Browsing by Author "Pugliese, Alberto"
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Item A genomic data archive from the Network for Pancreatic Organ donors with Diabetes(Springer Nature, 2023-05-26) Perry, Daniel J.; Shapiro, Melanie R.; Chamberlain, Sonya W.; Kusmartseva, Irina; Chamala, Srikar; Balzano-Nogueira, Leandro; Yang, Mingder; Brant, Jason O.; Brusko, Maigan; Williams, MacKenzie D.; McGrail, Kieran M.; McNichols, James; Peters, Leeana D.; Posgai, Amanda L.; Kaddis, John S.; Mathews, Clayton E.; Wasserfall, Clive H.; Webb-Robertson, Bobbie-Jo M.; Campbell-Thompson, Martha; Schatz, Desmond; Evans-Molina, Carmella; Pugliese, Alberto; Concannon, Patrick; Anderson, Mark S.; German, Michael S.; Chamberlain, Chester E.; Atkinson, Mark A.; Brusko, Todd M.; Pediatrics, School of MedicineThe Network for Pancreatic Organ donors with Diabetes (nPOD) is the largest biorepository of human pancreata and associated immune organs from donors with type 1 diabetes (T1D), maturity-onset diabetes of the young (MODY), cystic fibrosis-related diabetes (CFRD), type 2 diabetes (T2D), gestational diabetes, islet autoantibody positivity (AAb+), and without diabetes. nPOD recovers, processes, analyzes, and distributes high-quality biospecimens, collected using optimized standard operating procedures, and associated de-identified data/metadata to researchers around the world. Herein describes the release of high-parameter genotyping data from this collection. 372 donors were genotyped using a custom precision medicine single nucleotide polymorphism (SNP) microarray. Data were technically validated using published algorithms to evaluate donor relatedness, ancestry, imputed HLA, and T1D genetic risk score. Additionally, 207 donors were assessed for rare known and novel coding region variants via whole exome sequencing (WES). These data are publicly-available to enable genotype-specific sample requests and the study of novel genotype:phenotype associations, aiding in the mission of nPOD to enhance understanding of diabetes pathogenesis to promote the development of novel therapies.Item A set of circulating microRNAs belonging to the 14q32 chromosome locus identifies two subgroups of individuals with recent-onset type 1 diabetes(Elsevier, 2024) Sebastiani, Guido; Grieco, Giuseppina Emanuela; Bruttini, Marco; Auddino, Stefano; Mori, Alessia; Toniolli, Mattia; Fignani, Daniela; Licata, Giada; Aiello, Elena; Nigi, Laura; Formichi, Caterina; Fernandez-Tajes, Juan; Pugliese, Alberto; Evans-Molina, Carmella; Overbergh, Lut; Tree, Timothy; Peakman, Mark; Mathieu, Chantal; Dotta, Francesco; INNODIA investigators; Pediatrics, School of MedicineCirculating microRNAs (miRNAs) are linked to the onset and progression of type 1 diabetes mellitus (T1DM), thus representing potential disease biomarkers. In this study, we employed a multiplatform sequencing approach to analyze circulating miRNAs in an extended cohort of prospectively evaluated recent-onset T1DM individuals from the INNODIA consortium. Our findings reveal that a set of miRNAs located within T1DM susceptibility chromosomal locus 14q32 distinguishes two subgroups of individuals. To validate our results, we conducted additional analyses on a second cohort of T1DM individuals, confirming the identification of these subgroups, which we have named cluster A and cluster B. Remarkably, cluster B T1DM individuals, who exhibit increased expression of a set of 14q32 miRNAs, show better glycemic control and display a different blood immunomics profile. Our findings suggest that this set of circulating miRNAs can identify two different T1DM subgroups with distinct blood immunomics at baseline and clinical outcomes during follow-up.Item Altered β-Cell Prohormone Processing and Secretion in Type 1 Diabetes(American Diabetes Association, 2021) Rodriguez-Calvo, Teresa; Chen, Yi-Chun; Verchere, C. Bruce; Haataja, Leena; Arvan, Peter; Leete, Pia; Richardson, Sarah J.; Morgan, Noel G.; Qian, Wei-Jun; Pugliese, Alberto; Atkinson, Mark; Evans-Molina, Carmella; Sims, Emily K.; Pediatrics, School of MedicineAnalysis of data from clinical cohorts, and more recently from human pancreatic tissue, indicates that reduced prohormone processing is an early and persistent finding in type 1 diabetes. In this article, we review the current state of knowledge regarding alterations in