Suppressed Insulin Signaling and Increased Apoptosis in<i>Cd38</i>-Null Islets

Aims/hypothesis The functional maturity of pancreatic beta cells is impaired in diabetes mellitus. We sought to define factors that can influence adult beta cell maturation status and function. Methods MIN6 cells labelled with a Pdx1 monomeric red fluorescent protein-Ins1 enhanced green fluorescent protein dual reporter lentivirus were used to screen candidate growth and/or differentiation factors using image-based approaches with confirmation by real-time RT-PCR and assays of beta cell function using primary mouse islets.Results Activin A strikingly decreased the number of mature beta cells and increased the number of immature beta cells. While activins are critical for pancreatic morphogenesis, their role in adult beta cells remains controversial. In primary islets and MIN6 cells, activin A significantly decreased the expression of insulin and several genes associated with beta cell maturity (e.g. Pdx1, Mafa, Glut2 [also known as Slc2a2]). Genes found in immature beta cells (e.g. Mafb) tended to be upregulated by activin A. Insulin secretion was also reduced by activin A. In addition, activin A-treated MIN6 cells proliferated faster than non-treated cells. The effects of endogenous activin A on beta cells were completely reversed by exogenous follistatin. Conclusions/interpretation These results suggest that autocrine and/or paracrine activin A signalling exerts a suppressive effect on adult beta cell maturation and function. Thus, the maturation state of adult beta cells can be modulated by external factors in culture. Interventions inhibiting activin or its signalling pathways may improve beta cell function. Understanding of maturation and plasticity of adult pancreatic tissue has significant implications for islet regeneration and for in vitro generation of functional beta cells.

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“…Mouse islets were isolated from 10-to 12-week-old C57BL/6J mice as described [25] and cultured overnight in RPMI 1640 with 10% (vol./vol.) FBS.…”

Section: Methodsmentioning

confidence: 99%

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

2010

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“…In addition, insulin has anti-apoptotic as well as enhancing proliferation effects on beta cells of islets (50). To assess whether the feedback-regulating effect on islets beta cells is through transcriptional factor Isl-1, we checked the changes of Isl-1 expression after the cultured NIT cells were treated with insulin, and the results showed that insulin significantly decreased the insulin receptor and Isl-1 gene expressions.…”

Section: Discussionmentioning

confidence: 99%

LIM-homeodomain Transcription Factor Isl-1 Mediates the Effect of Leptin on Insulin Secretion in Mice

Chen

Cui

et al. 2013

Journal of Biological Chemistry

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Background: Leptin and Isl-1 have functions to regulate the insulin secretion, but the interaction between Leptin and Isl-1 remains unknown. Results: Isl-1 mediates the signaling pathway of leptin affecting insulin secretion. Conclusion: Isl-1 and STAT3 are the keynote proteins linking the leptin and insulin signaling networks. Significance: These findings are crucial for understanding the mechanisms of insulin secretion and metabolism.

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“…Similar to ALX3, deficiency of other transcription factors that regulate insulin gene expression and beta cell function also leads to increased beta cell apoptosis and impaired islet function [4]. Increased apoptosis in pancreatic islets can lead to decreased beta cell mass to the point of compromising islet cell function [6,31,32].…”

Section: Discussionmentioning

confidence: 99%

“…In Alx3-deficient mice we observed altered islet architecture, evidenced by mislocalisation of a number of alpha and delta cells found scattered throughout the islet core (not shown). Defects in islet architecture have often been associated with increased beta cell apoptosis [6,31]. Nonetheless, lack of ALX3 may lead to apoptosis by other mechanisms that are unrelated to GCK production.…”

Section: Discussionmentioning

confidence: 99%

Alx3-deficient mice exhibit decreased insulin in beta cells, altered glucose homeostasis and increased apoptosis in pancreatic islets

et al. 2010

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Aims/hypothesis Homeodomain transcription factors play an important role in the regulation of pancreatic islet function. In previous studies we determined that aristaless-like homeobox 3 (ALX3) is produced in islet cells, binds to the promoter of the insulin gene and regulates its expression. The purpose of the present study was to investigate the functional role of ALX3 in pancreatic islets and its possible involvement in the regulation of glucose homeostasis in vivo. Methods Alx3-knockout mice were used. Glucose and insulin tolerance tests were carried out, and serum insulin concentrations were determined. Isolated islets were used to test insulin secretion and gene expression. The pancreatic islets were also studied using both confocal and conventional microscopy. Results ALX3 deficiency resulted in increased blood glucose levels and impaired glucose tolerance in the presence of normal serum insulin concentrations. Insulin, glucagon and glucokinase expression were reduced in Alx3-null pancreatic islets. Reduced insulin content was reflected by decreased insulin secretion from isolated islets. Alx3-deficient islets also showed increased apoptosis, and morphometric analyses indicated that they were, on average, of smaller size than islets from control mice. ALX3 deficiency resulted in reduced beta cell mass. Finally, mature Alx3-null mice developed age-dependent insulin resistance due to impaired peripheral insulin receptor signalling. Conclusions/interpretation ALX3 participates in the regulation of the expression of essential genes for the function of pancreatic islets, and its deficiency alters the regulation of glucose homeostasis in vivo. We suggest that ALX3 constitutes a potential candidate to consider in the aetiopathogenesis of diabetes mellitus.

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Suppressed Insulin Signaling and Increased Apoptosis inCd38-Null Islets

Cited by 48 publications

References 68 publications

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

LIM-homeodomain Transcription Factor Isl-1 Mediates the Effect of Leptin on Insulin Secretion in Mice

Alx3-deficient mice exhibit decreased insulin in beta cells, altered glucose homeostasis and increased apoptosis in pancreatic islets

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