this is due to 1) true autoimmune diabetes with a milder phenotype at older onset ages that initially appears similar to type 2 diabetes but later requires insulin, 2) a disease syndrome where the pathophysiologies of type 1 and type 2 diabetes are both present in each patient, or 3) a heterogeneous group resulting from difficulties in classification. Herein, we suggest that difficulties in classification are a major component resulting from defining LADA using a diagnostic test—islet autoantibody measurement—with imperfect specificity applied in low-prevalence populations. This yields a heterogeneous group of true positives (autoimmune type 1 diabetes) and false positives (nonautoimmune type 2 diabetes). For clinicians, this means that islet autoantibody testing should not be undertaken in patients who do not have clinical features suggestive of autoimmune diabetes: in an adult without clinical features of type 1 diabetes, it is likely that a single positive antibody will represent a false-positive result. This is in contrast to patients with features suggestive of type 1 diabetes, where false-positive results will be rare. For researchers, this means that current definitions of LADA are not appropriate for the study of autoimmune diabetes in later life. Approaches that increase test specificity, or prior likelihood of autoimmune diabetes, are needed to avoid inclusion of participants who have nonautoimmune (type 2) diabetes. Improved classification will allow improved assignment of prognosis and therapy as well as an improved cohort in which to analyze and better understand the detailed pathophysiological components acting at onset and during disease progression in late-onset autoimmune diabetes.     

Hyperproinsulinemia segregates young adult patients with newly diagnosed autoimmune (type 1) and non-autoimmune (type 2) diabetes

OBJECTIVE: To investigate whether measurements of proinsulin and/or intermediate proinsulin degradation products could be used to differentiate between autoimmune (type 1) and non-autoimmune (type 2) diabetes in young adults. MATERIAL AND METHODS: Total proinsulin, intact proinsulin and 32,33 split proinsulin concentrations were measured in 25 patients aged 15-34 years with type 1 diabetes, as defined by the presence of at least two positive islet autoantibodies, and in 23 antibody-negative patients of similar age with type 2 diabetes, at the time of clinical onset of diabetes and at 3-4 months thereafter. Comparisons were made with data from 25 healthy subjects matched for gender and age. RESULTS: Plasma levels of total proinsulin, intact proinsulin and 32,33 split proinsulin were significantly increased 2-3-fold in the patients with newly diagnosed type 2 diabetes as compared with the controls, both in absolute terms (p<0.0001) and when related to circulating insulin (p<0.01-0.0002). In contrast, absolute proinsulin and 32,33 split proinsulin concentrations were significantly lower in patients with onset of type 1 diabetes than in controls. When proinsulin and split proinsulin release were related to plasma insulin, however, similar ratios were found in the type 1 diabetes patients and in controls. Using the 90th percentile for total proinsulin in the control group as the cut-off, the sensitivity and specificity for differentiation between autoimmune and non-autoimmune diabetes were 87% and 92%, respectively. At 3-4 months after clinical onset of diabetes, proinsulin secretion was still 2-3 times higher in type 2 than in type 1 diabetes patients (p<0.001). CONCLUSIONS: Young adult patients with newly diagnosed type 2 diabetes display disproportionate hyperproinsulinemia, whereas proinsulin secretion appears to be normal in patients with clinical onset of type 1 diabetes. Evaluation of proinsulin and 32,33 split proinsulin concentrations may be useful as a diagnostic tool in differentiating between autoimmune and non-autoimmune diabetes in young adults, particularly in those lacking islet autoantibodies at diagnosis.     

A clinical screening tool identifies autoimmune diabetes in adults

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) is defined as adult-onset diabetes with circulating islet antibodies but not requiring insulin therapy initially. Diagnosing LADA has treatment implications because of the high risk of progression to insulin dependency. Currently, there are no recommendations for islet antibody testing in adult-onset diabetes. In this study, we aimed to develop a clinical screening tool to identify adults at high risk of LADA who require islet antibody testing. RESEARCH DESIGN AND METHODS: Subjects with LADA (n = 102, GAD antibody [GADA]+) and type 2 diabetes (n = 111, GADA-) (aged 30-75 years) were interviewed retrospectively. The clinical features documented were age of onset, acute symptoms of hyperglycemia, BMI, and personal and family history of autoimmune disease. Any clinical feature that was significantly more frequent in LADA was designated as a distinguishing clinical feature. In each subject, a "LADA clinical risk score," based on the total number of distinguishing features, was calculated. A prospective study of adults with newly diagnosed diabetes (n = 130) was used to determine whether the LADA clinical risk score could identify LADA. RESULTS: In the retrospective study, five clinical features were more frequent in LADA compared with type 2 diabetes at diagnosis: 1) age of onset <50 years (P < 0.0001), 2) acute symptoms (P < 0.0001), 3) BMI <25 kg/m2 (P = 0.0004), 4) personal history of autoimmune disease (P = 0.011), and 5) family history of autoimmune disease (P = 0.024). In the prospective study, the presence of at least two of these distinguishing clinical features (LADA clinical risk score > or =2) had a 90% sensitivity and 71% specificity for identifying LADA and a negative predictive value for a LADA clinical risk score < or =1 of 99%. CONCLUSIONS: At least two distinguishing clinical features are found in a majority of patients with LADA at diagnosis and can be used to identify adults with diabetes at higher risk for LADA.     