islet prohormone expression and processing in type 1 diabetes and consider the clinical impact of these findings. Lingering questions, including pathologic etiologies and consequences of altered prohormone expression and secretion in type 1 diabetes, and the natural history of circulating prohormone production in health and disease, are considered. Finally, key next steps required to move forward in this area are outlined, including longitudinal testing of relevant clinical populations, studies that probe the genetics of altered prohormone processing, the need for combined functional and histologic testing of human pancreatic tissues, continued interrogation of the intersection between prohormone processing and autoimmunity, and optimal approaches for analysis. Successful resolution of these questions may offer the potential to use altered prohormone processing as a biomarker to inform therapeutic strategies aimed at personalized intervention during the natural history of type 1 diabetes and as a pathogenic anchor for identification of potential disease-specific endotypes.Item Expression of SARS-CoV-2 Entry Factors in the Pancreas of Normal Organ Donors and Individuals with COVID-19(Elsevier, 2020-11-13) Kusmartseva, Irina; Wu, Wenting; Syed, Farooq; Van Der Heide, Verena; Jorgensen, Marda; Joseph, Paul; Tang, Xiaohan; Candelario-Jalil, Eduardo; Yang, Changjun; Nick, Harry; Harbert, Jack L.; Posgai, Amanda L.; Paulsen, John David; Lloyd, Richard; Cechin, Sirlene; Pugliese, Alberto; Campbell-Thompson, Martha; Vander Heide, Richard S.; Evans-Molina, Carmella; Homann, Dirk; Atkinson, Mark A.; Medical and Molecular Genetics, School of MedicineDiabetes is associated with increased mortality from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Given literature suggesting a potential association between SARS-CoV-2 infection and diabetes induction, we examined pancreatic expression of angiotensin-converting enzyme 2 (ACE2), the key entry factor for SARS-CoV-2 infection. Specifically, we analyzed five public scRNA-seq pancreas datasets and performed fluorescence in situ hybridization, western blotting, and immunolocalization for ACE2 with extensive reagent validation on normal human pancreatic tissues across the lifespan, as well as those from coronavirus disease 2019 (COVID-19) cases. These in silico and ex vivo analyses demonstrated prominent expression of ACE2 in pancreatic ductal epithelium and microvasculature, but we found rare endocrine cell expression at the mRNA level. Pancreata from individuals with COVID-19 demonstrated multiple thrombotic lesions with SARS-CoV-2 nucleocapsid protein expression that was primarily limited to ducts. These results suggest SARS-CoV-2 infection of pancreatic endocrine cells, via ACE2, is an unlikely central pathogenic feature of COVID-19-related diabetes.Item HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression(American Diabetes Association, 2016-04) Pugliese, Alberto; Boulware, David; Yu, Liping; Babu, Sunanda; Steck, Andrea K.; Becker, Dorothy; Rodriguez, Henry; DiMeglio, Linda; Evans-Molina, Carmella; Harrison, Leonard C.; Schatz, Desmond; Palmer, Jerry P.; Greenbaum, Carla; Eisenbarth, George S.; Sosenko, Jay M.; Medicine, School of MedicineThe HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from the development of type 1 diabetes (T1D). However, it is not known at which stages in the natural history of T1D development this haplotype affords protection. We examined a cohort of 3,358 autoantibody-positive relatives of T1D patients in the Pathway to Prevention (PTP) Study of the Type 1 Diabetes TrialNet. The PTP study examines risk factors for T1D and disease progression in relatives. HLA typing revealed that 155 relatives carried this protective haplotype. A comparison with 60 autoantibody-negative relatives suggested protection from autoantibody development. Moreover, the relatives with DRB1*15:01-DQA1*01:02-DQB1*06:02 less frequently expressed autoantibodies associated with higher T1D risk, were less likely to have multiple autoantibodies at baseline, and rarely converted from single to multiple autoantibody positivity on follow-up. These relatives also had lower frequencies of metabolic abnormalities at baseline and exhibited no overall metabolic worsening on follow-up. Ultimately, they had a very low 5-year cumulative incidence of