Insulin antibodies are associated with lipoatrophy but also with lipohypertrophy in children and adolescents with type 1 diabetes.

AIM: To evaluate clinical and immunological factors that are associated with lipodystrophy, i.e. lipoatrophy and lipohypertrophy, in diabetic children and adolescents. METHODS: We investigated in a cross-sectional study 112 children and adolescents (age 1.1-19.1 yrs.) with type 1 diabetes. To grade lipodystrophy, we developed a clinical score ranging from normal (grade 0), moderate hypertrophy of subcutaneous tissue (grade 1), severe hypertrophy with increased density of tissue (grade 2) to lipoatrophy (grade 3). In all children, grade of lipodystrophy, antibodies against insulin (IA) or beta cell antigens (IA-2 and GAD) and clinical parameters were documented. RESULTS: The antibodies against insulin (IA) increased significantly after diabetes manifestation and initiation of insulin treatment, while beta cell specific antibodies (IA-2, GAD) did not. Lipoatrophy (grade 3) was seen in 4 children, severe lipohypertrophy (grade 2) in 18 and moderate lipohypertrophy (grade 1) in 27 children. No alteration of injection sites was found in 63 children. Amongst clinical and immunological parameters, IA levels were significantly associated with hypertrophy or atrophy of injection sites. CONCLUSION: The strong association of lipoatrophy and lipohypertrophy with insulin antibodies might suggest that autoimmune phenomena with insulin play a role in the development of both. Despite an association of IA and lipodystrophy in type 1 diabetic children, the causal link between the two remains unproven and requires further longitudinal exploration.     

Type 1 innate lymphoid cells are associated with type 2 diabetes

AimType 1 innate lymphoid cells (ILC1s) play a major role in regulating systemic inflammatory diseases. However, the relationship between ILC1s and type 2 diabetes (T2D) remains unclear. Thus, the present study investigated the relationship between ILC1s and glucose homoeostasis in humans.MethodsA total of 37 newly diagnosed T2D patients and 32 subjects with normal glucose tolerance (NGT), matched for age and body mass index (BMI), were enrolled in the study. Flow cytometric analysis of ILC1s derived from peripheral blood mononuclear cells (PBMCs) and omental adipose tissue was performed.ResultsT2D patients displayed greater numbers and frequencies of circulating and adipose tissue ILC1s (P < 0.05) compared with NGT subjects, and the two types of ILC1s correlated positively with each other. Circulating ILC1s were positively associated with glycated haemoglobin (HbA_1c), fasting plasma glucose (FPG), homoeostasis model assessment for insulin resistance (HOMA-IR), adipose tissue insulin resistance index (Adipo-IR) and serum free fatty acids (FFAs). A logistic regression model revealed that patients with higher ILC1 levels exhibited a 13.481-fold greater risk of developing T2D.ConclusionThis study is the first to provide evidence that ILC1 abnormalities are involved in the development of diabetes. The data also suggest a potential role of ILC1s as therapeutic indicators in the treatment of T2D.     

Diabetic complications are associated with liver enzyme activities in people with type 1 diabetes

This study was performed to clarify if diabetic complications are associated with liver enzyme activities in type 1 diabetic outpatients. Elevated activities of serum aminotransferases are a common sign of liver disease and are observed more frequently among people with diabetes than in the general population. Many studies have shown an association between specific diabetic complications and disturbances in various tissues, such as diabetic nephropathy and cardiovascular diseases, but only limited data are available on the possible association between diabetic complications and liver function. We studied 28 patients with type 1 diabetes. Mean age was 43.4+/-9.5 (S.D.), and duration of diabetes 25.2+/-9.7. Limited joint mobility (LJM) was assessed by the Rosenbloom's method. Background and proliferative retinopathy, and peripheral symmetrical polyneuropathy were also assessed. Activities of alanine amino transferase (ALT), gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) in serum were determined. The metabolic control of the diabetes was evaluated by the glycosylated haemoglobin A(1c) (HbA(1c)) level and lipid values were also measured. ALT activity was associated with LJM (P<0.01) and with neuropathy (P<0.01). Association between GGT activity and LJM (P<0.01) and neuropathy (P<0.01) were also found. GGT activity was also associated with the severity of retinopathy (P<0.01). None of these associations was explained by confounding effects of diabetes duration, age, body mass index (BMI), HbA(1c) or alcohol consumption. In conclusion, diabetic complications such as LJM, retinopathy and neuropathy are associated with liver enzyme activities independent of alcohol consumption, BMI and metabolic control of diabetes.     

