ABSTRACT
To investigate the risk of macro- and microvascular complications in patients with type 2 diabetes receiving rapid-acting insulin analogues (IA) or human regular insulin (HI).General practice diabetes patients with continuous prescription of any IA or HI for ≥3 years were selected from the German Disease Analyzer database (IMS Health). Logistic and Cox regression models were applied to analyze the incidence and time to onset of vascular outcomes (IA vs. HI).2764 patients on IA (insulin lispro, glulisine, aspart) and 4193 patients on HI were included (age, mean [SD]: 61.0 [11.3] and 64.7 [10.5] years, follow-up [Q1,Q3]: 4.6 [3.7,6.1] and 4.7 [3.7,5.9] years). No significant differences were detected between IA and HI regarding the incidence of vascular complications (OR [95%CI]: macrovascular 0.92 [0.72-1.18], microvascular 0.95 [0.77-1.17]) or regarding time to their onset, after adjustment for sex, age, comorbidities and time on IA/HI, or by propensity-score-based matching. However, in an additional short-term analysis (median [Q1,Q3] follow-up (IA 2.9 [1.2,4.6], HI 2.4 [0.8,4.4] years) of a larger sample (no continuous insulin treatment required) with more comorbidities, time to onset of macrovascular complications was significantly longer for AI than HI (HR 0.88 [0.81-0.97], p=0.009; microvascular complications: no difference).After long-term continuous treatment with IA or HI under real-life conditions, there was no different risk of macro- or microvascular complications, contradicting previous short-term analyses. Further prospective studies are needed to clarify whether selection bias may have been introduced by using strict entry criteria.
Subject(s)
Databases, Factual , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/administration & dosage , Insulin, Regular, Human/administration & dosage , Insulin, Short-Acting/administration & dosage , Microcirculation/drug effects , Adult , Age Factors , Aged , Diabetes Mellitus, Type 2/epidemiology , Female , Follow-Up Studies , Humans , Hypoglycemic Agents/adverse effects , Insulin, Regular, Human/adverse effects , Insulin, Short-Acting/adverse effects , Male , Middle Aged , Retrospective Studies , Sex FactorsABSTRACT
BACKGROUND: Despite high insulin doses, good glycaemic control is often lacking in type 2 diabetes patients and new therapeutic options are needed. METHODS: In a proof of principle study, an energy-restricted, protein-rich meal replacement (PRMR) was examined as a means of reducing insulin requirement, HbA1C and body weight. Obese type 2 diabetes patients (n = 22) with >100 U insulin per day replaced, in week 1, the three main meals with 50 g of PRMR (Almased-Vitalkost) each (= 4903 kJ day(-1) ). In weeks 2-4, breakfast and dinner were replaced, and, in weeks 5-12, only dinner was replaced. Clinical parameters were determined at baseline, and after 4, 8 and 12 weeks, as well as after 1.5 years of follow-up. The Wilcoxon signed-rank test was used for the intention-to-treat analysis and the Mann-Whitney U-test for subgroup analyses. RESULTS: The 12-week-programme was completed by 15 participants (68%). After 1 week, the mean insulin dose was reduced from 147 (75) U to 91 (55) U day(-1) (P = 0.0001), and to 65 (32) U (P < 0.0001) after 12 weeks of study. Over a period of 12 weeks, HbA1c decreased from 8.8% (1.4%) to 8.1% (1.6%) (P = 0.048) and weight decreased from 118.0 (19.7) kg to 107.4 (19.2) kg (P < 0.0001). Moreover, body mass index, waist and hip circumference, fasting blood glucose, triglycerides and high-density lipoprotein cholesterol improved significantly. After 1.5 years, insulin requirement and weight remained significantly lower than baseline. Participants who continued PRMR further reduced their HbA1c, weight and insulin dose. Two patients were able to stop insulin therapy altogether. CONCLUSIONS: Energy-restricted PRMR was effective in reducing insulin requirement of type 2 diabetes patients with intensified insulin therapy accompanied by a reduction of HbA1c, weight and other cardiometabolic risk factors. With the continuous use of PRMR, glycaemic control might be improved in the long term.
