Antibodies to pancreatic islet cell antigens in diabetes seen in Southern India with particular reference to fibrocalculous pancreatic diabetes

Fibrocalculous pancreatic diabetes (FCPD) is a type of diabetes secondary to tropical chronic non-alcoholic pancreatitis. Little is known about the aetiopathogenesis of FCPD. We studied glutamic acid decarboxylase antibodies (GAD-Ab) and islet cell antibodies (ICA) in patients with FCPD and compared the results with Type 1 (insulin dependent) diabetes mellitus, Type 2 (non-insulin-dependent) diabetes mellitus and non-diabetic subjects in Southern India. The prevalence of GAD-Ab was 7.0 % (95 % Confidence Interval (CI) 1.9–17.2) in FCPD, 47.5 % (CI 31.4–64.0) in Type 1 (p < 0.001 compared to FCPD), 5.6 % (CI 1.5–13.9) in Type 2 (non-significant (NS) compared to FCPD) and 0 % in controls. The prevalence of ICA was 6.3 % (CI 1.2–17.4) in FCPD, 53.8 % (CI 37.1–70.0) in Type 1 (p < 0.001 compared to FCPD), 9.9 % (CI 4.0–19.4) in Type 2 (NS compared to FCPD) and 4.7 % (CI 0.4–16.1) in controls. The data suggest that in FCPD, the frequency of auto-antibodies is low and its aetiology is probably not linked to autoimmunity in the majority of the patients. © 1998 John Wiley & Sons, Ltd.     

Ketoacidosis in young adults is not related to the islet antibodies at the diagnosis of Type 1 diabetes mellitus--a nationwide study.

AIMS: To test the hypothesis that there is lower prevalence of islet antibodies in subjects with newly diagnosed Type 1 diabetes mellitus in young adulthood than in children is associated with less severe diabetes at time of diagnosis. METHODS: This investigation was based on a nationwide study (Diabetes Incidence Study in Sweden) of 15-34-year-old newly diagnosed diabetic subjects. During 1992-1993, all diabetic subjects (excluding secondary and gestational diabetes) were reported on standardized forms, with information about clinical characteristics at diagnosis. The study examined islet cell antibodies (ICA) by indirect immunofluorescence, and autoantibodies to glutamic acid decarboxylase (GADA), tyrosine phosphatase-like antigen (IA-2A) and insulin (IAA) as well as C-peptide by radioimmunoassay. RESULTS: Blood samples were available from 78 patients with diabetic ketoacidosis (DKA) and 517 non-acidotic patients. The prevalence of ICA (63% vs. 57%), GADA (63% vs. 66%), IA-2A (35% vs. 44%) and IAA (20% vs. 15%) were very similar in patients with or without DKA. The median levels of the four autoantibodies did not differ between the two groups. High blood glucose (P < 0.001) and low C-peptide levels (P < 0.001) were the only parameters found to be related to DKA. CONCLUSIONS: The similarities in findings of newly diagnosed diabetic patients with or without DKA regarding ICA, GADA, IA-2A and IAA suggest that there is no relationship between the expression of antigenicity and the severity of beta-cell dysfunction. The lower prevalence of the four autoantibodies in 15-34-year-old diabetic subjects compared with previous findings in children is not explained by misclassification of diabetes type.     

Heterogeneity in young adult onset diabetes: aetiology alters clinical characteristics.

