Browsing by Author "Speake, Cate"
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Item Abnormalities in proinsulin processing in islets from individuals with longstanding T1D(Elsevier, 2019-11) Sims, Emily K.; Syed, Farooq; Nyalwidhe, Julius; Bahnson, Henry T.; Haataja, Leena; Speake, Cate; Morris, Margaret A.; Balamurugan, Appakalai N.; Mirmira, Raghavendra G.; Nadler, Jerry; Mastracci, Teresa L.; Arvan, Peter; Greenbaum, Carla J.; Evans-Molina, Carmella; Pediatrics, School of MedicineWe recently described the persistence of detectable serum proinsulin in a large majority of individuals with longstanding type 1 diabetes (T1D), including individuals with undetectable serum C-peptide. Here, we sought to further explore the mechanistic etiologies of persistent proinsulin secretion in T1D at the level of the islet, using tissues obtained from human donors. Immunostaining for proinsulin and insulin was performed on human pancreatic sections from the Network for Pancreatic Organ Donors with Diabetes (nPOD) collection (n = 24). Differential proinsulin processing enzyme expression was analyzed using mass spectrometry analysis of human islets isolated from pancreatic sections with laser capture microdissection (n = 6). Proinsulin processing enzyme mRNA levels were assessed using quantitative real-time PCR in isolated human islets (n = 10) treated with or without inflammatory cytokines. Compared to nondiabetic controls, immunostaining among a subset (4/9) of insulin positive T1D donor islets revealed increased numbers of cells with proinsulin-enriched, insulin-poor staining. T1D donor islets also exhibited increased proinsulin fluorescence intensity relative to insulin fluorescence intensity. Laser capture microdissection followed by mass spectrometry revealed reductions in the proinsulin processing enzymes prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE) in T1D donors. Twenty-four hour treatment of human islets with inflammatory cytokines reduced mRNA expression of the processing enzymes PC1/3, PC2, and CPE. Taken together, these data provide new mechanistic insight into altered proinsulin processing in long-duration T1D and suggest that reduced β cell prohormone processing is associated with proinflammatory cytokine-induced reductions in proinsulin processing enzyme expression.Item Assessing the Pathophysiology of Hyperglycemia in the Diabetes RElated to Acute Pancreatitis and Its Mechanisms (DREAM) Study: From the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC)(Wolters Kluwer, 2022) Dungan, Kathleen M.; Hart, Phil A.; Andersen, Dana K.; Basina, Marina; Chinchilli, Vernon M.; Danielson, Kirstie K.; Evans-Molina, Carmella; Goodarzi, Mark O.; Greenbaum, Carla J.; Kalyani, Rita R.; Laughlin, Maren R.; Pichardo-Lowden, Ariana; Pratley, Richard E.; Serrano, Jose; Sims, Emily K.; Speake, Cate; Yadav, Dhiraj; Bellin, Melena D.; Toledo, Frederico G. S.; Type 1 Diabetes in Acute Pancreatitis Consortium; Medicine, School of MedicineObjectives: The metabolic abnormalities that lead to diabetes mellitus (DM) following an episode of acute pancreatitis (AP) have not been extensively studied. This manuscript describes the objectives, hypotheses, and methods of mechanistic studies of glucose metabolism that comprise secondary outcomes of the Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM) Study. Methods: Three months after an index episode of AP, participants without pre-existing DM will undergo baseline testing with an oral glucose tolerance test. Participants will be followed longitudinally in three sub-cohorts with distinct metabolic tests. In the first and largest subcohort, oral glucose tolerance tests will be repeated 12 months after AP and annually to assess changes in β-cell function, insulin secretion, and insulin sensitivity. In the second, mixed meal tolerance tests will be performed at 3 and 12 months, then annually, and following incident DM to assess incretin and pancreatic polypeptide