Dietary saturated fat intake contributes to diabetes and cardiovascular disease, as shown in numerous animal and human studies. However, the hypothesis that stearic acid, a saturated fat, has beneficial effects on these conditions has not been adequately tested. Leptin receptor deficient mice (db/db) and wild-type mice were fed either chow or a high fat diet enriched in either stearic acid or oleic acid for ten weeks. The progression of diabetes was evaluated with blood glucose, insulin, and metabolic parameter measurements. At the conclusion of the study, pancreatic islet organization was examined, and blood, liver and feces were assayed for fatty acid content. The stearic acid enriched diet prevented increases in blood glucose levels independently of weight loss in db/db mice compared to an oleic acid or chow diet. Diabetic mice fed stearic acid maintained insulin responsiveness and pancreatic islet organization compared to the db/db mice fed chow and oleic diets. The islet organization of the stearic acid fed mice did not change over the course of the study and was similar to that of wild-type mice fed the same diet. Conversely, diabetic mice fed oleic acid and chow diets had decreased insulin responsiveness and disorganized islets. Stearic acid fed db/db mice had high fecal fat content and caloric intake calculations indicated low absorption of this fat. Switching to stearic acid after prolonged hyperglycemia had a rescue effect on blood glucose levels. After feeding diabetic and wild-type mice standard chow diets for 6, 8, and 10 weeks to establish hyperglycemia, mice switched to a high fat diet enriched in stearic acid, but not one enriched in oleic acid diet, had significant reductions in blood glucose levels. The ability of a stearic acid enriched high fat diet to slow the progression of diabetes and reverse hyperglycemia in db/db mice argues that risks and benefits of fats in the diet depend on the chemical structure, rather than the chemical class, of fats ingested. The beneficial effect of stearic acid appears to be associated with a decreased absorption of dietary fat.

Given the high and increasing social, health and economic costs of type 2 diabetes, early diagnosis and prevention are critical. Insulin sensitivity and insulin secretion are important etiological factors of type 2 diabetes and are used to define an individual’s risk or progression to the disease state. The dynamic insulin sensitivity and secretion test (DISST) concurrently measures insulin sensitivity and insulin secretion. The protocol uses glucose and insulin boluses as stimulus, and the participant response is observed during a relatively short protocol via glucose, insulin and C-peptide assays. In this research, the DISST insulin sensitivity value was successfully validated against the gold standard euglycaemic clamp with a high correlation (R=0.82), a high insulin resistance diagnostic equivalence (ROC c-unit=0.96), and low bias (-10.6%). Endogenous insulin secretion metrics obtained via the DISST were able to describe clinically important distinctions in participant physiology that were not observed with euglycaemic clamp, and are not available via most established insulin sensitivity tests. The quick dynamic insulin sensitivity test (DISTq) is a major extension of the DISST that uses the same protocol but uses only glucose assays. As glucose assays are usually available immediately, the DISTq is capable of providing insulin sensitivity results immediately after the final blood sample, creating a real-time clinical diagnostic. The DISTq correlated well with the euglycaemic clamp (R=0.76), had a high insulin resistance diagnostic equivalence (ROC c-unit=0.89), and limited bias (0.7%). These DISTq results meet or exceed the outcomes of most validation studies from established insulin sensitivity tests such as the IVGTT, HOMA and OGTT metrics. Furthermore, none of the established insulin sensitivity tests are capable of providing immediate or real-time results. Finally, and most of the established tests require considerably more intense clinical protocols than the DISTq. A range of DISST-based tests that used the DISST protocol and varying assay regimens were generated to provide optimum compromises for any given clinical or screening application. Eight DISST-based variants were postulated and assessed via their ability to replicate the fully sampled DISST results. The variants that utilised insulin assays correlated well to the fully sampled DISST insulin sensitivity values R~0.90 and the variants that assayed C-peptide produced endogenous insulin secretion metrics that correlated well to the fully-sampled DISST values (R~0.90 to 1). By taking advantage of the common clinical protocol, tests in the spectrum could be used in a hierarchical system. For example, if a DISTq result is close to a diagnostic threshold, stored samples could be re-assayed for insulin, and the insulin sensitivity value could be ‘upgraded’ without an additional protocol. Equally, adding C-peptide assays would provide additional insulin secretion information. Importantly, one clinical procedure thus yields potentially several test results. In-silico investigations were undertaken to evaluate the