AIMS: To describe the characteristics of hepatocyte nuclear factor (HNF) 1 alpha mutation carriers diagnosed with diabetes after 25 years and compare them with young-onset Type 2 diabetic patients (YT2D) diagnosed at the same age. SUBJECTS AND METHODS: We studied 44 (21 male, 23 female) patients with HNF-1 alpha mutations diagnosed with diabetes at ages 25-45 years and 44 YT2D subjects matched for sex and age of diagnosis. RESULTS: Median age of onset of diabetes was 35 years in both groups. The HNF-1 alpha group demonstrated: lower body mass index (25.1 vs. 30.7 kg/m2; P < 0.001) and lower fasting triglycerides (1.37 vs. 2.96 mmol/l; P = 0.001) with similar fasting cholesterol level. They had lower glycated haemoglobin A1c (7.3 vs. 8.5%; P = 0.015) despite greater duration of diabetes (24 vs. 16 years; P = 0.02) and less frequent treatment with insulin (21% vs. 55%; P = 0.002). They were less likely to be treated for hypertension (13.3% vs. 56.3%; P = 0.009). Importantly, no difference was observed in reported parental history of diabetes between the two groups (65.9% vs. 63.6%; P = 0.92). Logistic regression showed that triglyceride levels and presence of anti-hypertensive treatment were the most important independent variables. CONCLUSIONS: Patients with HNF-1 alpha mutations may present with diabetes as young adults between the ages of 25-45 years. In this age range a wide differential diagnosis of diabetes is observed. Conventional criteria of age of onset and family history will not differentiate HNF-1 alpha mutation carriers from YT2D subjects in this age range, but features of the metabolic syndrome, in particular fasting triglycerides and hypertension, are helpful. In patients diagnosed before 45 years without features of insulin resistance the diagnosis of HNF-1 alpha should be considered.     

线粒体tRNALeu(UUR)基因点突变与1型糖尿病

目的　线粒体ｔ Ｒ Ｎ Ａ Ｌｅｕ（ Ｕ Ｕ Ｒ） 基因３２４３ 位点 Ａ→ Ｇ 突变是糖尿病的致病基因之一。本研究是为了了解该基因的突变在中国１ 型糖尿病患者中的情况以及与自身免疫导致１ 型糖尿病有无关联。方法　对１１６ 例随机收集的１ 型糖尿病患者用聚合酶链反应限制性内切酶消化作该点突变的筛选；８２ 例患者同时进行了谷氨酸脱羧酶（ Ｇ Ａ Ｄ） 抗体的测定。结果　发现１ 例该点突变（０ ．８６ ％ ） ，４８ 例 Ｇ Ａ Ｄ 抗体阳性（５８ ．５ ％ ） 。线粒体ｔ Ｒ Ｎ Ａ Ｌｅｕ（ Ｕ Ｕ Ｒ） 基因突变携带者 Ｇ Ａ Ｄ 抗体阴性，其家系成员糖尿病有不同的发病方式，但均表现为胰岛素缺乏。结论　线粒体ｔ Ｒ Ｎ Ａ Ｌｅｕ（ Ｕ Ｕ Ｒ） 基因异常所致糖尿病表现为胰岛素缺乏可能与自身免疫胰岛炎无关，而是一种独特的糖尿病亚型。     

Coeliac autoimmunity in type I diabetes mellitus

Background and study aimsCoeliac autoimmunity (CA) has a known association with type 1 diabetes mellitus (T1DM) for which screening is routinely recommended but less frequently followed. The impact of CA in T1DM has been variably reported. The aims of this study are as follows: (1) to study the prevalence of CA in patients with T1DM and (2) to study the impact of CA not only on nutritional parameters but also on glycaemic control, endocrine axes and bone health.Patients and methodsEighty-six consecutive patients with T1DM were screened for CA using immunoglobulin A (IgA) tissue transglutaminase as a marker (TTG; IgG anti-gliadin in IgA-deficient case). CA positive (CA+) cases were compared with age-matched and sex-matched CA negative (CA−) T1DM cases for anthropometry, glycaemic control (assessed by glycated haemoglobin (HbA1c) and hypoglycaemic/hyperglycaemic episodes), endocrine (thyroid function, cortisol, growth hormone (GH) axis, gonadal axes), haematological (haemoglobin, iron profile and vitamin B₁₂ status) and calcium metabolism parameters and bone densitometry (by dual-energy X-ray absorptiometry (DXA)). Consenting patients with CA also underwent upper gastrointestinal (GI) endoscopy with duodenal biopsy.ResultsOut of 86 patients, 11 (12.75%) screened positive for CA (seven patients underwent duodenal biopsies which were suggestive of Marsh grade III(2), II(3) and I(2) disease). The CA+ T1DM patients were comparable with CA− T1DM in terms of anthropometry. CA+ patients had higher HbA1c (10.7 ± 1.8 vs. 8.4 ± 1.0 (93 ± 19 vs. 68 ± 11 mmol/mol); p < 0.01), more hypoglycaemic episodes (five vs. two; p < 0.05), higher prevalence of iron and vitamin B₁₂ deficiency, lower insulin-like growth factor-1 (IGF-1) levels and lower bone mineral density (BMD) z-score at total body (−1.91 ± 1.05 vs. −0.63 ± 0.73; p < 0.05) and lumbar spine (−1.69 ± 0.92 vs. −0.36 ± 0.93; p < 0.05). The incidence of fractures in the past 3 years was also more in CA+ patients than in CA− patients (four vs. one; p < 0.05).ConclusionCA has an important autoimmune association with T1DM. The concomitant presence of CA adversely affects stature, bone health, glycaemic control and iron and B₁₂ levels in T1DM. IgA sufficiency should be ensured before using an IgA-based screening test for CA.     

