Clinical Onset Of Diabetes Research Articles

Risk for progression to type 1 diabetes in first-degree relatives under 50 years of age.

The detection of pancreatic autoantibodies in first-degree relatives of patients with type 1 diabetes (T1D) is considered a risk factor for disease. Novel available immunotherapies to delay T1D progression highlight the importance of identifying individuals at risk who might benefit from emerging treatments. The objective was to assess the autoimmunity in first-degree relatives of patients with T1D, estimate the time from autoimmunity detection to the onset of clinical diabetes, and identify the associated risk factors. Retrospective multicenter study of 3,015 first-degree relatives of patients with T1D recruited between 1992 and 2018. Pancreatic autoantibodies (IAA, GADA, IA2A, and ZnT8A) were determined by radioimmunoassay, starting the analyses at diagnosis of the proband. All those with positive autoimmunity and normal fasting blood glucose without clinical symptoms of diabetes were followed up in the study. The progression rate to T1D was assessed according to sex, relationship with the proband, age at autoimmunity detection, type/number of autoantibodies, and HLA-DRB1 genotype. Cox proportional-hazard models and Kaplan-Meier survival plots were used for statistical analyses. Among the relatives, 21 progenitors [43.7 years (IQR: 38.1-47.7)] and 27 siblings [7.6 years (IQR: 5.8-16.1)] had positive autoantibodies. Of these, 54.2% (95% CI: 39.2%-68.6%) developed T1D (age at autoimmunity detection 11 months to 39 years) in a median of 5 years (IQR: 3.6-8.7; ranged from 0.9 to 22.6 years). Risk factors associated with faster progression to T1D were multiple autoimmunity and <20 years at autoimmunity detection. Younger relatives (<20 years) with multiple autoantibodies had a 5-year cumulative risk of developing diabetes of 52.9% (95% CI: 22.1%-71.6%) and a 20-year risk of 91.2% (95% CI: 50.5%-98.4%). The 20-year risk decreased to 59.9% (95% CI: 21.9%-79.5%) if only one risk factor was met and to 35.7% (95% CI: 0.0%-66.2%) if the relative was older than 20 years with one autoantibody. In first-degree relatives with autoimmunity, the time to progression to T1D is faster in children and adolescents with multiple autoantibodies. Young adults are also at risk, which supports their consideration in screening strategies for people at risk of developing T1D.

Changes in foveal avascular zone parameters in individuals with prediabetes compared to normoglycemic controls: a systematic review and meta-analysis.

To investigate changes in foveal avascular zone parameters in individuals with prediabetes compared to normoglycemic controls. PUBMED, Scopus and Cochrane Library were searched for published articles comparing the foveal avascular zone between prediabetic individuals and normoglycemic controls as assessed by optical coherence tomography angiography (OCTA). Standardised Mean Difference (SMD) with 95% confidence interval (CI) was computed for the comparison. A total of seven studies were included in our analysis, 6 provided data for the superficial capillary plexus from 345 eyes of individuals with prediabetes and 347 eyes of controls and 4 provided data on the deep capillary plexus from 285 eyes from individuals with prediabetes and 325 eyes of controls. Foveal avascular zone (FAZ) area in the superficial capillary plexus was enlarged in individuals with prediabetes compared to normoglycemiccontrols (SMD = 0.23, 95% CI = 0.03-0.44, p = 0.03, I2 = 27%, 6 studies). There was no statistically significant change in the deep capillary plexus FAZ area between the two groups (SMD = 1.14, 95% CI = -0.06-2.34, p = 0.06, I2 = 97%, 4 studies). FAZ area in the superficial capillary plexus was larger in individuals diagnosed with prediabetes compared to normoglycemic controls. This finding suggests that prediabetes could induce retinal microvascular changes before the onset of clinical diabetes. More original studies are needed to validate the results of the current meta-analysis.