Serum adipocytokines are associated with microalbuminuria in patients with type 1 diabetes and incipient chronic complications

AimsRecent studies have implicated possible contribution of adipocytokines in development and progression of microvascular complications in patients with type 1 diabetes (T1DM). The aim of our study was to investigate relationship between adipocytokines, namely leptin, resistin, adiponectin and dipeptidyl peptidase-4 (DPP-4) activity, with albuminuria in T1DM.MethodsThis study included 202 T1DM without or with incipient microvascular complications. Urinary albumin excretion rate (UAE) was measured from at least two 24-h urine samples. Serum DPP-4 activity was measured by a colorimetric assay, and the level of adiponectin, leptin, and resistin was determined by the ELISA method.ResultsSerum DPP-4 activity and adiponectin were significantly higher in patients with normoalbuminuria compared to patients with microalbuminuria (47 vs 36 U/L, and 10.9 vs 7.3 μg/mL, respectively, p ≤ 0.02). In multivariate logistic regression analysis adiponectin and serum DPP-4 activity were significantly associated with risk of microalbuminuria in our subjects (p ≤ 0.04), with odds ratios of 0.72–0.99. However, after adjustment for age, sex, HbA1c, duration of diabetes and BMI, only serum DPP-4 activity was significantly associated with risk of microalbuminuria (p = 0.008).ConclusionThe results of our study suggest that serum DPP-4 activity is lower in T1DM with microalbuminuria. Prospective studies are warranted to evaluate the relationship between serum DPP-4 activity and progression and development of albuminuria and nephropathy in T1DM.     

Prevalence, characteristics and diabetes risk associated with transient maternally acquired islet antibodies and persistent islet antibodies in offspring of parents with type 1 diabetes

Accurate assessment of type 1 diabetes risk in young children requires discrimination between antibodies that are produced by the child and antibodies acquired through the placenta from an islet antibody-positive mother. We studied 682 offspring from mothers with type 1 diabetes and 329 offspring from fathers with type 1 diabetes and nondiabetic mothers for insulin (auto)antibodies, glutamic acid decarboxylase antibodies, and tyrosine phosphatase IA-2 antibodies before age 1 yr and again at age 2 yr to ascertain transience or persistence. Antibodies were detected at age 9 months in 5 (1.5%) offspring from fathers with type 1 diabetes; all were insulin (auto)antibodies only, all persisted and developed multiple antibodies, and 1 developed type 1 diabetes. In contrast, 31 (4.5%) offspring from mothers with type 1 diabetes had antibodies at 9 months; 12 (1.8%) persisted at age 2 yr, and 19 (2.8%) did not persist, suggestive of transient residual maternal antibodies. Multiple antibodies at 9 months were usually persistent (3 of 4 offspring), as were single insulin (auto)antibodies in offspring from mothers with type 1 diabetes (8 of 13 offspring), whereas persistent glutamic acid decarboxylase antibodies (1 of 12) and tyrosine phosphatase IA-2 antibodies (0 of 2) were rare. Offspring with persistent antibodies at age 9 months had a high type 1 diabetes risk (100% by age 5 yr for those with multiple antibodies and 27% for single antibodies at 9 months), whereas offspring with transient antibodies had 0% type 1 diabetes risk (P < 0.01). Transience was associated with very high antibody levels at birth. For insulin (auto)antibodies, the measurement of subclass was also informative. Residual maternal antibody was indicated by similar insulin (auto)antibodies subclasses at 9 months and at birth, whereas different subclasses were indicative of nonmaternal antibody. Moreover, the presence of IgG1-insulin (auto)antibodies was associated with antibody persistence and type 1 diabetes risk. These strategies are helpful in discriminating high and low risk antibodies before age 1 yr and should be important for prognosis and reducing unnecessary parent anxiety.     