A comparative study of the clinical profile of fibrocalculous pancreatic diabetes and type 2 diabetes mellitus

AimsThe present study aimed to compare the clinical characteristics of patients with fibrocalculous pancreatic diabetes (FCPD) and those with type 2 diabetes mellitus (T2DM) to identify the characteristics distinctive of FCPD.MethodsA total of 133 patients with FCPD were compared with 665 patients with T2DM matched for duration of diabetes. Biochemical parameters and microvascular and macrovascular complications were assessed in all patients. Multivariate regression analyses were performed to study the determinants of microvascular and macrovascular complications in both groups.ResultsThe mean duration of diabetes was 4.42 ± 5.65 years in the FCPD group and 4.51 ± 3.88 years in the T2DM group. FCPD participants were significantly younger at diagnosis and leaner than patients with T2DM. The FCPD group had higher fasting and postprandial glucose and HbA1c levels than the T2DM group. The FCPD group had significantly lower triglyceride, total cholesterol, low-density lipoprotein cholesterol, serum total calcium, hemoglobin, and serum creatinine values than the T2DM group. The prevalence of coronary artery disease, stroke, and retinopathy was significantly higher in the T2DM patients while the prevalence of distal symmetric polyneuropathy was significantly lower. On multivariate logistic regression analysis, duration of diabetes and HbA1c (OR = 1.17, P = 0 0.04) in FCPD patients and age (OR = 1.04, P < 0 0.001), duration of diabetes (OR = 1.17, P < 0 0.001) and HbA1c (OR = 1.28, P < 0.001) in T2DM patients were associated with microvascular complications.ConclusionsThere are several differences in the phenotype, biochemical parameters, and prevalence of diabetic complications between patients with FCPD and T2DM. Timely diagnosis may have implications in the follow-up and management of patients.     

Type 1 diabetes developed in a type 2 diabetic patient with severe insulin resistance

We report a 38-year-old female with severe insulin resistance who developed type 1 diabetes after being diagnosed with type 2 diabetes. At the initial examination, BMI was 31.8 kg/m² and HbA1c 10.8%. Her insulin secretion was sufficient (urinary CPR 80 μg/day) and the GAD antibody was negative. Following treatment with insulin and glimepiride, HbA1c decreased to 6.3%, though diabetic control deteriorated after 1 year (HbA1c, 11.0%) and her body weight was reduced in a short period, from 78 to 67 kg. Re-examination revealed that the GAD antibody was high (1870 U/mL, normal <1.5) and the anti-islet cell antibody positive, and insulin secretion decreased (urinary CPR 18 μg/day). Further, a hyperinsulinemic–euglycemic cramp study using an artificial pancreas showed that the patient had severe insulin resistance [glucose infusion rate 1.8 mg/(min kg); normal, 7.4 ± 2.4 (mean ± S.D.)]. An HLA-analysis showed that she was a homozygote of haplotype DRB1*0901-DQB1*0303. In spite of strict insulin therapy, glucose control was not improved. Pioglitazone could not be used because of side effects, however, metformin was effective for glucose control. The accumulation of case reports of patients with type 1 diabetes and insulin resistance is important for studying the relationship between the onset of the disease and insulin resistance, and for developing an effective treatment strategy.     