THU353 Late Onset Of Immune Checkpoint Inhibitor-Related Diabetes After 3 Years

Abstract Disclosure: S. Avula: None. A. Ahmed: None. M. Salim: None. Z.J. Anderson: None. A. Kumar: None. A. Estrada: None. Background: Immune checkpoint inhibitor-induced diabetes mellitus (ICI-DM) is characterized by acute onset of dramatic hyperglycaemia with severe insulin deficiency following exposure to PD-1/PD-L1 inhibitors. The frequency of type 1 diabetes related to ICIs is estimated to be ∼3.5%. Endogenous insulin secretion is depleted within a few weeks of the clinical onset of diabetes. Moreover, the positive rate for islet-related autoantibodies varies from 5% to 50%. Case: 51-year-old male with a PMH of stage 4 adenocarcinoma of the lung with metastasis to brain, bone, and kidneys was sent to the ED for a POC BG above 700 mg/dl. He was diagnosed with stage 4 lung adenocarcinoma three years prior to the current presentation. He received stereotactic radiotherapy for the brain metastases, Carboplatin/pemetrexed/pembrolizumab x4 cycles, then continued maintenance therapy of pemetrexed/pembrolizumab with the last dose given 3 weeks prior. He had recent evidence of progression, so chemotherapy adjustment was planned, and he started dexamethasone 4mg on the day prior to presentation. Upon ED presentation, he reported new onset polyuria and polydipsia for 1 week accompanied by 10% weight loss over the last 3 months. His vitals were stable. Physical examination was unremarkable. Serum glucose level was found to be 726 mg/dl, Bicarbonate level 28 mEq/L (22-30), creatinine 1.99 mg/dl (baseline 1.2), venous blood PH was 7.29, Bicarbonate 24 mEq/L (24-28), anion gap 15 mEq/L (8-16), B-hydroxybutyrate 2.91 mmol/L (0.02-0.27), sodium 127 mEq/L(135-148) and HbA1c 6.3%. He received normal saline boluses and NPH insulin 15 units SQ, after which his repeat BG level was 426 mg/dl. Given prediabetic Hba1c with recent dexamethasone therapy he was thought to have steroid-induced hyperglycaemia. He was discharged on NPH 15 units daily with Novolog sliding scale. Upon clinic follow-up 1 week later, his BGs did not improve significantly despite stopping steroids. His C-peptide level was low at 0.22 ng/ml (1.10-4.40) with BG 443mg/dl, and GAD -65 antibodies were negative. He continued to have hyperglycaemia while on NPH /Novolog regimen, thus he was switched to Lantus and Novolog regimen with better glycaemic control. He continues to have significant insulin requirements 3 months later. Conclusion: Although the mean interval between the first ICI administration and T1DM development was found to be 201 ± 187 days, the development of type 1 DM may occur with longer intervals from initiating the ICI therapy. In our case, the patient developed new-onset diabetes with low C-peptide after 1,095 days from receiving the first dose of pembrolizumab. On the previous case reports, the presence of GAD-65 antibodies is typically associated with shortened intervals between receiving the ICI therapy and the development of DM. Presentation: Thursday, June 15, 2023

Association of prediabetes with reduced brain volume in a general elderly Japanese population.

Diabetes frequently results in cognitive impairment, but it is less clear if brain health is adversely affected during the prediabetic stage. Our aim is to identify possible changes in brain volume as measured by magnetic resonance imaging (MRI) in a large elderly population stratified according to level of "dysglycemia." This is a cross-sectional study of 2144 participants (median age 69years, 60.9% female) who underwent 3-T brain MRI. Participants were divided into 4 dysglycemia groups based on HbA1c levels (%): normal glucose metabolism (NGM) (< 5.7%), prediabetes (5.7 to < 6.5%), undiagnosed diabetes (6.5% or higher), and known diabetes (defined by self-report). Of the 2144 participants, 982 had NGM, 845 prediabetes, 61 undiagnosed diabetes, and 256 known diabetes. After adjustment for age, sex, education, body weight, cognitive status, smoking, drinking, and disease history, total gray matter volume was significantly lower among participants with prediabetes (0.41% lower, standardized β = - 0.0021 [95% CI - 0.0039, - 0.00039], p = 0.016), undiagnosed diabetes (1.4% lower, standardized β = - 0.0069 [95% CI - 0.012, - 0.002], p = 0.005), and known diabetes (1.1% lower, standardized β = - 0.0055 [95% CI - 0.0081, - 0.0029], p < 0.001) compared to the NGM group. After adjustment, total white matter volume and hippocampal volume did not differ significantly between the NGM group and either the prediabetes group or the diabetes group. Sustained hyperglycemia may have deleterious effects on gray matter integrity even prior to the onset of clinical diabetes. • Sustained hyperglycemia has deleterious effects on gray matter integrity even prior to the onset of clinical diabetes.