efficacy of two additional, specific DISTq protocol variations and to observe the pharmacokinetics of anti-diabetic drugs. The first variation combined the boluses used in the DISTq and reduced the overall test time to 20 minutes with only two glucose assays. The results of this investigation implied no significant degradation of insulin sensitivity values is caused by the change in protocol and suggested that clinical trials of this protocol are warranted. The second protocol variant added glucose content to the insulin bolus to enable observation of first phase insulin secretion concurrently with insulin sensitivity from glucose data alone. Although concurrent observation was possible without simulated assay noise, when clinically realistic noise was added, model identifiability was lost. Hence, this protocol is not recommended for clinical investigation. Similar analyses are used to apply the overall dynamic, model-based clinical test approach to other therapeutics. In-silico analysis showed that although the pharmacokinetics of insulin sensitizers drugs were described well by the dynamic protocol. However, the pharmacokinetics of insulin secretion enhancement drugs were less observable. The overall thesis is supported by a common model parameter identification method. The iterative integral parameter identification method is a development of a single, simple integral method. The iterative method was compared to the established non-linear Levenberg-Marquardt parameter identification method. Although the iterative integral method is limited in the type of models it can be used with, it is more robust, accurate and less computationally intense than the Levenberg-Marquardt method. Finally, a novel, integral-based method for the evaluation of a-priori structural model identifiability is also presented. This method differs significantly from established, derivative based approaches as it accounts for sample placement, measurement error, and probable system responses. Hence, it is capable of defining the true nature of identifiability, which is analogous, not binary as assumed by the established methods. The investigations described in this thesis were centred on model-based insulin sensitivity and secretion identification from dynamic insulin sensitivity tests with a strong focus on maximising clinical efficacy. The low intensity and informative DISST was successfully validated against the euglycaemic clamp. DISTq further reduces the clinical cost and burden, and was also validated against the euglycaemic clamp. DISTq represents a new paradigm in the field of low-cost insulin sensitivity testing as it does not require insulin assays. A number of in-silico investigations were undertaken and provided insight regarding the suitability of the methods for clinical trials. Finally, two novel mathematical methods were developed to identify model parameters and asses their identifiability, respectively.

Placental insufficiency-induced intrauterine growth restriction (IUGR) increases risk of mortality and morbidity in newborn infants and domestic animals. IUGR fetuses are typically exposed to prolonged hypoxemia, hypoglycemia, and hypercatecholaminemia, which results in perinatal pancreatic β-cell dysfunction. Recent evidence indicates that chronic exposure to norepinephrine in utero suppresses insulin secretion through α2-adrenergic receptors (ARs), but if the adrenergic actions are blocked compensatory hyper insulin secretion response is observed in the IUGR sheep fetus. In the current studies, we demonstrate that chronic NE exposure alone can produce the compensatory enhancement of β-cell responsiveness following termination of a chronic NE infusion. In the fetus NE was continuously infused at 1-4 μg/min for seven days starting at 131 days of gestational age (term = 145 days). During treatment, NE infused fetuses had higher (P < 0.05) plasma NE concentrations and lower (P < 0.01) insulin concentrations than vehicle infused control fetuses. Glucose stimulated insulin secretion (GSIS), which measures β-cell function, prior to NE treatment was not different between treatments. However, insulin concentrations during hyperglycemic steady state period of GSIS studies and area under the curve of glucose-potentiated arginine-induced insulin secretion were higher (P < 0.01) than control values and this augmentation was confirmed at 3 hours, 24 hours, and five days in NE-infused fetuses after discontinuing the infusion. Pancreatic islets isolated within 10 hours post NE infusion had lower (P < 0.05) mRNA expression of α1D (58%), α2A (43%), α2C (42%), α1 (67%) adrenergic receptors (ARs), and uncoupling protein 2 (40%) compared to islets from controls. Isolated islets from NE-infused fetuses 5 days after NE treatment had lower (P < 0.05) inhibitory responsiveness from NE and a greater (P < 0.05) maximal insulin release with glucose simulation in static incubations compared to controls. These findings show that following chronic NE exposure insulin secretion responsiveness was augmented and was coupled with desensitized adrenergic signaling. Moreover, this compensatory β-cell enhancement persists for days indicating chronic NE exposure permanently alters β-cell responsiveness.