Immunoglobulin heavy chain switch region polymorphisms are not associated with type 1 diabetes

In order to ascertain whether the immunoglobulin heavy chain genes are important in the aetiology of Type 1 diabetes, we have used restriction fragment length polymorphism (RFLP) analysis of genomic DNA to study 148 Caucasoid subjects with Type 1 diabetes and 146 normal Caucasoid subjects. A DNA probe homologous to the switch regions for the IgM (S mu) and IgA1 (S alpha 1) genes when used in conjunction with the restriction endonuclease Sst I detects RFLPs at both these loci. There were no significant differences in phenotype or gene frequencies for the alleles of S mu or S alpha 1 in the patients when compared with control subjects; nor were there significant associations of S mu or S alpha 1 with HLA-DR type or gender.     

新发现的1型糖尿病相关基因

1型糖尿病(T1DM)是一种由T细胞介导的自身免疫性疾病,与多种基因有关。除了位于人白细胞抗原基因区的IDDM1和位于人胰岛素基因区的IDDM2被公认为是T1DM的主效基因外,不断有新的潜在致病基因被发现。几个参与自身免疫反应的重要因子的编码基因如维生素D受体、白细胞介素6、白细胞介素12B、PTPN22、SUMO4以及Tbet相继在一些人群研究中被发现与T1DM相关,本文就针对这些相关性研究结果及其中可能涉及的免疫学机制作一综述。     

Hand abnormalities are associated with the complications of diabetes in type 2 diabetes

Limited finger joint mobility, Dupuytren's contracture, and the complications of diabetes were assessed in 233 Type 2 diabetic patients. Limited joint mobility was present in 34% and Dupytren's contracture in 26%. The prevalence of limited joint mobility and Dupuytren's contracture increased with duration of diabetes and with age. Logistic regression analysis showed that, after allowing for age and duration of diabetes, limited joint mobility was independently associated with Dupuytren's contracture (odds ratio 5.7, 95% CI 2.0-16.4) and retinopathy (odds ratio 3.1, CI 1.5-6.4). Dupuytren's contracture was independently associated with vision-threatening retinopathy (odds ratio 2.6, CI 1.1-6.4), limited joint mobility (odds ratio 2.5, CI 1.3-4.8), and foot ulceration (odds ratio 4.9, CI 1.4-16.4). Both Dupuytren's contracture and limited joint mobility were associated with peripheral neuropathy but neither hand abnormality was associated with neuropathy independently of other complications of diabetes. The association of connective tissue abnormalities in the hand with the complications of diabetes suggests that similar factors may be contributing to their pathogenesis.     

Heritability of quantitative traits associated with type 2 diabetes mellitus in large multiplex families from South India

India is a major contributor to the global public health burden of diabetes. We have undertaken a family study of large multiplex families from Chennai, South India, and report on the familial aggregation of quantitative traits associated with type 2 diabetes mellitus in these pedigrees. Five hundred twenty-four individuals older than 19 years from 26 large multiplex pedigrees were ascertained. Detailed questionnaires and phenotype data were obtained on all participating individuals including fasting blood glucose, fasting insulin, lipid profiles, height, weight, and other anthropometric and clinical measures. Heritability estimates were calculated for all quantitative traits at the univariate level, and bivariate analyses were done to determine the correlation in genetic and environmental control across these quantitative traits. Heritability estimates ranged from 0.21 to 0.72. The heritability estimates for traits most directly related to type 2 diabetes mellitus were 0.24 ± 0.08 for fasting blood glucose and 0.41 ± 0.09 for fasting insulin. In addition, there was evidence for common genetic control for many pairs of these traits. These bivariate analyses suggested common genes for fasting insulin and central obesity measures (body mass index, waist, and hip), with complete genetic correlation between fasting insulin and waist. Quantitative traits associated with type 2 diabetes mellitus have heritabilities suggestive of some familial or genetic effect. The evidence for pleiotropic control of insulin and central obesity-related traits supports the presence of an insulin resistance syndrome in South Asians with a tendency for central obesity.     