Subject(s)
Body Weight , Diabetes Mellitus, Type 2/diet therapy , Food, Formulated , Glycated Hemoglobin/metabolism , Insulin/administration & dosage , Adult , Aged , Blood Glucose/metabolism , Body Mass Index , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Diabetes Mellitus, Type 2/blood , Diet , Dietary Proteins/administration & dosage , Dose-Response Relationship, Drug , Fasting , Female , Follow-Up Studies , Humans , Insulin/blood , Male , Meals , Middle Aged , Obesity/blood , Obesity/diet therapy , Pilot Projects , Triglycerides/bloodABSTRACT
Fatty acids, uric acid and glucose are thought to contribute to subclinical inflammation associated with diabetes mellitus. We tested whether co-incubation of free fatty acids and uric acid or glucose influences the secretion of immune mediators from stimulated human whole blood in vitro. Fresh whole blood samples from 20 healthy subjects, 20 patients with type 1 diabetes and 23 patients with type 2 diabetes were incubated for 24 h with palmitic acid (PAL), linolenic acid (LIN) or eicosapentaenoic acid (EPA) alone or together with elevated concentrations of uric acid or glucose. Concentrations of proinflammatory cytokines interleukin (IL)-1ß, IL-2, IL-12(p70), IL-18, IFN-γ, of regulatory cytokines IL-4, IL-10, IL-17 and chemokine CCL2 (MCP-1) were measured by multiplex-bead technology from supernatants. Co-incubation of fatty acids with uric acid resulted in a significant reduction of IL-10, IL-12(p70), IFN-γ and CCL2 (MCP-1) concentrations in supernatants compared to incubation with uric acid alone (P < 0·0001). In contrast, IL-18 was up-regulated upon co-stimulation with fatty acids and uric acid. Similarly, co-incubation of fatty acids with glucose diminished secretion of IL-10, IFN-γ and CCL2 (monocyte chemotactic protein-1), while IL-8 was up-regulated (P < 0·001). Samples from healthy and diabetic subjects did not differ after adjustment for age, sex, body mass index and diabetes type. All three fatty acids similarly influenced whole blood cytokine release in vitro and modulated uric acid or glucose-stimulated cytokine secretion. Although the ω-3-fatty acid EPA showed slightly stronger effects, further studies are required to elaborate the differential effects of PAL, LIN and EPA on disease risk observed previously in epidemiological studies.
Subject(s)
Chemokines/blood , Cytokines/blood , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Fatty Acids, Nonesterified/pharmacology , Adult , Case-Control Studies , Drug Interactions , Eicosapentaenoic Acid/administration & dosage , Eicosapentaenoic Acid/pharmacology , Fatty Acids, Nonesterified/administration & dosage , Female , Glucose/administration & dosage , Glucose/pharmacology , Humans , Inflammation Mediators/blood , Male , Middle Aged , Palmitic Acid/administration & dosage , Palmitic Acid/pharmacology , Phytohemagglutinins/pharmacology , Uric Acid/administration & dosage , Uric Acid/pharmacology , alpha-Linolenic Acid/administration & dosage , alpha-Linolenic Acid/pharmacologyABSTRACT
