[MUSIC] My name is Bente Klarlund Pedersen, I'm a medical doctor specialized in infectious diseases. And I'm a professor of Integrative Medicine at the University of Copenhagen, I'm also the director of the Center for Physical Activity Research. In this lecture, I will discuss the role of inflammation in type 2 diabetes. In subjects with type 2 diabetes, cardiovascular complications are of particular interest, as these are mainly responsible for the increased morbidity and mortality in diabetic patients compared with healthy subjects. As seen here, atherosclerosis is an inflammatory disease. It's a bolic dysregulation and chronic inflammation is considered to be responsible for the increased cardiovascular morbidity and mortality in diabetes. And the link between metabolic dysfunction and inflammation is well established. In order to understand why diabetes is an inflammatory disease, I will start with the acute phase response. Let us first look at the response triggered by an invasion. As a model of sepsis, we and others have injected the bolus of E coli endotoxin to healthy humans, thereby simulating sepsis. When E Coli endotoxin is infused as a bolus, we see a rapid increase in the cytokine CNF. We see significantly, already, after half an hour. Shortly thereafter, there is an increase in first interleukin six and thereafter an increase in the anti-inflammatory cytokines IL-1 receptor antagonist and IL-10. The classical markers of inflammation are seen much later. Here we see the increase in neutrophils and there we see the temperature response. And much later, we see an increase in the acute phase protein, C-reactive protein. In essence, we see the same cascade of inflammatory response in old people. However the magnitude of this response differs between individuals. Here is a simple outline of the acute cytokine cascade in relation to sepsis, and the later increase in C-reactive protein. The inflammatory response is a double edged sword. The body's ability to react to inflammation is central to human survival. If one has a reduced ability to make inflammation it can't fight infections and trauma. However, the acute inflammatory response can be so powerful that the body collapses. During the past years, it has also become clear that also a low-grade systemic inflammation can kill in the long term. Systemic Inflammation characterized by high levels of circulating inflammatory cytokines has been cautiously associated with the development of progression of many chronic diseases such as type 2 diabetes, cardiovascular disease, cancer, depression and dementia. Several cross-sectional and prospective studies have described elevated circulatory levels of C-reactive protein as well as elevated levels of various cytokines in patients with type 2 diabetes. And elevated levels of various proinflammatory cytokines and C-reactive protein are predictive of diabetes. Both physical inactivity, independent of body weight and obesity are associated with chronic systemic inflammation. Infiltration of immune cells into white adipose tissue and subsequently local inflammation in fat tissue is correlated with a development of insulin resistance and type 2 diabetes. Similarly activated immune cells and inflammation have an important role in cardiovascular diseases. Moreover Alzheimer's disease which, like diabetes, is a progressive disease leading to mental deterioration, is linked to local inflammation in the brain as systemic inflammation appears to exacerbate the progression of this disease. And an increase in the levels of circulatory, inflammatory cytokines is involved in the initiation of tumor growth. This is just some examples how chronic systemic inflammation may influence several organs and predisposed to chronic diseases. When we got to Type 2 diabetes, let us take a closer look at IL-1 and TNF alpha, as these are key pro inflammatory mediators in beta cell damage and insulin resistance. Strong evidence exists that IL-1 beta is a key pro-inflammatory mediator of beta cell damage in type 2 diabetes. In support of this, it has been shown the therapeutic inhibition of IL-1 beta ameliorates beta cell dysfunction and glucose homeostasis in individuals with diabetes. Evidence also exists that the pro-inflammatory cytokines TNF- alpha is a key molecule in insulin resistance. This evidence is based on classical studies in cultured cells and in TNF- alpha knockout mice. The question was whether TNF-alpha could also induce insulin resistance in humans? We infused TNF-alpha to humans to mimic the low grade systemic inflammation. TNF-alpha inhibited whole-body insulin-mediated glucose uptake and cyclo-transduction by inhibiting peripheral insulin-stimulated glucose uptake via impaired phosphorylation of Akt substrate S160. This is a key step in the canonical insulin signaling cascade, regulating Glut4 translocation and glucose uptake. So in metabolism TNF is a bad guy, however, the role of IL-6 in metabolism is debated. In correlational studies, increased plasma levels of IL-6 have been associated