IL-6 is a pleiotropic cytokine with complex roles in inflammation and metabolic disease. The role of IL-6 as a pro- or anti-inflammatory cytokine is still unclear. Within the pancreatic islet, IL-6 stimulates secretion of the prosurvival incretin hormone glucagon-like peptide 1 (GLP-1) by α cells and acts directly on β cells to stimulate insulin secretion Uncovering physiologic mechanisms promoting β-cell survival under conditions of inflammation and stress can identify important pathways for diabetes prevention and treatment. Given the established role of GLP-1 in promoting β-cell survival, we hypothesized that IL-6 may also directly protect β cells from apoptosis. Herein, we show that IL-6 robustly activates signal transducer and activator of transcription 3 (STAT3), a transcription factor that is involved in autophagy. IL-6 stimulates LC3 conversion and autophagosome formation in cultured β cells. IL-6 infusion stimulates a robust increase in lysosomes in the pancreas that is restricted to the islet. Autophagy is critical for β-cell homeostasis, particularly under conditions of stress and increased insulin demand. The stimulation of autophagy by IL-6 is regulated multiple complementary mechanisms including inhibition of mammalian target of rapamycin complex 1 (mTORC1) and activation of Akt, ultimately leading to increases in autophagy enzyme production. Pretreatment with IL-6 renders β cells resistant to apoptosis induced by proinflammatory cytokines, and inhibition of autophagy with chloroquine prevents the ability of IL-6 to protect from apoptosis. Importantly, we find that IL-6 can activate STAT3 and the autophagy enzyme GABARAPL1 in human islets. We also see evidence of decreased IL-6 pathway signaling in islets from donors with type 2 diabetes. On the basis of our results, we propose direct stimulation of autophagy as a novel mechanism for IL-6-mediated protection of β cells from stress-induced apoptosis.-Linnemann, A. K., Blumer, J., Marasco, M. R., Battiola, T. J., Umhoefer, H. M., Han, J. Y., Lamming, D. W., Davis, D. B. Interleukin 6 protects pancreatic β cells from apoptosis by stimulation of autophagy.

Risk of type 1 diabetes at 3 years is high for initially multiple and single Ab+ IT and multiple Ab+ NT. Genetic predisposition, age, and male sex are significant risk factors for development of Ab+ in twins.

Transcription factor 19 (TCF19) is a gene associated with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in genome-wide association studies. Prior studies have demonstrated that Tcf19 knockdown impairs β-cell proliferation and increases apoptosis. However, little is known about its role in diabetes pathogenesis or the effects of TCF19 gain-of-function. The aim of this study was to examine the impact of TCF19 overexpression in INS-1 β-cells and human islets on proliferation and gene expression. With TCF19 overexpression, there was an increase in nucleotide incorporation without any change in cell cycle gene expression, alluding to an alternate process of nucleotide incorporation. Analysis of RNA-seq of TCF19 overexpressing cells revealed increased expression of several DNA damage response (DDR) genes, as well as a tightly linked set of genes involved in viral responses, immune system processes, and inflammation. This connectivity between DNA damage and inflammatory gene expression has not been well studied in the β-cell and suggests a novel role for TCF19 in regulating these pathways. Future studies determining how TCF19 may modulate these pathways can provide potential targets for improving β-cell survival.

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Transcription factor 19 (Tcf19) is a putative transcription factor associated with both Type 1 and Type 2 diabetes. Tcf19 is expressed in human and rodent pancreatic β‐cells and is upregulated in proliferating islets and obesity. We generated a whole body knockout (wbKO) of Tcf19 and the resulting lean, 15‐week‐old mice have normal fasting glucose, insulin secretion, and glucose tolerance compared to control. RNASeq led to the identification of 733 upregulated and 763 downregulated genes in wbKO islets compared to control. Overrepresented GO terms include upregulated apoptotic process, and negative regulation of cell proliferation, and downregulated vesicle‐mediated transport. We verified markers of proliferation, β‐cell identity, cell stress, and pro‐apoptosis using RTqPCR. Ki67, Pdx1, Nkx6.1, and Nkx2.2 were significantly decreased while Chop, Bak, Gadd45α, and Dtx3l were significantly increased in islets from wbKO mice. Whole pancreas was harvested to measure β‐cell area and although total area is not different, wbKO mice have altered islet size distribution with an increased number of small islets. Next, β‐cell proliferation and apoptosis were measured in frozen pancreatic sections using Ki67 and TUNEL staining, which revealed significantly less proliferation with no change in apoptosis rates in wbKO mice. In adulthood, β‐cell mass expansion occurs due to proliferation as an early compensation for insulin resistance in response to obesity. To determine the role of Tcf19 in this adaptive response wbKO and control mice were put on a one‐week high fat diet (HFD). After one week on HFD, islets from wbKO do not appropriately upregulate Ki67 and cyclin D2 as measured by RTqPCR. In summary, Tcf19 is involved in proliferation and stress related processes both of which are involved in regulating β‐cell mass, which declines in Type 1 and Type 2 diabetes. Support or Funding Information VA Merit Award 1I01BX001880VA Merit Award 1I01BX004715TL1 Award TR000429ICTR Clinical and Translational Science Award UL1TR000427NIDDK 5R01DK110324