AIMS/HYPOTHESIS: Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes. METHODS: The beta cell function of 118 patients with type 1 diabetes of duration of 0.75-4.97 years was tested using a standardised liquid mixed meal test (MMT). Serum samples obtained at -5 to 120 min were analysed by multiplex bead-based technology for proinflammatory (IL-6, TNF-α), anti-inflammatory (IL-1 receptor antagonist [IL-1RA]) and regulatory (IL-10, TGF-ß1-3) cytokines, and by standard procedures for C-peptide. Differences in beta cell function between patient groups were assessed using stepwise multiple regression analysis adjusting for sex, age, duration of diabetes, BMI, HbA1c and fasting blood glucose. RESULTS: High fasting systemic concentrations of the proinflammatory cytokines IL-6 and TNF-α were associated with increased fasting and stimulated C-peptide concentrations even after adjustment for confounders (p < 0.03). Interestingly, increased concentrations of anti-inflammatory/regulatory IL-1RA, IL-10, TGF-ß1 and TGF-ß2 were associated with lower fasting and stimulated C-peptide levels (p < 0.04), losing significance on adjustment for anthropometric variables. During the MMT, circulating concentrations of IL-6 and TNF-α increased (p < 0.001) while those of IL-10 and TGF-ß1 decreased (p < 0.02) and IL-1RA and TGF-ß2 remained unchanged. CONCLUSIONS/INTERPRETATION: The association between better preserved beta cell function in longer term type 1 diabetes and increased systemic proinflammatory cytokines and decreased anti-inflammatory and regulatory cytokines is suggestive of ongoing inflammatory disease activity that might be perpetuated by the remaining beta cells. These findings should be considered when designing immune intervention studies aimed at patients with longer term type 1 diabetes and residual beta cell function.
Subject(s)
Cytokines/blood , Diabetes Mellitus, Type 1/blood , Fasting , Gene Expression Regulation , Insulin-Secreting Cells/cytology , Adolescent , Adult , Blood Glucose/metabolism , Body Mass Index , C-Peptide/blood , Child , Diabetes Mellitus, Type 1/metabolism , Diet , Female , Humans , Inflammation , Male , Time Factors , Young AdultABSTRACT
A 9-year-old cynomolgus monkey (Macaca fascicularis) infected orally with bovine spongiform encephalopathy (BSE) was presented for necropsy following euthanasia 4 years post infection (p.i.). This macaque R984 was exposed to a BSE dose that causes a simian form of variant Creutzfeldt-Jakob disease (vCJD) within 5 years p.i. in other macaques. All orally BSE-infected macaques developed a significant weight gain within the first 2 years p.i. compared with non-BSE-infected age- and sex-matched control animals, suggesting increased risk of type 2 diabetes (T2D). In contrast, macaque R984 developed rapid weight loss, hyperglycemia, and glucosuria and had to be euthanatized 4 years p.i. before clinical signs of vCJD. Pancreas histopathological evaluation revealed severe islet degeneration but, remarkably, no islet amyloid deposits were present. Immunostaining of pancreas sections for insulin and glucagon confirmed the loss of endocrine cells. In addition, prions were present in the adenohypophysis but not in other areas of the brain, indicating centripetal prion spread from the gut during the preclinical phase of BSE infection. Plasma glucose and insulin concentrations of macaque R984 became abnormal with age and resembled T2D. This unusual case of spontaneous T2D in the absence of islet amyloid deposits could have been due to early prion spread from the periphery to the endocrine system or could have occurred spontaneously.
