Type 2 diabetes is a common chronic disease, which has a negative health impact and results in enormous economic burden. The prevalence of type 2 diabetes is increasing dramatically and it affects older people disproportionately. The healthcare system in China is faced with an overwhelming burden due to a large ageing population, high prevalence of diabetes and limited healthcare resources. Self-management has been widely accepted as the cornerstone of the clinical management of type 2 diabetes. Since self-management usually involves complex behaviour change and can be emotionally challenging, effective education is essential to facilitate this transition. However, there has been no existing program of type 2 diabetes self-management for older patients in China until now. Furthermore, the generalisation of any health education programs is often hampered due to limited healthcare resources in China. The primary purpose of this study was to develop a socially and culturally suitable self-management program, which addressed self-efficacy and social support to facilitate behaviour change and subsequent health improvement, for older people with type 2 diabetes living in the community in China. The secondary purpose was to test a feasible delivery model of the program through involvement of peer leaders and existing community networks. This study was conducted in three phases. Phase one gathered information about barriers related to self-management behaviours and help needed to address them, from the perspective of older people with type 2 diabetes and community health professionals, through focus group discussion. Data from Phase One, together with guidelines of the selected theoretical frame work, results from an extensive literature review, and experiences of previous relevant studies provided the basis for development of a peer-led type 2 diabetes self-management program (Phase Two). Phase Three involved a pre-test, post-test non-equivalent control group design to test the effectiveness of the self-management program on older people with type 2 diabetes in the community. The impact of the program on peer leaders was examined using a one group pre-test, post-test design. In addition, evaluation of the program from peer leaders’ and older people’s perceptions was conducted through a post-test questionnaire. Older people with type 2 diabetes and health professionals expressed broadly the same concerns, which were: social support; confidence to practice self-management behaviours; self-management behaviours; barriers to self-management behaviours; and advice for ongoing health education. However, their points of view were not always identical and different emphases were identified. The peer-led program produced significant improvement in social support, self-efficacy, self-management behaviours and depressive status in the experimental group, as compared to the non-equivalent control group. However, there was no significant effect on quality of life nor health care utilisation. Therefore, the effectiveness of the program among older people with type 2 diabetes was partially confirmed. In addition, the participants were supportive, giving positive feedback about the program. Suggestions for future improvement were provided as well. After receiving specific peer leader training and assisting in most of the delivery process of the program, the peer leaders improved, significantly, in overall self-management behaviours and in specific areas of social support and self-efficacy, though they did not improve in depressive status, quality of life and health care utlisation. In addition, these peer leaders enjoyed being peer leaders, and gave very positive feedback about the whole program. In conclusion, this study has implications for understanding and facilitating self-management behaviours for older people with type 2 diabetes in China. The peer-led self-management program was effective in improving levels of self-efficacy, social support, self-management behaviours and depressive status among older people with type 2 diabetes living in the community in China. The delivery process involving peer leaders was deemed feasible to implement within the health care system in China. The program is suitable to be used by community health professionals in their practice in China. The study also has potential wider benefit to nursing practice and global health practice.

Beta-cell failure is a key step in the progression from metabolic disorder to overt type 2 diabetes (T2D). This failure is characterised by both secretory defects and loss of beta-cell mass, the latter most likely through increases in the rate of apoptosis. Although the mechanisms underlying these beta-cell defects are unclear, evidence suggests that chronic exposure of beta-cells to elevated fatty acid (FA) plays a role in disease development in genetically susceptible individuals. Furthermore, it has been postulated that endoplasmic reticulum (ER) stress signalling pathways (the unfolded protein response; UPR) play a role in FA-induced beta-cell dysfunction. The broad aim of this thesis was to explore the nature of these relationships. Experiments detailed in this thesis demonstrate that MIN6 beta-cells mount a comprehensive ER stress response with exposure to elevated saturated fatty acid palmitate, but not the unsaturated fatty acid, oleate, within the low elevated physiological range. This response was time-dependent and involved both transcriptional and translational changes in UPR transducers and targets. The differential activation of ER stress in MIN6 beta-cells by saturated, but not unsaturated FA species may represent a mechanism of differential beta-cell death described in many studies with these FA. Furthermore, these experiments describe defects in ER to Golgi trafficking with chronic palmitate treatment, but not oleate or thapsigagin treatment, identifying this as a potential mechanism by which palmitate treatment induces ER stress. Moreover, these studies have shown the relevance to ER stress to a whole body model of T2D by demonstrating UPR activation in the islets of the db/db mouse. In conclusion, studies detailed in this thesis have demonstrated that ER stress occurs in in vitro and in vivo models of beta-cell lipotoxicity and apoptosis. In addition, these studies have identified defects in ER to Golgi trafficking as a mechanism by which palmitate treatment induces ER stress. These studies highlight the importance of ER stress in the development of T2D.