Bakgrund: Diabetes mellitus typ 2 är en vanlig folksjukdom som innebär en stor börda för patienter. Kostförändringar har visats kunna förbättra patienters situation, men följsamheten av kostråd brister dock ofta och det tillhör sjuksköterskans roll att främja och stödja en effektiv egenvård bland patienter med diabetes. Syfte: Syftet av denna litteraturstudie är att undersöka utifrån patienters perspektiv vad som påverkar till en ökad samt minskad följsamhet av kostråd vid diabetes typ 2. Metod: Litteraturöversikten är baserad på 19 artiklar av både kvantitativa och kvalitativa ansats som valts ut från databaserna PubMed, Cinahl och PsycINFO. De valda artiklarna vetenskaplig kvalitet granskades med checklistor för kvasi-experimentella eller kvalitativa studier. De inkluderade artiklarnas resultat analyserades av båda författarna för att hitta faktorer som påverkar följsamhet av kostråd. Relevant data sorterades i teman beroende på likheter och skillnader. Resultat: Totalt identifierades sex teman som beskriver vad som kan ha betydelse för följsamheten till kostråd: (1) förhållningssätt till förändring, (2) sociala aspekter, (3) mental hälsa, (4) kultur, (5) kunskapsbrist och (6) socioekonomisk situation. Slutsats: Sjukdomsinsikt, self-efficacy och socialt stöd är väsentliga aspekter att beakta när sjuksköterskor vårdar patienter med diabetes, för att främja deras följsamhet till kostråd. Stödjande insatser borde bygga på individens egen förmåga att ändra sin kost genom att inkludera tidig och anpassad information, delaktighet av närstående samt empati gällande personens socioekonomiska, kulturella och psykiska förhållande. / Background: Prevalence of type 2 diabetes mellitus increases worldwide and represents a major disease burden. Effective self-care, including diet changes, has been shown to prevent complications and improve quality of life. However, adherence to diet therapy is often insufficient and it belongs to the nurse’s role to promote and support adequate self-care. Aim: The purpose of this study is to examine, from patients perspectives, what increases and decreases compliance to dietary advice for diabetes type 2. Method: The literature review is based on 19 articles of both quantitative and qualitative approaches, selected from the databases PubMed, CINAHL and PsycINFO. The scientific quality of the selected articles was assessed with checklists for quasi-experimental or qualitative studies. Both authors analyzed the results of the included articles, to identify factors that influence adherence to dietary advice. Relevant data were sorted into themes depending on similarities and differences. Results: Six themes were identified: (1) attitude to change, (2) social relations, (3) mental health, (4) culture, (5) lack of knowledge and (6) socio-economic condition. Conclusion: Disease insight, self-efficacy and social support are essential aspects to consider when nurses care for patients with diabetes, to promote their adherence to dietary advice. Supporting interventions should strengthen the individual's own capability to change their diet, by including early and tailored information, participation of family members and empathy regarding the person's socio-economic, cultural as well as their psychological condition.

Bakgrund: Diabetes mellitus typ 2 är ett globalt problem som blir allt vanligare. Den nödvändiga egenvården kräver mycket av diabetes typ 2-patienten, och vårdpersonalen behöver adekvat kompetens för att kunna stötta dessa individer på bästa sätt. Syfte: Att undersöka patienters upplevelse av egenvård vid diabetes mellitus typ 2. Metod: En litteraturöversikt har gjorts baserat på elva originalartiklar tillgängliga på databaserna CINAHL Complete och PubMed. Artiklarna analyserades enligt Friberg, och teman och subteman skapades. Resultat: Resultatet presenteras i fyra teman. Det första temat är Patienters upplevelse av kostförändringar och har tre subteman: Kunskap och motivation, Kostförändringars inverkan på livskvalitet samt Egenvårdskontroll. Två andra teman som presenteras är Upplevelsen av läkemedelsbehandling och Upplevelsen av egenvård genom motion. Det fjärde och sista temat är Sjukvårdens roll i egenvården och presenteras genom tre subteman: Upplevelsen av gruppbaserad utbildning, Behov av stöd i egenvården samt Upplevelsen av mötet med sjukvården. Diskussion: Huvudfynden i resultatet analyserades för att se likheter och olikheter i de upplevelser som patienterna beskrivit. Dessa upplevelser diskuteras under två rubriker; Stödjande faktorer för egenvård och Försvårande faktorer för egenvård. Resultatet diskuterades utifrån Dorothea Orems egenvårdsteori samt konsensusbegreppet hälsa. / Background: Type 2 diabetes mellitus is a global problem that is increasing worldwide. The necessary self-management is demanding a lot of the type 2 diabetes-patient, and the health professionals needs adequate competence to be able to support these individuals in the best way. Aim: To examine patients' experience of self-management in type 2 diabetes mellitus. Method: A literature review has been made based on eleven original articles available on the databases CINAHL Complete and PubMed. The articles were analysed according to Friberg, and themes and subthemes were created. Results: The result is presented in four themes. The first theme is Patients´ experience of dietary changes and has three subthemes: Knowledge and motivation, Dietary changes and its impact on the quality of life and Self-management control. Two other themes are presented as The experience of drug treatment and The experience of self-management through physical activity. The fourth and last theme is The role of healthcare in self-management and is presented through three subthemes: The experience of group based education, The need of support in self-management and The experience of the meeting with the healthcare. Discussion: The main findings in the result were analysed to discover similarities and differences within the experiences as described by patients. These experiences were then discussed under two subtitles; Supporting factors for self-management and Aggravating factors for self-management. The result was discussed from the theory of self-care by Dorothea Orem and the consensus concept of health.

