Critical role of c-Kit in beta cell function: increased insulin secretion and protection against diabetes in a mouse model

Feng, Zhichao; Li, Jun; Turco, B. A.; Riopel, Matthew; Yee, Siu‐Pok; Wang, R.

doi:10.1007/s00125-012-2566-5

Cited by 43 publications

(52 citation statements)

References 43 publications

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“…In most cases, these studies have been performed using nonspecific mast cell "stabilizers" (48) or Kit mutant mice that, although mast cell-deficient, have other immune (18) and relevant nonimmune abnormalities, which include, notably, the recent discovery of the role of Kit in pancreatic b-cell function (49). Taking into account the pleiotropic abnormalities in Kit mutant mice, it is conceivable that several roles that have been attributed to mast cells are not mast cell-specific, but instead caused by the Kit mutations.…”

Section: Discussionmentioning

confidence: 99%

Type 1 Diabetes in NOD Mice Unaffected by Mast Cell Deficiency

Gutierrez

Schönefeldt

et al. 2014

Diabetes

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Mast cells have been invoked as important players in immune responses associated with autoimmune diseases. Based on in vitro studies, or in vivo through the use of Kit mutant mice, mast cells have been suggested to play immunological roles in direct antigen presentation to both CD4+ and CD8+ T cells, in the regulation of T-cell and dendritic cell migration to lymph nodes, and in Th1 versus Th2 polarization, all of which could significantly impact the immune response against self-antigens in autoimmune disease, including type 1 diabetes (T1D). Until now, the role of mast cells in the onset and incidence of T1D has only been indirectly tested through the use of low-specificity mast cell inhibitors and activators, and published studies reported contrasting results. Our three laboratories have generated independently two strains of mast cell–deficient nonobese diabetic (NOD) mice, NOD.Cpa3Cre/+ (Heidelberg) and NOD.KitW-sh/W-sh (Leuven and Boston), to address the effects of mast cell deficiency on the development of T1D in the NOD strain. Our collective data demonstrate that both incidence and progression of T1D in NOD mice are independent of mast cells. Moreover, analysis of pancreatic lymph node cells indicated that lack of mast cells has no discernible effect on the autoimmune response, which involves both innate and adaptive immune components. Our results demonstrate that mast cells are not involved in T1D in the NOD strain, making their role in this process nonessential and excluding them as potential therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Type 1 Diabetes in NOD Mice Unaffected by Mast Cell Deficiency

Gutierrez

Schönefeldt

et al. 2014

Diabetes

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“…SCF is produced and released by various cells, including fibroblasts, keratinocytes and endothelial cells [10,11]. It has also been reported that into two parts by the kinase insert domain [4,5,[10][11][12][13]. (b) sSCF is generated by cleavage of mSCF (220 or 248) [6-9, 14, 15].…”

Section: Structure Of C-kit and Scfmentioning

confidence: 99%

“…(b) sSCF is generated by cleavage of mSCF (220 or 248) [6-9, 14, 15]. Primary proteolytic cleavage sites are indicated by the arrows both Scf (also known as Kitl) mRNA and protein expression occur in adult mouse islets [12].…”

Section: Structure Of C-kit and Scfmentioning

confidence: 99%

“…Furthermore, W and Sl mutant mice display increased germ cell apoptosis, with a corresponding degree of sterility [41]. More importantly, accumulating evidence suggests that c-Kit expression is also linked to the development of the endocrine pancreas, as well as to beta cell survival and function [11,12,[42][43][44][45][46][47][48][49][50][51][52][53].…”

Section: C-kit Function In Organ Developmentmentioning

confidence: 99%

“…Stimulation of c-Kit activity promoted gene transcription and proliferation in INS-1 rat insulinoma cells [12,46,51]. Furthermore, treatment by exogenous SCF induced differentiation of human pancreatic carcinoma, epithelial-like Fetal islet-epithelium (human)…”

Section: Scf-c-kit In Islet Differentiationmentioning

confidence: 99%

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A survival Kit for pancreatic beta cells: stem cell factor and c-Kit receptor tyrosine kinase

et al. 2015

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The interactions between c-Kit and its ligand, stem cell factor (SCF), play an important role in haematopoiesis, pigmentation and gametogenesis. c-Kit is also found in the pancreas, and recent studies have revealed that c-Kit marks a subpopulation of highly proliferative pancreatic endocrine cells that may harbour islet precursors. c-Kit governs and maintains pancreatic endocrine cell maturation and function via multiple signalling pathways. In this review we address the importance of c-Kit signalling within the pancreas, including its profound role in islet morphogenesis, islet vascularisation, and beta cell survival and function. We also discuss the impact of c-Kit signalling in pancreatic disease and the use of c-Kit as a potential target for the development of cell-based and novel drug therapies in the treatment of diabetes.

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The platelet-derived growth factor (PDGF) family of tyrosine kinase receptors: a Kit to fix the beta cell?

Welsh

2012

Diabetologia

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Overexpression of c-Kit has recently been shown to ameliorate beta cell function by increasing the beta cell mass and insulin secretion, thus counteracting the deleterious effects of a high-fat diet on glucose homeostasis. The c-Kit-dependent effects are due to enhanced Akt activity that phosphorylates and inhibits glycogen synthase kinase 3β (GSK3β), thereby increasing the expression of numerous genes that promote insulin production and cell proliferation. Regulating the c-Kit/Akt/GSK3β pathway may provide novel means for improving beta cell function in type 2 diabetes. The importance of PDGF for beta cells has been known for many years and early studies indicated that PDGF stimulates beta cell replication [4], that this effect is promoted by overexpression of PDGF receptors [5] and that PDGF receptors are expressed in pancreatic epithelial cells during embryonic development [6]. Recently, an age-dependent decrease in PDGF receptor expression was described that diminished the proliferative potential of beta cells, and beta cell-specific inactivation of the gene encoding PDGF receptor α (Pdgfra) aggravated susceptibility to the beta cell toxin streptozotocin [7]. These results implicate PDGF receptors as potential targets for additional treatment regimens for diabetes. This could involve the administration of PDGF ligands and/or increased expression of PDGF receptors in beta cells. KeywordsOur understanding of the involvement of c-Kit in beta cell function has a more recent history. Expression of c-Kit was detected in embryonic pancreatic epithelial cells or adult islets, and the addition of the c-Kit ligand, stem cell factor SCF, to a culture of fetal islet-like structures increased

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Critical role of c-Kit in beta cell function: increased insulin secretion and protection against diabetes in a mouse model

Cited by 43 publications

References 43 publications

Type 1 Diabetes in NOD Mice Unaffected by Mast Cell Deficiency

Type 1 Diabetes in NOD Mice Unaffected by Mast Cell Deficiency

A survival Kit for pancreatic beta cells: stem cell factor and c-Kit receptor tyrosine kinase

The platelet-derived growth factor (PDGF) family of tyrosine kinase receptors: a Kit to fix the beta cell?

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