Adipose tissue secreted proteins (adipokines) have been proposed to form a link between obesity and type 2 diabetes (T2D). Resistin and visfatin are two adipokines which have been previously suggested as having roles in the pancreatic islet. The aim of this study was therefore to investigate the regulatory role of the adipokines resistin and visfatin in the pancreatic beta-cell. In order to do this, pancreatic β-cell lines from rat (BRIN-BD11) and mouse (βTC-6) were used to study the effect of exogenous incubation with physiological and pathological concentrations of resistin and visfatin on diverse elements of beta-cell biology including cell viability, gene expression and insulin secretion. In addition to this the expression levels of these two adipokines was also measured in the beta-cell. PCR array analysis showed that resistin and visfatin treatment resulted in significant changes in the expression of key beta-cell specific genes. Interestingly, both resistin and visfatin are highly expressed in the beta-cells. This suggests that the roles of these adipokines are not confined to adipose tissue but also in other endocrine organs. Resistin treatment significantly increased viability of the beta-cells at physiological concentrations however there was no increase with the elevated pathological concentrations. Resistin at elevated concentrations decreased insulin receptor expression in the beta-cells however there was no significant effect at lower concentrations. Both physiological and elevated resistin concentrations did not have any effect on glucose stimulated insulin secretion. Incubation of visfatin induced phosphorylation of insulin receptor and the intracellular signalling MAPK, ERK1/2. Visfatin treatment at 200ng/ml also significantly increased insulin secretion. These effects were replicated by incubation of beta-cells with the product of visfatin’s enzymatic action, nicotinamide mononucleotide and were reversed by visfatin inhibitor FK866. Visfatin treatment at low concentrations did not have any effect on cell viability however the elevated concentrations resulted in a decline. These data indicate that both resistin and visfatin potentially play important roles in beta-cell function and viability and that they form a significant link between adipose tissue and the pancreatic islet in type 2 diabetes.

Background: Inflammation is the natural reaction of the body to an antigen. In some conditions, this reaction continues even after the elimination of the antigen, entering a chronic stage; it targets normal cells of the body and causes extensive damage. Rheumatoid arthritis (RA) is such a condition. It associates with significant metabolic alterations that lead to changes in body composition and especially body fat (BF) increases. In the general population, increased body fat (i.e. obesity) associates with a number of health disorders such as systemic low grade inflammation and a significantly increased risk for cardiovascular disease (CVD). Both effects of obesity could have detrimental effects in RA. Increased inflammation could worsen disease activity while obesity could further increase the already high CVD risk in RA. However, obesity in RA has attracted minimal scientific attention. Aims: The present project aimed to: 1) assess whether the existing measures of adiposity are able to identify the changes in body composition of RA patients, 2) if necessary develop RA-specific measures of adiposity, 3) investigate the association of obesity with disease characteristics and CVD profile of the patients, 4) and identify factors that might affect body weight and composition in these patients. Methods: A total of 1167 volunteers were assessed. Of them 43 suffered from osteoarthritis and 82 were healthy controls. These, together with 516 RA patients were used in the first study. Their body mass index (BMI), BF, and disease characteristics were assessed. In the second, third, fourth and fifth studies a separate set of 400 RA patients was assessed. In addition to the above assessments, their cardiovascular profile and more detailed disease characteristics were obtained. For the final study, 126 RA patients were assessed for all the above and also data on their physical activity levels and their diet were collected. Results: Assessments of adiposity for the general population are not valid for RA patients. Thus, we proposed RA-specific measures of adiposity. These are able to better identify RA patients with increased BF. We were also able to find associations between obesity and disease activity. Both underweight and obese RA patients had more active disease compared to normal-weight patients. Obese patients had significantly worse CVD profile compared to normal-weight. The newly devised measures of adiposity were able to identify those at increased risk. However, not all obese individuals were unhealthy and not all normal-weight healthy. Among our patients we were able to identify subtypes of obesity with distinct phenotypic characteristics that warrant special attention. Finally, we were able to identify factors that influence body weight and composition. Cigarette smoking protected against obesity while its cessation associated with increased adiposity. Physical activity was also found to be protective against obesity while diet or inflammation of the disease failed to produce any significant results. Conclusions: Obesity is a significant threat to the health of RA patients. The measures of adiposity developed herein should be used to identify obese RA patients. Physical activity seems like the sole mode for effective weight management in this population. Health and exercise professionals should actively encourage their patients to exercise as much as they can. This study has created more questions than it answered; further research in the association of obesity and inflammation, as well as in ways to treat it, is essential.