## 4 Conclusions  
Inflammation is associated with tissue dysfunction in various human diseases, including T1 DM and T2 DM. Inflammatory signaling pathways are inducible within pancreatic islets, promoting alterations in tissue function. If this inflammation does not resolve, eventual losses in overall function and total numbers of islet \(\beta\)-cells leads to overt hyperglycemia, _sine qua non_ for diagnosis of diabetes mellitus. The pancreas is constantly accessible to immune cells [77] and the islet \(\beta\)-cells synthesize chemokines that recruit most, if not all, types of leukocytes. Importantly, innate immune cells, such as macrophages and neutrophils, are also capable of secreting chemokines that support leukocyte infiltration [78,79]. Thus, insulitis is a carefully coordinated event between the tissue being infiltrated (e.g., islets) and the immune cell populations participating in the response. Because leukocytes enter pancreatic islets during various pathophysiologic states, we propose that regulatory signals, such as chemokines, produced by endogenous islet \(\beta\)-cells in response to an inflammatory stimulus (e.g., IL-1\(\beta\)) produce two possible outcomes: (1) a feed-forward cycle of immune cell recruitment and activity that ultimately results in \(\beta\)-cell death and dysfunction; (2) Influencing the activity of leukocytes already present in either endocrine or exocrine tissues. These two possibilities are not mutually exclusive. Islet \(\beta\)-cell production of chemokines is fitting with insulin-positive islets being more strongly associated with insulitis [80,81]. It is thus possible that the inflammatory actions of immune cells are targeted against the \(\beta\)-cells themselves rather than islets in general, which is consistent with data demonstrating that specific genes expressed in \(\beta\)-cells are markers of autoimmune diabetes [82,83]. Because cells of the innate and adaptive immune system are linked to T1 DM [14,84,85], obesity [86,87,88] and T2 DM [12,75], this indicates an overall importance for understanding signals and mechanisms associated with the production of immunomodulatory proteins, such as the chemokines, produced by islet \(\beta\)-cells. Additionally, the pancreatic islets may be impacted by an overall increase in local and/or systemic mediators of inflammation, including in response to viral infection [15], and thus produce chemokines in order to inform the immune system of their response to such stimuli. Therapies to prevent immunological responses targeted against pancreatic islets have thus far included various approaches, such as the targeting of specific enzymes, e.g., HDACs [89] and IKKs [90, 91]. Additionally, antibody-based and low molecular weight inhibitors of chemokine receptors have been suggested as therapeutics to prevent rejection of transplanted islet tissue [92]. Interference with cell surface receptors, such as the IL-1R, has shown promise towards improving islet \(\beta\)-cell function [93, 94]. Novel ligands that activate the intracellular receptors, (e.g., NR3C1 aka glucocorticoid receptor; NR1C3 aka PPAR\(\gamma\), _etc._) may also have a future role in suppressing inflammatory responses that impair islet \(\beta\)-cell mass and function [95, 96, 97]. The use of various botanicals, including polyhedral combinations delivered via the diet [98], also show promise as direct treatments and/or as adjuvants to existing therapeutic strategies. The most efficacious of these approaches remains to be determined. In summary, the production of various chemokines from islet \(\beta\)-cells exposed to pro-inflammatory stimuli, such as cytokines and lipids, likely influences leukocyte activity and infiltration into the pancreas and more specifically into the islets of Langerhans.