109-OR: T-Cell Responses to Hybrid Insulin Peptides Precede Type 1 Diabetes Development

Type 1 diabetes (T1D) results from the T cell-mediated destruction of insulin-producing beta-cells within pancreatic islets. T cell responses to post-translationally modified hybrid insulin peptides (HIPs) have been implicated in T1D pathogenesis, and we hypothesized that CD4 T cell responses to HIPs precede clinical diabetes onset. Therefore, we measured longitudinal T cell responses to native and hybrid insulin peptides in a cohort of genetically at-risk individuals from the Diabetes AutoImmunity Study in the Young (DAISY). Using cytokine ELISPOT assays, both pro-inflammatory (IFN-γ) and anti-inflammatory (IL-10) cytokine responses to HIPs were more robust than to native peptides. Three of the 38 autoantibody negative individuals (med. age 18.7 yrs) developed islet autoimmunity during 2 years of follow-up, and the C-peptide-islet amyloid polypeptide-2 (C:IAPP-2), C-peptide-neuropeptide Y (C:NPY), and C-peptide-insulin A chain (C:A chain) HIPs induced more frequent pro-inflammatory T cell responses compared to those that did not develop autoantibodies. Five of the 25 autoantibody positive individuals (med. age 18.7 yrs) progressed to clinical T1D during the study, and the C:IAPP-2 HIP more frequently induced a pro-inflammatory response compared to those that did not progress (p=0.037). Additionally, length of time from autoantibody seroconversion correlated with proinflammatory T cell responses to the insulin B:9-23 (B22E) HIP (p=0.007) and the native B:9-23 peptide (p=0.022). T cell responses to the B22E HIP also strongly correlated with insulin autoantibody levels (p=0.0001). Furthermore, responses to the C:IAPP-2 HIP correlated with worsening measurements of blood glucose (A1c %, p=0.046; glucose area under the curve, p=0.054). Monitoring T cell responses to post-translationally modified antigens prior to T1D onset holds promise for determining which individuals are likely to progress to clinical disease and may benefit from immune intervention to prevent T1D onset. Disclosure A. M. Mitchell: None. M. Rewers: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; RTI, Research Support; Self; Janssen Research &amp; Development, LLC, JDRF. A. W. Michels: Stock/Shareholder; Self; IM Therapeutics. A. Alkanani: None. K. Mcdaniel: None. L. Pyle: None. K. Waugh: None. A. Steck: None. M. Nakayama: None. L. Yu: None. P. Gottlieb: Advisory Panel; Self; Janssen Research &amp; Development, LLC, Tolerion, Inc., Viacyte, Inc., Other Relationship; Self; ImmunoMolecular Therapeutics, Inc., Research Support; Self; Caladrius Biosciences, Inc., Immune Tolerance Network, Mercia Pharma Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Precigen, Inc., Tolerion, Inc. Funding National Institutes of Health (DK108868, DK110845, DK032083, DK032493, DK116073); JDRF (3-PDF-2020-943-A-N); Children’s Diabetes Foundation; Colorado Clinical and Translational Science Institute (TR002535)

Type 1 diabetes in Africa: an immunogenetic study in the Amhara of North-West Ethiopia

