The Caspase Selective Inhibitor EP1013 Augments Human Islet Graft Function and Longevity in Marginal Mass Islet Transplantation in Mice

Emamaullee, Juliet; Davis, Joy; Pawlick, Rena; Toso, Christian; Merani, Shaheed; Cai, Sui-Xiong; Tseng, Ben; Shapiro, A.M. James

doi:10.2337/db07-1452

Cited by 60 publications

(46 citation statements)

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“…The present findings are in agreement with several others demonstrating an association between reduced viability and impaired insulin secretion (16,24,30,38,43,46). Indeed, the protective effect of PDTC on insulin secretion occurs in parallel with a reduction in human islet cell death.…”

Section: Discussionsupporting

confidence: 82%

SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets

Hajmrle

Ferdaoussi

Plummer

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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tional modification by the small ubiquitin-like modifier (SUMO) peptides, known as SUMOylation, is reversed by the sentrin/SUMOspecific proteases (SENPs). While increased SUMOylation reduces ␤-cell exocytosis, insulin secretion, and responsiveness to GLP-1, the impact of SUMOylation on islet cell survival is unknown. Mouse islets, INS-1 832/13 cells, or human islets were transduced with adenoviruses to increase either SENP1 or SUMO1 or were transfected with siRNA duplexes to knockdown SENP1. We examined insulin secretion, intracellular Ca 2ϩ responses, induction of endoplasmic reticulum stress markers and inducible nitric oxide synthase (iNOS) expression, and apoptosis by TUNEL and caspase 3 cleavage. Surprisingly, upregulation of SENP1 reduces insulin secretion and impairs intracellular Ca 2ϩ handling. This secretory dysfunction is due to SENP1-induced cell death. Indeed, the detrimental effect of SENP1 on secretory function is diminished when two mediators of ␤-cell death, iNOS and NF-B, are pharmacologically inhibited. Conversely, enhanced SUMOylation protects against IL-1␤-induced cell death. This is associated with reduced iNOS expression, cleavage of caspase 3, and nuclear translocation of NF-B. Taken together, these findings identify SUMO1 as a novel antiapoptotic protein in islets and demonstrate that reduced viability accounts for impaired islet function following SENP1 up-regulation. islets of Langerhans; SUMOylation; inducible nitric oxide synthase; sentrin/SUMO-specific protease 1; SENP1 SMALL UBIQUITIN-RELATED MODIFIER (SUMO) peptides are involved in the posttranslational modification of numerous cellular proteins (19,20,26). SUMO modification, known as SUMOylation, occurs through a cascade of well-characterized enzymatic events that rely on the E2 conjugating enzyme Ubc9 (19,20,22). SUMOylation is made reversible by the sentrin/ SUMO-specific proteases (SENPs), which remove SUMO from target proteins (49). Due to the large number of SUMOylatable targets, the cellular outcomes of SUMO modification are diverse, ranging from the control of DNA repair to the regulation of transcription factors and plasma membrane proteins (9,10,20,28,39,42,44). SUMO1 modification has a negative impact on ␤-cell secretory function (35). Upregulation of SUMO1 decreases insulin gene expression (28, 44), glucagon-like peptide-1 (GLP-1) receptor signaling (42), and both glucose-and exendin-4-stimulated insulin secretion (10, 42), suggesting that deSUMOylation may improve secretory function. Indeed, knockdown of the SUMOylating enzyme Ubc9 enhances exendin-4-stimulated insulin secretion (42), and upregulation of the deSUMOylating enzyme SENP1 increases exocytosis from rodent ␤-cells at low glucose (10, 48). Whether this elevates insulin secretion above that stimulated by glucose is unclear, as SENP1 does not increase ␤-cell exocytosis above the levels seen with high glucose (10). Thus, while increased SUMOylation results in secretory impairment (10, 42, 48), the effect of the deSUMOylating enzyme SENP1 remains unknown.SUMOyla...

