## 2 Islet-Derived Chemokines in T1 DM and T2 DM  
Pancreatic islets isolated from various rodent models of diabetes reveal the expression of genes linked to immune cell recruitment and \(\beta\)-cell dysfunction; islets isolated from human diabetic subjects show similar elevated gene expression patterns (Table 1). In addition, isolated rodent and human pancreatic islets exposed to either cytokines or elevated lipid levels display an increase in a variety of inflammatory markers, which includes elevated expression of specific genes linked to leukocyte recruitment. While the ability of pro-inflammatory cytokines (e.g., IL-1\(\beta\) and IFN-\(\gamma\)), and excess lipid (e.g., palmitate) to \begin{table}
\begin{tabular}{c c c c c} \hline \hline \multirow{2}{*}{**Chemokine**} & **Chemokine** & **Immune Cell** & \multirow{2}{*}{**Elevated in Islets During**} & \multirow{2}{*}{**References**} \\  & **Receptor** & **Recruited** & & \\ \hline \multirow{2}{*}{CCL2} & \multirow{2}{*}{CCR2} & Monocyte/macrophage/ & Chemical Induction, Cytokine Exposure, & \\  & & T-lymphocyte & T1 DM, T2 DM & \\ \multirow{2}{*}{CXCL1} & \multirow{2}{*}{CXCR2} & \multirow{2}{*}{Neutrophil} & Cytokine Exposure, T1 DM, & \\  & & & T2 DM, Viral Infection & \\ \multirow{2}{*}{CXCL2} & \multirow{2}{*}{CXCR2} & \multirow{2}{*}{Neutrophil} & Cytokine Exposure, T1 DM, T2 DM & \\  & & & Chemical Induction, Cytokine Exposure, & \\ \multirow{2}{*}{CXCL10} & \multirow{2}{*}{CXCR3} & \multirow{2}{*}{T-lymphocyte} & \multirow{2}{*}{T1 DM, T2 DM, Viral Infection} & \multirow{2}{*}{[10, 13, 15, 17, 18, 19, 20, 21]} \\ \hline \hline \end{tabular}
\begin{tabular}{c c c} \hline \hline \multirow{2}{*}{Chemical induction includes: Alloxan, high-dose streptozotocinocin, and/or multiple low-dose streptozotocinocin injection.} \\ \multirow{2}{*}{Cytokine exposure includes IL-1\(\beta\), IFN-\(\gamma\), TNF-\(\alpha\), or combinations of these molecules. T1 DM, Type 1 diabetes mellitus; T2 DM, Type 2 diabetes mellitus.} \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Chemokines elevated in pancreatic islets during pathophysiological states. Figure 1: Rise in the number of publications involving chemokines, diabetes, and islet inflammation over a recent 15 year period. The number of publications (y-axis) identified using the search string shown in quotations above each graph (**A** and **B**) is shown by year (x-axis). suppress glucose-stimulated insulin secretion has been observed for more than a decade [22, 23, 24], less is known about the transcriptional reprogramming associated with inflammatory stimuli that lead to losses in islet \(\beta\)-cell function and mass. One major class of genes, which are rapidly activated in response to pancreatic \(\beta\)-cell exposure to inflammatory stimuli, encode the chemotactic cytokine (aka chemokines) family of soluble, secreted, signaling proteins. Increasing the production and cellular release of specific chemokines influences immune cell movement and immunological activity. Once secreted, chemokines influence both innate and adaptive immune cell recruitment and activity by signaling through specific G-protein coupled receptors (GPCRs). For example, inducing \(\beta\)-cell damage using the multiple low dose streptozotocin protocol promotes global chemokine production within pancreatic islets, which leads to leukocyte recruitment, \(\beta\)-cell death, and hyperglycemia [4]. Additionally, several chemokines are elevated in the circulation of rodents and humans during diverse pathophysiological states (Table 2). The chemokines are separated into four categories based on the positioning of their first cysteine residue: C chemokines have no adjacent Cys, while C-C chemokines have the first two Cys residues (out of four total) adjacent to each other; the C-X-C and CX\({}_{3}\)C chemokines contain intramolecular cysteine residues separated by one or three amino acids, respectively [25].