T1D. In conclusion, the protective influence of DRB1*15:01-DQA1*01:02-DQB1*06:02 spans from autoantibody development through all stages of progression, and relatives with this allele only rarely develop T1D.Item Index60 as an additional diagnostic criterion for type 1 diabetes(Springer, 2021) Redondo, Maria J.; Nathan, Brandon M.; Jacobsen, Laura M.; Sims, Emily; Bocchino, Laura E.; Pugliese, Alberto; Schatz, Desmond A.; Atkinson, Mark A.; Skyler, Jay; Palmer, Jerry; Geyer, Susan; Sosenko, Jay M.; Type 1 diabetes TrialNet Study Group; Pediatrics, School of MedicineAims/hypothesis: We aimed to compare characteristics of individuals identified in the peri-diagnostic range by Index60 (composite glucose and C-peptide measure) ≥2.00, 2 h OGTT glucose ≥11.1 mmol/l, or both. Methods: We studied autoantibody-positive participants in the Type 1 Diabetes TrialNet Pathway to Prevention study who, at their baseline OGTT, had 2 h blood glucose ≥11.1 mmol/l and/or Index60 ≥2.00 (n = 354, median age = 11.2 years, age range = 1.7-46.6; 49% male, 83% non-Hispanic White). Type 1 diabetes-relevant characteristics (e.g., age, C-peptide, autoantibodies, BMI) were compared among three mutually exclusive groups: 2 h glucose ≥11.1 mmol/l and Index60 <2.00 [Glu(+), n = 76], 2 h glucose <11.1 mmol/l and Index60 ≥2.00 [Ind(+), n = 113], or both 2 h glucose ≥11.1 mmol/l and Index60 ≥2.00 [Glu(+)/Ind(+), n = 165]. Results: Participants in Glu(+), vs those in Ind(+) or Glu(+)/Ind(+), were older (mean ages = 22.9, 11.8 and 14.7 years, respectively), had higher early (30-0 min) C-peptide response (1.0, 0.50 and 0.43 nmol/l), higher AUC C-peptide (2.33, 1.13 and 1.10 nmol/l), higher percentage of overweight/obesity (58%, 16% and 30%) (all comparisons, p < 0.0001), and a lower percentage of multiple autoantibody positivity (72%, 92% and 93%) (p < 0.001). OGTT-stimulated C-peptide and glucose patterns of Glu(+) differed appreciably from Ind(+) and Glu(+)/Ind(+). Progression to diabetes occurred in 61% (46/76) of Glu(+) and 63% (71/113) of Ind(+). Even though Index60 ≥2.00 was not a Pathway to Prevention diagnostic criterion, Ind(+) had a 4 year cumulative diabetes incidence of 95% (95% CI 86%, 98%). Conclusions/interpretation: Participants in the Ind(+) group had more typical characteristics of type 1 diabetes than participants in the Glu(+) did and were as likely to be diagnosed. However, unlike Glu(+) participants, Ind(+) participants were not identified at the baseline OGTT.Item Persistence of b-Cell Responsiveness for Over Two Years in Autoantibody-Positive Children With Marked Metabolic Impairment at Screening(American Diabetes Association, 2022-12-01) Sims, Emily K.; Cuthbertson, David; Felton, Jamie L.; Ismail, Heba M.; Nathan, Brandon M.; Jacobsen, Laura M.; Paprocki, Emily; Pugliese, Alberto; Palmer, Jerry; Atkinson, Mark; Evans-Molina, Carmella; Skyler, Jay S.; Redondo, Maria J.; Herold, Kevan C.; Sosenko, Jay M.; Pediatrics, School of MedicineOBJECTIVE We studied longitudinal differences between progressors and nonprogressors to type 1 diabetes with similar and substantial baseline risk. RESEARCH DESIGN AND METHODS Changes in 2-h oral glucose tolerance test indices were used to examine variability in diabetes progression in the Diabetes Prevention Trial–Type 1 (DPT-1) study (n = 246) and Type 1 Diabetes TrialNet Pathway to Prevention study (TNPTP) (n = 503) among autoantibody (Ab)+ children (aged <18.0 years) with similar baseline metabolic impairment (DPT-1 Risk Score [DPTRS] of 6.5–7.5), as well as in TNPTP Ab− children (n = 94). RESULTS Longitudinal analyses revealed annualized area under the curve (AUC) of C-peptide increases in nonprogressors versus decreases in progressors (P ≤ 0.026 for DPT-1 and TNPTP). Vector indices for AUC glucose and AUC C-peptide changes (on a two-dimensional grid) also differed significantly (P < 0.001). Despite marked baseline metabolic impairment of nonprogressors, changes in AUC C-peptide, AUC glucose, AUC C-peptide–to–AUC glucose ratio (AUC ratio), and Index60 did not differ from Ab− relatives during follow-up. Divergence between nonprogressors and progressors occurred by 6 months from baseline in both cohorts (AUC glucose, P ≤ 0.007; AUC ratio, P ≤ 0.034; Index60, P < 0.001; vector indices of change, P < 0.001). Differences in 6-month change were positively associated with