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Section: Discussionsupporting

confidence: 82%

SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets

Hajmrle

Ferdaoussi

Plummer

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Loss of insulin secretion and biosynthesis is often associated with increased cell death; this is particularly true for islet transplantation where a significant fraction of the functional mass of islets is lost (Ryan et al 2005). A short treatment with caspase inhibitor reduces apoptosis and promotes long-term islet graft function (Emamaullee et al 2007(Emamaullee et al , 2008. This suggests that the rate of apoptosis and outcome of islet functions are mechanistically linked.…”

Section: Discussionmentioning

confidence: 99%

mTORC1 and mTORC2 regulate insulin secretion through Akt in INS-1 cells

Bacquer

Quéniat

Gmyr

et al. 2012

Journal of Endocrinology

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Regulated associated protein of mTOR (Raptor) and rapamycin-insensitive companion of mTOR (rictor) are two proteins that delineate two different mTOR complexes, mTORC1 and mTORC2 respectively. Recent studies demonstrated the role of rictor in the development and function of b-cells. mTORC1 has long been known to impact b-cell function and development. However, most of the studies evaluating its role used either drug treatment (i.e. rapamycin) or modification of expression of proteins known to modulate its activity, and the direct role of raptor in insulin secretion is unclear. In this study, using siRNA, we investigated the role of raptor and rictor in insulin secretion and production in INS-1 cells and the possible cross talk between their respective complexes, mTORC1 and mTORC2. Reduced expression of raptor is associated with increased glucose-stimulated insulin secretion and intracellular insulin content. Downregulation of rictor expression leads to impaired insulin secretion without affecting insulin content and is able to correct the increased insulin secretion mediated by raptor siRNA. Using dominant-negative or constitutively active forms of Akt, we demonstrate that the effect of both raptor and rictor is mediated through alteration of Akt signaling. Our finding shed new light on the mechanism of control of insulin secretion and production by the mTOR, and they provide evidence for antagonistic effect of raptor and rictor on insulin secretion in response to glucose by modulating the activity of Akt, whereas only raptor is able to control insulin biosynthesis.

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“…The retrieval process itself causes significant ischemic and mechanical injury, rendering islets more susceptible to posttransplant stress (26)(27)(28). The islets are deprived of their vascular supply and microenvironment.…”

mentioning

confidence: 99%

“…The islets are deprived of their vascular supply and microenvironment. However, to be metabolically active, the islets require access to oxygen, nutrients, and other metabolites at a physiological pH and with exclusion of toxic metabolites and oxidative stress (26,28,29). As in the early posttransplant setting, revascularization of transplanted islets has not yet occurred, and the islets are supplied with oxygen by diffusion only; close proximity to a proper vascular system is therefore essential (12,30).…”

mentioning

confidence: 99%

Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone

Schubert

Schmid

Lehmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Here, we evaluate an alternative approach of preconditioning pancreatic islets before transplantation using a potent agonist of growth-hormone-releasing hormone (GHRH) to promote islet viability and function, and we explore the adrenal gland as an alternative transplantation site for islet engraftment. The endocrine microenvironment of the adrenal represents a promising niche with the unique advantages of exceptional high oxygen tension and local antiinflammatory and immunosuppressive properties. GHRH agonists have been shown to promote islet graft survival and function, which may help to reduce the islet mass necessary to reverse diabetes. In the present study, the most potent GHRH agonist MR403 was tested on insulinoma cells, isolated rat islets, and adrenal β-cell cocultures in vitro. GHRH receptor is expressed on both adrenal cells and islets. MR403 caused a significant increase in cell viability and proliferation and revealed an antiapoptotic effect on insulinoma cells. Viability of rat islets was increased after treatment with the agonist and in coculture with adrenal cells. Rat islets were transplanted into diabetic mice to the intraadrenal transplant site and compared with the classical transplants underneath the kidney capsule. Graft function and integration were tested by metabolic follow-up and immunohistochemical staining of intraadrenal grafts. A rapid decrease occurred in blood glucose levels in both models, and all animals reached normoglycemia within the first days after transplantation. Our studies demonstrated that the adrenal may be an attractive site for islet transplantation and that GHRH analogs might allow reduction of the islet mass needed to reverse a diabetic status.β-cell replacement | regenerative therapy | type 1 diabetes mellitus

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The Caspase Selective Inhibitor EP1013 Augments Human Islet Graft Function and Longevity in Marginal Mass Islet Transplantation in Mice

Cited by 60 publications

References 47 publications

SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets

SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets

mTORC1 and mTORC2 regulate insulin secretion through Akt in INS-1 cells

Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone

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