Secreted Frizzled-Related Protein 4 Reduces Insulin Secretion and Is Overexpressed in Type 2 Diabetes

Mahdi, Taman; Hänzelmann, Sonja; Salehi, Albert; Muhammed, Sarheed Jabar; Reinbothe, Thomas; Tang, Yunzhao; Axelsson, A.; Zhou, Yunan; Jing, Xuefang; Almgren, Peter; Krus, Ulrika; Taneera, Jalal; Blom, Anna M.; Lyssenko, Valeriya; Esguerra, Jonathan L.S.; Hansson, Ola; Eliasson, Lena; Derry, Jonathan M.J.; Zhang, Enming; Wollheim, Claes B.; Groop, Leif; Renström, Erik; Rosengren, Anders H.

doi:10.1016/j.cmet.2012.10.009

Cited by 170 publications

(195 citation statements)

References 45 publications

Supporting

Mentioning

169

Contrasting

Unclassified

Order By: Relevance

“…At any rate, little is known about the role of SFRP5 in the control of Wnt signalling in pancreatic beta cells. Only one recent study reported another SFRP gene, SFRP4 , as overexpressed in pancreatic islets taken from type 2 diabetic patients, but the authors did not find any changes in SFRP5 [16].…”

Section: Introductionmentioning

confidence: 92%

Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat

et al. 2013

View full text Add to dashboard Cite

Aims/hypothesis During obesity, the increment in beta cell mass in response to the rising demand for insulin is essential to maintain normal glucose homeostasis. However, the precise cellular and molecular mechanisms involved in beta cell mass plasticity remain poorly understood. The Wnt signalling pathway has been suggested as one possible modulator of beta cell proliferation, which represents the principal process involved in beta cell mass expansion. Here, we sought to determine the mechanisms involved in beta cell mass proliferation using diet-induced obese rats. Methods Wistar rats aged 8 weeks old were fed a standard or cafeteria diet. Global transcriptomic analysis of pancreatic rat islets was performed using microarray analysis. Genetic lossof-function approaches were performed in dispersed primary rat islets and the beta cell line INS1E. Gene expression was measured by real-time PCR, protein levels by immunoblot analysis, proliferation rates by ELISA and apoptosis by flow cytometry. Results Sfrp5, coding for secreted frizzled-related protein 5, is downregulated in the pancreatic islets of cafeteria-diet-fed rats as well as in the pancreatic islets of human obese patients. We demonstrate that silencing Sfrp5 increases beta cell proliferation, which correlates with activation of Wnt signalling and enhanced levels of proliferation markers. In addition, we show that expression of Sfrp5 in beta cells is modulated by IGF binding protein 3 (IGFBP3) secreted from visceral adipose tissue. Conclusions/interpretation Together, these findings reveal an important role for SFRP5 and Wnt signalling in the regulation of beta cell proliferation in obesity.

show abstract

Section: Introductionmentioning

confidence: 92%

Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat

et al. 2013

View full text Add to dashboard Cite

show abstract

“…D, BMDMs were treated with LPS (10 ng/ml) for 3 h (signal 1) followed by the indicated activation stimulus for 16 h (signal 2). E, BMDMs were treated with the indicated priming stimulus (signal 1) for 3 h followed by 1 h or (F) 16 deposition was present, as in obese hIAPP transgenic mice (26). Thus, two distinct species of aggregated hIAPP each provide one of the two signals necessary for IL-1␤ secretion.…”

Section: Discussionmentioning

confidence: 99%

“…Increased expression of IL-1-related genes is a characteristic of islets from patients with type 2 diabetes (16). Remarkably, multiple clinical trials have now demonstrated improved insulin secretion in response to anti-IL-1 therapy with no detectable effects on insulin resistance (17).…”