胰岛细胞自身抗体对1型糖尿病诊断价值的研究

目的 评价胰岛细胞ICA、GADA、IA-2A、IAA四种自身抗体在1型糖尿病患者中的诊断价值.方法 1型糖尿病患者51例,其中男性33例,女性18例,发病年龄20～40岁;2型糖尿病患者80例,其中男性44例,女性36例,平均年龄40～70岁;120例健康者血清,采用免疫印迹法检测血清ICA、GADA、IA-2A、IAA四种自身抗体.结果 1型糖尿病患者中,ICA、GADA、IA-2A、IAA四种自身抗体阳性率分别为:35.3%、52.9%、19.6%、15.7%,1型糖尿病患者中四种抗体阳性率均高于2型糖尿病患者和健康对照组,差异有统计学意义(P＜0.05).四种抗体之间在1型糖尿病患者中阳性率有差异,提示不同抗体出现在1型糖尿病患者的不同阶段.结论 ICA、GADA、IA-2A、IAA的测定对1型糖尿病的诊断具有一定价值,联合检测四种自身抗体可以提高对1型糖尿病诊断的灵敏度和互补性.     

Type 2 diabetes worldwide according to the new classification and criteria

Two major reports have recently revised the classification of and diagnostic criteria for diabetes. Classification was previously based on the need for insulin (insulin-dependent or non-insulin-dependent), but this has become increasingly confusing. Now, the type of diabetes is determined by the etiological process rather than the treatment modality. Type 1 diabetes is thus characterized by islet cell destruction and type 2 diabetes by a combination of defects in insulin secretion and action. An individual with either type of diabetes may be on any treatment modality. This classification should prove to be more logical and, for example, allow latent autoimmune diabetes in adults, which typically does not require insulin at presentation, to be classified as type 1 diabetes. The fasting plasma glucose diagnostic threshold for diabetes has been lowered to 7.0 mmol/l (126 mg/dl), and impaired fasting glucose (fasting plasma glucose 6.1-6.9 mmol/l [110-125 mg/dl]) has been introduced as a new category of intermediate glucose metabolism. These changes recognize that the old fasting threshold did not match the 2-h (postload) threshold well and that both micro- and macrovascular disease develop at lower fasting glucose levels than previously recognized. Although the prevalences of diabetes according to the new fasting and 2-h criteria are now similar in most populations, the actual individuals identified as having diabetes are often different. Over 30% of all those with diabetes have a nondiabetic fasting glucose but still have increased cardiovascular mortality. Thus, it is important to retain the oral glucose tolerance test for the diagnosis of diabetes.     

Identifying hepatic nuclear factor 1alpha mutations in children and young adults with a clinical diagnosis of type 1 diabetes

OBJECTIVE: HNF-1alpha gene mutations (MODY3) present with marked hyperglycemia in lean young adults and may, therefore, be mistaken for type 1 diabetes, with implications for individual treatment and risk of diabetes in other family members. We examined the prevalence of HNF-1alpha mutations in families with three generations of diabetes identified in a population-based study of childhood diabetes, representing a subpopulation in which misclassification was likely. RESEARCH DESIGN AND METHODS: In a study population of 1,470 families, 36 families (2.4%) with three affected generations were identified. In the 18 families in whom DNA samples were available, islet autoantibody testing, HLA class II genotyping, and HNF-1alpha sequencing were performed. RESULTS: At least one islet autoantibody was found in 13 of 14 probands, and diabetes-associated HLA class II haplotypes were found in 17 of 18. One proband, who had no islet autoantibodies and was homozygous for the protective HLA haplotype DRB1*02-DQB1*0602, had a novel HNF-1alpha heterozygous nonsense mutation (R54X). This mutation cosegregated with diabetes in the family. The proband, his brother, mother, and maternal grandmother were diagnosed with type 1 diabetes aged 14-18 years and treated with insulin (0.39-0.74 units/kg) from diagnosis. The mother has since been successfully transferred to sulfonylurea treatment. CONCLUSIONS: Family history alone is of limited value in identification of individuals with HNF-1alpha mutations, and we propose a stepwise approach that restricts sequencing of the HNF-1alpha gene to those with a family history of diabetes who also test negative for islet autoantibodies.     

