**7. Influence of regular physical exercise in L-arginine/L-glutamine coupling in -cells**

During physical exercise sessions, pro-inflammatory cytokine production is downregulated and anti-inflammatory cytokines, such as IL-1 receptor antagonist (IL-1ra), IL-10 and IL-6, are upregulated (Drenth et al., 1995; Nieman & Pedersen, 1999; Rohde et al., 1997). In this sense, IL-6 seems to play a capital role during exercise-induced changes in immune function. In fact, the level of circulating IL-6 has been shown to increase dramatically (up to 100-fold) in response to exercise (Pedersen & Hoffman-Goetz, 2000; Febbraio et al., 2002; Pedersen & Steensberg, 2002; Pedersen et al., 2001). Most studies have also reported that exercise, *per se*, does not increase plasma levels of TNF, although some have shown that strenuous, prolonged exercise, such as marathon running, results in a small increase in the plasma concentration of TNF (Pedersen et al., 1998; Suzuki et al., 2000). This long-term effect of exercise may be ascribed to the anti-inflammatory response elicited by an acute bout of exercise, which is partly mediated by muscle-derived IL-6.

Physiological concentrations of IL-6 stimulate the appearance, in the circulation, of the antiinflammatory cytokines IL-1ra and IL-10, and inhibit the production of the proinflammatory cytokine TNF. Hence, exercise-induced IL-6 release downregulates proinflammatory cytokine production while increasing anti-inflammatory cytokine production and action, which may induce a very strong anti-inflammatory cytokine response. The main modulator of these responses is likely to be the appearance of IL-6 in the circulation. Since IL-6 strongly downregulates NF-B activation, we believe that moderate exercise-induced IL-6 production may suppress NF-B-dependent iNOS while stimulating L-arginase activity/expression with a consequent decrease in NO-dependent -cell death upon Th1 driven -cell assault. Therefore, besides any possible beneficial effect that moderate exercise may have on L-glutamine/L-arginine coupling that is responsible for the maintenance of -cell redox homeostasis and insulin secreting capacity (see above), mild physical exercise may shut off pro-inflammatory cytokine machinery, which gives rise to an additional protection against the development of type 1 diabetes.

Even though the effects of IL-6 on -cells remains a matter of debate and controversies (Wadt et al., 1998), it has been found that IL-6 hinders the development of type 1 diabetes in different mouse models (Campbell et al., 1994; DiCosmo et al., 1994). Moreover, IL-6 has proven to be effective in protecting insulin-secreting MIN6 cells and freshly isolated pancreatic islets against Th1-derived cytokine (IL-1, TNF and IFN) induced apoptosis while improving cellular viability and insulin secretion (Choi et al., 2004). Altogether, the above propositions support an important protective effect of exercise-dependent muscle-derived IL-6 on -cells against the development of diabetes. Moreover, exercise-induced HSP70 expression in non-muscular cells may have a critical influence in maintaining an anti-inflammatory status, as discussed above. However, exercise-induced HSP70 in pancreatic -cells has never been addressed. Therefore, we are currently evaluating the effects of acute and chronic (training) exercise sessions (swimming) on HSP70 pathways and L-glutamine/L-arginine coupling enzymes in animal pancreatic islets and isolated -cells.
