Children with recurring acute or chronic pancreatitis are at risk for pancreatitis related diabetes mellitus (DM). Pancreatic endocrine and exocrine concerns are managed by different subspecialists. ...Our center has a unique pediatric pancreatitis multidisciplinary clinic (MDC) with pediatric gastroenterology, endocrinology, pain, and nutrition experts. We obtain point-of-care (POC) HbA1c during clinic check-in for immediate DM screening. Our study describes the utility of POC HbA1c testing in our MDC. We analyzed a retrospective chart review of MDC patients from 2018-2023 with a diagnosis of pancreatitis and DM (n=27). Twelve were diagnosed with DM prior to presentation and 2 presented after total pancreatectomy with islet autotransplantation (TPIAT). Eight patients eventually developed DM and 5 later underwent TPIAT resulting in DM. We evaluated baseline characteristics at presentation to our MDC and longitudinal follow up. Of the 12 patients with previously diagnosed DM, 42% were Hispanic/Latino, 50% were female. On presentation to the MDC, patients were 15.4±2.1 years old with BMI 23.2±4.0 kg/m2 and HbA1c 9.6±2.9%. Eight patients developed DM within 1.1±1.2 years of follow up. Six were diagnosed by POC HbA1c in our MDC. Of all whom developed DM, 88% were Hispanic/Latino, 88% were female. DM was diagnosed at 14.3±1.6 years old with BMI 34.5±4.8 kg/m2 and HbA1c 8.5±2.5%. Of our 27 patients with DM, 4 had type 1 DM autoantibodies. At most recent visit HbA1c was 8.9±3.2%. DM treatment involved oral agents (15%), insulin (85%) and nutrition counseling for all patients. Total daily dose of insulin was 0.75±0.53 u/kg/day and 48% of patients used continuous glucose monitors. Instituting POC HbA1c screening in pancreatitis clinic identifies patients with new onset DM, supporting multidisciplinary care. Despite intensive care, HbA1c for these patients remains above guideline goals. More research is needed in providing DM care for children with pancreatitis.
Disclosure
E. Vargas: None. J. Mark: None. G. P. Forlenza: Advisory Panel; Medtronic, Consultant; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc., Lilly Diabetes, Research Support; Medtronic, Abbott, Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc. T. M. Triolo: None.
Type 1 diabetes (T1D) is a serious chronic autoimmune condition. Even though the root cause of T1D development has yet to be determined, enough is known about the natural history of T1D pathogenesis ...to allow study of interventions that may delay or even prevent the onset of hyperglycemia and clinical T1D. Primary prevention aims to prevent the onset of beta cell autoimmunity in asymptomatic people at high genetic risk for T1D. Secondary prevention strategies aim to preserve functional beta cells once autoimmunity is present, and tertiary prevention aims to initiate and extend partial remission of beta cell destruction after the clinical onset of T1D. The approval of teplizumab in the United States to delay the onset of clinical T1D marks an impressive milestone in diabetes care. This treatment opens the door to a paradigm shift in T1D care. People with T1D risk need to be identified early by measuring T1D related islet autoantibodies. Identifying people with T1D before they have symptoms will facilitate better understanding of pre-symptomatic T1D progression and T1D prevention strategies that may be effective.
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•The natural history of T1D is well understood, and T1D related islet autoantibodies are measurable in serum, making it possible to consider interventions to slow the autoimmune disease process.•Predicting the timing of clinical type 1 diabetes development in people who are at risk is difficult and deserves continued study.•The first therapy to delay the onset of stage 3 type 1 diabetes was recently approved in the United States for use in people 8 years of age and older with stage 2 type 1 diabetes.
