**8. Conclusion**

266 Type 1 Diabetes – Complications, Pathogenesis, and Alternative Treatments

(Newsholme et al., 2003) have demonstrated that, in the postabsorptive state, 60% of the amino acids released comprise L-alanine plus L-glutamine (**Fig. 1A**). Therefore, moderate physical exercise, which is known to accelerate the rate of L-glutamine delivery into the circulation, may be of value in protecting L-glutamine/L-arginine metabolic coupling

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

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

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

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

bout of exercise, which is partly mediated by muscle-derived IL-6.

protection against the development of type 1 diabetes.

between the gut and -cells.

**-cells** 

Continued supply of L-arginine, physiologically provided by the metabolism of L-glutamine via the intestinal-renal axis and from skeletal muscle, which is enhanced during exercise, is essential for -cell functional integrity and, indeed, for -cell defence. The dysregulation of immune system function, characteristic of Th1-elicited -cell toxicity and impaired insulin secretion, which accompany the onset of type 1 diabetes, may be triggered when an individual faces a strong **psychological stress** that determines an enhanced L-glutamine utilisation by Th1 lymphocytes. The oxidative stress that takes place upon reduced intracellular GSH levels allows for the activation of NF-B, which, in turn, positively feeds back on iNOS expression and activity, thus perpetuating the inflammatory process within -cells where **excess** NO is harmful. Defective HSP70 induction in response to physiological levels of intraislet NO may also be involved in the pathogenesis of type 1 diabetes. Physical exercise, on the other hand, is capable of inducing a huge production and release of IL-6, which is a key anti-inflammatory mediator that suppresses NF-B-dependent responses. Moreover, exercise-elicited activation of HSP70 biochemical pathways completely blocks NF-B activation, impedes apoptosis and is cytoprotective due to HSP70 chaperone activity, which protects against protein denaturation. HSP70 induction is also associated with enhanced Th2 cell activity over Th1. Metabolically, exercise may restore L-glutamine supply thus normalizing pancreatic production of NO from kidney-derived L-arginine, and not from L-glutamate which is necessary for GSH synthesis and antioxidant defence. Thus the enormous changes in human life style, compared with that of our 3-4 million-old ancestors, could be related with our current inability in maintaining healthy -cells. As previously argued (Krause & Homem de Bittencourt, 2008), we advocate that present-day levels of physical activity and dietary patterns (Simopoulos, 2006; Wisloff et al., 2005) seem to have changed much faster than the time needed to allow evolutionary metabolic changes. In other words, our metabolism evolved to fit a level of physical activity and availability of a variety of food supplies different from those of nowadays (favouring energy conservation and storage). As a corollary, unless humans enhance their pattern of physical activity, diabetes will become more and more of a risk factor in the population. Therefore, the notion that -cells are solely bystanders of oxidative stress-mediated cell toxicity because their antioxidant defences fail in managing physiological stress is an unfortunate misconception. Since the L-glutamine/L-arginine duet may influence -cell function and survival, the knowledge of physiologically adequate levels and fluxes of both amino acids may serve as a predictor of -cell susceptibility to dysfunction or death in diabetes. Additionally, although the possibility of pharmacologically exploiting Th1/Th2 duality relative to L-arginine metabolism may open new avenues for diabetes therapeutics, physical exercise is still the cheapest and easiest physiological measure to avoid the onset and/or worsening of diabetes. In summary, if the prevention of diabetes is dependent on HSP70 expression and

both restoration of adequate L-arginine supply to -cells and blockage of NF-B overstimulation, moderate physical exercise is presented as the most convenient solution for these two lacunes.

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**Part 4** 

**Identification and Monitoring** 

**of Diabetes Mellitus** 