Genetic, autoimmune, and clinical characteristics of childhood- and adult-onset type 1 diabetes

OBJECTIVE: To assess whether there are any differences in genetic, autoimmune, or clinical features between type 1 diabetes presenting in childhood and that diagnosed later. RESEARCH DESIGN AND METHODS: We studied 352 individuals (252 children and adolescents <20 years of age and 100 adults > or =20 years of age) manifesting clinical signs of type 1 diabetes over a period of 7.5 years at a university hospital in northern Finland with a primary catchment area population of approximately 300,000. The patients were analyzed for susceptible and protective HLA-DQB1 alleles (*02, *0302, *0301, *0602, *0603, and *0604), islet cell antibodies (ICA), insulin autoantibodies, and antibodies to GAD and IA-2 (IA-2A). Their clinical symptoms and signs were recorded at diagnosis. RESULTS: The adult patients carried the high-risk DQB1*02/0302 genotype less frequently than the children and more often had protective genotypes. They also had a decreased frequency of all 4 single autoantibody specificities and of multiple (> or =3) autoantibodies. The proportion of patients testing negative for all autoantibodies was lower among the children than among the adults. IA-2A were associated with the DQB1*0302/x genotype in both the children and adults, and the same held true for ICA among the adults. The adults were characterized by a higher proportion of males, a longer duration of symptoms, and a lower frequency of infections during the preceding 3 months. In addition, they had a higher relative body weight on admission and milder signs of metabolic decompensation (higher pH, base excess, and bicarbonate concentrations) and a lower glycated hemoglobin level at diagnosis than the children. CONCLUSIONS: Clinical manifestation of type 1 diabetes before the age of 20 years is associated with a strong HLA-defined genetic disease susceptibility, an intensive humoral immune response to various beta-cell antigens, a higher frequency of preceding infections, and a shorter duration of symptoms and more severe metabolic decompensation at diagnosis. Taken together, these observations suggest that the age at clinical onset of type 1 diabetes is determined by the intensity of the beta-cell-destructive process, which is modulated by both genetic and environmental factors.     

Hyperproinsulinemia segregates young adult patients with newly diagnosed autoimmune (type 1) and non‐autoimmune (type 2) diabetes

ObjectiveTo investigate whether measurements of proinsulin and/or intermediate proinsulin degradation products could be used to differentiate between autoimmune (type 1) and non‐autoimmune (type 2) diabetes in young adults. Material and methods Total proinsulin, intact proinsulin and 32,33 split proinsulin concentrations were measured in 25 patients aged 15–34 years with type 1 diabetes, as defined by the presence of at least two positive islet autoantibodies, and in 23 antibody‐negative patients of similar age with type 2 diabetes, at the time of clinical onset of diabetes and at 3–4 months thereafter. Comparisons were made with data from 25 healthy subjects matched for gender and age. Results Plasma levels of total proinsulin, intact proinsulin and 32,33 split proinsulin were significantly increased 2–3‐fold in the patients with newly diagnosed type 2 diabetes as compared with the controls, both in absolute terms (p<0.0001) and when related to circulating insulin (p<0.01–0.0002). In contrast, absolute proinsulin and 32,33 split proinsulin concentrations were significantly lower in patients with onset of type 1 diabetes than in controls. When proinsulin and split proinsulin release were related to plasma insulin, however, similar ratios were found in the type 1 diabetes patients and in controls. Using the 90th percentile for total proinsulin in the control group as the cut‐off, the sensitivity and specificity for differentiation between autoimmune and non‐autoimmune diabetes were 87% and 92%, respectively. At 3–4 months after clinical onset of diabetes, proinsulin secretion was still 2–3 times higher in type 2 than in type 1 diabetes patients (p<0.001). Conclusions. Young adult patients with newly diagnosed type 2 diabetes display disproportionate hyperproinsulinemia, whereas proinsulin secretion appears to be normal in patients with clinical onset of type 1 diabetes. Evaluation of proinsulin and 32,33 split proinsulin concentrations may be useful as a diagnostic tool in differentiating between autoimmune and non‐autoimmune diabetes in young adults, particularly in those lacking islet autoantibodies at diagnosis.     