mentioning

confidence: 99%

Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates

Westwell‐Roper¹,

Denroche

Ehses

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Aggregation of islet amyloid polypeptide (IAPP) contributes to beta cell dysfunction in type 2 diabetes and islet transplantation. Like other amyloidogenic peptides, human IAPP induces macrophage IL-1␤ secretion by stimulating both the synthesis and processing of proIL-1␤, a pro-inflammatory cytokine that (when chronically elevated) impairs beta cell insulin secretion. We sought to determine the specific mechanism of IAPP-induced proIL-1␤ synthesis. Soluble IAPP species produced early during IAPP aggregation provided a Toll-like-receptor-2-(TLR2-) dependent stimulus for NF-B activation in HEK 293 cells and bone marrow-derived macrophages (BMDMs). Nonamyloidogenic rodent IAPP and thioflavin-T-positive fibrillar amyloid produced by human IAPP aggregation failed to activate TLR2. Blockade of TLR6 but not TLR1 prevented hIAPP-induced TLR2 activation, consistent with stimulation of a TLR2/6 heterodimer. TLR2 and its downstream adaptor protein MyD88 were required for IAPP-induced cytokine production by BMDMs, a process that is partially dependent on autoinduction by IL-1. BMDMs treated with soluble but not fibrillar IAPP provided a TLR2-dependent priming stimulus for ATP-induced IL-1␤ secretion, whereas late IAPP aggregates induced NLRP3-dependent IL-1␤ secretion by LPS-primed macrophages. Moreover, inhibition of TLR2 and depletion of islet macrophages prevented up-regulation of Il1b and Tnf expression in human IAPP-expressing transgenic mouse islets. These data suggest participation by both soluble and fibrillar aggregates in IAPPinduced islet inflammation. IAPP-induced activation of TLR2 and secretion of IL-1 may be important therapeutic targets to prevent amyloid-associated beta cell dysfunction.

show abstract

“…They have nonetheless pointed at a central role of the pancreatic islets and β-cell dysfunction in the development of the disease (4,5). It therefore seems pertinent to focus on human pancreatic islets to obtain insights into the molecular mechanisms causing the disease (6,7). Given that most SNPs associated with T2D lie in noncoding regions, the majority of causal variants are likely to regulate gene expression rather than protein function per se.…”

mentioning

confidence: 99%

Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism

Fadista

Vikman

Laakso

et al. 2014

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

Self Cite

407

535

View full text Add to dashboard Cite

Genetic variation can modulate gene expression, and thereby phenotypic variation and susceptibility to complex diseases such as type 2 diabetes (T2D). Here we harnessed the potential of DNA and RNA sequencing in human pancreatic islets from 89 deceased donors to identify genes of potential importance in the pathogenesis of T2D. We present a catalog of genetic variants regulating gene expression (eQTL) and exon use (sQTL), including many long noncoding RNAs, which are enriched in known T2D-associated loci. Of 35 eQTL genes, whose expression differed between normoglycemic and hyperglycemic individuals, siRNA of tetraspanin 33 (TSPAN33), 5′-nucleotidase, ecto (NT5E), transmembrane emp24 protein transport domain containing 6 (TMED6), and p21 protein activated kinase 7 (PAK7) in INS1 cells resulted in reduced glucose-stimulated insulin secretion. In addition, we provide a genome-wide catalog of allelic expression imbalance, which is also enriched in known T2D-associated loci. Notably, allelic imbalance in paternally expressed gene 3 (PEG3) was associated with its promoter methylation and T2D status. Finally, RNA editing events were less common in islets than previously suggested in other tissues. Taken together, this study provides new insights into the complexity of gene regulation in human pancreatic islets and better understanding of how genetic variation can influence glucose metabolism.T ype 2 diabetes (T2D) is an increasing global health problem (1). Although genome-wide association studies (GWAS) have yielded more than 70 loci associated with T2D or related traits (2, 3), they have not provided the expected breakthrough in our understanding of the pathogenesis of the disease. They have nonetheless pointed at a central role of the pancreatic islets and β-cell dysfunction in the development of the disease (4, 5). It therefore seems pertinent to focus on human pancreatic islets to obtain insights into the molecular mechanisms causing the disease (6, 7). Given that most SNPs associated with T2D lie in noncoding regions, the majority of causal variants are likely to regulate gene expression rather than protein function per se. Therefore, combination of DNA and RNA sequencing in the same individuals may help to disentangle the role these SNPs play in the pathogenesis of the disease (8). Although the human pancreatic islet transcriptome has been previously described (6, 9-18), using microarrays or RNA sequencing of a limited number of nondiabetic individuals, this has not allowed a more global analysis of the complexity of the islet transcriptome in T2D. Here we combined genotypic imputation, expression microarrays, and exome and RNA sequencing (ExomeSeq and RNA-Seq) in a large number of human pancreatic islets from deceased donors with and without T2D. This study identified a number of novel genes, including long intergenic noncoding RNAs (lincRNAs), whose expression and/or splicing influences insulin secretion and is associated with glycemia. In addition, we provide a catalog of RNA editing and allele-specific expr...

show abstract

Secreted Frizzled-Related Protein 4 Reduces Insulin Secretion and Is Overexpressed in Type 2 Diabetes

Cited by 170 publications

References 45 publications

Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat

Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat

Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates

Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism

Contact Info

Product

Resources

About