Maturity‐onset diabetes of the young as a model for elucidating the multifactorial origin of type 2 diabetes mellitus

Maturity‐onset diabetes of the young (MODY) is a form of diabetes classically characterized as having autosomal dominant inheritance, onset before the age of 25 years in at least one family member and partly preserved pancreatic β‐cell function. The 14 responsible genes are reported to be MODY type 1~14, of which MODY 2 and 3 might be the most common forms. Although MODY is currently classified as diabetes of a single gene defect, it has become clear that mutations in rare MODYs, such as MODY 5 and MODY 6, have small mutagenic effects and low penetrance. In addition, as there are differences in the clinical phenotypes caused by the same mutation even in the same family, other phenotypic modifying factors are thought to exist; MODY could well have characteristics of type 2 diabetes mellitus, which is of multifactorial origin. Here, we outline the effects of genetic and environmental factors on the known phenotypes of MODY, focusing mainly on the examples of MODY 5 and 6, which have low penetrance, as suggestive models for elucidating the multifactorial origin of type 2 diabetes mellitus.     

PET技术在糖尿病研究领域中的应用

正电子发射断层成像（PET）技术是一种通过体外测量放射性元素在人体内的代谢轨迹,进行三维成像的无创检测技术。运用PET技术对注入人体的放射性元素进行断层扫描,采集数据及成像,可更深入地研究糖尿病的发病机制。PET技术还可用于研究糖尿病并发症如血管疾病、神经病变的发病机制及其早期诊断,并可评价降糖药物对糖尿病及部分并发症的干预疗效。     

天然免疫细胞在1型糖尿病中的作用

1型糖尿病（T1DM）是一种复杂的自身免疫性疾病,主要是由T、B细胞破坏胰岛β细胞所致.虽然病因不明,但最终一系列天然免疫细胞及特异性免疫细胞相互作用,导致胰岛β细胞损伤和T1DM的发生.对动物模型和T1DM患者的研究发现,单核/巨噬细胞、自然杀伤细胞、自然杀伤T细胞、树突状细胞和淋巴细胞相互作用可影响T1DM的发生、发展.因此,研究天然免疫细胞在T1DM发生、发展中的作用,可能为防治T1DM提供新的方向.     

Perinatal mortality in Type 2 diabetes mellitus.

AIMS: In many parts of the world the number of pregnancies in women with Type 2 diabetes mellitus (DM) now exceeds that in women with Type 1 DM, but there are few data published on perinatal mortality in Type 2 DM. This study reports observational data on perinatal mortality in Type 2 DM from a population with a high background rate of this disorder. METHODS: Over a 12-year period (1985-1997) at the Diabetes Clinic at National Women's Hospital, Auckland, there were 434 pregnancies in women with Type 2 DM (256 known and 178 diagnosed with gestational diabetes mellitus (GDM), but confirmed to have Type 2 DM early post-partum), 160 pregnancies in women with Type 1 DM and 932 in women with GDM. Perinatal mortality was classified as either intermediate fetal death (20-28 weeks' gestation), late fetal death (28 weeks' gestation to term) or early neonatal death (up to 1 month post-partum). RESULTS: The perinatal mortality in Type 2DM was 46.1/1,000, significantly higher than the rates for the general population (12.5), Type 1 DM (12.5) and GDM (8.9) (P < 0.0001). Congenital malformations accounted for only 10% of the perinatal mortality. There was a seven-fold increase in the rate of late fetal death and 2.5-fold increase in the rates of intermediate fetal and late neonatal death. Subjects with Type 2 DM were significantly older and more obese than subjects with Type 1 DM, and presented later to the diabetes service. CONCLUSIONS: Perinatal mortality in Type 2 DM is significantly increased, mainly owing to an excess of late fetal death. Maternal factors such as obesity may be important contributors to the high perinatal mortality. Women diagnosed with GDM who have unrecognized Type 2 DM are also at high risk, but perinatal mortality is low in women with milder degrees of glucose intolerance in pregnancy.     