Islet cell and glutamic acid decarboxylase antibodies present at diagnosis of diabetes predict the need for insulin treatment. A cohort study in young adults whose disease was initially labeled as type 2 or unclassifiable diabetes

OBJECTIVE: To clarify the predictive value of islet cell antibody (ICA) and GAD65 antibody (GADA) present at diagnosis with respect to the need for insulin treatment 6 years after diagnosis in young adults initially considered to have type 2 or unclassifiable diabetes. RESEARCH DESIGN AND METHODS: The patient material was representative of the entire Swedish population, consisting of patients who were 15-34 years old at diagnosis of diabetes in 1987-1988 but were not considered to have type 1 diabetes at onset. At follow-up, 6 years after the diagnosis, it was noted whether the patient was treated with insulin. The presence of ICA was determined by an immunofluorescence assay, and GADAs were measured by a radioligand assay. RESULTS: Six years after diagnosis, 70 of 97 patients were treated with insulin, and 27 of 97 patients were treated with oral drugs or diet alone. At diagnosis, ICAs and GADAs were present in 41 (59%) of 70 patients and 41 (60%) of 68 patients, respectively, of those now treated with insulin, compared with only 1 (4%) of 26 patients and 2 (7%) of 27 patients who were still not treated with insulin. For either ICA or GADA, the corresponding frequencies were 50 (74%) of 68 for patients who were later treated with insulin and 3 (12%) of 26 for those who were still not treated with insulin, respectively. The sensitivity for later insulin treatment was highest (74%) for the presence of ICA or GADA, and the specificity was highest (100%) for ICA and GADA. The positive predictive value was 100% for the combination of ICA and GADA, 98% for ICA alone, and approximately 95% for GADA alone. CONCLUSIONS: Determination of the presence of ICA and GADA at diagnosis of diabetes improves the classification of diabetes and predicts the future need of insulin in young adults.     

Establishing surveillance for diabetes in American Indian youth

OBJECTIVE--To determine prevalence estimates in order to monitor diabetes, particularly type 2 diabetes, in American Indian youth. RESEARCH DESIGN AND METHODS--To explore the feasibility of developing a case definition using information from primary care records, all youth aged <20 years with an outpatient visit or hospitalization for diabetes were identified from the Billings Area Indian Health Service database in Montana and Wyoming from 1997 to 1999, and the medical records were reviewed. Classification for probable type 1 diabetes was based on age < or =5 years, weight per age < or =15th percentile at diagnosis, or positive results of islet cell antibody test. Classification for probable type 2 diabetes was based on weight per age > or =85th percentile or presence of acanthosis nigricans at diagnosis, elevated C-peptide or insulin, family history for type 2 diabetes, or use of oral hypoglycemic agents with or without insulin or absence of current treatment 1 year after diagnosis. RESULTS--A total of 52 case subjects with diabetes were identified, 3 of whom had diabetes secondary to other conditions. Of the remaining 49 case subjects, 25 (51%) were categorized as having probable type 2 diabetes, 14 (29%) as having probable type 1 diabetes, and 10 (20%) could not be categorized because of missing or negative information. Prevalence estimates for diabetes of all types, type 1 diabetes, and type 2 diabetes were 2.3, 0.6, and 1.1, respectively, per 1,000 youth aged <20 years. CONCLUSIONS--Our definitions may be useful for surveillance in primary care settings until further studies develop feasible case definitions for monitoring trends in diabetes among youth.     

Development of new strategies to prevent type 1 diabetes: the role of animal models

Type 1 diabetes is an immune‐mediated disease typically preceded by a long preclinical stage during which a growing number of islet‐cell‐specific autoantibodies appear in the serum. Although antigen‐specific T lymphocytes and cytokines rather than these autoantibodies are the likely executors of β‐cell‐destruction, these autoantibodies reflect the existence of autoimmunity that targets islet β‐cells. Abrogation of this autoimmunity during the preclinical stage would be the key to the prevention of type 1 diabetes. However, the quest of protecting islet‐cells from the immune attack requires detailed knowledge of mechanisms that control islet‐inflammation and β‐cell‐destruction, and of mechanisms that control immune tolerance to peripheral self‐antigens in general. This knowledge can only be obtained through further innovative research in experimental animal models. In this review, we will first examine how research in non‐obese diabetic mice has already led to promising new strategies of diabetes prevention now being tested in human clinical trials. Thereafter, we will discuss how recent advances in understanding the mechanisms that control immune response to peripheral self‐antigens such as β‐cell antigens may help to develop even more selective and effective strategies to prevent diabetes in the future.     