Aims/hypothesisWe aimed to characterise the immunogenic background of insulin-dependent diabetes in a resource-poor rural African community. The study was initiated because reports of low autoantibody prevalence and phenotypic differences from European-origin cases with type 1 diabetes have raised doubts as to the role of autoimmunity in this and similar populations.MethodsA study of consecutive, unselected cases of recently diagnosed, insulin-dependent diabetes (n = 236, ≤35 years) and control participants (n = 200) was carried out in the ethnic Amhara of rural North-West Ethiopia. We assessed their demographic and socioeconomic characteristics, and measured non-fasting C-peptide, diabetes-associated autoantibodies and HLA-DRB1 alleles. Leveraging genome-wide genotyping, we performed both a principal component analysis and, given the relatively modest sample size, a provisional genome-wide association study. Type 1 diabetes genetic risk scores were calculated to compare their genetic background with known European type 1 diabetes determinants.ResultsPatients presented with stunted growth and low BMI, and were insulin sensitive; only 15.3% had diabetes onset at ≤15 years. C-peptide levels were low but not absent. With clinical diabetes onset at ≤15, 16–25 and 26–35 years, 86.1%, 59.7% and 50.0% were autoantibody positive, respectively. Most had autoantibodies to GAD (GADA) as a single antibody; the prevalence of positivity for autoantibodies to IA-2 (IA-2A) and ZnT8 (ZnT8A) was low in all age groups. Principal component analysis showed that the Amhara genomes were distinct from modern European and other African genomes. HLA-DRB1*03:01 (p = 0.0014) and HLA-DRB1*04 (p = 0.0001) were positively associated with this form of diabetes, while HLA-DRB1*15 was protective (p < 0.0001). The mean type 1 diabetes genetic risk score (derived from European data) was higher in patients than control participants (p = 1.60 × 10−7). Interestingly, despite the modest sample size, autoantibody-positive patients revealed evidence of association with SNPs in the well-characterised MHC region, already known to explain half of type 1 diabetes heritability in Europeans.Conclusions/interpretationThe majority of patients with insulin-dependent diabetes in rural North-West Ethiopia have the immunogenetic characteristics of autoimmune type 1 diabetes. Phenotypic differences between type 1 diabetes in rural North-West Ethiopia and the industrialised world remain unexplained.

Post-translational modifications contribute to neoepitopes in Type-1 diabetes: Challenges for inducing antigen-specific tolerance

Type-1 Diabetes (T1D) is the major autoimmune disease affecting the juvenile population in which insulin-producing pancreatic β-cells are destroyed by self-reactive T-cells and B-cells. Emerging studies have identified the presence of autoantibodies and altered T-cell reactivity against several autoantigens in individuals who are at risk of developing T1D even before the clinical onset of diabetes. Whilst these findings could lead to the development of predictive biomarkers for early diagnosis, growing evidence on the generation of neoepitopes, epitope spreading and diverse antigen repertoire in T1D poses a major challenge for developing approaches to induce antigen-specific tolerance. Mechanisms of neoepitope generation include post-translational modifications of existing epitopes, aberrant translational products, peptide fusion, and differences in MHC binding registers. Here, we focus our discussion on how post-translational modifications can give rise to immunogenic neoepitopes in T1D and present our perspective on how it could affect the development of therapeutic approaches to induce antigen-specific tolerance.

114-OR: T1DM in the Chronically Undernourished: Rural Ethiopia

T1DM results from the interaction of genetic and environmental factors; the classical phenotype has been based largely on people of European background. However, Africa is a continent of enormous genetic diversity and extreme environmental conditions; do these differences have an impact on the T1DM phenotype? A consecutive series of recently diagnosed insulin-dependent diabetic subjects (n=236, ≤35 years) and controls (n=200), were recruited from the ethnic Amhara of rural NW Ethiopia. We assessed their demographic and socio-economic characteristics, measured non-fasting C-peptide, diabetes-associated autoantibodies, and HLA-DRB1 alleles. With genome-wide genotyping we performed principal component analysis (PCA) and a genome-wide association study (GWAS), and calculated a T1DM genetic risk scores (GRS) to compare their genetic background with known European T1DM determinants. Patients presented with low BMI, stunted growth, and were insulin sensitive; only 15.3% had diabetes onset ≤15 years. C-peptide levels were low but not absent (P=0.03). With clinical diabetes onset at ≤15, 16-25, and 26-35 years, 86.1%, 59.7% and 50.0% were autoantibody positive, respectively. Most had GADA as a single antibody; the prevalence of IA-2A and ZnT8A was low in all age groups. PCA showed that the Amhara genomes falls between those of ancestral European and ancestral African genomes. HLA-DRB1*03:01 and HLA-DRB1*04 were positively associated with diabetes while HLA-DRB1*15 was protective (P&amp;lt;0.0008 for each). The mean T1DM GRS (derived from European data) was higher in patients than controls (P=1.50x10-6). Autoantibody positive patients showed suggestive GWAS significance (P&amp;lt;5x10-6) with SNPs in the MHC region known to explain half of the T1DM heritability in Europeans. Thus, insulin-dependent diabetes in rural Ethiopia does have the immunogenetic characteristics of T1DM. The phenotypic differences between T1DM in rural Ethiopia and the industrialized world could be due, at least in part, to chronic undernourishment. Disclosure E.R. Trimble: None. S.A. Balcha: None. A.G. Demisse: None. D.L. Cousminer: None. R. Mishra: Employee; Self; GlaxoSmithKline plc. B.F. Voight: None. K. Lorenz: None. T. Vartak: None. S.T. Jerram: None. K.M. Hodge: None. S. Schwartz: Advisory Panel; Self; Intarcia Therapeutics, Janssen Pharmaceuticals, Inc. Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Lilly Diabetes, Merck &amp; Co., Inc., Salix Pharmaceuticals. A. Holmes: None. A. Gamper: Stock/Shareholder; Self; GlaxoSmithKline plc., Unilever. H.F. Wilson: None. A.J. Williams: None. R.D. Leslie: None. S.F. Grant: None. D.I.W. Phillips: None. Funding American Diabetes Association (1-17-PDF-077 to D.L.C.); Association of Physicians of Great Britain and Ireland; National Institutes of Health (1K99HD099330-01, R01DK085212); Diabetes UK

