Metformin is the most common type 2 diabetes therapy, and may also reduce colorectal cancer growth. Currently, two mechanisms driving reduced cancer growth are considered: 1) Regulation of glucose and insulin levels, which may support cancer growth, and 2) Direct entry into cancer cells to activate the AMP-activated kinase (AMPK) protein, and inhibit cell growth pathways. The gut microbiome is the community of commensal microorganisms in the gastrointestinal tract. It is also affected by metformin, and may elevate production of short-chain fatty acids (SCFAs). Therefore, this thesis aimed to clarify how metformin may inhibit colorectal cancer growth and if the microbiome is involved. The hyperglycemic-responsive, murine-derived MC38 colon cancer cell line was used to test these effects. This model was confirmed to experience growth stimulation caused by high-fat diet (HFD) feeding in mice. Daily i.p. injections of metformin (100mg/kg) had no measurable effect on glucose and insulin sensitivity, or MC38 tumor growth. Oral metformin (250mg/kg) improved glucose tolerance and inhibited MC38 tumor growth in HFD-fed mice. To see if the gut microbiome is required for this effect, the antibiotic ampicillin was used to limit the gut microbiome. The addition of ampicillin blunted metformin’s glucose sensitization and tumor inhibition effects. A fecal microbiome transfer model was then used to isolate the role of the microbiome. Conventional mice fed HFD and gavaged with feces from metformin-treated donors experienced no glucose or insulin tolerance improvements. However, tumor growth was decreased by 30%, and serum SCFAs concentrations were elevated. The SCFA butyrate inhibited in vitro MC38 colony growth, but did not activate AMPK. These data suggest that metformin alters the gut microbiome, and fecal transfer from metformin-treated animals can uncouple MC38 tumor growth inhibition from the glucose homeostasis effects of metformin. These novel findings support a new mechanism for metformin to prevent cancer growth and development. / Thesis / Doctor of Philosophy (PhD) / Metformin is the most commonly used type 2 diabetes therapy, and may also reduce colorectal cancer growth. Anti-cancer effects may be caused by: 1) decreased glucose and insulin levels, which support cancer growth; or 2) entry into cancer cells to directly decrease cell growth. The gut microbiome, microorganisms that live symbiotically in the gastrointestinal tract, is also affected by metformin. This thesis aimed to clarify how metformin can inhibit cancer, and if the microbiome is involved. Mice treated with metformin had improved glucose metabolism and decreased colorectal tumor growth; when an antibiotic was introduced, this effect was lost. A fecal microbiome transfer model was used to determine if the microbiome is driving this effect. Mice receiving feces from metformin treated mice also experienced tumor growth inhibition. This suggests that the gut microbiome is involved in the anti-cancer effects of metformin, and is a new potential mechanism of action.

Approximately 8.3% of the U. S. population has type 2 diabetes. Preventing the onset and improving the management type 2 diabetes are crucial for health care professionals. The purpose of this project was to develop and evaluate a type 2 diabetes prevention and management education program in a primary care setting using group medical appointments (GMAs). The chronic care model provided the framework for the study. The education program consisted of information from the Centers for Disease Control on the management of type 2 diabetes to be delivered by clinic staff using a GMA approach, a timeline for implementing the education program, and evaluation strategies for assessing patient health outcomes. Staff participants included 9 females and 1 male. One week after the presentation, staff responded to open-ended questions addressing the plan for prevention and management of type 2 diabetes. Findings indicated that staff unanimously approved the content of the program, thought the program could realistically be implemented, thought the proposed evaluation methods were appropriate, and thought the program would have a positive influence on patient health outcomes. Prevention and management education programs using a GMA approach may be used to reduce incidence and improve management of type 2 diabetes.

Diabetes is a group of metabolic diseases characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both. Several models have been developed for describing the glucose-insulin system. Silber and Jauslin developed a semi-mechanistic integrated glucose insulin (IGI) model which simultaneously describe glucose and insulin profiles in either healthy subjects or type 2 diabetis mellitus (T2DM) patients. The model was developed for describing the basal system, i.e. when no drugs are present in the body. In this thesis the IGI model was extended to also include the effects of anti-diabetic drugs on glucose homeostasis. The model was extended to describe postprandial glucose and insulin excursions in T2DM patients treated with either biphasic insulin aspart or the GLP-1 receptor agonist liraglutide. These extensions make the model a useful tool in drug development as it can be used for elucidating the effects of new products as well as for clinical trial simulation. In this thesis several modelling tasks were also performed to get a more mechanistic description of the glucose-insulin system. A model was developed which describes the release of the incretin hormones glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 following the ingestion of various glucose doses. The effects of these hormones on the beta cell function were incorporated in a model describing both the C-peptide and insulin concentrations in healthy subjects and T2DM patients during either an oral glucose tolerance test or an isoglycaemic intravenous glucose infusion. By including measurements of both C-peptide and insulin concentrations in the model it could also be used to characterize the hepatic extraction of insulin.