responses. In the third, frequently-sampled intravenous glucose tolerance tests will be performed at 3 months and 12 months to assess the first-phase insulin response and more precisely measure β-cell function and insulin sensitivity. Conclusions: The DREAM study will comprehensively assess the metabolic and endocrine changes that precede and lead to the development of DM after AP.Item Carbonyl Posttranslational Modification Associated With Early-Onset Type 1 Diabetes Autoimmunity(American Diabetes Association, 2022) Yang, Mei-Ling; Connolly, Sean E.; Gee, Renelle J.; Lam, TuKiet T.; Kanyo, Jean; Peng, Jian; Guyer, Perrin; Syed, Farooq; Tse, Hubert M.; Clarke, Steven G.; Clarke, Catherine F.; James, Eddie A.; Speake, Cate; Evans-Molina, Carmella; Arvan, Peter; Herold, Kevan C.; Wen, Li; Mamula, Mark J; Medicine, School of MedicineInflammation and oxidative stress in pancreatic islets amplify the appearance of various posttranslational modifications to self-proteins. In this study, we identified a select group of carbonylated islet proteins arising before the onset of hyperglycemia in NOD mice. Of interest, we identified carbonyl modification of the prolyl-4-hydroxylase β subunit (P4Hb) that is responsible for proinsulin folding and trafficking as an autoantigen in both human and murine type 1 diabetes. We found that carbonylated P4Hb is amplified in stressed islets coincident with decreased glucose-stimulated insulin secretion and altered proinsulin-to-insulin ratios. Autoantibodies against P4Hb were detected in prediabetic NOD mice and in early human type 1 diabetes prior to the onset of anti-insulin autoimmunity. Moreover, we identify autoreactive CD4+ T-cell responses toward carbonyl-P4Hb epitopes in the circulation of patients with type 1 diabetes. Our studies provide mechanistic insight into the pathways of proinsulin metabolism and in creating autoantigenic forms of insulin in type 1 diabetes.Item Circulating Unmethylated Insulin DNA As a Biomarker of Human Beta Cell Death: A Multi-laboratory Assay Comparison(Endocrine Society, 2020-03-01) Speake, Cate; Ylescupidez, Alyssa; Neiman, Daniel; Shemer, Ruth; Glaser, Benjamin; Tersey, Sarah A.; Usmani-Brown, Sahar; Clark, Pamela; Wilhelm, Joshua J.; Bellin, Melena D.; Herold, Kevan C.; Mirmira, Raghavendra G.; Dor, Yuval; Evans-Molina, Carmella; Pediatrics, School of MedicineContext: There is an unmet need for biomarkers of pancreatic beta-cell death to improve early diagnosis of type 1 diabetes, enroll subjects into clinical trials, and assess treatment response. To address this need, several groups developed assays measuring insulin deoxyribonucleic acid (DNA) with unmethylated CpG sites in cell-free DNA. Unmethylated insulin DNA should be derived predominantly from beta-cells and indicate ongoing beta-cell death. Objective: To assess the performance of three unmethylated insulin DNA assays. Design and participants: Plasma or serum samples from 13 subjects undergoing total pancreatectomy and islet autotransplantation were coded and provided to investigators to measure unmethylated insulin DNA. Samples included a negative control taken post-pancreatectomy but pretransplant, and a positive control taken immediately following islet infusion. We assessed technical reproducibility, linearity, and persistence of detection of unmethylated insulin DNA for each assay. Results: All assays discriminated between the negative sample and samples taken directly from the islet transplant bag; 2 of 3 discriminated negative samples from those taken immediately after islet infusion. When high levels of unmethylated insulin DNA were present, technical reproducibility was generally good for all assays. Conclusions: The measurement of beta cell cell-free DNA, including insulin, is a promising approach, warranting further testing and development in those with or at-risk for type 1 diabetes, as well as in other settings where understanding the frequency or kinetics of beta cell death could