Measurement of Pro-Islet Amyloid Polypeptide (1–48) in Diabetes and Islet Transplants

Courtade, Jaques; Klimek‐Abercrombie, Agnieszka; Chen, Yi‐Chun; Patel, Nirja; Lu, Phoebe Y. T.; Speake, Cate; Orban, Paul C.; Najafian, Behzad; Meneilly, Graydon S.; Greenbaum, Carla J.; Warnock, Garth L.; Panagiotopoulos, Constadina; Verchere, C. Bruce

doi:10.1210/jc.2016-2773

Cited by 35 publications

(47 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to preproinsulin, the signal peptide of preproIAPP is first removed in the ER, creating the 67‐residue IAPP precursor prohormone, proIAPP. We have showed in mice that Pc1/3 first cleaves proIAPP C‐terminal, followed by the removal of the paired basic residues by Cpe to generate a processing intermediate . At the C‐terminus, the glycine overhang is removed and IAPP is amidated by Pam.…”

Section: Islet Endocrine Cell Prohormone Processingmentioning

confidence: 99%

Islet prohormone processing in health and disease

Chen

Taylor

Verchere

2018

Diabetes Obesity Metabolism

Self Cite

View full text Add to dashboard Cite

Biosynthesis of peptide hormones by pancreatic islet endocrine cells is a tightly orchestrated process that is critical for metabolic homeostasis. Like neuroendocrine peptides, insulin and other islet hormones are first synthesized as larger precursor molecules that are processed to their mature secreted products through a series of proteolytic cleavages, mediated by the prohormone convertases Pc1/3 and Pc2, and carboxypeptidase E. Additional posttranslational modifications including C-terminal amidation of the β-cell peptide islet amyloid polypeptide (IAPP) by peptidyl-glycine α-amidating monooxygenase (Pam) may also occur. Genome-wide association studies (GWAS) have showed genetic linkage of these processing enzymes to obesity, β-cell dysfunction, and type 2 diabetes (T2D), pointing to their important roles in metabolism and blood glucose regulation. In both type 1 diabetes (T1D) and T2D, and in the face of metabolic or inflammatory stresses, islet prohormone processing may become impaired; indeed elevated proinsulin:insulin (PI:I) ratios are a hallmark of the β-cell dysfunction in T2D. Recent studies suggest that genetic or acquired defects in proIAPP processing may lead to the production and secretion of incompletely processed forms of proIAPP that could contribute to T2D pathogenesis, and additionally that impaired processing of both PI and proIAPP may be characteristic of β-cell dysfunction in T1D. In islet α-cells, the prohormone proglucagon is normally processed to bioactive glucagon by Pc2 but may express Pc1/3 under certain conditions leading to production of GLP-1(7-36 ). A better understanding of how β-cell processing of PI and proIAPP, as well as α-cell processing of proglucagon, are impacted by genetic susceptibility and in the face of diabetogenic stresses, may lead to new therapeutic approaches for improving islet function in diabetes.

show abstract

Section: Islet Endocrine Cell Prohormone Processingmentioning

confidence: 99%

Islet prohormone processing in health and disease

Chen

Taylor

Verchere

2018

Diabetes Obesity Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…IAPP synthesis and secretion is disproportionately elevated (relative to insulin) in dysfunctional beta cells, including those following transplantation (Stadler et al 2006, Rickels et al 2008. We recently found elevated levels of the intermediate hproIAPP in islet transplant recipients (Courtade et al 2017a), suggesting that impaired proIAPP processing may be a characteristic of transplanted islets, as we and others have suggested may be the case for proinsulin (Davalli et al 2008, Fiorina et al 2008). Because proinsulin:insulin ratios were higher in recipients of fewer islets , it is possible that the secretory stress associated with sub-optimal mass islet transplantation exacerbates islet prohormone processing defects.…”

Section: Iapp Aggregation and Islet Transplant Dysfunctionmentioning

confidence: 76%

“…Indeed, we recently reported disproportionately elevated levels of the proIAPP processing intermediate hproIAPP in T1D (Courtade et al 2017a) suggesting that, along with impaired proinsulin processing (Roder et al 1994, Hartling et al 1997, Truyen et al 2005, Rodriguez-Calvo et al 2017, impaired proIAPP processing may be a characteristic of beta cells in T1D. While IAPP is normally secreted relative to insulin at a molar ratio of approximately 1:100 (Kautzky-Willer et al 1994, Dechenes et al 1998, Knowles et al 2002, Hull et al 2004, the ratio of IAPP:insulin secretion or expression may increase in states of beta cell dysfunction (O'Brien et al 1991, Pieber et al 1993, Hiramatsu et al 1994, Mulder et al 1995a, Ahrén & Gutniak 1997, Hull et al 2004, Krizhanovskii et al 2017.…”