Obesity and type 2 diabetes (T2D) are associated with insulin resistance and increased levels of inflammation markers, suggesting activation of the immune system. However, the link between this so called ??low-grade inflammation?? and insulin resistance is poorly understood. In this thesis we aimed to investigate the direct effects of insulin on immune cells, and if these effects are changed in the setting of insulin resistance. We showed that insulin has anti-inflammatory effects by shifting T cell differentiation into a T helper type 2 phenotype. This effect was lost in insulin resistant subjects, which resulted in a more pro-inflammatory T helper type 1 cell hyperpolarisation. We also demonstrated that the Th1/2 balance is related to the degree of insulin resistance, and varies accordingly in clinical models of increasing or decreasing insulin resistance. Furthermore, we demonstrated that in a very early stage of pre-diabetes, where normal glucose tolerance and insulin sensitivity are still preserved, we cannot detect any immune activation, but we see a blunted food response of the appetite suppressant hormone PYY. Whilst this could put subjects at risk for further weight gain and development of obesity and T2D, we also demonstrated for the first time that PYY itself has strong anti-inflammatory properties, and that a deficiency in PYY could result in promoting a pro-inflammatory environment. In summary, we could demonstrate strong evidence that both, insulin and PYY are potent anti-inflammatory hormones which modulate immune function, and the observed deficiency in these hormones could contribute to further increase in inflammation and disease progression. Further work is indicated in this area to better understand the sequence and mechanism of immune activation, which may open up new therapeutic avenues for prevention and treatment of T2D.