greater diabetes risk (respectively, P < 0.001, P ≤ 0.019, P < 0.001, and P < 0.001) in DPT-1 and TNPTP, except AUC ratio, which was inversely associated with risk (P < 0.001). CONCLUSIONS Novel findings show that even with similarly abnormal baseline risk, progressors had appreciably more metabolic impairment than nonprogressors within 6 months and that the measures showing impairment were predictive of type 1 diabetes. Longitudinal metabolic patterns did not differ between nonprogressors and Ab− relatives, suggesting persistent β-cell responsiveness in nonprogressors.Item The relationship between BMI and insulin resistance and progression from single to multiple autoantibody positivity and type 1 diabetes among TrialNet Pathway to Prevention participants(Springer, 2016-06) Meah, Farah A.; DiMeglio, Linda A.; Greenbaum, Carla J.; Blum, Janice S.; Sosenko, Jay M.; Pugliese, Alberto; Geyer, Susan; Xu, Ping; Evans-Molina, Carmella; Department of Medicine, IU School of MedicineAims/hypothesis The incidence of type 1 diabetes is increasing at a rate of 3–5% per year. Genetics cannot fully account for this trend, suggesting an influence of environmental factors. The accelerator hypothesis proposes an effect of metabolic factors on type 1 diabetes risk. To test this in the TrialNet Pathway to Prevention (PTP) cohort, we analysed the influence of BMI, weight status and insulin resistance on progression from single to multiple islet autoantibodies (Aab) and progression from normoglycaemia to diabetes. Methods HOMA1-IR was used to estimate insulin resistance in Aab-positive PTP participants. Cox proportional hazards models were used to evaluate the effects of BMI, BMI percentile (BMI%), weight status and HOMA1-IR on the progression of autoimmunity or the development of diabetes. Results Data from 1,310 single and 1,897 multiple Aab-positive PTP participants were included. We found no significant relationships between BMI, BMI%, weight status or HOMA1-IR and the progression from one to multiple Aabs. Similarly, among all Aab-positive participants, no significant relationships were found between BMI, weight status or HOMA1-IR and progression to diabetes. Diabetes risk was modestly increased with increasing BMI% among the entire cohort, in obese participants 13–20 years of age and with increasing HOMA1-IR in adult Aab-positive participants. Conclusions/interpretation Analysis of the accelerator hypothesis in the TrialNet PTP cohort does not suggest a broad influence of metabolic variables on diabetes risk. Efforts to identify other potentially modifiable environmental factors should continue.Item TCF7L2 Genetic Variants Do Not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-Positive Individuals at Risk for Type 1 Diabetes(American Diabetes Association, 2021) Redondo, Maria J.; Warnock, Megan V.; Libman, Ingrid M.; Bocchino, Laura E.; Cuthbertson, David; Geyer, Susan; Pugliese, Alberto; Steck, Andrea K.; Evans-Molina, Carmella; Becker, Dorothy; Sosenko, Jay M.; Bacha, Fida; Type 1 Diabetes TrialNet Study Group; Medicine, School of MedicineObjective: We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D). Research design and methods: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (N = 1,061) (mean age 16.3 years) with TCF7L2 single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, P values < 0.0086 were considered statistically significant. Results: None, one, and two T2D-linked TCF7L2 alleles were present in 48.1%, 43.9%, and 8.0% of the participants, respectively. Insulin sensitivity (as reflected by 1/fasting insulin [1/IF]) decreased with increasing BMI z score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI z score. Oral disposition index was negatively correlated with age, BMI z score, and Hispanic ethnicity. None of the indices were associated with TCF7L2 SNPs. In multivariable analysis models with age, BMI z score, ethnicity, sex, and TCF7L2 alleles as independent variables, C-peptide index increased with age, while BMI z score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/IF), and lower disposition index; there was no significant effect of TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with a normal OGTT (n = 743; 70%), the results were similar. Conclusions: In nondiabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI z score, age, sex, and ethnicity.