Subject(s)
Diabetes Mellitus, Type 2/pathology , Encephalopathy, Bovine Spongiform/complications , Macaca fascicularis , Monkey Diseases/pathology , Obesity/complications , Animals , Blood Glucose/metabolism , Body Weight , Cattle , Diabetes Mellitus, Type 2/etiology , Female , Histological Techniques/veterinary , Insulin/blood , Islet Amyloid Polypeptide/metabolism , Pancreas/pathology , Sex FactorsABSTRACT
AIMS: The relation of disease progression and age, serum interleukin 10 (IL-10) and interferon gamma (IFNγ) and their genetic correlates were studied in paediatric patients with newly diagnosed Type 1 diabetes. METHODS: Two hundred and twenty-seven patients from the Hvidoere Study Group were classified in four different progression groups as assessed by change in stimulated C-peptide from 1 to 6 months. CA repeat variants of the IL-10 and IFNγ gene were genotyped and serum levels of IL-10 and IFNγ were measured at 1, 6 and 12 months. RESULTS: IL-10 decreased (P < 0.001) by 7.7% (1 month), 10.4% (6 months) and 8.6% (12 months) per year increase in age of child, while a twofold higher C-peptide concentration at 1 month (p = 0.06), 6 months (P = 0.0003) and 12 months (P = 0.02) was associated with 9.7%, 18.6% and 9.7% lower IL-10 levels, independent of each other. IL-10 concentrations did not associate with the disease progression groups. By contrast, IFNγ concentrations differed between the four progression groups at 6 and 12 months (P = 0.02 and P = 0.01, respectively); patients with rapid progressing disease had the highest levels at both time points. Distribution of IL-10 and IFNγ genotypes was equal among patients from the progression groups. CONCLUSION: IL-10 serum levels associate inversely with age and C-peptide. As age and C-peptide also associate, a triangular association is proposed. Genetic influence on IL-10 production seems to be masked by distinct disease mechanisms. Increased serum IFNγ concentrations associate with rapid disease progression. Functional genetic variants do not associate with a single progression pattern group, implying that disease processes override genetically predisposed cytokine production.
Subject(s)
Aging/blood , C-Peptide/blood , Diabetes Mellitus, Type 1/blood , Interferon-gamma/blood , Interleukin-10/blood , Adolescent , Aging/genetics , Biomarkers/blood , C-Peptide/genetics , Child , Child, Preschool , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/physiopathology , Disease Progression , Fasting , Female , Genetic Predisposition to Disease , Humans , Infant , Interferon-gamma/genetics , Interleukin-10/genetics , MaleABSTRACT
AIMS: Systemic concentrations of adhesion molecules and chemokines are associated with increased risk of cardiovascular complications. We compared these factors between patients with Type 2 diabetes vs. Type 1 diabetes or latent autoimmune diabetes in adults. METHODS: Serum concentrations of adhesion molecules sE-selectin, sICAM-1 and sVCAM-1, and chemokines CCL2, CCL3 and CCL4 were measured in 61 patients with latent autoimmune diabetes in adults, 90 with Type 1 diabetes, 465 with Type 2 diabetes and in 41 control subjects, using multiple regression models to adjust for possible confounders. RESULTS: Patients with Type 2 diabetes exhibited greater concentrations of adhesion molecules (P < 0.02) than those with Type 1 diabetes, latent autoimmune diabetes in adults and control subjects. These differences persisted upon adjustments for age, sex, BMI, blood pressure and diabetes duration (P < 0.04). Higher BMI positively correlated with concentrations of adhesion molecules in all subjects (P < 0.0001). Concentrations of sE-selectin positively related to diastolic (ß = 0.31) and systolic (ß = 0.28) blood pressure in the adjusted model (P < 0.04). Concentrations of the chemokines, CCL2 and CCL4, did not differ between groups, while CCL3 was higher in patients with latent autoimmune diabetes in adults and Type 1 diabetes than in those with Type 2 diabetes and control subjects (P < 0.05). CONCLUSIONS: Systemic concentrations of adhesion molecules, but not chemokines, relate to cardiovascular risk factors, but remain higher after adjustments in Type 2 diabetes, suggesting a diabetes-type specific effect without difference between latent autoimmune diabetes in adults and Type 1 diabetes, despite their dissimilar phenotype.