Multifunctional in vivo imaging of pancreatic islets during diabetes development

Pancreatic islet dysfunction leading to insufficient glucose-stimulated insulin secretion triggers the clinical onset of diabetes. How islet dysfunction develops is not well understood at the cellular level, partly owing to the lack of approaches to study single islets longitudinally in vivo Here, we present a noninvasive, high-resolution system to quantitatively image real-time glucose metabolism from single islets in vivo, currently not available with any other method. In addition, this multifunctional system simultaneously reports islet function, proliferation, vasculature and macrophage infiltration in vivo from the same set of images. Applying our method to a longitudinal high-fat diet study revealed changes in islet function as well as alternations in islet microenvironment. More importantly, this label-free system enabled us to image real-time glucose metabolism directly from single human islets in vivo for the first time, opening the door to noninvasive longitudinal in vivo studies of healthy and diabetic human islets.

Multifunctional in vivo imaging of pancreatic islets during diabetes development.

Pancreatic islet dysfunction leading to insufficient glucose-stimulated insulin secretion triggers the clinical onset of diabetes. How islet dysfunction develops is not well understood at the cellular level, partly owing to the lack of approaches to study single islets longitudinally in vivo Here, we present a noninvasive, high-resolution system to quantitatively image real-time glucose metabolism from single islets in vivo, currently not available with any other method. In addition, this multifunctional system simultaneously reports islet function, proliferation, vasculature and macrophage infiltration in vivo from the same set of images. Applying our method to a longitudinal high-fat diet study revealed changes in islet function as well as alternations in islet microenvironment. More importantly, this label-free system enabled us to image real-time glucose metabolism directly from single human islets in vivo for the first time, opening the door to noninvasive longitudinal in vivo studies of healthy and diabetic human islets.

Islet Autoantibody Detection by Electrochemiluminescence (ECL) Assay.

Two fundamental aspects for precisely predicting the risk of developing type 1 diabetes by islet autoantibodies are assay sensitivity and disease specificity. We have recently developed electrochemiluminescent (ECL) insulin autoantibody (IAA) and GAD65 autoantibody (GADA) assays. ECL assays are sensitive, able to identify the initiation of islet autoimmunity earlier in life among high-risk young children before clinical onset of diabetes and are more disease specific because they are able to discriminate high-affinity, high-risk diabetes specific islet autoantibodies from low-affinity, low-risk autoantibodies.

Circulating microRNAs in Diabetes Progression: Discovery, Validation, and Research Translation.

Diabetes, in all of its forms, is a disease state that demonstrates wide ranging pathological effects throughout the body. Until now, the only method of diagnosing and monitoring the progression of diabetes was through the measurement of blood glucose. Unfortunately, beta cell dysfunction initiates well before the clinical onset of diabetes, and so the development of an effective biomarker signature is of paramount importance to predict and monitor the progression of this disease. MicroRNAs (miRNAs/miRs) are small (18-22 nucleotide) noncoding (nc)RNAs that post-transcriptionally regulate endogenous gene expression by targeted inhibition or degradation of messenger (m)RNA. Recently, miRNAs have shown great promise as biomarkers as some exhibit differential expression in multiple disease states, including type 1 and type 2 diabetes (T1D/T2D). Furthermore, miRNAs are quite stable in circulation, resistant to freeze-thaw and pH-mediated degradation, and are relatively easy to detect using quantitative (q)PCR. Here, we discuss microRNAs that may form a diabetes biomarker signature. To identify these transcripts we outline miRNAs that play a central role in pancreas development and diabetes, as well as previously identified miRNAs with differential expression in individuals with T1D and T2D. Validation and refinement of a miRNA biomarker signature for diabetes would allow identification and intervention of individuals at risk of this disease, as well as stratification and monitoring of patients with established diabetes.