Pre-eclampsia and pregnancy-induced hypertension are associated with severe diabetic retinopathy in type 1 diabetes later in life

To investigate whether pre-eclampsia (PE) or pregnancy-induced hypertension (PIH) predicts the development of severe diabetic retinopathy (SDR) in type 1 diabetes. Altogether, 203 women with type 1 diabetes who were followed during pregnancy were re-examined within the Finnish Diabetic Nephropathy Study. After excluding patients with pre-pregnancy hypertension and those who had had laser treatment or whose retinopathy was graded as proliferative at the index pregnancy, 158 were prospectively studied. As a surrogate marker for SDR, retinal laser photocoagulation was used. The time from pregnancy to SDR (N = 21) or follow-up was 16 years (interquartile range, 11–19). HbA_1c was repeatedly measured both during pregnancy and follow-up. Women with prior PE (26 % vs. 6 %, P = 0.003) or PIH (24 % vs. 6 %, P = 0.008) had more often incident SDR during follow-up compared to those with normotensive pregnancy. The hazard ratios (HR) remained associated with the progression to SDR after adjustment for duration of diabetes and diabetic nephropathy in a Cox regression analysis [PE: 3.5 (95 % CI 1.1–10.9); P = 0.03 and for PIH: 3.2 (1.1–9.8); P = 0.04]. The association between PIH and incident SDR did not change after inclusion of mean HbA_1c, measured during pregnancy (all 3 trimesters) and serial HbA_1c measurements during follow-up, 3.5 (1.1–11.8; P = 0.03). However, in a similar model, the HR for PE was no more significant 2.0 (0.6–6.8; P = NS). The results suggest that women with type 1 diabetes and a hypertensive pregnancy have an increased risk of severe diabetic retinopathy later in life.     

Factors associated with type 1 diabetes in Kuwaiti children

Abstract Type 1 diabetes is a common chronic disease in childhood, and the outcome of environmental, genetic and immunologic interactions. The aim was to study the social and metabolic characteristics (lipids, lipoproteins, apolipoproteins, lipoprotein(a) (Lp(a)) and total sialic acid) and predisposing factors in 6–18-year-old Kuwaiti children with type 1 diabetes. This pair-matched case-control study included 348 type 1 diabetic children (131 males, 217 females) matched by age and gender to 348 non-diabetic controls. Diabetic children were identified, according to the WHO and the American Diabetes Association criteria, at 182 randomly selected schools. Social and metabolic characteristics were adversely affected in diabetic children compared to their controls. The logistic regression analysis showed that the predisposing factors: family history of type 1 and type 2 diabetes and thyroid disease, were significant associated factors with type 1 diabetes after adjusting for demographic and social variables. The significant correlations of Lp(a) and total sialic acid with glycated haemoglobin, lipoproteins and apolipoproteins partially explain reporting them as possible markers for coronary heart disease. There are adverse metabolic changes in children with type 1 diabetes. As these changes are associated with early onset atherogenesis, metabolic markers need to be measured and possibly corrected at an early stage in children with diabetes.     

