Elevated islet prohormone ratios as indicators of insulin dependency in auto-islet transplant recipients

Chen, Yi‐Chun; Klimek‐Abercrombie, Agnieszka; Potter, Kathryn; Pallo, Lindsay; Soukhatcheva, Galina; Lei, D.; Bellin, Melena D.; Verchere, C. Bruce

doi:10.1111/ajt.17076

Cited by 5 publications

(2 citation statements)

References 72 publications

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“…Depletion of this store explains the insufficient correction of the MMTT-induced hyperglycemic state. An increased plasma proinsulin to C-peptide ratio was also observed in patients receiving an intrahepatic islet transplant and was related to an insufficient β cell mass 42 , also related to MMTT-induced hyperglycemia 43 . The circulating hormonal markers plasma proinsulin and C-peptide can be used to evaluate clinical studies that aim to achieve a larger β cell mass.…”

Section: Discussionmentioning

confidence: 89%

Encapsulated stem cell–derived β cells exert glucose control in patients with type 1 diabetes

Keymeulen,

De Groot,

Jacobs-Tulleneers-Thevissen

et al. 2023

Nat Biotechnol

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Clinical studies on the treatment of type 1 diabetes with device-encapsulated pancreatic precursor cells derived from human embryonic stem cells found that insulin output was insufficient for clinical benefit. We are conducting a phase 1/2, open-label, multicenter trial aimed at optimizing cell engraftment (ClinicalTrials.gov identifier: NCT03163511). Here we report interim, 1-year outcomes in one study group that received 2–3-fold higher cell doses in devices with an optimized membrane perforation pattern. β cell function was measured by meal-stimulated plasma C-peptide levels at 3-month intervals, and the effect on glucose control was assessed by continuous glucose monitoring (CGM) and insulin dosing. Of 10 patients with undetectable baseline C-peptide, three achieved levels ≥0.1 nmol l−1 from month 6 onwards that correlated with improved CGM measures and reduced insulin dosing, indicating a glucose-controlling effect. The patient with the highest C-peptide (0.23 nmol l−1) increased CGM time-in-range from 55% to 85% at month 12; β cell mass in sentinel devices in this patient at month 6 was 4% of the initial cell mass, indicating directions for improving efficacy.

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Section: Discussionmentioning

confidence: 89%

Encapsulated stem cell–derived β cells exert glucose control in patients with type 1 diabetes

Keymeulen,

De Groot,

Jacobs-Tulleneers-Thevissen

et al. 2023

Nat Biotechnol

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“…This resource continues to evolve through the ongoing collection of datasets outlined in this report, and by the addition of new data types for additional analyses. Examples of the latter, include donor genotyping; genetically predicted ancestry, and genetic risk scores for diabetes; 55,56 prohormone processing; 57,58 metabolomics; 59 and the pancreatic accumulation of environmental contaminants 60,61 and lipids, 62 among other data types that will be added in the future. In time, we hope to allow all ADI IsletCore islet and tissue recipients to provide/upload data for integration.…”

Section: Discussionmentioning

confidence: 99%

HumanIslets: An integrated platform for human islet data access and analysis

Ewald,

Lu,

Ellis

et al. 2024

Preprint

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SUMMARYComprehensive molecular and cellular phenotyping of human islets can enable deep mechanistic insights for diabetes research. We established the Human Islet Data Analysis and Sharing (HI-DAS) consortium to advance goals in accessibility, usability, and integration of data from human islets isolated from donors with and without diabetes at the Alberta Diabetes Institute (ADI) IsletCore. Here we introduceHumanIslets.com, an open resource for the research community. This platform, which presently includes data on 547 human islet donors, allows users to access linked datasets describing molecular profiles, islet function and donor phenotypes, and to perform various statistical and functional analyses at the donor, islet and single-cell levels. As an example of the analytic capacity of this resource we show a dissociation between cell culture effects on transcript and protein expression, and an approach to correct for exocrine contamination found in hand-picked islets. Finally, we provide an example workflow and visualization that highlights links between type 2 diabetes status, SERCA3b Ca2+-ATPase levels at the transcript and protein level, insulin secretion and islet cell phenotypes.HumanIslets.comprovides a growing and adaptable set of resources and tools to support the metabolism and diabetes research community.

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Quantitative analysis of islet prohormone convertase 1/3 expression in human pancreas donors with diabetes

Apaolaza,

Chen,

Grewal

et al. 2024

Diabetologia

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Aims/hypothesis Islet prohormone-processing enzymes convert peptide hormone precursors to mature hormones. Defective beta cell prohormone processing and the release of incompletely processed peptide hormones are observed prior to the onset of diabetes, yet molecular mechanisms underlying impaired prohormone processing during the development of diabetes remains largely unknown. Previous studies have shown that prohormone convertase 1/3 (PC1/3) protein and mRNA expression levels are reduced in whole islets from donors with type 1 diabetes, although whether PC1/3-mediated prohormone processing in alpha and beta cells is disrupted in type 1 diabetes remained to be explored. Herein, we aimed to analyse the expression of PC1/3 in islets from non-diabetic donors, autoantibody-positive donors and donors diagnosed with type 1 diabetes or type 2 diabetes. Methods Immunostaining and high-dimensional image analysis were performed on pancreatic sections from a cross-sectional cohort of 54 donors obtained from the Network for Pancreatic Organ Donors with Diabetes (nPOD) repository, to evaluate PC1/3 expression patterns in islet alpha, beta and delta cells at different stages of diabetes. Results Alpha and beta cell morphology were altered in donors with type 1 diabetes, including decreased alpha and beta cell size. As expected, the insulin-positive and PC1/3-positive areas in the islets were both reduced, and this was accompanied by a reduced percentage of PC1/3-positive and insulin-positive/PC1/3-positive cells in islets. PC1/3 and insulin co-localisation was also reduced. The glucagon-positive area, as well as the percentage of glucagon-positive and glucagon-positive/PC1/3-positive cells in islets, was increased. PC1/3 and glucagon co-localisation was also increased in donors with type 1 diabetes. The somatostatin-positive cell area and somatostatin staining intensity were elevated in islets from donors with recent-onset type 1 diabetes. Conclusions/interpretation Our high-resolution histomorphological analysis of human pancreatic islets from donors with and without diabetes has uncovered details of the cellular origin of islet prohormone peptide processing defects. Reduced beta cell PC1/3 and increased alpha cell PC1/3 in islets from donors with type 1 diabetes pinpointed the functional deterioration of beta cells and the concomitant potential increase in PC1/3 usage for prohormone processing in alpha cells during the pathogenesis of type 1 diabetes. Our finding of PC1/3 loss in beta cells may inform the discovery of new prohormone biomarkers as indicators of beta cell dysfunction, and the finding of elevated PC1/3 expression in alpha cells may encourage the design of therapeutic targets via leveraging alpha cell adaptation in diabetes. Graphical Abstract

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Elevated islet prohormone ratios as indicators of insulin dependency in auto-islet transplant recipients

Cited by 5 publications

References 72 publications

Encapsulated stem cell–derived β cells exert glucose control in patients with type 1 diabetes

Encapsulated stem cell–derived β cells exert glucose control in patients with type 1 diabetes

HumanIslets: An integrated platform for human islet data access and analysis

Quantitative analysis of islet prohormone convertase 1/3 expression in human pancreas donors with diabetes

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