Diabetes mellitus is characterized by the body's inability to control blood glucose levels within a physiological range due to loss and/or dysfunction of insulin producing beta cells. Progressive ...beta cell loss leads to hyperglycemia and if untreated can lead to severe complications and/or death. Treatments at this time are limited to pharmacologic therapies, including exogenous insulin or oral/injectable agents that improve insulin sensitivity or augment endogenous insulin secretion. Cell transplantation can restore physiologic endogenous insulin production and minimize hyper- and hypoglycemic excursions. Islet isolation procedures and management of transplant recipients have advanced over the last several decades; both tight glycemic control and insulin independence are achievable. Research has been conducted in isolating islets, monitoring islet function, and mitigating the immune response. However, this procedure is still only performed in a small minority of patients. One major barrier is the scarcity of human pancreatic islet donors, variation in donor pancreas quality, and variability in islet isolation success. Advances have been made in generation of glucose responsive human stem cell derived beta cells (sBCs) and islets from human pluripotent stem cells using directed differentiation. This is an emerging promising treatment for patients with diabetes because they could potentially serve as an unlimited source of functional, glucose-responsive beta cells. Challenges exist in their generation including long term survival of grafts, safety of transplantation, and protection from the immune response. This review focuses on the progress made in islet allo- and auto transplantation and how these advances may be extrapolated to the sBC context.
Magnetic resonance imaging (MRI) has detected changes in pancreas volume and other characteristics in type 1 and type 2 diabetes. However, differences in MRI technology and approaches across ...locations currently limit the incorporation of pancreas imaging into multisite trials. The purpose of this study was to develop a standardized MRI protocol for pancreas imaging and to define the reproducibility of these measurements. Calibrated phantoms with known MRI properties were imaged at five sites with differing MRI hardware and software to develop a harmonized MRI imaging protocol. Subsequently, five healthy volunteers underwent MRI at four sites using the harmonized protocol to assess pancreas size, shape, apparent diffusion coefficient (ADC), longitudinal relaxation time (T1), magnetization transfer ratio (MTR), and pancreas and hepatic fat fraction. Following harmonization, pancreas size, surface area to volume ratio, diffusion, and longitudinal relaxation time were reproducible, with coefficients of variation less than 10%. In contrast, non-standardized image processing led to greater variation in MRI measurements. By using a standardized MRI image acquisition and processing protocol, quantitative MRI of the pancreas performed at multiple locations can be incorporated into clinical trials comparing pancreas imaging measures and metabolic state in individuals with type 1 or type 2 diabetes.
Electrochemiluminescence (ECL) assays are high-affinity autoantibody (Ab) tests that are more specific than Abs detected by traditional radiobinding assays (RBA) for risk screening and prediction of ...progression to type 1 diabetes. We sought to characterize the association of high-risk human leukocyte antigen (HLA) haplotypes and genotypes with ECL positivity and levels in relatives of individuals with type 1 diabetes.
We analyzed 602 participants from the TrialNet Pathway to Prevention Study who were positive for at least 1 RBA diabetes-related Ab glutamic acid decarboxylase autoantibodies (GADA) or insulin autoantibodies (IAA) and for whom ECL and HLA data were available. ECL and RBA Ab levels were converted to SD units away from mean (z-scores) for analyses.
Mean age at initial visit was 19.4 ± 13.7 years; 344 (57.1%) were female and 104 (17.3%) carried the high-risk HLA-DR3/4*0302 genotype. At initial visit 424/602 (70.4%) participants were positive for either ECL-GADA or ECL-IAA, and 178/602 (29.6%) were ECL negative. ECL and RBA-GADA positivity were associated with both HLA-DR3 and DR4 haplotypes (all Ps < 0.05), while ECL and RBA-GADA z-score titers were higher in participants with HLA-DR3 haplotypes only (both Ps < 0.001). ECL-IAA (but not RBA-IAA) positivity was associated with the HLA-DR4 haplotype (P < 0.05).
ECL-GADA positivity is associated with the HLA-DR3 and HLA-DR4 haplotypes and levels are associated with the HLA-DR3 haplotype. ECL-IAA positivity is associated with HLA-DR4 haplotype. These studies further contribute to the understanding of genetic risk and islet autoimmunity endotypes in type 1 diabetes.