Sustainable Built Environments Senior Capstone Project / For over a century, Pima Indians living just south of Phoenix, Arizona on the Gila River Indian Reservation have suffered from an epidemic of type 2 Diabetes Mellitus. Over half of the Pima population living on the reservation is diagnosed with diabetes while the socioeconomic conditions of the tribal community are in an unstable and dilapidated state (Unnatural Causes 2008). Fifty percent of the Pimas living on the Gila River Indian Community live below the poverty level (Unnatural Causes 2008). Displacement from traditional customs and neglect from the U.S. federal government are just some of the detrimental impacts the people have faced over the last century (Unnatural Causes 2008). The discussions within this paper will attempt to address how and why the Pima Indians have experienced such severe changes in lifestyle and economy over the last century and what affect this has had on the physical health of the people in the community. By addressing these overarching issues, one should find that socioeconomics and conditions of physical health are strongly connected. Looking even closer though, specifically at the epidemic of type 2 diabetes and the contributing risk factors that this population suffers from, one will begin to question how within just a matter of 3 decades the number of diagnosed cases of type 2 diabetes doubled among the Pima and how the rates are some of the highest recorded in the entire world. Moreover, the underlying issue is not simply a cause of poor diet, change in activity levels and unfavorable genetics, rather - being robbed of a critical natural resource, forced to adapt to unfavorable economic changes and in the end, the U.S. government failure to intervene – are truly the underlying causes that have impacted the health of the Pima Indians of Southern Arizona. The Pimas are people of their natural environment. Having a long history of living along the Gila River, the Pima were water irrigation engineers (Unnatural Causes 2008). Cultivating local crops, living off the land and providing for themselves using waters of the Gila River in an arid climate is as much a part of their culture as is their ancestral bloodline. The research presented in these discussions will look at the identical ancestry of Pima Indians living in Southwestern Sonora, Mexico in the Sierra Madre Mountains of Maycoba in order to evaluate the Pima tribe’s predisposition to the disease. The significance of looking at these groups is that their genetic history is the same based upon linguistic and genealogy studies (Schulz, Bennett, Ravussin, Kidd, Kidd, Esparza, Valencia, 2006). However, the Pima living in Sonora have not seen the same ever-increasing rates of type 2 diabetes or even obesity, as their northern counterparts have. Notably, the Mexican Pima have not experienced the same environmental changes (i.e. drought) either. Subsequently, the Pima of Sonora have been able to continue their traditional ways of life including subsistence farming and healthy diet and exercise. A historical background of the Arizona Pimas will be provided, from their cultural traditions as irrigation engineers to their participation in federal subsidy programs and their current economic state. In-depth historical accounts will also be made for the history of water law in the Southwestern United States, including what drove white settlers’ demand for water west of the Mississippi over the course of two centuries, to the attempts to mitigate the severity of drought on Native American reservations through multiple legislative acts. Information regarding the Mexican Pima’s current economy, levels of physical activity and typical diet will be presented in comparison to the present health and economic conditions of the Arizona Pima.