Adult Oral Health Programme: The Effect of Periodontal Treatment and the Use of a Triclosan Containing Toothpaste on Glycaemic Control in Diabetics Abstract Aim: The aim of the research study is to establish an adult oral health programme for diabetics in Majuro, Republic of the Marshall Islands in order to determine the impact of non-surgical periodontal treatment followed by the use of a triclosan containing dentifrice on the maintenance of periodontal health and glycaemic control in type 2 diabetic patients. Hypothesis: Non-surgical periodontal treatment results in improved periodontal health and better glycaemic control in diabetics and use of a triclosan containing toothpaste is effective in maintaining this improvement in diabetics. Methods: An adult oral health programme was created, within which was conducted a two-group randomised clinical trial to address the hypothesis that non-surgical periodontal treatment results in improved periodontal health and better glycaemic control in type 2 diabetics and that the use of a triclosan containing toothpaste is effective in maintaining this improvement in diabetics. In this double blind controlled trial, sixty adult patients (aged 35 to 65 years) with type 2 diabetes mellitus having a minimum of 16 teeth received non-surgical periodontal treatment. Half of the patients were randomly assigned to use a triclosan containing toothpaste, Colgate Total, and the other group a non-triclosan toothpaste, Colgate Fluoriguard. The study evaluated the improvement in periodontal health by recording Probing Pocket Depth (PPD) on 6 sites of each tooth, and the number of sites bleeding on probing (BOP) at baseline, and at 6 months and 12 months after treatment. The second part of the study evaluated the impact of improvement of periodontal health on glycaemic control in type 2 diabetics by measuring HbA1c and RBS, and also assessing the levels of C-Peptides and CRP at baseline, and at 6 months and 12 months after treatment. The study also evaluated the effectiveness of a triclosan containing toothpaste in maintaining the improvement in periodontal health after non-surgical periodontal treatment. Results: The results showed that it was feasible to establish an oral health programme for the diabetics and could improve their periodontal health, and that toothpaste containing triclosan is effective in maintaining the improved periodontal heath in type 2 diabetics. Mean PPD dropped from 2.35mm to 1.95mm in the triclosan group and from 2.49mm to 2.24 mm in the non-triclosan group and the mean number of BOP sites dropped from 4.9 to 2.8 in the triclosan group and from 4.7 to 3.2 in the fluoriguard at 12 month visits. However, the results did not show improvement of HbA1c nor RBS levels in either group. C-Peptide levels increased and C-Reactive Protein levels decreased in both groups, however, not to significant levels at 12 month visits. Conclusion: The results of this research study lead to the conclusion that treating periodontal infection has effect of periodontal health of type 2 diabetic patients and following-up with simple personal oral hygiene of regular tooth-brushing helps maintain their periodontal health. This programme also proved that this type of oral health programme is feasible and valuable for diabetics in isolated places like the Marshall Islands, where infrastructure, personnel and resources are limited to treat microvascular and macrovascular complications of diabetes. As for the effectiveness of treating periodontal infections on glycaemic control of diabetics, this study failed to support the hypothesis that non-surgical treatment plus triclosan containing toothpaste would lead to better glycaemic management through improved periodontal health.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2007. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Washington, 1995. / Vita. Includes bibliographical references (leaves [188]-209).

Includes bibliographical references and index.

The misfolding and aggregation of the beta cell hormone islet amyloid polypeptide (IAPP) into amyloid fibrils is the main pathological finding in islets of Langerhans in type 2 diabetes. Pathological assemblies of IAPP are cytotoxic and believed to contribute to the loss of insulin-producing beta cells. Changes in the microenvironment that could trigger the aggregation of IAPP are largely unknown. So is the possibility that islet amyloid can spread within or between tissues. The present thesis have explored the roles of glycosaminoglycan heparan sulfate (HS) and the novel anti-amyloid chaperone Bri2 BRICHOS domain in the assembly of IAPP amyloid and cytotoxic IAPP aggregates. Furthermore, cross-seeding as a molecular interaction between the observed connection of type 2 diabetes and Alzheimer disease has been examined. The N-terminal region of IAPP was required for binding to HS structures and induction of binding promoted amyloid formation. Interference in the HS-IAPP interaction by heparanase degradation of HS or by introducing short, soluble HS-structure fragments reduced amyloid deposition in cultured islets. Cytotoxicity induced by extracellular, aggregating IAPP was mediated via interactions with cell-surface HS. This suggests that HS plays an important role in islet amyloid deposition and associated toxicity. BRICHOS domain containing protein Bri2 was highly expressed in human beta cells and colocalized with IAPP intracellularly and in islet amyloid deposits. The BRICHOS domain effectively attenuated both IAPP amyloid formation and IAPP-induced cytotoxicity. These results propose Bri2 BRICHOS as a novel chaperone preventing IAPP aggregation in beta cells. The intravenous injection of IAPP, proIAPP or amyloid-β (Aβ) fibrils enhanced islet amyloidosis in transgenic human IAPP mice, demonstrating that both homologous- and heterologous seeding of islet amyloid can occur in vivo. IAPP colocalized with Aβ in brain amyloid from AD patients, and AD patients diagnosed with T2D displayed increased proportions of neuritic plaques, the more pathogenic plaque subtype. In conclusion, both IAPP amyloid formation and the cytotoxic effects of IAPP is dependent on interactions with HS whereas interactions with Bri2 BRICHOS is protective. Cross-seeding between Aβ and IAPP can occur in vivo and the two peptides colocalize in brain amyloid in AD patients.