Section: Proiapp Processing and Iapp Epitopesmentioning

confidence: 89%

“…This is plausible given that beta cell dysfunction increase IAPP:insulin ratios (O'Brien et al 1991, Pieber et al 1993, Hiramatsu et al 1994, Mulder et al 1995a, Ahrén & Gutniak 1997 and impairs proIAPP processing (Courtade et al 2017a), and beta cell dysfunction is thought to occur early in T1D (Roder et al 1994, Hartling et al 1997, Keskinen et al 2002, Truyen et al 2005, Ferrannini et al 2010, RodriguezCalvo et al 2017. As TLR signalling and the NLRP3 inflammasome have been implicated in T1D pathogenesis (Tai et al 2016), it follows that, if pre-fibrillar hIAPP aggregates form in T1D, the inflammatory properties of hIAPP aggregates might also play a role in T1D pathology.…”

Section: Journal Of Molecular Endocrinologymentioning

confidence: 99%

See 1 more Smart Citation

IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants

Denroche

Verchere

2018

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Islet amyloid polypeptide (IAPP), the main component of islet amyloid in type 2 diabetes and islet transplants, is now recognized as a contributor to beta cell dysfunction. Increasingly, evidence warrants its investigation in type 1 diabetes owing to both its immunomodulatory and metabolic actions. Autoreactive T cells to IAPP-derived epitopes have been described in humans, suggesting that IAPP is an islet autoantigen in type 1 diabetes. In addition, although aggregates of IAPP have not been implicated in type 1 diabetes, they are potent pro-inflammatory stimuli to innate immune cells, and thus, could influence autoimmunity. IAPP aggregates also occur rapidly in transplanted islets and likely contribute to islet transplant failure in type 1 diabetes through sterile inflammation. In addition, since type 1 diabetes is a disease of both insulin and IAPP deficiency, clinical trials have examined the potential benefits of IAPP replacement in type 1 diabetes with the injectable IAPP analogue, pramlintide. Pramlintide limits postprandial hyperglycemia by delaying gastric emptying and suppressing hyperglucagonemia, underlining the possible role of IAPP in postprandial glucose metabolism. Here, we review IAPP in the context of type 1 diabetes: from its potential involvement in type 1 diabetes pathogenesis, through its role in glucose metabolism and use of IAPP analogues as therapeutics, to its potential role in clinical islet transplant failure and considerations in this regard for future beta cell replacement strategies.

show abstract

“…Recently, accumulation of vesicles containing proinsulin in β‐cells from islet autoantibody positive pancreas donors, suggesting a defect in proinsulin conversion or an accumulation of immature vesicles caused by an increase in insulin demand and/or a dysfunction in vesicular trafficking . In a similar process, accumulation of islet amyloid polypeptide protein (IAPP) and the formation of amyloid fibrils has been associated with disease progression in type 1 diabetes as seen by the increased CD8 T‐cell response to ppIAPP in T1D patients . Moreover, downregulation of derlin1, Hrd1 or p97 were shown to reduce proinsulin degradation, suggesting that these factors may participate to the generation of stress‐induced proinsulin‐derived peptides (Figure ).…”

Section: Degradation and Regulatory Mechanismsmentioning

confidence: 98%

Islet stress, degradation and autoimmunity

Thomaidou

Zaldumbide

Roep

2018

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

β‐cell destruction in type 1 diabetes (T1D) results from the effect of inflammation and autoimmunity. In response to inflammatory signals, islet cells engage adaptive mechanisms to restore and maintain cellular homeostasis. Among these mechanisms, the unfolded protein response (UPR) leads to a reduction of the general protein translation rate, increased production of endoplasmic reticulum chaperones and the initiation of degradation by activation of the ER associated degradation pathway (ERAD) in which newly synthetized proteins are ubiquitinylated and processed through the proteasome. This adaptive phase is also believed to play a critical role in the development of autoimmunity by the generation of neoantigens. While we have previously investigated the effect of stress on transcription, translation and post‐translational events as possible source for neoantigens, the participation of the degradation machinery, yet crucial in the generation of antigenic peptides, remains to be investigated in the context of T1D pathology. In this review, we will describe the relation between the unfolded protein response and the Ubiquitin Proteasome System (UPS) and address the role of the cellular degradation machinery in the generation of antigens. Learning from tumour immunology, we propose how these processes may unmask β‐cells by triggering the generation of aberrant peptides recognized by the immune cells.

show abstract

Measurement of Pro-Islet Amyloid Polypeptide (1–48) in Diabetes and Islet Transplants

Abstract: The β cells in T1D and islet transplants have impaired processing of the proIAPP1-48 intermediate. The ratio of proIAPP1-48-to-IAPP immunoreactivity may have value as a biomarker of β-cell stress and dysfunction.

Cited by 35 publications

References 31 publications

Islet prohormone processing in health and disease

Islet prohormone processing in health and disease

IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants

Islet stress, degradation and autoimmunity

Contact Info

Product

Resources

About