The pancreatic β cell and type 1 diabetes: innocent bystander or active participant?

Soleimanpour, Scott A.; Stoffers, Doris A.

doi:10.1016/j.tem.2013.03.005

Cited by 59 publications

(44 citation statements)

References 99 publications

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“…These include several genes near DNA sequence variants (single nucleotide polymorphisms; SNPs) implicated by genome-wide association studies (GWAS) in genetic susceptibility to type 1 (T1D) and type 2 diabetes (T2D). These data support current views of the importance of islet (dys)regulation in T2D pathophysiology [19] and have rekindled interest in potential roles for islet transcriptional dysregulation in early or progressive pathophysiologic events leading to T1D [7], [20]. MicroRNA (miRNA) have also been profiled in human islets [21], [22]; a recent review describes their roles in post-transcriptional regulation and islet biology [23].…”

Section: The Expanding Islet Transcriptomesupporting

confidence: 61%

Transcriptional Regulation of the Pancreatic Islet: Implications for Islet Function

et al. 2015

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Islets of Langerhans contain multiple hormone-producing endocrine cells controlling glucose homeostasis. Transcription establishes and maintains islet cellular fates and identities. Genetic and environmental disruption of islet transcription triggers cellular dysfunction and disease. Early transcriptional regulation studies of specific islet genes, including insulin (INS) and the transcription factor PDX1, identified the first cis-regulatory DNA sequences and trans-acting factors governing islet function. Here, we review how human islet “omics” studies are reshaping our understanding of transcriptional regulation in islet (dys)function and diabetes. First, we highlight the expansion of islet transcript number, form, and function and of DNA transcriptional regulatory elements controlling their production. Next, we cover islet transcriptional effects of genetic and environmental perturbation. Finally, we discuss how these studies’ emerging insights should empower our diabetes research community to build mechanistic understanding of diabetes pathophysiology and to equip clinicians with tailored, precision medicine options to prevent and treat islet dysfunction and diabetes.

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Section: The Expanding Islet Transcriptomesupporting

confidence: 61%

Transcriptional Regulation of the Pancreatic Islet: Implications for Islet Function

et al. 2015

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“…ER stress in turn may serve as a trigger for autoimmunity (Tersey et al, 2012). The expression of ~60% of T1DM-associated genes in pancreatic islets further supports that the β-cell is more than an innocent bystander in its own demise, (Eizirik et al, 2012; Soleimanpour and Stoffers, 2013). …”

Section: Discussionmentioning

confidence: 70%

“…While T1DM is an autoimmune disease, many T1DM-associated genes are expressed in pancreatic β-cells, suggesting functions directly in β-cells that may contribute to disease pathogenesis (Eizirik et al, 2009; Soleimanpour and Stoffers, 2013). We previously found that Clec16a is expressed in pancreatic islets and that its expression is reduced in Pdx1 +/− islets (Sachdeva et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

The Diabetes Susceptibility Gene Clec16a Regulates Mitophagy

Soleimanpour

Gupta

Bakay

et al. 2014

Cell

186

232

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SUMMARY Clec16a has been identified as a disease susceptibility gene for type 1 diabetes, multiple sclerosis and adrenal dysfunction, but its function is unknown. Here we report that Clec16a is a membrane-associated endosomal protein that interacts with E3 ubiquitin ligase Nrdp1. Loss of Clec16a leads to an increase in the Nrdp1 target Parkin, a master regulator of mitophagy. Islets from mice with pancreas-specific deletion of Clec16a have abnormal mitochondria with reduced oxygen consumption and ATP concentration, both of which are required for normal β-cell function. Indeed, pancreatic Clec16a is required for normal glucose-stimulated insulin release. Moreover, patients harboring a diabetogenic SNP in the Clec16a gene have reduced islet Clec16a expression and reduced insulin secretion. Thus, Clec16a controls β-cell function and prevents diabetes by controlling mitophagy. This novel pathway could be targeted for prevention and control of diabetes and may extend to the pathogenesis of other Clec16a and Parkin associated diseases.

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“…This cytokine cocktail induces expression of genes encoding for IL-12 and IFNγ in islets and beta cells [27]. With relevance to clinical diabetes, inflammation is a recognised component of the development of both type 1 and type 2 diabetes [1][2][3]. Concomitant with beta cell dysfunction and decreased islet survival, inflammatory cytokine stimulation increased 12-lipoxygenase gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…Islet inflammation is a key contributor to loss of functional pancreatic beta cell mass in both type 1 and type 2 diabetes [1][2][3]. Studies have implicated inflammatory cytokines and immune cell infiltration leading to pathways, including oxidative and endoplasmic reticulum (ER) stress activation, that damage beta cell viability [4][5][6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

et al. 2014

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Aims/hypothesis Islet inflammation leads to loss of functional pancreatic beta cell mass. Increasing evidence suggests that activation of 12-lipoxygenase leads to inflammatory beta cell loss. This study evaluates new specific small-molecule inhibitors of 12-lipoxygenase for protecting rodent and human beta cells from inflammatory damage. Methods Mouse beta cell lines and mouse and human islets were treated with inflammatory cytokines IL-1β, TNFα and IFNγ in the absence or presence of novel selective 12-lipoxygenase inhibitors. Glucose-stimulated insulin secretion (GSIS), gene expression, cell survival and 12-Shydroxyeicosatetraenoic acid (12-S-HETE) levels were evaluated using established methods. Pharmacokinetic analysis was performed with the lead inhibitor in CD1 mice. Results Inflammatory cytokines led to the loss of human beta cell function, elevated cell death, increased inflammatory gene expression and upregulation of 12-lipoxygenase expression and activity (measured by 12-S-HETE generation). Two 12-lipoxygenase inhibitors, Compounds 5 and 9, produced a concentration-dependent reduction of stimulated 12-S-HETE levels. GSIS was preserved in the presence of the 12-lipoxygenase inhibitors. 12-Lipoxygenase inhibition preserved survival of primary mouse and human islets. When administered orally, Compound 5 reduced plasma 12-S-HETE in CD1 mice. Compounds 5 and 9 preserved the function and survival of human donor islets exposed to inflammatory cytokines. Conclusions/interpretation Selective inhibition of 12-lipoxygenase activity confers protection to beta cells during exposure to inflammatory cytokines. These concept validation studies identify 12-lipoxygenase as a promising target in the prevention of loss of functional beta cells in diabetes.

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The pancreatic β cell and type 1 diabetes: innocent bystander or active participant?

Cited by 59 publications

References 99 publications

Transcriptional Regulation of the Pancreatic Islet: Implications for Islet Function

Transcriptional Regulation of the Pancreatic Islet: Implications for Islet Function

The Diabetes Susceptibility Gene Clec16a Regulates Mitophagy

Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

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