Islet cell antibodies are not specifically associated with insulin-dependent diabetes in Tanzanian Africans

The prevalence of islet cell antibodies (ICA and CF-ICA) together with other organ-specific auto-antibodies was investigated in 122 newly presenting black Tanzanian diabetic patients in Dar es Salaam. ICA were found in three (8.6%) IDDM patients and five (6.8%) insulin-requiring NIDDM patients; six of the eight were also CF-ICA positive. Altogether 22% of patients showed one or more positive autoantibody result but there was no clustering of response, and no association of ICA with other antibodies except for two NIDDM subjects who showed one other positive result. There were no differences between insulin-requiring (IDDM) and NIDDM subjects or between younger (less than 30 years) and older patients. We conclude that there is no major association between diabetes and islet cell antibodies in black Tanzanians.     

SPINK1/PSTI mutations are associated with tropical pancreatitis and type II diabetes mellitus in Bangladesh

BACKGROUND & AIMS: Tropical pancreatitis, including tropical calcific pancreatitis and fibrocalculous pancreatic diabetes, is endemic in parts of Asia and Africa. In a preliminary study, we found serine protease inhibitor, Kazal type 1 (SPINK1) mutations in 6 of 8 patients with fibrocalculous pancreatic diabetes in Bangladesh. A more extensive investigation of patients with pancreatic diseases in Bangladesh, including non-insulin-dependent diabetes mellitus, was undertaken. METHODS: Patients with fibrocalculous pancreatic diabetes (n = 22), tropical calcific pancreatitis (n = 15), and non-insulin-dependent diabetes mellitus (n = 43) and controls (n = 76) from Bangladesh were studied. DNA was extracted, and the SPINK1 gene was sequenced in all patients and 50 controls. Exon 3 was sequenced in an additional 26 controls. RESULTS: SPINK1 N34S mutations appeared in 1 of 76 controls (1.3%), 12 of 22 patients with fibrocalculous pancreatic diabetes (55%; odds ratio, 83; P < 0.00001), 3 of 15 with tropical calcific pancreatitis (20%; odds ratio, 11.2; P = 0.04), and 6 of 43 with non-insulin-dependent diabetes mellitus (14%; odds ratio, 11.9; P = 0.009). P55S was present in 2 of 76 controls (3%) and in 1 of 22 patients with fibrocalculous pancreatic diabetes (5%; P = not significant). A novel Y54H (160T>C) mutation was identified in 1 of 15 tropical calcific pancreatitis patients. CONCLUSIONS: In Bangladesh, the SPINK1 N34S mutation increases the risk of several forms of pancreatic disease, including fibrocalculous pancreatic diabetes, tropical calcific pancreatitis, and non-insulin-dependent diabetes mellitus.     

Plasma leptin levels are associated with coronary atherosclerosis in type 2 diabetes

Leptin signaling may promote atherothrombosis and lead to cardiovascular disease. However, whether leptin is associated with human atherosclerosis, distinct from thrombosis, is unknown. We determined the association of plasma leptin levels with coronary artery calcification (CAC), a measure of coronary atherosclerosis, in a cross-sectional study of type 2 diabetes. Leptin levels were associated with CAC after adjusting for established risk factors [odds ratio (95% confidence interval) for 5 ng/ml leptin increase: 1.31 (1.10-1.55); P = 0.002]. Leptin remained associated with CAC after further controlling for body mass index (BMI) [1.29 (1.07-1.55); P = 0.008], waist circumference [1.30 (1.09-1.57); P = 0.003], C-reactive protein (CRP) levels [1.28 (1.07-1.55); P = 0.008], and subclinical vascular disease [1.30 (1.08-1.57); P = 0.006]. Addition of BMI (P = 0.97), waist (P = 0.55), or CRP (P = 0.39) to a model with leptin failed to improve the model's explanatory power, whereas addition of leptin to a model with BMI (P = 0.029), waist (P = 0.006), or CRP (P = 0.005) improved the model significantly. Plasma leptin levels were associated with CAC in type 2 diabetes after controlling adiposity and CRP. Whether leptin signaling promotes atherosclerosis directly or represents a therapeutic target for the prevention of atherosclerotic cardiovascular disease remains to be explored.