Altered β-Cell Prohormone Processing and Secretion in Type 1 Diabetes

Rodríguez-Calvo, Teresa; Chen, Yi Chun; Verchere, C. Bruce; Haataja, Leena; Arvan, Peter; Leete, Pia; Richardson, Sarah J.; Morgan, Noel G.; Qian, Wei; Pugliese, Alberto; Atkinson, Mark A.; Evans‐Molina, Carmella; Sims, Emily K.

doi:10.2337/dbi20-0034

Cited by 32 publications

(19 citation statements)

References 63 publications

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“…In contrast, a lack of both mature and immature insulin, as observed in the context of type 1 diabetes, leads to severe catabolism. Noteworthy, defective islet prohormone processing and increased proinsulin levels were also described in individuals prior to and after the onset of type 1 diabetes (reviewed: 43 ). However, it is currently unknown whether an islet intrinsic prohormone processing defect predisposes individuals to develop autoimmune diabetes or whether increased secretory demand due to autoimmune β-cell destruction leads to a relative increase in proinsulin to insulin ratio.…”

Section: Discussionmentioning

confidence: 99%

Prohormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing

et al. 2022

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Defective insulin processing is associated with obesity and diabetes. Prohormone convertase 1/3 (PC1/3) is an endopeptidase required for the processing of neurotransmitters and hormones. PC1/3 deficiency and genome-wide association studies relate PC1/3 with early onset obesity. Here, we find that deletion of PC1/3 in obesity-related neuronal cells expressing proopiomelanocortin mildly and transiently change body weight and fail to produce a phenotype when targeted to Agouti-related peptide- or nestin-expressing tissues. In contrast, pancreatic β cell-specific PC1/3 ablation induces hyperphagia with consecutive obesity despite uncontrolled diabetes with glucosuria. Obesity develops not due to impaired pro-islet amyloid polypeptide processing but due to impaired insulin maturation. Proinsulin crosses the blood-brain-barrier but does not induce central satiety. Accordingly, insulin therapy prevents hyperphagia. Further, islet PC1/3 expression levels negatively correlate with body mass index in humans. In this work, we show that impaired PC1/3-mediated proinsulin processing, as observed in human prediabetes, promotes hyperphagic obesity.

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Section: Discussionmentioning

confidence: 99%

Prohormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing

et al. 2022

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“…The cause of islet dysfunction and elevated PI/C and proIAPP/IAPP ratios remains largely unknown, but may involve changes in prohormone convertase activity associated with islet secretory and/or ER stress 24 . We transplanted varying doses of human islets into STZ-diabetic, immune-deficient (NSG) mice, and analyzed circulating human islet (pro)hormone levels and prohormone processing machinery in human islet grafts.…”

Section: Discussionmentioning

confidence: 99%

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

Chen¹,

Klimek‐Abercrombie²,

Potter³

et al. 2021

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Autologous pancreatic islet transplantation is an established therapy for patients with chronic pancreatitis. However, the long-term transplant outcomes are modest. Identifying indicators of graft function will aid the preservation of transplanted islets and glycemic control. To this end, we analyzed beta cell prohormone peptide levels in a retrospective cohort of total pancreatectomy autologous islet transplant patients (n=28). Proinsulin-to-C-peptide (PI/C) and proIAPP-to-total IAPP (proIAPP/IAPP) ratios measured at 3 months post-transplant were significantly higher in patients who remained insulin dependent at 1 year follow-up. In a mouse model of human islet transplantation, recipient mice that later became hyperglycemic displayed significantly higher PI/C ratios than mice that remained normoglycemic. Histological analysis of islet grafts showed reduced insulin- and proinsulin-positive area, but elevated glucagon-positive area in grafts that experienced greater secretory demand. Increased prohormone convertase 1/3 was detected in glucagon-positive cells, and glucagon-like peptide 1 (GLP-1) area was elevated in grafts from mice that displayed hyperglycemia or elevated plasma PI/C ratio, demonstrating intra-islet incretin production in metabolically challenged human islet grafts. These data indicate that in failing grafts, alpha cell prohormone processing is likely altered, and incomplete beta cell prohormone processing may be an early indicator of insulin dependency.

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“…This approach involves staging of disease progression in at-risk individuals into metabolic "checkpoints" (65,66). The goal of metabolic staging for clinical trial is to identify a window of opportunity for optimal therapeutic intervention with immune therapy and/or b-cell protective agents, aided by the application of new biomarkers of b-cell function such as the proinsulin-to-C-peptide ratio (67,68). Such approaches could complement standard measures such as meal-stimulated C-peptide response, as well as potentially newer, experimental measures of b-cell stress and function in diabetes such as exosomal microRNAs (69).…”

Section: Diabetesjournalsorg/diabetes Cefalu and Associatesmentioning

confidence: 99%

Heterogeneity of Diabetes: β-Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research’s Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases

et al. 2021

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One hundred years have passed since the discovery of insulin—an achievement that transformed diabetes from a fatal illness into a manageable chronic condition. The decades since that momentous achievement have brought ever more rapid innovation and advancement in diabetes research and clinical care. To celebrate the important work of the past century and help to chart a course for its continuation into the next, the Canadian Institutes of Health Research’s Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases recently held a joint international symposium, bringing together a cohort of researchers with diverse interests and backgrounds from both countries and beyond to discuss their collective quest to better understand the heterogeneity of diabetes and thus gain insights to inform new directions in diabetes treatment and prevention. This article summarizes the proceedings of that symposium, which spanned cutting-edge research into various aspects of islet biology, the heterogeneity of diabetic phenotypes, and the current state of and future prospects for precision medicine in diabetes.

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Altered β-Cell Prohormone Processing and Secretion in Type 1 Diabetes

Cited by 32 publications

References 63 publications

Prohormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing

Prohormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing

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

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