Long-term retention of non-funcionalized carbon nanotubes in nod mice and its influence on the evolution of autoimmune diabetes

Results Histological data confirmed that the non-functionalized MWCTN had been absorbed and kept retained into the phagocytes of the peri-pancreatic lymph nodes, spleen and liver, causing a granulomatous inflammatory response. Even though no differences were found in the frequency of the development of clinical diabetes or in the morphological characteristics of the pancreatic insulitis, female NOD mice treated with MWCTN presented a significant higher fluctuation of the average glycaemia compared to the control group during the entire study (p<0.0001; Wilcoxon), with a tendency to an abbreviation of clinical diabetes onset. Analyses of the pro-inflammatory and the antiinflammatory responses in the peri-pancreatic lymph nodes revealed the induction of a Th1 response in the treated animals, between 8 and 14 after MWCTN exposition, with an increase of the expression of IFNg and a reduced expression of TGFb. This profile remained until the end of the study, 24 weeks after MWCTN injection.

Prevention or early cure of type 1 diabetes by intranasal administration of gliadin in NOD mice.

Induction of long-term tolerance to β-cell autoantigens has been investigated both in animal models and in human type 1 diabetes (T1D) in order to prevent the disease. As regards external compounds, the dietary plant protein fraction has been associated with high penetrance of the disease, whereas gluten-free diets prevent T1D in animal models. Herewith we investigated whether intranasal (i.n.) administration of gliadin or gluten may arrest the diabetogenic process. I.n. administration of gliadin to 4-week-old NOD mice significantly reduced the diabetes incidence. Similarly, the insulitis was lowered. Intranasal gliadin also rescued a fraction of prediabetic 13-week-old NOD mice from progressing to clinical onset of diabetes compared to OVA-treated controls. Vaccination with i.n. gliadin led to an induction of CD4+Foxp3+ T cells and even more significant induction of γδ T cells in mucosal, but not in non-mucosal lymphoid compartments. This prevention strategy was characterized by an increased proportion of IL-10 and a decreased proportion of IL-2, IL-4 and IFN-γ-positive CD4+Foxp3+ T cells, and IFN-γ-positive γδ T cells, preferentially in mucosal lymphoid organs. In conclusion, i.n. vaccination with gliadin, an environmental antigen with possible etiological influence in T1D, may represent a novel, safer strategy for prevention or even early cure of T1D.

Insulin Micro-secretionin Patients with Long Duration Type 1 Diabetes: Implications of Interferon-γ?

Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease characterized by the destruction of pancreatic β-cells leading to absolute insulin deficiency [1]. Exogenous insulin represents the core of therapy for T1D that is fatal unless treated[2]. Several years of progressive autoimmune β-cells damage generally precede the clinical onset of diabetes [2]. Moreover, it has been found that the decline in insulin production in patients with T1D is variable [2]. The majority of patients with long-duration T1D has been demonstrated to be insulin microsecretors and to have residual functioning β-cells [2,3]. On this regard, it has been speculated that the small still functional β-cells could have escaped immune attack or have undergone a regeneration process known to be so far extremely limited in human adult [2,4]. Multiple immunological mechanisms have been proposed to contribute to β-cell destruction[5]. Although cytotoxic T lymphocytes directly attack β-cell in T1D, cytokines produced by immune system cells infiltrating pancreatic islets are candidate mediators of islet β-cell dysfunction and death [2-7]. Apoptosis represents the main form of cytokine-induced pancreatic β-cell death [5]. Different proinflammatory cytokines, such as Tumor necrosis factor-α (TNF-α), Interleukin-1 (IL-1) and Interferon-γ (IFN-γ), have been involved in T1D pathogenesis [1]. Among these cytokines, IFN-γ has been conventionally described as responsible for driving pancreatic islets autoimmune damage, leading to β-cell apoptosis and the initial destruction of pancreatic β-cells in the onset of diabetes [1,2,4-8]. IFNγ has been reported to influence immune and autoimmune responses by supporting the homing of diabetogenic activated T cells [8]. The development of diabetes has been linked to the accumulation of IFN-γ producing T-cells in the islets [6]. Furthermore, an association between IFN-γ polymorphism and T1D onset has been corroborated [7]. On the contrary, it has been provided evidence that IFN-γ receptor deficiency prevents diabetes [9]. What is more, reduced diabetes incidence was observed by neutralizing endogenous IFN-γ with anti IFN-γ antibodies [9,10]. Interestingly, IFN-γ has also been shown to play a major role in β-cell dysfunction associated with chronic pancreatitis [11]. The different biological effects of IFN-γ have been connected with its action in regulating gene transcription [5,7,12].