be useful.Item Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes(Springer, 2024-09) Phillip, Moshe; Achenbach, Peter; Addala, Ananta; Albanese-O'Neill, Anastasia; Battelino, Tadej; Bell, Kirstine J.; Besser, Rachel E. J.; Bonifacio, Ezio; Colhoun, Helen M.; Couper, Jennifer J.; Craig, Maria E.; Danne, Thomas; de Beaufort, Carine; Dovc, Klemen; Driscoll, Kimberly A.; Dutta, Sanjoy; Ebekozien, Osagie; Elding Larsson, Helena; Feiten, Daniel J.; Frohnert, Brigitte I.; Gabbay, Robert A.; Gallagher, Mary P.; Greenbaum, Carla J.; Griffin, Kurt J.; Hagopian, William; Haller, Michael J.; Hendrieckx, Christel; Hendriks, Emile; Holt, Richard I. G.; Hughes, Lucille; Ismail, Heba M.; Jacobsen, Laura M.; Johnson, Suzanne B.; Kolb, Leslie E.; Kordonouri, Olga; Lange, Karin; Lash, Robert W.; Lernmark, Åke; Libman, Ingrid; Lundgren, Markus; Maahs, David M.; Marcovecchio, M. Loredana; Mathieu, Chantal; Miller, Kellee M.; O'Donnell, Holly K.; Oron, Tal; Patil, Shivajirao P.; Pop-Busui, Rodica; Rewers, Marian J.; Rich, Stephen S.; Schatz, Desmond A.; Schulman-Rosenbaum, Rifka; Simmons, Kimber M.; Sims, Emily K.; Skyler, Jay S.; Smith, Laura B.; Speake, Cate; Steck, Andrea K.; Thomas, Nicholas P. B.; Tonyushkina, Ksenia N.; Veijola, Riitta; Wentworth, John M.; Wherrett, Diane K.; Wood, Jamie R.; Ziegler, Anette-Gabriele; DiMeglio, Linda A.; Pediatrics, School of MedicineGiven the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk of (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb+; (2) when people who are IAb+ are initially identified there is a need for confirmation using a second sample; (3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care.Item Correction to: Consensus guidance for monitoring individuals with islet autoantibody‑positive pre‑stage 3 type 1 diabetes(Springer, 2024) Phillip, Moshe; Achenbach, Peter; Addala, Ananta; Albanese-O'Neill, Anastasia; Battelino, Tadej; Bell, Kirstine J.; Besser, Rachel E. J.; Bonifacio, Ezio; Colhoun, Helen M.; Couper, Jennifer J.; Craig, Maria E.; Danne, Thomas; de Beaufort, Carine; Dovc, Klemen; Driscoll, Kimberly A.; Dutta, Sanjoy; Ebekozien, Osagie; Elding Larsson, Helena; Feiten, Daniel J.; Frohnert, Brigitte I.; Gabbay, Robert A.; Gallagher, Mary P.; Greenbaum, Carla J.; Griffin, Kurt J.; Hagopian, William; Haller, Michael J.; Hendrieckx, Christel; Hendriks, Emile; Holt, Richard I. G.; Hughes, Lucille; Ismail, Heba M.; Jacobsen, Laura M.; Johnson, Suzanne B.; Kolb, Leslie E.; Kordonouri, Olga; Lange, Karin; Lash, Robert W.; Lernmark, Åke; Libman, Ingrid; Lundgren, Markus; Maahs, David M.; Marcovecchio, M. Loredana; Mathieu, Chantal; Miller, Kellee M.; O'Donnell, Holly K.; Oron, Tal; Patil, Shivajirao P.; Pop-Busui, Rodica; Rewers, Marian J.; Rich, Stephen S.; Schatz, Desmond A.; Schulman-Rosenbaum, Rifka; Simmons, Kimber M.; Sims, Emily K.; Skyler, Jay S.; Smith, Laura B.; Speake, Cate; Steck, Andrea K.; Thomas, Nicholas P. B.; Tonyushkina, Ksenia N.; Veijola, Riitta; Wentworth, John M.; Wherrett, Diane K.; Wood, Jamie R.; Ziegler, Anette-Gabriele; DiMeglio, Linda A.; Pediatrics, School of MedicineItem Disease-modifying therapies and features linked to treatment response in type 1 diabetes prevention: a systematic review(Springer Nature, 2023-10-05) Felton, Jamie L.; Griffin, Kurt J.; Oram, Richard A.; Speake, Cate; Long, S. Alice; Onengut-Gumuscu, Suna; Rich, Stephen S.; Monaco, Gabriela S. F.; Evans-Molina, Carmella; DiMeglio, Linda A.; Ismail, Heba M.; Steck, Andrea K.; Dabelea, Dana; Johnson, Randi K.; Urazbayeva, Marzhan; Gitelman, Stephen; Wentworth, John M.; Redondo, Maria J.; Sims, Emily K.; Pediatrics, School of MedicineBackground: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification. Methods: To understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with ≥50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument. Results: We identify and summarize 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss at disease onset. Seventeen