Impaired NH2-Terminal Processing of Human Proislet Amyloid Polypeptide by the Prohormone Convertase PC2 Leads to Amyloid Formation and Cell Death

Marzban, Lucy; Rhodes, Christopher J.; Steiner, Donald F.; Haataja, Leena; Halban, Philippe A.; Verchere, C. Bruce

doi:10.2337/db05-1566

Cited by 95 publications

(107 citation statements)

References 54 publications

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“…Surprisingly, even with rapid islet graft failure and a ∼20% reduction in insulin-positive cells in islet transplants expressing human proIAPP and lacking PC2, we were unable to detect increases in amyloid deposition or beta cell apoptosis. These observations are in contrast with our previous in vitro findings [29]. Mature amyloid fibrils appear to be less deleterious to beta cells than prefibrillar species and improvements in glucose tolerance do not always correlate with reduced amyloid formation [10].…”

Section: Discussioncontrasting

confidence: 56%

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Loss of prohormone convertase 2 promotes beta cell dysfunction in a rodent transplant model expressing human pro-islet amyloid polypeptide

et al. 2016

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Aims/hypothesis A contributor to beta cell failure in type 2 diabetes and islet transplants is amyloid formation by aggregation of the beta cell peptide, islet amyloid polypeptide (IAPP). Similar to the proinsulin processing pathway that generates insulin, IAPP is derived from a prohormone precursor, proIAPP, which requires cleavage by prohormone convertase (PC) 1/3 and PC2 in rodent pancreatic beta cells. We hypothesised that loss of PC2 would promote beta cell death and dysfunction in a rodent model of human beta cell proIAPP overexpression. Methods We generated an islet transplant model wherein immune-deficient mouse models of diabetes received islets expressing amyloidogenic human proIAPP and lacking PC2, leading to restoration of normoglycaemia accompanied by increased secretion of human proIAPP. Blood glucose levels were analysed for up to 16 weeks in transplant recipients and grafts were assessed for islet amyloid and beta cell number and death. Results Hyperglycaemia (blood glucose >16.9 mmol/l) returned in 94% of recipients of islets expressing human proIAPP and lacking PC2, whereas recipients of islets that express human proIAPP and normal PC2 levels remained normoglycaemic for at least 16 weeks. Islet graft failure was accompanied by a ∼20% reduction in insulin-positive cells, yet the degree of amyloid deposition and beta cell apoptosis was similar to those of controls expressing human proIAPP with functional PC2 levels. Conclusions/interpretation PC2 deficiency in transplanted mouse islets expressing human proIAPP promotes beta cell loss and graft failure. Our data suggest that impaired NH 2 -terminal processing and increased secretion of human proIAPP promote beta cell failure.

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Section: Discussioncontrasting

confidence: 56%

“…We have previously demonstrated that cultured human proIAPP-overexpressing islets lacking PC2 develop increased amyloid formation and cell apoptosis compared with islets with normal PC2 levels [29]. We hypothesised that impaired beta cell proIAPP processing would further promote beta cell dysfunction in vivo.…”

Section: Introductionmentioning

confidence: 99%

Loss of prohormone convertase 2 promotes beta cell dysfunction in a rodent transplant model expressing human pro-islet amyloid polypeptide

et al. 2016

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“…Male hIAPP +/− mice on a high-fat diet form islet amyloid and develop amyloid-associated diabetes in about 1 year [20], whereas isolated islets from hIAPP +/− mice form amyloid within days during culture with elevated glucose [7,19,36]. Mice with beta cell-specific Casp8 deletion (RIPcre + Casp8 fl/fl ) were generated from Casp8 fl/fl mice [37] using the Cre/loxP recombinase system [38] and maintained by inter-breeding RIPcre + Casp8 fl/+ mice.…”

Section: Methodsmentioning

confidence: 99%

“…Three major factors contribute to human islet amyloid polypeptide (hIAPP) aggregation in type 2 diabetes: (1) presence of an amyloidogenic sequence in the hIAPP molecule [4]; (2) elevated beta cell production and secretion of hIAPP due to increased insulin demand [16,17]; and (3) impaired prohIAPP processing and/or trafficking due to beta cell dysfunction [17][18][19]. Impaired clearance of secreted hIAPP because of disrupted blood vessels in isolated islets may also potentiate amyloid formation.…”

