Transforming Growth Factor-β/Smad3 Signaling Regulates Insulin Gene Transcription and Pancreatic Islet β-Cell Function

Lin, Huei-Min; Lee, Ji-Hyeon; Yadav, Hariom; Kamaraju, Anil K.; Liu, Eric; Duan, Zhenfeng; Vieira, Anthony; Kim, Seong‐Jin; Collins, Heather W.; Matschinsky, Franz M.; Harlan, David M.; Roberts, Anita B.; Rane, Sushil G.

doi:10.1074/jbc.m805379200

Cited by 157 publications

(171 citation statements)

References 55 publications

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“…Similarly, Glut2 was significantly decreased in Pdx1 + /Ins low immature beta cells [1]. Consistent with our findings, Glut2 was elevated in Smad3 knockout islets [38]. A strong reduction in Glut2 expression is an early indicator of beta cell stress and possibly dedifferentiation in many mouse models of glucose intolerance or diabetes [45], including mice with reduced Pdx1 [46].…”

Section: Discussionsupporting

confidence: 89%

“…Follistatin increased the expression of these genes. Consistent with these negative effects of activin A, the TGFβ/SMAD pathway is known to restrict pancreatic progenitor specification, in part by restraining Pdx1 expression during early embryonic development [37] genes and also that downregulation of Smad3 improved beta cell function [38]. Bone morphogenetic protein (BMP) signalling, also mediated via SMADs, prevented beta cell differentiation in zebrafish [39].…”

Section: Discussionmentioning

confidence: 93%

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

2010

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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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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 93%

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

2010

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“…In line with our observation that Smad3 overexpression suppresses GSIS, a previous study reported that pancreatic islets isolated from Smad3 knockout mice showed enhanced insulin secretion in response to glucose as well as altered expression of several genes involved in beta cell function [38]. On the other hand, overexpression in adult islets of Smad7, which inhibits Smad signalling by all TGF-β superfamily proteins, has been shown to reduce GSIS by affecting islet insulin content and the expression of several key genes for beta cell function, such as Mafa and Menin (also known as Men1) [39].…”

Section: Discussionsupporting

confidence: 73%

Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by activin ligands

Mezghenna

Mármol

et al. 2013

Diabetologia

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Aims/hypothesis Glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells is regulated by paracrine factors, the identity and mechanisms of action of which are incompletely understood. Activins are expressed in pancreatic islets and have been implicated in the regulation of GSIS. Activins A and B signal through a common set of intracellular components, but it is unclear whether they display similar or distinct functions in glucose homeostasis. Methods We examined glucose homeostatic responses in mice lacking activin B and in pancreatic islets derived from these mutants. We compared the ability of activins A and B to regulate downstream signalling, ATP production and GSIS in islets and beta cells. Results Mice lacking activin B displayed elevated serum insulin levels and GSIS. Injection of a soluble activin B antagonist phenocopied these changes in wild-type mice. Isolated pancreatic islets from mutant mice showed enhanced GSIS, which could be rescued by exogenous activin B. Activin B negatively regulated GSIS and ATP production in wild-type islets, while activin A displayed the opposite effects. The downstream mediator Smad3 responded preferentially to activin B in pancreatic islets and beta cells, while Smad2 showed a preference for activin A, indicating distinct signalling effects of the two activins. In line with this, overexpression of Smad3, but not Smad2, decreased GSIS in pancreatic islets. Conclusions/interpretation These results reveal a tug-of-war between activin ligands in the regulation of insulin secretion by beta cells, and suggest that manipulation of activin signalling could be a useful strategy for the control of glucose homeostasis in diabetes and metabolic disease.

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“…Our results show that pancreatic islets in mice are affected by systemic aging, and aged mice exhibit age-dependent deterioration of glucose homeostasis, despite beta cells being fully competent in advanced age. In particular, aged mice were insulin-resistant and glucoseintolerant, although intolerance was only observed when aged mice were forced to release more insulin; for example, after a higher glucose load (37,38). Our results concur with those of several previous studies (3,5,6,39) but contrast with studies reporting insulin secretory defects with age (1,2,4,8).…”

Section: Discussioncontrasting

confidence: 57%

Young capillary vessels rejuvenate aged pancreatic islets

Almaça

Molina

Drigo

et al. 2014

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

116

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Pancreatic islets secrete hormones that play a key role in regulating blood glucose levels (glycemia). Age-dependent impairment of islet function and concomitant dysregulation of glycemia are major health threats in aged populations. However, the major causes of the age-dependent decline of islet function are still disputed. Here we demonstrate that aging of pancreatic islets in mice and humans is notably associated with inflammation and fibrosis of islet blood vessels but does not affect glucose sensing and the insulin secretory capacity of islet beta cells. Accordingly, when transplanted into the anterior chamber of the eye of young mice with diabetes, islets from old mice are revascularized with healthy blood vessels, show strong islet cell proliferation, and fully restore control of glycemia. Our results indicate that beta cell function does not decline with age and suggest that islet function is threatened by an age-dependent impairment of islet vascular function. Strategies to mitigate age-dependent dysregulation in glycemia should therefore target systemic and/or local inflammation and fibrosis of the aged islet vasculature.A ging leads to progressive decline of various homeostatic processes in mammals, including a deteriorating regulation of blood glucose levels. Pancreatic islets are small organs composed of endocrine cells that secrete the major hormones insulin, glucagon, and somatostatin, which play a key role in regulating blood glucose levels. Age-dependent dysfunction of islets and the concomitant dysregulation of blood glucose levels increase the risk for type 2 diabetes (1), which in turn contributes to other age-related chronic diseases. In general, it has been assumed that aging causes an intrinsic dysfunction of the insulin-secreting beta cells through reduced proliferative capacity and/or defective insulin secretion (1-9). However, there have been numerous reports that age-dependent impairment of glucose homeostasis is not just a result of intrinsic, age-dependent dysfunction of islets but is also caused by systemic factors. For example, islet function may be compromised by age-related increases in adiposity (10, 11) and by bloodborne factors (12), or it could be affected indirectly by agerelated deficiencies in vascular remodeling (13). Thus, the replicative decline of old pancreatic beta cells can be attributed to systemic factors (12). Recent studies identified factors present in young blood that reverse age-related cognitive impairments and induce vascular remodeling and regeneration in the brain and skeletal muscle (14-16), but so far it has not been feasible to discriminate systemic influences from aging factors intrinsic to islet endocrine cells. Here we address the long-standing question of whether the age-dependent impairment of glucose homeostasis is caused by intrinsic, age-dependent dysfunction of islets or by systemic aging factors.Our strategy to discern age-related intrinsic changes in islet function was to study islets from young mature (2 mo) and aged (18 mo) mice and to fol...

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Transforming Growth Factor-β/Smad3 Signaling Regulates Insulin Gene Transcription and Pancreatic Islet β-Cell Function

Cited by 157 publications

References 55 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

Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by activin ligands

Young capillary vessels rejuvenate aged pancreatic islets

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