Background: Type 2 diabetes mellitus (T2DM) is a welfare disease increasing with such a high rate that it, in popular speech, is being called epidemic. To prevent the spread of this disease, future health care workers are in need of a deeper, science-based education. Purpose: The aim of this study is to research the knowledge about T2DM regarding risk factors, nutrition, activity and foot hygiene among public health students at Thammasat University in Bangkok, Thailand. Method: A cross-sectional study was made using a questionnaire. A convenience sampling of public health students were approached and 121 decided to participate. Results: The majority of the students knew that obesity and an unhealthy diet (containing a high amount of fat, sugar and fast food) was correlated with T2DM and associated with negative outcomes of the disease. The students were uncertain or had less knowledge that smoking is a risk factor (79%). The greater part of the participants (73%) thought that people with T2DM should let their feet air dry. 74% of the respondents underestimated the amount of time that was needed to exercise per week to achieve positive results and 63% of the students were dissatisfied with their education regarding T2DM. Conclusion: Although the students overall had good knowledge about T2DM, they also showed a lot of uncertainty and insufficient knowledge in several questions. This was especially distinguished in the questions regarding activity, foot hygiene and risk factors. / Bakgrund: Typ 2 diabetes mellitus (T2DM) är en välfärdssjukdom som ökar i så snabb takt att den i folkmun kallas för en epidemi. För att förhindra spridningen av sjukdomen behöver framtida vårdpersonal en djupare, evidensbaserad grundutbildning. Syfte: Syftet med denna studie var att undersöka kunskapen kring T2DM, med avseende på riskfaktorer, nutrition, aktivitet och fothygien bland studerande folkhälsovetare vid Thammasat University i Bangkok, Thailand. Metod: Ett bekvämlighetsurval på studerande folkhälsovetare gjordes, varav 121 av 136 studenter deltog. Enkäter användes i denna studie. Resultat: Majoriteten av eleverna visste att fetma och en ohälsosam kost (innehållande hög fetthalt, socker och snabbmat) var korrelerat med T2DM och associerat med negativa konsekvenser av sjukdomen. Majoriteten av studenterna visste inte att rökning var en riskfaktor (79%). Större delen av deltagarna (73%) tyckte att personer med T2DM skulle låta fötterna lufttorka. 74% av respondenterna underskattade mängden fysisk aktivitet som behövdes varje vecka för att uppnå positiva resultat och 63% av eleverna var missnöjda med sin utbildning avseende T2DM. Slutsats: Även om eleverna i allmänhet hade goda kunskaper om T2DM visade de också en hel del osäkerhet och otillräcklig kunskap i flera frågor. Detta särskilt i frågorna gällande aktivitet, fothygien och riskfaktorer.