Section: Introductionmentioning

confidence: 99%

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

et al. 2014

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Aims/hypothesis Reduced beta cell mass due to increased beta cell apoptosis is a key defect in type 2 diabetes. Islet amyloid, formed by the aggregation of human islet amyloid polypeptide (hIAPP), contributes to beta cell death in type 2 diabetes and in islet grafts in patients with type 1 diabetes. In this study, we used human islets and hIAPP-expressing mouse islets with beta cell Casp8 deletion to (1) investigate the role of caspase-8 in amyloid-induced beta cell apoptosis and (2) test whether caspase-8 inhibition protects beta cells from amyloid toxicity. Methods Human islet cells were cultured with hIAPP alone, or with caspase-8, Fas or amyloid inhibitors. Human islets and wild-type or hIAPP-expressing mouse islets with or without caspase-8 expression (generated using a Cre/loxP system) were cultured to form amyloid. Caspase-8 and -3 activation, Fas and FLICE inhibitory protein (FLIP) expression, islet beta cell and amyloid area, IL-1β levels, and the beta:alpha cell ratio were assessed. Results hIAPP treatment induced activation of caspase-8 and -3 in islet beta cells (via Fas upregulation), resulting in apoptosis, which was markedly reduced by blocking caspase-8, Fas or amyloid. Amyloid formation in cultured human and hIAPP-expressing mouse islets induced caspase-8 activation, which was associated with Fas upregulation and elevated islet IL-1β levels. hIAPP-expressing mouse islets with Casp8 deletion had comparable amyloid, IL-1β and Fas levels with those expressing hIAPP and Casp8, but markedly lower beta cell apoptosis, higher beta:alpha cell ratio, greater beta cell area, and enhanced beta cell function. Conclusions/interpretation Beta cell Fas upregulation by endogenously produced and exogenously applied hIAPP aggregates promotes caspase-8 activation, resulting in beta cell apoptosis. The prevention of amyloid-induced caspase-8 activation enhances beta cell survival and function in islets.

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“…Three factors have been proposed to contribute to amyloid formation in type 2 diabetes: (1) presence of an amyloidogenic sequence in the hIAPP molecule [26]; (2) elevated hIAPP production and secretion from beta cells associated with an increased demand for insulin [27][28][29] and (3) impaired prohIAPP processing associated with beta cell dysfunction [28,30,31]. The mechanisms underlying amyloid formation in cultured and transplanted human islets are still unclear but lower clearance of hIAPP secreted from beta cells due to the disrupted vasculature and beta cell dysfunction caused by islet culture and transplantation may contribute to this process.…”

Section: Introductionmentioning

confidence: 99%

The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation

Park

Kieffer

et al. 2012

Diabetologia

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Aims/hypothesis Islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), is associated with beta cell death in type 2 diabetes as well as in cultured and transplanted human islets. Impaired prohIAPP processing due to beta cell dysfunction is implicated in hIAPP aggregation. We examined whether the glucagon-like peptide-1 receptor (GLP-1R) agonist exenatide can restore impaired prohIAPP processing and reduce hIAPP aggregation in cultured human islets and preserve beta cell function/mass during culture conditions used in clinical islet transplantation. Methods Isolated human islets (n010 donors) were cultured with or without exenatide in normal or elevated glucose for 2 or 7 days. Beta cell apoptosis, proliferation, mass, function, cJUN N-terminal kinase (JNK) and protein kinase B (PKB) activation and amyloid formation were assessed. ProhIAPP, its intermediates and mature hIAPP were detected. Results Exenatide-treated islets had markedly lower JNK and caspase-3 activation and beta cell apoptosis, resulting in higher beta/alpha cell ratio and beta cell area than nontreated cultured islets. Exenatide improved beta cell function, manifested as higher insulin response to glucose and insulin content, compared with non-treated cultured islets. Phospho-PKB immunoreactivity was detectable in exenatide-treated but not untreated cultured islets. Islet culture caused impaired prohIAPP processing with decreased mature hIAPP and increased NH 2 -terminally unprocessed prohIAPP levels resulting in higher release of immature hIAPP. Exenatide restored prohIAPP processing and reduced hIAPP aggregation in cultured islets. Conclusions/interpretation Exenatide treatment enhances survival and function of cultured human islets and restores impaired prohIAPP processing in normal and elevated glucose conditions thereby reducing hIAPP aggregation. GLP-1R agonists may preserve beta cells in conditions associated with islet amyloid formation.

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Impaired NH2-Terminal Processing of Human Proislet Amyloid Polypeptide by the Prohormone Convertase PC2 Leads to Amyloid Formation and Cell Death

Cited by 95 publications

References 54 publications

Loss of prohormone convertase 2 promotes beta cell dysfunction in a rodent transplant model expressing human pro-islet amyloid polypeptide

Loss of prohormone convertase 2 promotes beta cell dysfunction in a rodent transplant model expressing human pro-islet amyloid polypeptide

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation

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