interventions, mostly immunotherapies, show benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employ precision analyses to assess features linked to treatment response. Age, beta cell function measures, and immune phenotypes are most frequently tested. However, analyses are typically not prespecified, with inconsistent methods of reporting, and tend to report positive findings. Conclusions: While the quality of prevention and intervention trials is overall high, the low quality of precision analyses makes it difficult to draw meaningful conclusions that inform clinical practice. To facilitate precision medicine approaches to T1D prevention, considerations for future precision studies include the incorporation of uniform outcome measures, reproducible biomarkers, and prespecified, fully powered precision analyses into future trial design.Item Islet autoantibodies as precision diagnostic tools to characterize heterogeneity in type 1 diabetes: a systematic review(Springer Nature, 2024-04-06) Felton, Jamie L.; Redondo, Maria J.; Oram, Richard A.; Speake, Cate; Long, S. Alice; Onengut-Gumuscu, Suna; Rich, Stephen S.; Monaco, Gabriela S. F.; Harris-Kawano, Arianna; Perez, Dianna; Saeed, Zeb; Hoag, Benjamin; Jain, Rashmi; Evans-Molina, Carmella; DiMeglio, Linda A.; Ismail, Heba M.; Dabelea, Dana; Johnson, Randi K.; Urazbayeva, Marzhan; Wentworth, John M.; Griffin, Kurt J.; Sims, Emily K.; ADA/EASD PMDI; Pediatrics, School of MedicineBackground: Islet autoantibodies form the foundation for type 1 diabetes (T1D) diagnosis and staging, but heterogeneity exists in T1D development and presentation. We hypothesized that autoantibodies can identify heterogeneity before, at, and after T1D diagnosis, and in response to disease-modifying therapies. Methods: We systematically reviewed PubMed and EMBASE databases (6/14/2022) assessing 10 years of original research examining relationships between autoantibodies and heterogeneity before, at, after diagnosis, and in response to disease-modifying therapies in individuals at-risk or within 1 year of T1D diagnosis. A critical appraisal checklist tool for cohort studies was modified and used for risk of bias assessment. Results: Here we show that 152 studies that met extraction criteria most commonly characterized heterogeneity before diagnosis (91/152). Autoantibody type/target was most frequently examined, followed by autoantibody number. Recurring themes included correlations of autoantibody number, type, and titers with progression, differing phenotypes based on order of autoantibody seroconversion, and interactions with age and genetics. Only 44% specifically described autoantibody assay standardization program participation. Conclusions: Current evidence most strongly supports the application of autoantibody features to more precisely define T1D before diagnosis. Our findings support continued use of pre-clinical staging paradigms based on autoantibody number and suggest that additional autoantibody features, particularly in relation to age and genetic risk, could offer more precise stratification. To improve reproducibility and applicability of autoantibody-based precision medicine in T1D, we propose a methods checklist for islet autoantibody-based manuscripts which includes use of precision medicine MeSH terms and participation in autoantibody standardization workshops.Item ISPAD Clinical Practice Consensus Guidelines 2024: Screening, Staging, and Strategies to Preserve Beta-Cell Function in Children and Adolescents with Type 1 Diabetes(Karger, 2024) Haller, Michael J.; Bell, Kirstine J.; Besser, Rachel E. J.; Casteels, Kristina; Couper, Jenny J.; Craig, Maria E.; Larsson, Helena Elding; Jacobsen, Laura; Lange, Karin; Oron, Tal; Sims, Emily K.; Speake, Cate; Tosur, Mustafa; Ulivi, Francesca; Ziegler, Anette-G.; Wherrett, Diane K.; Marcovecchio, M. Loredana; Pediatrics, School of MedicineThe International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines represent a