Different genetic backgrounds for malnutrition-related diabetes and Type 1 (insulin-dependent) diabetes mellitus in South Indians

Summary HLA-DRB, -DQA and -DQB genes were studied in ten South Indian malnutrition-related diabetic patients, ten Type 1 (insulin-dependent) diabetic patients and 45 control subjects, by TaqI restriction fragment length polymorphism analysis. The DR7,DQw9 haplotype was found to be frequent in patients with malnutrition-related diabetes (p<0.01). The DRw17,DQw2 haplotype was overrepresented in the patients with Type 1 diabetes compared to control subjects (p<0.05). In vitro amplification of the polymorphic second exon of DQB genes by the polymerase chain reaction technique was performed on DNA from 10 malnutrition-related diabetic patients, 10 Type 1 diabetic patients and 13 control subjects, as they belong to a new population. Hybridization with sequence-specific oligonucleotide probes for DQB1 alleles showed homozygosity of aspartic acid at position 57 in 7 of 10 malnutrition-related diabetic patients compared to 2 of 10 Type 1 diabetic (p<0.05) and 15 of 45 control subjects (p<0.05). Homozygosity of non-aspartic acid at position 57 was present in 7 of 10 Type 1 diabetic compared to 0 of 10 malnutrition-related diabetic patients (p<0.005) and 3 of 45 control subjects (p<0.05). This study has confirmed the association of DQB1 57 non-asp in South Indians with Type 1 diabetes. In addition, our data clearly show that the genetic background of malnutrition-related diabetes mellitus is different from that of Type 1 diabetes.     

2型糖尿病胰岛细胞胰岛素抵抗的机制

胰岛素抵抗是2型糖尿病(T2DM)主要病理生理机制之一.肝脏、肌肉和脂肪组织存在胰岛素抵抗.近年来研究显示,胰岛α细胞与β细胞也存在胰岛素抵抗.高糖、高游离脂肪酸(FFA)、氧化应激、炎性反应均可导致胰岛素抵抗:高糖作用可下调胰岛α、β细胞磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(PKB)途径;高FFA抑制胰岛素受体底物(IRS)及PI3K活性;氧化应激使胰岛α、β细胞的IRS表达下降;炎性因子可干扰IRS/PI3K信号通路.     

High prevalence of type 2 diabetes mellitus in affluent urban Indians

The highest prevalence of type 2 diabetes mellitus in developing countries occurs in the upper socio-economic group, but this has not been well documented in Indians. The age and sex standardized prevalence of diabetes in 1112 affluent adult Indian subjects was 21.1%. This is the highest prevalence of diabetes reported from India.     

Coeliac disease and Type 1 diabetes mellitus - the case for screening.