Electrochemiluminescence (ECL) assays are high-affinity autoantibodies (Abs) that are more specific than radiobinding assay (RBA) Abs for the prediction of type 1 diabetes (T1D) in natural history ...studies screening for risk and progression to T1D. We analyzed 603 subjects from the TrialNet Pathway to Prevention Study who were positive for at least one RBA diabetes related Ab and for whom ECL and HLA data were available. We sought to characterize ECL-GADA and ECL-IAA positivity and levels (z-scores) by HLA genotype and haplotypes. Mean age at initial visit was 19.4 ± 13.7 years; 345 (57.2%) were female and 104 (17.2%) carried the high-risk HLA- DR3/4*0302 genotype. At initial visit 425 (70%) of subjects were positive for either ECL-GADA or ECL-IAA, with 207 (34.3%) ECL-IAA positive subjects and 367 (60.9%) ECL-GADA positive subjects. For subjects with high-risk HLA-DR3/4 genotype (n=104), 80 (76.9%) were positive for ECL-GADA, while 42 (40.4%) were positive for ECL-IAA. ECL and RBA-GADA z-scores were higher in subjects with HLA-DR3 haplotypes, while ECL-IAA (but not RBA-IAA) z-scores were associated with HLA-DR4 haplotypes. Associations of ECL and RIA Abs with high-risk HLA haplotypes are shown in the Table.
In conclusion, ECL and RBA-GADA positivity are associated with both HLA-DR3 and DR4 haplotypes, whereas only ECL-IAA (but not RBA-IAA) positivity and levels are associated with HLA-DR4 haplotype.
Disclosure
T.M. Triolo: None. L. Pyle: None. L. Yu: None. P. Gottlieb: Advisory Panel; Self; Janssen Scientific Affairs, LLC., Tolerion, Inc., Viacyte, Inc. Research Support; Self; Caladrius Biosciences, Inc., Immune Tolerance Network, Janssen Pharmaceuticals, Inc., JDRF, Leona M. and Harry B. Helmsley Charitable Trust, Mercia/Nova Laboratories, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk Inc. Stock/Shareholder; Self; IM Therapeutics. A. Steck: None.
Funding
American Diabetes Association (1-14-CD-17 to A.S.); National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF
We sought to determine whether the type 1 diabetes genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms (SNPs) are associated with C-peptide preservation before type 1 diabetes ...diagnosis.
We conducted a retrospective analysis of 713 autoantibody-positive participants who developed type 1 diabetes in the TrialNet Pathway to Prevention Study who had T1DExomeChip data. We evaluated the relationships of 16 known SNPs and T1D-GRS2 with area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted in the 9 months before diagnosis.
Higher T1D-GRS2 was associated with lower C-peptide AUC in the 9 months before diagnosis in univariate (β=-0.06, P<0.0001) and multivariate (β=-0.03, P=0.005) analyses. Participants with the JAZF1 rs864745 T allele had lower C-peptide AUC in both univariate (β=-0.11, P=0.002) and multivariate (β=-0.06, P=0.018) analyses.
The type 2 diabetes-associated JAZF1 rs864745 T allele and higher T1D-GRS2 are associated with lower C-peptide AUC prior to diagnosis of type 1 diabetes, with implications for the design of prevention trials.