Prevalence of type 2 diabetes mellitus (T2DM) is still rising and even so in the juvenile population. Obesity is highly associated with increased risk for developing T2DM. The development has been related to elevated fasting concentrations of the pancreatic islet hormones insulin and glucagon as well as to an increase in plasma lipids that occurs during obesity. Specifically, research has indicated that chronic exposure to high levels of saturated free fatty acids cause dysfunction in islet alpha- and beta-cells. Fatty acids can affect islet cells by various mechanisms one of which is the G-protein coupled receptor FFAR1/GPR40. The role of the receptor in the effects of fatty acids on pancreatic islet-cell function is not clear. The aim of this thesis was to clarify the role of FFAR1 in how fatty acids, and more specifically the long-chain saturated fatty acid palmitate, affect insulin and glucagon secretion. In children and adolescents with obesity elevated fasting levels of insulin and glucagon were positively correlated with lipid parameters. Specifically, plasma triglycerides and free fatty acids were positively correlated with insulin and glucagon at fasting as well as with visceral adipose tissue volume. Elevated glucagon levels at fasting were associated with worsening of glucose tolerance in the same population. In in vitro studies of isolated human islets palmitate stimulated basal insulin and glucagon secretion as well as mitochondrial respiration at fasting glucose levels. The effect was mediated by FFAR1 and fatty acid beta-oxidation. At higher glucose concentrations the receptor was involved in the potentiation of insulin secretion from isolated human islets and insulin-secreting MIN6 cells. Furthermore, we found that the effects of palmitate on hormone secretion were associated with enhanced mitochondrial respiration mediated by FFAR1 Gαq signaling and PKC activity as well as increased intracellular metabolism induced by the fatty acid. When islets were exposed to palmitate for long time periods and in the presence of FFAR1 antagonist, normalized insulin and glucagon secretion during culture and insulin response to glucose after culture were observed. In MIN6 cells chronic palmitate treatment increased mitochondrial uncoupling irrespective of FFAR1 involvement. However, FFAR1 antagonism during palmitate exposure resulted in elevated respiration and reduced apoptosis. In conclusion, children and adolescents with obesity have elevated fasting concentrations of insulin and glucagon that correlate with free fatty acids and fatty acid sources. High glucagon levels are linked to worsening of glucose tolerance in these subjects. In vitro the combination or synergy of FFAR1 activation and intracellular metabolism caused by palmitate is decisive for both the short-term enhancement effects and the negative chronic effects on insulin and glucagon secretion.

The IL-6 system is key in the development of chronic low-grade inflammation. It is known to be upregulated in response to acute exercise and lowered at rest after exercise training. IL-6 has both anti- and pro-inflammatory properties and moderation of this cytokine could alleviate chronic low-grade inflammation which is associated with obesity and Type 2 diabetes mellitus (T2DM). This thesis investigated the interplay between inflammation, glycaemic control and high intensity intermittent training (HIIT) - an exercise regimen that has been shown to yield many health benefits. There was a greater increase in IL-6 after an acute bout of HIIT than continuous moderate intensity exercise, where external work was matched (Chapter 4). Although sIL-6R and the IL-6/sIL-6R complex were both significantly increased after acute exercise there were no differences between HIIT and moderate intensity exercise. In response to 2 weeks HIIT there was a significant reduction in IL-6 and increase in IL-6R in adipose tissue in overweight and obese males (Chapter 5). It was also determined that IL-6R present in adipose tissue is at least partly composed of the membrane-bound IL-6R isoform (Chapter 6). Reductions in circulating sIL-6R, the IL-6/sIL-6R complex, MCP-1 and adiponectin, as well as a decrease in waist circumference and increase in peak oxygen uptake during exercise were also induced after 2 weeks HIIT (Chapter 5). Young adults with T2DM (< 40 y) displayed elevated levels of inflammatory proteins in comparison to lean controls, however there were no significant differences in comparison to obese controls (Chapter 7). In conclusion, the findings of this thesis demonstrate that acute and repeated bouts of HIIT have positive effects on the inflammatory profile in the circulation and adipose tissue, particularly in relation to the IL-6 system. It should be determined if HIIT is an achievable mode of exercise for patient populations, including T2DM patients, in order to downregulate the inflammatory profile.

