Abstract
BackgroundPancreatic islets are exposed to strong pro-apoptotic stimuli: inflammation and hyperglycemia, during the progression of the autoimmune diabetes (T1D). We found that the Cdk11(Cyclin Dependent Kinase 11) is downregulated by inflammation in the T1D prone NOD (non-obese diabetic) mouse model. The aim of this study is to determine the role of CDK11 in the pathogenesis of T1D and to assess the hierarchical relationship between CDK11 and Cyclin D3 in beta cell viability, since Cyclin D3, a natural ligand for CDK11, promotes beta cell viability and fitness in front of glucose.MethodsWe studied T1D pathogenesis in NOD mice hemideficient for CDK11 (N-HTZ), and, in N-HTZ deficient for Cyclin D3 (K11HTZ-D3KO), in comparison to their respective controls (N-WT and K11WT-D3KO). Moreover, we exposed pancreatic islets to either pro-inflammatory cytokines in the presence of increasing glucose concentrations, or Thapsigargin, an Endoplasmic Reticulum (ER)-stress inducing agent, and assessed apoptotic events. The expression of key ER-stress markers (Chop, Atf4 and Bip) was also determined.ResultsN-HTZ mice were significantly protected against T1D, and NS-HTZ pancreatic islets exhibited an impaired sensitivity to cytokine-induced apoptosis, regardless of glucose concentration. However, thapsigargin-induced apoptosis was not altered. Furthermore, CDK11 hemideficiency did not attenuate the exacerbation of T1D caused by Cyclin D3 deficiency.ConclusionsThis study is the first to report that CDK11 is repressed in T1D as a protection mechanism against inflammation-induced apoptosis and suggests that CDK11 lies upstream Cyclin D3 signaling. We unveil the CDK11/Cyclin D3 tandem as a new potential intervention target in T1D.
Highlights
In Type 1 Diabetes (T1D), the proinflammatory milieu has been reported to impair the functioning of beta cells and induce apoptosis [1,2,3,4]
We confirmed the microarray results by performing quantitative real time PCR assays (Figure 1A) and found that the pancreatic endocrine cells (PEC) from the 11-weekold Non Obese Diabetic (NOD) females exhibited a threefold reduction in the mRNA expression levels of Cdk11 compared to those from age-matched
We performed Quantitative Real-Time PCR (qRT-PCR) to detect Cdk11 in the PECs of the NOD/ SCID islets from the 11-week-old female mice that had been adoptively transferred with increasing amounts of total leukocytes from prediabetic NOD female donors 2 weeks before the islet isolation
Summary
In T1D, the proinflammatory milieu has been reported to impair the functioning of beta cells and induce apoptosis [1,2,3,4]. A series of reports have focused on studying the effects of the main proinflammatory cytokines alone or in combination on the proteome/transcriptome of insulinoma/islet cells in vitro [6,7,8,9]. Those reports included a discrete combination of cytokines that partially resembles the complex inflammatory niche hosting the pancreatic islet; and most studies used insulinoma tumor cell lines. We found that the Cdk11(Cyclin Dependent Kinase 11) is downregulated by inflammation in the T1D prone NOD (non-obese diabetic) mouse model. The aim of this study is to determine the role of CDK11 in the pathogenesis of T1D and to assess the hierarchical relationship between CDK11 and Cyclin D3 in beta cell viability, since Cyclin D3, a natural ligand for CDK11, promotes beta cell viability and fitness in front of glucose
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