rich repository that serves as the only comprehensive set of clinical recommendations for children, adolescents, and young adults living with diabetes worldwide. This guideline serves as an update to the 2022 ISPAD consensus guideline on staging for type 1 diabetes (T1D). Key additions include an evidence-based summary of recommendations for screening for risk of T1D and monitoring those with early-stage T1D. In addition, a review of clinical trials designed to delay progression to Stage 3 T1D and efforts seeking to preserve beta-cell function in those with Stage 3 T1D are included. Lastly, opportunities and challenges associated with the recent US Food and Drug Administration (FDA) approval of teplizumab as an immunotherapy to delay progression are discussed. The International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines represent a rich repository that serves as the only comprehensive set of clinical recommendations for children, adolescents, and young adults living with diabetes worldwide. This guideline serves as an update to the 2022 ISPAD consensus guideline on staging for type 1 diabetes (T1D). Key additions include an evidence-based summary of recommendations for screening for risk of T1D and monitoring those with early-stage T1D. In addition, a review of clinical trials designed to delay progression to Stage 3 T1D and efforts seeking to preserve beta-cell function in those with Stage 3 T1D are included. Lastly, opportunities and challenges associated with the recent US Food and Drug Administration (FDA) approval of teplizumab as an immunotherapy to delay progression are discussed.Item Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes(American Diabetes Association, 2019-02) Sims, Emily K.; Bahnson, Henry T.; Nyalwidhe, Julius; Haataja, Leena; Davis, Asa K.; Speake, Cate; DiMeglio, Linda A.; Blum, Janice; Morris, Margaret A.; Mirmira, Raghavendra G.; Nadler, Jerry; Mastracci, Teresa L.; Marcovina, Santica; Qian, Wei-Jun; Yi, Lian; Swensen, Adam C.; Yip-Schneider, Michele; Schmidt, C. Max; Considine, Robert V.; Arvan, Peter; Greenbaum, Carla J.; Evans-Molina, Carmella; T1D Exchange Residual C-peptide Study Group; Pediatrics, School of MedicineOBJECTIVE: Abnormally elevated proinsulin secretion has been reported in type 2 and early type 1 diabetes when significant C-peptide is present. We questioned whether individuals with long-standing type 1 diabetes and low or absent C-peptide secretory capacity retained the ability to make proinsulin. RESEARCH DESIGN AND METHODS: C-peptide and proinsulin were measured in fasting and stimulated sera from 319 subjects with long-standing type 1 diabetes (≥3 years) and 12 control subjects without diabetes. We considered three categories of stimulated C-peptide: 1) C-peptide positive, with high stimulated values ≥0.2 nmol/L; 2) C-peptide positive, with low stimulated values ≥0.017 but <0.2 nmol/L; and 3) C-peptide <0.017 nmol/L. Longitudinal samples were analyzed from C-peptide-positive subjects with diabetes after 1, 2, and 4 years. RESULTS: Of individuals with long-standing type 1 diabetes, 95.9% had detectable serum proinsulin (>3.1 pmol/L), while 89.9% of participants with stimulated C-peptide values below the limit of detection (<0.017 nmol/L; n = 99) had measurable proinsulin. Proinsulin levels remained stable over 4 years of follow-up, while C-peptide decreased slowly during longitudinal analysis. Correlations between proinsulin with C-peptide and mixed-meal stimulation of proinsulin were found only in subjects with high stimulated C-peptide values (≥0.2 nmol/L). Specifically, increases in proinsulin with mixed-meal stimulation were present only in the group with high stimulated C-peptide values, with no increases observed among subjects with low or undetectable (<0.017 nmol/L) residual C-peptide. CONCLUSIONS: In individuals with long-duration type 1 diabetes, the ability to secrete proinsulin persists, even in those with undetectable serum C-peptide.