The environment and the origins of islet autoimmunity and Type 1 diabetes

Type1 diabetes involves the specific destruction of the pancreatic islet β-cells, eventually resulting in a complete dependency of exogenous insulin. The clinical onset of diabetes is preceded by the appearance of autoantibodies against β-cell antigens. The human leukocyte antigen (HLA) region is the single most important genetic determinant of Type1 diabetes susceptibility, yet variability in the HLA region has been estimated to explain only approximately 60% of the genetic influence of the disease. Over 50 identified non-HLA genetic polymorphisms support the notion that genetics alone cannot explain Type1 diabetes. Several lines of evidence indicate that environmental triggers may be integral in inducing the onset of islet autoimmunity in genetically susceptible individuals. The association between environmental factors and the clinical onset is complicated by observation that the rate of progression to clinical onset may be affected by environmental determinants. Hence, the environment may be aetiological as well as pathogenic. Putative inductive mechanisms include viral, microbial, diet-related, anthropometric and psychosocial factors. Ongoing observational cohort studies such as The Environmental Determinants of Diabetes in the Young (TEDDY) study aim to ascertain environmental determinants that may trigger islet autoimmunity and either speed up or slow down the progression to clinical onset in subjects with persistent islet autoimmunity.

Pancreatic islet autoimmunity

Type 1 diabetes (T1D) represents 10 to 15% of all forms of diabetes. Its incidence shows a consistent rise in all countries under survey. Evidence for autoimmunity in human T1D relies on the detection of insulitis, of islet cell antibodies, of activated β-cell-specific T lymphocytes and on the association of T1D with a restricted set of class II major histocompatibility complex (MHC) alleles. However, mechanisms that initiate the failure of immune tolerance to β-cell autoantigens remain elusive in common forms of T1D. T1D commonly develop as a multifactorial disease in which environmental factors concur with a highly multigenic background. The disease is driven by the activation of T-lymphocytes against pancreatic β-cells. Several years elapse between initial triggering of the autoimmune response to β cells, as evidenced by the appearance or islet cell autoantibodies, and the onset of clinical diabetes, defining a prediabetes stage. Active mechanisms hold back autoreactive effector T-cells in prediabetes, in particular a subset of CD4+ T-cells (T(reg)) and other regulatory T-cells, such as invariant NKT cells. There is evidence in experimental models that systemic or local infections can trigger autoimmune reactions to β-cells. However, epidemiological observations that have accumulated over years have failed to identify undisputable environmental factors that trigger T1D. Moreover, multiple environmental factors may intervene in the disease evolution and protective as weel as triggering environmental factors may be involved. Available models also indicate that local signals within the islets are required for full-blown diabetes to develop. Many autoantigens that are expressed by β-cells but also by the other endocrine islet cells and by neurons are recognized by lymphocytes along the development of T1D. The immune image of β-cells is that of native components of the β-cell membrane, as seen by B-lymphocytes, and of fragments of intracellular β-cell proteins in the form of peptides loaded onto class I MHC molecules on the β-cell surface and class I and class II molecules onto professional antigen presenting cells. Given the key role of T lymphocytes in T1D, the cartography of autoantigen-derived peptides that are presented to class I-restricted CD8(+) T-cells and class II-restricted CD4(+) T-cells is of outmost importance and is a necessary step in the development of diagnostic T-cell assays and of immunotherapy of T1D.