Subject(s)
Cardiovascular Diseases/blood , Chemokines/blood , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 2/blood , Diabetic Angiopathies/blood , Vascular Cell Adhesion Molecule-1/blood , Adult , Aged , Blood Pressure , Body Mass Index , Cardiovascular Diseases/immunology , Cardiovascular Diseases/physiopathology , Cross-Sectional Studies , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/physiopathology , Diabetes Mellitus, Type 2/immunology , Diabetes Mellitus, Type 2/physiopathology , Diabetic Angiopathies/immunology , Diabetic Angiopathies/physiopathology , Female , Humans , Male , Middle Aged , PhenotypeABSTRACT
BACKGROUND: Islet-antigen-specific CD4+ T cells are known to promote auto-immune destruction in T1D. Measuring T-cell number and function provides an important biomarker. In response to this need, we evaluated responses to proinsulin and GAD epitopes in a multicentre study. METHODS: A tetramer-based assay was used in five participating centres to measure T-cell reactivities to DR0401-restricted epitopes. Three participating centres concurrently performed ELISPOT or immunoblot assays. Each centre used blind-coded, centrally distributed peptide and tetramer reagents. RESULTS: All participating centres detected responses to auto-antigens and the positive control antigen, and in some cases cloned the corresponding T cells. However, response rates varied among centres. In total, 74% of patients were positive for at least one islet epitope. The most commonly recognized epitope was GAD270-285. Only a minority of the patients tested by tetramer and ELISPOT were concordant for both assays. CONCLUSIONS: This study successfully detected GAD and proinsulin responses using centrally distributed blind-coded reagents. Centres with little previous experience using class II tetramer reagents implemented the assay. The variability in response rates observed for different centres suggests technical difficulties and/or heterogeneity within the local patient populations tested. Dual analysis by tetramer and ELISPOT or immunoblot assays was frequently discordant, suggesting that these assays detect distinct cell populations. Future efforts should investigate shared blood samples to evaluate assay reproducibility and longitudinal samples to identify changes in T-cell phenotype that correlate with changes in disease course.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Diabetes Mellitus, Type 1/immunology , Epitopes, T-Lymphocyte/immunology , HLA-DR Antigens/immunology , Histocompatibility Antigens Class II/immunology , Adult , Enzyme-Linked Immunospot Assay , Humans , Proinsulin/immunologyABSTRACT
BACKGROUND: Type 1 diabetes (T1D) is a cell-mediated autoimmune disease characterized by destruction of the pancreatic islet cells. The use of cryopreserved cells is preferable to the use of freshly isolated cells to monitor clinical trials to decrease assay and laboratory variability. METHODS: The T-Cell Workshop Committee of the Immunology of Diabetes Society compared two widely accepted T-cell freezing protocols (warm and cold) to freshly isolated peripheral blood mononuclear cells from patients with T1D and controls in terms of recovery, viability, cell subset composition, and performance in functional assays currently in use in T1D-related research. Nine laboratories participated in the study with four different functional assays included. RESULTS: The cold freezing method yielded higher recovery and viability compared with the warm freezing method. Irrespective of freezing protocol, B cells and CD8+ T cells were enriched, monocyte fraction decreased, and islet antigen-reactive responses were lower in frozen versus fresh cells. However, these results need to take in to account that the overall response to islet autoantigens was low in some assays. CONCLUSIONS: In the current study, none of the tested T-cell functional assays performed well using frozen samples. More research is required to identify a freezing method and a T-cell functional assay that will produce responses in patients with T1D comparable to responses using fresh peripheral blood mononuclear cells.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cryopreservation/methods , Diabetes Mellitus, Type 1/immunology , Islets of Langerhans/immunology , Cell Survival , Humans , Proinsulin/immunologyABSTRACT
AIMS/HYPOTHESIS: Systemic pro- and anti-inflammatory cytokines are associated with both type 1 and type 2 diabetes, while their role in latent autoimmune diabetes in adults (LADA) is unclear. Therefore, we compared cytokine concentrations in patients with LADA, type 1 or type 2 diabetes and healthy individuals to test the hypothesis that differences of cytokine concentrations between all groups are attributable to diabetes type and BMI. METHODS: The pro-inflammatory cytokines IL-6 and TNF-α, and the anti-inflammatory cytokines IL-1 receptor antagonist (IL-1RA) and IL-10 were measured in 90 participants with type 1 diabetes, 61 with LADA, 465 with type 2 diabetes and 41 control participants using multiple regression models adjusted for BMI, sex, age, blood pressure and diabetes duration. RESULTS: Patients with type 2 diabetes had higher concentrations of systemic IL-1RA, IL-6 and TNF-α cytokines than patients with either LADA or type 1 diabetes (p < 0.0001 for all differences). Cytokine concentrations in controls were lower than those in all diabetes types (p < 0.04). Increased BMI was positively associated with higher systemic cytokine concentrations in all diabetes types (p < 0.0001). Despite the association of cytokines with anthropometric data, differences between diabetes forms persisted also after adjusting analysis for the confounders BMI, age, sex, disease duration and blood pressure (p < 0.04). CONCLUSIONS/INTERPRETATION: Although body mass associates positively with pro- and anti-inflammatory cytokine levels, patients with type 2 diabetes have higher cytokine levels independent of the prevailing BMI. LADA and type 1 diabetes could not be distinguished by systemic cytokines.