Published research on diabetes in Ghana is quite limited and relates mainly to incidence and prevalence of the disease with little research on the patients experiences of coping with the diabetes. It is estimated that diabetes affects 6.3% of the Ghanaian population with type 2 diabetes accounting for 90-95% of all cases of diabetes. In Ghana, individuals diagnosed with type 2 diabetes mellitus are confronted with difficulties including the high cost of treatment of the condition, stigmatization, and interruptions to normal physiological processes. In addition, the patients experience, limited clinic accessibility, inadequate drug availability, inadequate numbers of trained staff, as well as limited availability of equipment needed for adequate care of the condition. The review of literature for this current thesis also showed that none of the studies on coping were undertaken in Ghana, but were conducted in the western world where socio-cultural factors are quite diverse from the Ghanaian situation. In the light of the challenges facing diabetic patients as well as the gap observed in literature, the study set out to explore the coping strategies of patients with type 2 diabetes mellitus at a hospital in Ghana. A hermeneutic phenomenological approach to qualitative research was utilized. Twenty seven (27) in-depth interviews carried out with newly diagnosed patients with type 2 diabetes, between August and October 2009 at a hospital in Ghana. Interviews were conducted in the local Ghanaian Twi language and English. Participants who could not speak English were interviewed in Twi language and later translated into English by the researcher. Data analysis used Creswell (1998) approach to qualitative data analysis, which provided a rich description of the essential structures of the phenomenon under study. The study identified patients’ perceptions as to the causes of diabetes mellitus, the social meanings attributed to diabetes (with particular attention paid to the language by Ghanaian people to describe disease condition), and subsequently reactions and resolutions to diagnosis. Patients discussed treatment options, while at the same time remaining hopeful of finding a cure. All patients had a firm spiritual belief system that underpinned their understanding of the causation and treatment of their illness. This combined with various degrees of understanding and acceptance of western explanations of illness influenced the coping strategies employed by patients, which variously reported as positive, negative, and alternative strategies. The study establishes a platform upon which health providers can develop educational programmes for diabetic patients in Ghana, which will address misconceptions about diabetes mellitus in Ghana and the importance of programmes of care, which take account of and build upon the cultural context of ‘being Ghanaian’. Diabetes, at least for Ghanaian patients is more than a biomedical disease. In this sense a biomedical framework in and of itself will not enable healthcare providers to effectively manage this chronic disease in the Ghanaian population, but through the inclusion of an understanding of their spiritual beliefs, healthcare providers can understand the realities of what it is like for Ghanaian diabetes patients to live with diabetes. It is argued that a stronger collaboration and integration between traditional healthcare systems and orthodox healthcare systems will provide the optimum opportunity to maximize patient care in Ghana. Future research should concentrate on better understanding how lay knowledge and health related attitudes, beliefs and behaviours are associated with diabetes in Ghana.

People with type 2 diabetes are at increased risk of age-related cognitive impairment. Previous literature has focused on case-control studies comparing rates of cognitive impairment in patients with and without diabetes. Investigations of potential risk factors for cognitive impairment (including those with increased prevalence in diabetes, such as macrovascular disease, and diabetes-specific factors such as hypoglycaemia) in study populations consisting exclusively of patients with type 2 diabetes have been largely neglected. Moreover, previous studies have failed to take advantage of the extensive characterisation and prospective nature of longitudinal cohort studies to investigate the relative predictive ability of a wider range of potential risk factors for cognitive decline. Using data from the prospective Edinburgh Type 2 Diabetes Study (ET2DS) the present thesis aimed (i) to determine associations of cognitive decline with macrovascular disease and with severe hypoglycaemia, and (ii) to compare a wider range of potential risk factors in their ability to predict cognitive decline. In 2006/2007, 1066 patients with type 2 diabetes (aged 60 to 75 years) attended the baseline ET2DS clinic and 831 returned for the follow-up at year 4. Subjects were extensively characterised for risk factor profiles at baseline, and at year 4 for incidence of severe hypoglycaemia. Socioeconomic status was estimated using postcode data. Scores on seven tests of age-sensitive ‘fluid’ cognitive function, which were administered at baseline and at year 4, were used to derive a general cognitive component (‘g’). A vocabulary-based test, administered at baseline, estimated pre-morbid ability. Findings are reported in three parts. 1.) Macrovascular disease and cognition: Subjects with higher levels of biomarkers indicative of subclinical macrovascular disease, including plasma N-terminal pro-brain natriuretic peptide and carotid intima-media thickness, had significantly steeper four-year cognitive decline, independent of traditional cardiovascular risk factors, stroke, socioeconomic status and estimated pre-morbid cognitive ability. For ankle-brachial pressure index, the association fell just short of statistical significance. Effect sizes were overall modest, with fully adjusted standardised beta coefficients ranging from 0.06 to -0.12. Little evidence was found for associations of the symptomatic markers of macrovascular disease with four-year change in cognitive function that was independent of participants’ pre-morbid ability and socioeconomic status. 2.) Severe hypoglycaemia and cognition: Subjects with lower cognitive ability at baseline were at two-fold increased risk of experiencing their first-ever incident severe hypoglycaemia during follow-up. The rate of four-year cognitive decline was significantly steeper in those exposed to hypoglycaemia compared with hypoglycaemia-free participants, independently of cardiovascular risk factors, microand macrovascular disease and of estimated pre-morbid cognitive ability. Effect sizes again were overall modest (Cohen’s d = 0.2 to 0.3 for statistically significant differences in four-year cognitive decline between subjects with and those without hypoglycaemia, following multivariable adjustment) 3.) Consideration of a wider range of risk factors and cognition: A stepwise linear regression model including a total of 15 metabolic and vascular risk factors identified inflammation, smoking and poorer glycaemic control (in addition to some of the subclinical markers of macrovascular disease) as predictive of a steeper four-year cognitive decline. Other traditional cardiovascular risk factors, diabetic retinopathy, clinical macrovascular disease and a baseline history of severe hypoglycaemia were not included in this model. The interpretation of the latter finding is limited, however, by the fact that the stepwise regression procedure may exclude true predictors from a model when they correlate with already included risk factors. This thesis has demonstrated associations of later-life cognitive decline in people with type 2 diabetes with markers of subclinical macrovascular disease and poor glycaemic control (including hypoglycaemia) as well as other cardiometabolic risk factors (inflammation, smoking). Findings suggest that associations are relatively weak and complex due to inter-relationships amongst risk factors, and indicate a role of pre-morbid ability and socioeconomic status (which as risk factors are difficult to modify) in the relationships of risk factors with cognitive decline. Future research including case-control studies to compare risk factor associations between people with type 2 diabetes and non-diabetic older adults and randomised controlled trials to evaluate potential causal effects of individual modifiable risk factors on cognitive decline, will help to evaluate the mechanisms underlying the observation that people with type 2 diabetes are at risk of cognitive impairment in later life.

