## 2 Islet-Derived Chemokines in T1 DM and T2 DM
The C-C subfamily is the largest, and together with the C-X-C family, controls a large portion of leukocyte migration during innate and adaptive immune responses [26, 27]. We note that all chemokine genes expressed in rodent and human pancreatic \(\beta\)-cells that we have examined thus far contain genomic elements recognized by the NF-kB family of transcription factors. This is in agreement with other bioinformatics based approaches [28]. Many chemokine genes also contain either gamma activated sequences (GAS), interferon-stimulated response elements (ISREs) or both types of genomic response elements within their proximal gene promoter regions. Signals that activate NF-kB (e.g., IL-1\(\beta\), TLR2/4 ligands, _etc._) and Type I and II interferons are associated with islet inflammation and \(\beta\)-cell death and dysfunction [29, 30, 31]. Thus, in our view, a broad understanding of pro-inflammatory signal integration at chemokine gene promoters (e.g., in response to IL-1\(\beta\) and IFN-\(\gamma\)) is essential to understanding inflammation in general and for identification of new targets for therapeutic intervention. Transcriptomic technologies (e.g., oligonucleotide microarrays, RNA-sequencing, _etc._) have yielded novel insights into global changes in gene expression patterns in normal pancreatic islets (_i.e._, non-diseased states) _versus_ inflammatory, pathological states [6, 7, 45]. As shown in Table 1, a commonality in various models of disease revealed by transcriptomic studies is that multiple genes encoding chemokines are markedly upregulated in pancreatic islets from various disease models and from islets exposed to either pro-inflammatory cytokines (e.g., IL-1\(\beta\), IFN-\(\gamma\), _etc._) or to fatty acids (e.g., palmitate). Islets isolated for transplantation also display patterns of gene expression that are indicative of inflammation, including \begin{table}
\begin{tabular}{c c c} \hline \hline
**Chemokine** & **Elevated in Circulation During** & **References** \\ \hline CCL2 & Obesity, T1 DM, T2 DM & [32, 33, 34, 35, 36] \\ CXCL1 & Obesity, T1 DM, T2 DM & [18, 37, 38] \\ CXCL2 & Obesity & [39] \\ CXCL10 & T1 DM, T2 DM, Viral Infection & [37, 40, 41, 42, 43, 44] \\ \hline \hline \end{tabular} T1 DM, Type 1 diabetes mellitus; T2 DM, Type 2 diabetes mellitus.  
\end{table} 
Table 2: Chemokines elevated in circulation during pathophysiological states. increased expression of chemokine genes [46]. This is important because immune cell infiltration and/or increased immune cell activity within pancreatic islets or islets at extra-pancreatic sites have been documented in the following situations: islet transplantation, palmitate infusion, STZ-induced \(\beta\)-cell injury, T1 DM, T2 DM, and viral infection. The most likely biochemical reason for infiltration of leukocytes into a tissue is the secretion of a chemoattractant molecule that induces movement of such cells into a site of inflammation [47]. Therefore, it is plausible to postulate that a series of soluble factors (e.g., chemokines) synthesized and secreted directly from \(\beta\)-cells contribute to early and sustained leukocyte modulation via their cognate receptors. Consequently, the insulitis seen in rodents and humans with diabetes mellitus may be a consequence of direct islet \(\beta\)-cell production of chemokines. The transcriptional regulation of specific chemokine genes in pancreatic \(\beta\)-cells exposed to pro-inflammatory stimuli is therefore considered below.