with type 2 diabetes. We know that TNF and IL-6 co-exist in epidemiological studies and TNF induces the production of IL-6. However, in experimental studies, the two cytokines have opposite effects where we got true metabolism. TNF inhibits and IL-6 enhances glucose and lipid oxidation, I will show later that IL-6 can inhibit TNF production. There is evidence to suggest that chronically elevated levels of IL-6, IL-1ra C-reactive protein reflect local ongoing TNF-alpha production. Given that TNF-alpha mainly works locally, TNF transcription may not allows be reflected in an enhanced systemic level of TNF. Rather TNF stimulates IL-6 production and consequently interleukin 1ra and C-reactive protein. As well-described in both longitudinal and cross-sectional studies, the regular physical activity, also without weight loss, diminishes systemic chronic inflammation. However, the prescription of exercise as a potential anti-inflammatory tool is a relatively new concept. The anti-inflammatory effects of exercise may, at least in part, be mediated by secretory peptides, so-called myokines, produced by working skeletal muscle. Skeletal muscle can communicate with other organs by secreting these myokines. Some myokines can induce an anti-inflammatory response with each bout of exercise. IL-6 are produced by musculature exercise and its plasma levels increase in an exponential fashion with exercise. Of note, in contrast to the cytokinic response elicited by sepsis, most of derived IL-6 occurs without preceding increase in TNF- alpha. In relation to exercise, IL-6 introduces a subsequent increase in the production of IL-1ra and IL-10. Thus, stimulating the occurrence of ends inflammatory cytokines. A model of low grade inflammation which previously established in our laboratory. A very low dose of E coli endotoxin was administered to healthy subjects who were randomized to either rest or exercise prior to endotoxin administration. In resting subjects, Endotoxin induced a two to three-fold increase in circulating levels of TNF-alfa. In contrast, when participant performed three hours of a [INAUDIBLE] cycling, then received the Endotoxin bolus at two-point-five hours, the TNF response was totally blunted. Suggesting that acute exercise may inhibit TNF production. The effects of exercise could be mimicked by infusion IL-6 which suppressed the endotoxin induced TNF-alpha production. Thus an acute part of exercise induces a strong anti-inflammatory effect which at least in part is mediated by IL-6. Given that TNF is a key molecule in insulin resistance, the finding that exercise inhibits TNF production may contribute to explain why exercise enhances insulin sensitivity. In parallel, it is well documented that IL-1 beta is involved in pancreatic beta cell damage. They're finding that exercise provokes an increase in circulating interleukin-1 receptor antagonists, make a tribute to protect against interleukin-1 mediated destruction of beta cells. It has been shown that IL-6 stimulates alpha cell proliferation, prevents apoptosis created by metabolic stress, and regulates alpha cell mass in vivo. Thus it appears that exercise induced IL-6 production could be involved in the expansion on pancreatic alpha cell mass that is needed for functional beta cell compensation when an increased metabolic demand is present. Thus, although the role of IL-6 in metabolism is still debated and although increased plasma levels of IL-6 have been associated with type 2 diabetes in correlational studies. Mechanistic studies in humans suggest that moderate, acute elevation in IL-6, as provoked by exercise, exert anti inflammatory effects by an inhibition of TNF and by stimulating IL-1ra, thereby limiting IL-1 beta signaling. When levels of pro-inflammatory cytokines are elevated, it may promote dysfunction of brown adipose tissue and, consequently, promote diabetes progression. Another possibility is regular physical exercise may induce anti-inflammatory effects by limiting the amount of ectopic fat accumulation. Strong evidence exist that the accumulation of visceral fat stimulate an inflammatory response. Physical inactivity leads to abdominal adiposity. Visceral fat becomes invaded by macrophages and secretes proinflammatory cytokines and cause cell damage. Thus, avoiding a physical inactive life style will limit the amount of visceral fat and hence lower chronic low grade inflammation. Taken together, there is good evidence to suggest that regular exercise mediates anti-inflammatory actions. That this is a benefit for individuals with type 2 diabetes. As good evidence also to support that inflammation plays a role in type 2 diabetes, targeting inflammation with anti-inflammatory drugs has a lot of potential in the future treatment of diabetes. As diabetic, vascular complications are partly mediated by inflammatory processes, targeting inflammation may not only improve glycemic control. It slowed the progressive B-cell secretory dysfunction but also prevents such comorbidities. Thank you for listening. [MUSIC]