<p>The delivery of therapeutic peptides and proteins is often challenged by a short circulation half-life, necessitating frequent injections that limit efficacy, reduce patient compliance and increase treatment cost. The covalent conjugation of therapeutic peptides and proteins, and more recently oligonucleotide-based drugs, with the “stealth” polymer poly(ethylene glycol) (PEG), termed PEGylation, is one of the most commonly used approaches to increase the in vivo half-life and reduce the immunogenicity of these therapeutic biomolecules. However, after several decades of research and clinical use, the limitations of PEGylation have begun to emerge.</p><p>Conventional methods for synthesizing peptide/protein-polymer conjugates have drawbacks including low yield, non-trivial separation of conjugates from reactants, and lack of control over site and stoichiometry of conjugation, which results in heterogeneous products with significantly compromised biological activity. Additionally, anti-PEG antibodies have been induced in patients treated with PEGylated drugs and have been shown to correlate with rapid clearance of these drugs. High levels of pre-existing anti-PEG antibodies have also been found in individuals naïve to PEGylated agents, which are associated with serious first-exposure allergic reactions.</p><p>To address the synthetic limitations of PEGylation, a general approach for the high-yield synthesis of site-specific (C-terminal) and stoichiometric (1:1) peptide/protein-polymer conjugates, named sortase-catalyzed polymer conjugation, was developed. Demonstrating proof-of-concept of the approach with green fluorescent protein (GFP) as a model protein, sortase A from Staphylococcus aureus was used to site-specifically attach an initiator solely at the C-terminus of GFP, followed by in situ growth of the PEG-based brush polymer, poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) from the protein macroinitiator by atom transfer radical polymerization (ATRP). Sortase-catalyzed initiator attachment proceeded with high specificity and near-complete (~ 95%) product conversion. Subsequent in situ ATRP in aqueous buffer produced 1:1 stoichiometric conjugates with > 90% yield, tunable MW, low dispersity, and no denaturation of the protein. The extraordinarily high yield compares favorably to order of magnitude losses typically seen in conventional PEGylation processes.</p><p>Next, the therapeutic potential of POEGMAlation, or the conjugation of POEGMA to a peptide or protein, was demonstrated by implementing the developed sortase-catalyzed polymer conjugation strategy with exendin-4 (exendin), a therapeutic peptide for treating type 2 diabetes, to synthesize exendin-C-POEGMA conjugates with a wide and tunable range of molecular weights (MWs) and low dispersity. A single subcutaneous injection of exendin-C-POEGMA conjugates lowered blood glucose for up to 120 h in a diabetic mouse model. Most intriguingly, we showed that appending PEG as oligomeric side-chains on the conjugated POEGMA and tuning the side-chain length completely eliminated the reactivity of exendin-C-POEGMA conjugates toward patient-derived anti-PEG antibodies without compromising in vivo efficacy. Clinically, the lack of anti-PEG antigenicity of POEGMA conjugates is expected to completely eliminate serious first-exposure allergic reactions and the accelerated blood clearance of POEGMA-drug conjugates due to pre-existing anti-PEG antibodies in patients.</p><p>Collectively, these results establish POEGMAlation as a next-generation PEGylation technology that is highly useful for improving the pharmacological performance of therapeutic biomolecules while providing a timely solution to the increasing levels of pre-existing anti-PEG antibodies in patients that are seriously hindering the safety and efficacy of traditional PEGylated drugs.</p> / Dissertation

Genome-wide association studies (GWAS) have made substantial progress in implicating genomic regions in type 2 diabetes (T2D) susceptibility. Whilst attributing causal mechanisms to loci has proved non trivial, these studies have provided insights into the genetic architecture underlying the disease. GWAS findings indicate a causal role for gene regulatory processes, and suggest that pancreatic beta-cells play a pivotal role in mediating common T2D association. Work presented in this thesis therefore sought to generate novel regulatory annotations from human islets, and to assess whether T2D-associated loci can be accurately fine-mapped using statistical approaches, with the aim of improving understanding of causal mechanisms underlying these associations through integration of the two approaches. Using small RNA sequencing in human islets and enriched beta-cell populations (both n=3) and mRNA sequencing in a large number of human islets (n=130), I increased the number of available human islet annotations. These studies identified high or islet-specific expression in many micro RNAs (miRNAs) without previously known roles in human islets. It also provided the largest study of quantitative trait loci (eQTLs) and allele-specific expression (ASE) in human islets to date, identifying significant eQTLs for 1,636 genes and significant ASE at 8,754 genes. There was enrichment of active islet chromatin, compared to other tissues, at the best eQTL variant for each gene, but also substantial sharing of significant eQTLs between islets and other tissues. Simulations were used to assess the utility of fine-mapping approaches for refining common disease-associated loci to smaller intervals or sets of variants likely to include the causal variant. The results demonstrated that fine-mapping can indeed refine these loci to sets or intervals of a size more amenable to functional follow-up or focussed intersection with high quality annotations. Furthermore, using an approximated Bayesian approach, I was able to refine twenty-one of the known common T2D-associated loci. Finally, using the newly generated annotations, I demonstrated enrichment of T2D association signal for regulatory RNA annotations (islet lncRNAs and miRNA target gene sets). I also identified examples in which these types of annotation overlap common and rare variation suggestive of a role in T2D pathogenesis. Using further islet annotations, I also uncovered potential causal mechanisms at four of the twentyone fine-mapped common T2D loci. These data therefore provide many novel islet regulatory annotations that can be intersected with T2D genetics, and provide a first example of how such an approach can lead to novel potential causal mechanisms underlying association loci.