Similar genetic features and different islet cell autoantibody pattern of latent autoimmune diabetes in adults (LADA) compared with adult-onset type 1 diabetes with rapid progression

OBJECTIVE: To compare the clinical parameters, C-peptide levels, pattern of islet cell-specific autoantibodies, and prevalence of predisposing genotypes in subjects with latent autoimmune diabetes in adults (LADA) and those with adult-onset type 1 diabetes with rapid progression. RESEARCH DESIGN AND METHODS: We evaluated the clinical parameters, C-peptide levels, and islet cell-specific autoantibodies in 54 LADA, 57 adult-onset type 1 diabetic, and 190 type 2 diabetic patients. Islet cell autoantibodies were also compared between subgroups of newly diagnosed patients with LADA and those with newly diagnosed adult-onset and childhood-onset type 1 diabetes. The genetic study was performed in subjects with LADA and those with adult-onset type 1 diabetes in comparison with a control population. RESULTS: There were no differences in the clinical parameters between LADA and adult-onset type 1 diabetes. Patients with LADA had lower BMI (P < 0.0001), waist-to-hip ratio (0.0029), total cholesterol (P = 0.001), and triglycerides (P = 0.001); higher HDL cholesterol levels (P < 0.0001); and lower prevalence of hypertension (P = 0.0028) compared with patients with type 2 diabetes. C-peptide levels were similar at onset (P = 0.403) but decreased less rapidly in LADA than in adult-onset type 1 diabetes (P = 0.0253). Single-autoantibody positivity was more often seen in LADA than in type 1 diabetes (P = 0.0001). The prevalence of predisposing HLA-DQB1*0302, -DR4, -DR3, and -DR3/DR4 genotypes and the DR4-DQB1*0302 haplotype were increased in both LADA and adult-onset type 1 diabetic subjects compared with the control population. There were no differences in the frequencies of these risk alleles and haplotypes between the two patient groups. CONCLUSIONS: Subjects with LADA had clinical characteristics similar to those with adult-onset type 1 diabetes with rapid progression. C-peptide levels did not differ at onset but decreased less rapidly in LADA. Patients with LADA rather had single islet cell-specific autoantibody positivity. The prevalence of HLA-DQB1*0302, -DR4, -DR3, and -DR3/DR4 risk alleles and the DR4-DQB1*0302 high-risk haplotype did not differ in the two forms of autoimmune diabetes.     

糖尿病患者血清ICA、IAA、GAD-Ab、IA-2-Ab的检测及临床意义

目的：探讨ICA、IAA、GAD—Ab、IA-2-Ab对糖尿病患者的检测及临床意义。方法：用ELISA法测定155例1型糖尿病患者和44例2型糖尿病患者以及32例正常人血清中的ICA、IAA、GAD—Ab、IA-2抗体。结果：1型糖尿病组和2型糖尿病组ICA的阳性率分别为36．8％和11．4％，IAA的阳性率分别为23．2％和16．0％，GAD—Ab的阳性率分别为58．7％和16．0％，IA-2-Ab的阳性率分别为20．0％和6．8％。结论：ICA、IAA、GAD—Ab、IA-2抗体对1型糖尿病的早期诊断及预测有重要的临床意义，且联合测定以上抗体能提高检出率，避免漏诊。     

Progressive autoimmune beta cell insufficiency: occurrence in the absence of high-risk HLA alleles DR3, DR4

In a prospective screening program for type I diabetes mellitus, we identified a unique family in which several members (mother and three siblings) expressed an unusual set of HLA-DR alleles (DR2+, DR3/4-) and were in different phases of immunologically mediated islet beta cell dysfunction. Immunologic and/or clinical manifestations of type I diabetes were absent in all siblings not sharing both HLA haplotypes in common with the proband. This article illustrates: the clinical utility of prospective family screening for predictive markers, such as islet cell antibodies, progressive autoimmune beta cell destruction can occur in the absence of the "high-risk" alleles HLA-DR3 and DR4, and HLA identity with the proband, rather than specific HLA alleles, i.e., presence of DR3, DR4 and absence of DR2, is an essential factor.     