Subject(s)
Cytokines/blood , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 2/blood , Adult , Aged , Female , Humans , Interleukin 1 Receptor Antagonist Protein/blood , Interleukin-10/blood , Interleukin-6/blood , Male , Middle Aged , Tumor Necrosis Factor-alpha/bloodABSTRACT
INTERVENTIONAL APPROACHES TO BETA CELL PRESERVATION: In a pilot study, initial attempts at primary prevention by preserving islet beta cells have been successful with highly hydrolyzed milk formula in children who are at high genetic risk of diabetes. Attempts at secondary prevention by intranasal application in children with a high-risk HLA genotype and positive islet autoantibodies have been disappointing. But in tertiary prevention anti-inflammatory, antigen-directed and T-cell targeted treatment has been partially successful in slowing down the destruction of beta cells. BIOLOGICAL BETA CELL SUBSTITUTION: Transplantation of a vascularised pancreas or islet cells results in disease regression and the prevention of secondary/tertiary complications of diabetes. A principal aim is the avoidance of frequent, severe hypoglycaemic episodes resulting from markedly reduced awareness of hypoglycaemia or its counter-regulation.
Subject(s)
Diabetes Mellitus, Type 1/therapy , Administration, Intranasal , Administration, Oral , Adolescent , Adult , Autoantibodies/blood , Cell Survival/physiology , Child , Child, Preschool , Diabetes Complications/immunology , Diabetes Complications/prevention & control , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/physiopathology , Genotype , Humans , Hydrolysis , Hypoglycemic Agents/administration & dosage , Infant , Infant Formula/administration & dosage , Insulin/administration & dosage , Insulin/blood , Insulin-Secreting Cells/immunology , Insulin-Secreting Cells/physiology , Insulin-Secreting Cells/transplantation , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Islets of Langerhans Transplantation , Milk Proteins , Multicenter Studies as Topic , Pancreas Transplantation , Pilot Projects , Receptors, Interleukin-1/antagonists & inhibitors , Risk Factors , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Young AdultABSTRACT
Autoimmune T cell responses directed against insulin-producing ß cells are central to the pathogenesis of type 1 diabetes (T1D). Detection of such responses is therefore critical to provide novel biomarkers for T1D 'immune staging' and to understand the mechanisms underlying the disease. While different T cell assays are being developed for these purposes, it is important to optimize and standardize methods for processing human blood samples for these assays. To this end, we review data relevant to critical parameters in peripheral blood mononuclear cell (PBMC) isolation, (cryo)preservation, distribution and usage for detecting antigen-specific T cell responses. Based on these data, we propose recommendations on processing blood samples for T cell assays and identify gaps in knowledge that need to be addressed. These recommendations may be relevant not only for the analysis of T cell responses in autoimmune disease, but also in cancer and infectious disease, particularly in the context of clinical trials.