Long-term remission of diabetes in NOD mice is induced by nondepleting anti-CD4 and anti-CD8 antibodies.

Residual β-cells found at the time of clinical onset of type 1 diabetes are sufficient to control hyperglycemia if rescued from ongoing autoimmune destruction. The challenge, however, is to develop an immunotherapy that not only selectively suppresses the diabetogenic response and efficiently reverses diabetes, but also establishes long-term β-cell–specific tolerance to maintain remission. In the current study, we show that a short course of nondepleting antibodies (Abs) specific for the CD4 and CD8 coreceptors rapidly reversed clinical disease in recent-onset diabetic NOD mice. Once established, remission was maintained indefinitely and immunity to foreign antigens unimpaired. Induction of remission involved selective T-cell purging of the pancreas and draining pancreatic lymph nodes and upregulation of transforming growth factor (TGF)-β1 by pancreas-resident antigen-presenting cells. Neutralization of TGF-β blocked the induction of remission. In contrast, maintenance of remission was associated with tissue-specific immunoregulatory T cells. These findings demonstrate that the use of nondepleting Ab specific for CD4 and CD8 is a robust approach to establish long-term β-cell–specific T-cell tolerance at the onset of clinical diabetes.

Prognostic accuracy of immunologic and metabolic markers for type 1 diabetes in a high-risk population: receiver operating characteristic analysis.

OBJECTIVETo establish and compare the prognostic accuracy of immunologic and metabolic markers in predicting onset of type 1 diabetes in those with high risk in a prospective study.RESEARCH DESIGN AND METHODSA total of 339 subjects from the Diabetes Prevention Trial–Type 1 (DPT-1) parenteral study, who were islet cell antibody (ICA)-positive, with low first-phase insulin response (FPIR) and/or abnormal glucose tolerance at baseline, were followed until clinical diabetes onset or study end (5-year follow-up). The prognostic performance of biomarkers was estimated using receiver operating characteristic (ROC) curve analysis and compared with nonparametric testing of ROC curve areas. Pearson correlation was used to assess the relationship between the markers.RESULTSIndividually, insulin autoantibody titer, ICA512A titer, peak C-peptide, 2-h glucose, FPIR, and FPIR/homeostasis model assessment of insulin resistance provided modest but significant prognostic values for 5-year risk with a similar level of area under ROC curve ranging between 0.61 and 0.67. The combination of 2-h glucose, peak C-peptide, and area under the curve C-peptide significantly improved the prognostic accuracy compared with any solitary index (P < 0.05) with an area under ROC curve of 0.76 (95% CI 0.70–0.81). The addition of antibody titers and/or intravenous glucose tolerance test (IVGTT) markers did not increase the prognostic accuracy further (P = 0.46 and P = 0.66, respectively).CONCLUSIONSThe combination of metabolic markers derived from the oral glucose tolerance test improved accuracy in predicting progression to type 1 diabetes in a population with ICA positivity and abnormal metabolism. The results indicate that the autoimmune activity may not alter the risk of type 1 diabetes after metabolic function has deteriorated. Future intervention trials may consider eliminating IVGTT measurements as an effective cost-reduction strategy for prognostic purposes.

Worth the wait: type 1 diabetes prospective birth cohort studies enter adolescence

Autoantibodies to islet cell proteins currently provide the only reliable indication that the process leading to type 1 diabetes has started. The period from the first detection of islet autoantibodies to clinical onset of diabetes can last months or years. Longitudinal birth cohort family studies give crucial information concerning the natural history of islet autoimmunity and have already shown that islet autoantibodies, which precede diabetes development, often appear in early infancy. In this issue of Diabetologia, Ziegler et al (DOI: 10.1007/s00125-012-2472-x ) and Parikka et al (DOI: 10.1007/s00125-012-2523-3 ) report findings from their birth cohort studies after numerous children have entered adolescence, allowing a more complete picture of islet autoimmunity in childhood to be revealed. Both groups are in accord that, between 6months and 3years of age, there is an explosion of islet autoimmunity in susceptible children and that the great majority (approximately 80%) of genetically at-risk children who present with diabetes before adolescence develop islet autoimmunity at this young age. These findings emphasise the importance of early life events in disease pathogenesis and have major implications for efforts aimed at preventing type 1 diabetes.