Family characteristics and life events before the onset of autoimmune type 1 diabetes in young adults: a nationwide study

OBJECTIVE--To elucidate whether family characteristics and stressful life events were associated with onset of autoimmune type 1 diabetes in young adults. RESEARCH DESIGN AND METHODS--This investigation was based on a nationwide study (Diabetes Incidence Study in Sweden) of newly diagnosed patients aged 15-34 years. Patients clinically classified as type 1 diabetic with antibodies to islet cells and/or to GAD65 were compared with age- and sex-matched control subjects via questionnaire. The questionnaire covered diabetes heredity, social environment, educational level, and life events experienced during the 12 months before diagnosis. RESULTS--The rate of response was 82% for the diabetic patients and 65% for the control subjects. Questionnaires from 349 diabetic patients and 979 control subjects were considered. Diabetes in relatives was more frequent in the patients (odds ratio [OR]2.6) who were born in Sweden and whose mothers were of Swedish origin. No major stress factors were detected in the diabetic patients; however, in comparison with the control subjects, the diabetic patients had experienced fewer conflicts with their parents and had less often broken contacts with friends. CONCLUSIONS--Young adults with recent-onset type 1 diabetes were more exposed to heredity for diabetes, but no major prediabetic stress factors were detected. Our study does not directly support the concept that psychosocial stressful life events are involved in the development of autoimmune type 1 diabetes in young adults.     

Circumscribed cognitive dysfunction in middle-aged adults with type 2 diabetes

OBJECTIVE: To examine the extent to which type 2 diabetes is associated with poorer performance on measures of learning, memory, psychomotor speed, and problem-solving in middle-aged adults. RESEARCH DESIGN AND METHODS: This cross-sectional study evaluated 50 adults (age range 34-65 years, mean 50.8) with type 2 diabetes and 50 demographically similar community control subjects without diabetes. Each subject received a thorough physical examination and a detailed neuropsychological assessment. Factor analysis was used to assign specific tests to 1 of 4 cognitive domains (learning, memory for stories, problem-solving, and psychomotor speed). Hierarchical regression analysis was used to identify demographic and biomedical variables associated with cognitive dysfunction. RESULTS: Learning, memory, and problem-solving skills were unaffected by type 2 diabetes. In contrast, psychomotor slowing was predicted by a diagnosis of diabetes (r2 change = 0.075, P < 0.002) with additional variance in psychomotor efficiency explained independently by HbA1 (r2 = 0.064, P < 0.003) and vibratory threshold (r2 = 0.112, P < 0.0001). The magnitude of psychomotor slowing on specific tests ranged from 12% (Digit Vigilance) to 23% (Grooved Pegboard). CONCLUSIONS: Middle-aged adults with type 2 diabetes manifest psychomotor slowing that is associated with poorer metabolic control, whereas learning, memory, and problem-solving skills appear to be largely intact. The development of psychomotor slowing may be a manifestation of a "central neuropathy" induced by chronic hyperglycemia.     

Adult-Onset Type 1 Diabetes: Current Understanding and Challenges

Recent epidemiological data have shown that more than half of all new cases of type 1 diabetes occur in adults. Key genetic, immune, and metabolic differences exist between adult- and childhood-onset type 1 diabetes, many of which are not well understood. A substantial risk of misclassification of diabetes type can result. Notably, some adults with type 1 diabetes may not require insulin at diagnosis, their clinical disease can masquerade as type 2 diabetes, and the consequent misclassification may result in inappropriate treatment. In response to this important issue, JDRF convened a workshop of international experts in November 2019. Here, we summarize the current understanding and unanswered questions in the field based on those discussions, highlighting epidemiology and immunogenetic and metabolic characteristics of adult-onset type 1 diabetes as well as disease-associated comorbidities and psychosocial challenges. In adult-onset, as compared with childhood-onset, type 1 diabetes, HLA-associated risk is lower, with more protective genotypes and lower genetic risk scores; multiple diabetes-associated autoantibodies are decreased, though GADA remains dominant. Before diagnosis, those with autoantibodies progress more slowly, and at diagnosis, serum C-peptide is higher in adults than children, with ketoacidosis being less frequent. Tools to distinguish types of diabetes are discussed, including body phenotype, clinical course, family history, autoantibodies, comorbidities, and C-peptide. By providing this perspective, we aim to improve the management of adults presenting with type 1 diabetes.