Subject(s)
Blood Preservation/methods , Cell Separation/methods , Cryopreservation/methods , Diabetes Mellitus, Type 1/immunology , Insulin-Secreting Cells/immunology , Monocytes/immunology , T-Lymphocytes/immunology , Animals , Antigens, Surface/immunology , Autoimmune Diseases/immunology , Blood Preservation/standards , Cell Separation/standards , Clinical Trials as Topic , Cryopreservation/standards , Humans , Infections/immunology , Mice , Neoplasms/immunologyABSTRACT
Type 1 diabetes (T1D) is an autoimmune disease caused by the T cell-mediated destruction of the pancreatic insulin-producing beta cells. Currently there are no widely accepted and standardized assays available to analyse the function of autoreactive T cells involved in T1D. The development of such an assay would greatly aid efforts to understand the pathogenesis of T1D and is also urgently required to guide the development of antigen-based therapies intended to prevent, or cure, T1D. Here we describe some of the assays used currently to detect autoreactive T cells in human blood and review critically their strengths and weaknesses. The challenges and future prospects for the T cell assays are discussed.
Subject(s)
Autoantigens/immunology , Diabetes Mellitus, Type 1/immunology , Immunologic Tests/methods , Islets of Langerhans/immunology , T-Lymphocytes/immunology , Humans , Lymphocyte Activation , T-Lymphocytes/cytologyABSTRACT
The progression of type 1 diabetes after diagnosis is poorly understood. Our aim was to assess the relation of disease progression of juvenile-onset type 1 diabetes, determined by preserved beta cell function the first year after diagnosis, with systemic cytokine concentrations and number of autoantibodies. Juvenile patients (n = 227) had a meal-stimulated C-peptide test 1 and 6 months after diagnosis. On the basis of the C-peptide course for the duration of 1-6 months, four progression groups were defined: patients with persistently low beta cell function ('stable-low'), rapid progressers, slow progressers and remitters. Serum concentrations of adiponectin, interleukin (IL)-1ra, inducible protein 10 (IP-10), IL-6 and glutamic acid decarboxylase (GAD), IA-2A and islet-cell antibodies (ICA) were measured at 1, 6 and 12 months. We found that adiponectin concentrations at 1 month predicted disease progression at 6 months (P = 0·04). Patients with low adiponectin had a higher probability of becoming remitters than rapid progressers, odds ratio 3·1 (1·3-7·6). At 6 and 12 months, adiponectin differed significantly between the groups, with highest concentrations among stable-low and rapid progressers patients (P = 0·03 and P = 0·006). IL-1ra, IP-10 and IL-6 did not differ between the groups at any time-point. The number of autoantibodies differed significantly between the groups at 1 month (P = 0·04), where rapid progressers had the largest number. There was no difference between the groups in human leucocyte antigen-associated risk. We define progression patterns distinguishing patients diagnosed with low beta cell function from those with rapid decline, slow decline or actual increase in beta cell function, pointing to different mechanisms of disease progression. We find that adiponectin concentration at 1 month predicts, and at 6 and 12 months associates with, distinct progression patterns.
Subject(s)
Adiponectin/blood , Autoantibodies/blood , Chemokine CXCL10/blood , Diabetes Mellitus, Type 1/blood , Interleukin 1 Receptor Antagonist Protein/blood , Interleukin-6/blood , Adolescent , C-Peptide/blood , Child , Child, Preschool , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/immunology , Disease Progression , Female , Humans , Infant , Male , Predictive Value of Tests , Prospective Studies , Time FactorsABSTRACT
Type 1 diabetes is a chronic immune mediated disease leading to selective loss of insulin producing ss-cells. The incidence of type 1 diabetes has been rising. In past years quite a number of studies have been performed that aim to mitigate disease progression after diagnosis (tertiary prevention), in islet-antibody positive subjects at increased diabetes risk (secondary prevention) or in subjects genetically at risk but without autoantibodies (primary prevention). Studies of tertiary prevention are based on anti-inflammatory, T-cell directed, antigen-specific or stem cell approaches. Amelioration of disease course has been seen in a few of these trials, but no therapeutic regimen has so far been developed to cure type 1 diabetes after its clinical manifestation.