OBJECTIVE: We sought to define the prevalence of nonislet, organ-specific autoantibodies at diagnosis of type 1 diabetes and to determine the prevalence of comorbid autoimmune diseases. RESEARCH ...DESIGN AND METHODS: Children (n = 491) diagnosed with type 1 diabetes at the Barbara Davis Center for Childhood Diabetes were screened for autoimmune thyroid disease (thyroid peroxidase autoantibodies TPOAb), celiac disease (tissue transglutaminase autoantibodies TTGAb), and Addison disease (21-hydroxylase autoantibodies 21OHAb). RESULTS: Of the 491 children, 161 had at least one nonislet autoantibody, and of these, 122 (24.8%) were positive for TPOAb, and 15 of the 122 (12.3%) had autoimmune thyroid disease. There were 57 (11.6%) who were positive for TTGAb, of whom 14 (24.6%) had celiac disease. Five (1.0%) were positive for 21OHAb, of whom one had Addison disease. CONCLUSIONS: Many autoantibody-positive subjects present with additional autoimmune disorders. Detection of these autoantibodies at type 1 diabetes onset may prevent complications associated with delayed diagnosis of these disorders.
Development of islet autoimmunity (IA) and type 1 diabetes (T1D) are associated with high-risk HLA class II loci as well as non-HLA genes. Monozygotic (MZ) twins have a high rate of concordance to ...T1D progression after the first twin develops T1D, especially for those diagnosed at a young age. We analyzed 52 T1D-associated non-HLA SNPs from ImmunoChip data in 159 MZ twins from the Twin Family Study: 79 twin probands with T1D and their 80 unaffected cotwins/triplets (including one set of triplets). Subjects are enrolled into the Twin Study when the proband is diagnosed with T1D and cotwins are followed longitudinally for the development of IA and/or T1D. In the cotwins, we analyzed the association between each of the non-HLA SNPs and IA after adjusting for HLA DR3/4*0302. In the twin probands with T1D, we used a linear regression model to evaluate the association of non-HLA SNPs with diabetes age at onset after adjusting for HLA DR3/4*0302. Median (IQR) age of diagnosis of the twin probands was 9.9 (5.4-13.9) years and age of last visit for the cotwins was 17.5 (11.2-26.7) years. Of the 80 cotwins, 41 (51.3%) developed IA and 15 (18.8%) were diagnosed with T1D. After adjusting for HLA DR3/4*0302, SNPs in CTLA4 (rs3087243), IL2 (rs4505848), IKZF1 (rs62447205), and INS (rs7111341) were found to be associated with the development of IA in cotwin subjects (all p<0.04). After adjusting for HLA DR3/4*0302, SNPs in CTSH (rs3825932) and TYK2 (rs34536443) were found to be associated with younger age of diabetes onset in the twin probands (p<0.05). In this cohort of MZ twins, non-HLA SNPs in CTSH and TYK2, which function both in the immune system and in beta cells, were associated with younger age of onset in the twin probands. Further studies are needed to evaluate the specific role of these genes for immunity and T1D onset.
Disclosure
T. M. Triolo: None. F. Dong: None. H. C. Broncucia: None. S. Onengut-gumuscu: None. A. Steck: None. S. S. Rich: None.
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K12DK094712)
Type 1 diabetes is a polygenic disease that results in an autoimmune response directed against insulin-producing beta cells.
is a known high-risk type 1 diabetes associated gene expressed in both ...immune- and pancreatic beta cells, but how genes affect the development of autoimmune diabetes is largely unknown. We employed CRISPR/Cas9 technology to generate a functional knockout of
in human pluripotent stem cells (hPSC) followed by differentiating stem-cell-derived beta-like cells (sBC) and detailed phenotypical analyses. The differentiation efficiency of
knockout (PTPN2 KO) sBC is comparable to wild-type (WT) control sBC. Global transcriptomics and protein assays revealed the increased expression of HLA Class I molecules in PTPN2 KO sBC at a steady state and upon exposure to proinflammatory culture conditions, indicating a potential for the increased immune recognition of human beta cells upon differential
expression. sBC co-culture with autoreactive preproinsulin-reactive T cell transductants confirmed increased immune stimulations by PTPN2 KO sBC compared to WT sBC. Taken together, our results suggest that the dysregulation of
expression in human beta cell may prime autoimmune T cell reactivity and thereby contribute to the development of type 1 diabetes.
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