AIM: To review the relationship between coeliac disease and Type 1 diabetes mellitus with emphasis on prevalence of coeliac disease, presentation and implications for screening. METHODS: Papers collected over many years by the author have been included in the review and a literature search employing Medline was undertaken to August 2000. Search words used were coeliac disease and diabetes mellitus. RESULTS: Twenty papers exploring the prevalence of coeliac disease by serological screening of Type 1 diabetes in children, eight in adults and two including both groups were found. An additional 48 papers are included and relate to serological screening tests for coeliac disease, expressions and complications of coeliac disease, the value of GFD and the genetics of the two conditions. Unless formal screening studies are undertaken coeliac disease will not be diagnosed because patients are asymptomatic, have atypical symptoms or even in those with symptoms the diagnosis is overlooked. Based on small bowel biopsy, diagnosis the prevalence of coeliac disease in Type 1 diabetes in children is 1:6 to 1:103 and in adults 1:16 to 1:76. Patients may improve following the start of a gluten-free diet (GFD) in terms of symptoms, growth in children, serum antibody levels, haematological and biochemical indices, morphology of the small intestinal mucosa and control of diabetes. CONCLUSION: Coeliac disease commonly occurs in Type 1 diabetes. It is recommended that screening for coeliac disease should be part of the routine investigation and offered to all patients because of the high prevalence and the potential benefits of treatment with a GFD. This includes control of symptoms, stabilization of diabetes and prevention of complications associated with coeliac disease. The cost per patient diagnosed with coeliac disease from the existing population with Type 1 diabetes would be pound860 and for those newly arising pound950.     

Alteration in CD8+ T cell subsets in enterovirus-infected patients: An alarming factor for type 1 diabetes mellitus

Type 1 diabetes is a multi-factorial disease that can develop due to the combination of genetic and environmental factors. Viruses, particularly enteroviruses, are major environmental candidates in the pathogenesis of type 1 diabetes, even though the mechanisms of pathogenicity of these viruses and their effects on the immune system have not been understood very well yet. Previous studies show that any imbalance in the population of different lymphocyte subsets could develop autoimmune diseases. Our theory is that enteroviral infection causes an impairment in the distribution of lymphocyte subtypes and consequently results in the diabetes onset in some individuals. Therefore, in this project, we evaluated the distribution of T CD8+ lymphocytes and their subsets in type 1 diabetes patients. This study was conducted to investigate the relationship between enteroviral infection and type 1 diabetes mellitus in an Iranian population, and suggestion a predicting approach for susceptible subjects.     

Apolipoprotein (a) levels in type 1 and type 2 diabetes mellitus

Type 1 and type 2 diabetes mellitus are both characterized by increased cardiovascular mortality and morbidity. Since several reports have indicated that apolipoprotein (a) [apo (a)] levels are positively associated with an increased risk of macrovascular disease, we investigated whether apo (a) levels are elevated in both types of diabetes mellitus and may thus represent an independent risk factor for atherosclerotic disease. Apo(a) concentrations in type 1 diabetic patients were not significantly different from matched controls (276±78 vs 149±46 units/l). Type 2 diabetic patients had considerably higher levels of apo (a) than matched controls (471±89 vs 221±61 units/l,P=0.06), though the difference was not statistically significant. However, concentrations of apo (a) were above 300 units/l in 36% of type 1 and 67% of type 2 diabetic patients, but in only 14% and 25% respectively of matched control subjects. Plasma triglycerides were positively and independently correlated with apo (a) levels in both diabetic and non-diabetic subjects. On the other hand, no significant correlation was found between apo (a) levels and glycosylated haemoglobin, total cholesterol or high density lipoprotein cholesterol in any of the groups studied. In conclusion, apo (a) levels are not significantly elevated either in type 1 or type 2 diabetic patients without proteinuria and in moderate metabolic control; however, levels above 300 units/l were 2.6 times more frequent in both types of diabetes mellitus than in carefully age-, sex-, and weight-matched control subjects.     

Role of hematological parameters in pathogenesis of diabetes mellitus: A review of the literature

Diabetes mellitus (DM) is characterized by hyperglycemia and abnormalities in insulin secretion and activity. There are numerous hematological parameters; however, this review article only focuses on red blood cells, hemoglobin, hematocrit, red blood cell indices, platelet count, white blood cells, lymphocytes, neutrophils, monocytes, eosinophils, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio, which play an essential role in the pathogenesis of DM. Also, this review article aims to report the relationship between these hematological parameters and the development of DM. In con-clusion, this article shows that increased levels of platelets, red blood cells, hematocrit, lymphocytes, eosinophils, neutrophils, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio and decreased levels of hemoglobin are involved in the pathogenesis of DM. However, the role of basophils in DM is unknown yet.