Subject(s)
Autoantibodies/blood , Diabetes Mellitus, Type 1/immunology , Immunologic Factors/therapeutic use , Immunomodulation , Insulin-Secreting Cells/immunology , HumansSubject(s)
Diabetes Mellitus, Type 1/therapy , Flavonoids/therapeutic use , Peptide Hydrolases/therapeutic use , Administration, Oral , Adolescent , Adult , Bromelains/therapeutic use , Child , Child, Preschool , Cytokines/blood , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/epidemiology , Double-Blind Method , Drug Therapy, Combination , Humans , Incidence , Placebos , Prospective Studies , Risk , Rutin/therapeutic use , Trypsin/therapeutic use , Young AdultSubject(s)
Autoantibodies/immunology , Interferon-beta , Multiple Sclerosis , Adult , Autoantigens/immunology , Female , Glutamate Decarboxylase/immunology , Humans , Interferon-beta/immunology , Interferon-beta/therapeutic use , Iodide Peroxidase/immunology , Middle Aged , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Peptide Fragments/immunology , Thyroglobulin/immunologyABSTRACT
Diseases gain identity from clinical phenotype as well as genetic and environmental aetiology. The definition of type 1 diabetes is clinically exclusive, comprising patients who are considered insulin dependent at diagnosis, whilst the definition of type 2 diabetes is inclusive, only excluding those who are initially insulin dependent. Ketosis-prone diabetes (KPD) and latent autoimmune diabetes in adults (LADA) are each exclusive forms of diabetes which are, at least initially, clinically distinct from type 2 diabetes and type 1 diabetes, and each have a different natural history from these major types of diabetes.KPD can be diagnosed unequivocally as diabetes presenting with the categorical clinical feature, ketoacidosis. In contrast, LADA can be diagnosed by the co-occurrence of three traits, not one of which is categorical or exclusive to the condition: adult-onset non-insulin-requiring diabetes, an islet autoantibody such as glutamic acid decarboxylase autoantibodies (GADA) or cytoplasmic islet cell autoantibodies (ICA), and no need for insulin treatment for several months post-diagnosis. But while some would split diabetes into distinct subtypes, there is a strong case that these subtypes form a continuum of varying severity of immune and metabolic dysfunction modified by genetic and non-genetic factors. This article discusses the nature of disease classification in general, and KPD and LADA in particular, emphasizing the potential value and pitfalls in classifying diabetes and suggesting a need for more research in this area.
Subject(s)
Autoimmune Diseases/classification , Diabetes Mellitus, Type 1/classification , Diabetes Mellitus, Type 2/classification , Adult , Autoantibodies/analysis , Autoimmune Diseases/genetics , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 2/genetics , Diabetic Ketoacidosis/classification , Diabetic Ketoacidosis/genetics , Genetic Predisposition to Disease , Glutamate Decarboxylase/immunology , Humans , Insulin/metabolism , Insulin Resistance/genetics , Insulin Secretion , Islets of Langerhans/immunologyABSTRACT
Th1 related chemokines CCL3 and CCL5 and Th2 related CCL4 as ligands of the receptor CCR5 contribute to disease development in animal models of type 1 diabetes. In humans, no data are available addressing the role of these chemokines regarding disease progression and remission. We investigated longitudinally circulating concentrations of CCR5 ligands of 256 newly diagnosed patients with type 1 diabetes. CCR5 ligands were differentially associated with beta-cell function and clinical remission. CCL5 was decreased in remitters and positively associated with HbA1c suggestive of a Th1 associated progression of the disease. Likewise, CCL3 was negatively related to C-peptide and positively associated with the beta-cell stress marker proinsulin but increased in remitters. CCL4 associated with decreased beta-cell stress shown by negative association with proinsulin. Blockage of chemokines or antagonism of CCR5 by therapeutic agents such as maraviroc may provide a new therapeutic target to ameliorate disease progression in type 1 diabetes.