Type 2 Diabetes Mellitus (T2DM) was once a disease process found only in the adult population. However, incidence rates of T2DM in children and adolescents are increasing at alarming rates and becoming a grave public health concern. As many as 5,089 individuals under the age of 20 are newly diagnosed with T2DM each year. The military community is not immune to these national trends and T2DM among military dependents is growing at similar rates to that of the civilian population. The primary aim of this DNP project was to investigate if barriers exist with regard to pediatric military dependents, ages 10-17 years, receiving appropriate diagnosis, and treatment of T2DM. Previously published literature has identified health disparities exist within the Military Health System (MHS), despite beneficiaries having equal access to care. This project also sought to assess providers' use of Evidence Based Practice (EBP) and Clinical Practice Guidelines (CPGs) in the treatment of pediatric patients' ages 10-17 with T2DM, as it has been indicated that use of evidence based guidelines for management of T2DM vary among military treatment facilities. Results of the DNP Project reflected information found in previous evidence based literature. Fifty percent of providers felt there is "probably" a health disparity among Type 2 Diabetic youth who seek care at a Military Treatment Facility (MTF). Diverse responses were received regarding applicable health disparity indicators among MHS beneficiaries, indicating these disparities may be multifactorial. Routine incorporation of EBP and CPGs into clinical practice also appeared to vary among participants. It is evident that further research may positively contribute to current understanding of health disparities among MHS beneficiaries.

This thesis explores the impact of type 2 diabetes among Indian and Pakistani migrants. Indians and Pakistanis living in the UK have a high incidence of type 2 diabetes and associated complications. Research is needed in order to understand factors that make it difficult to adhere to lifestyle advice about diet, exercise and medication. Drawing on data collected during a sixteen-month ethnographic investigation, this thesis explores Indians’ and Pakistanis’ perceptions of diabetes. The research revealed that Indians and Pakistanis related the onset of diabetes to processes of migration and settling in the UK as well as to stress and depression. In particular, holding on to negative thoughts and worries, were perceived by respondents as directly affecting the body by causing stress, depression and eventually illness. Struggles over diabetes control were also perceived as to cause distress. Specifically, respondents struggled to adhere to a healthy diet regime, since food, especially taste, played a crucial role in forming, reinforcing and demarcating social relations and in ensuring cultural continuity. In addition, respondents struggled to ‘adhere’ to their prescriptions of diabetes medications due to the uncomfortable side effects that they experienced, particularly in the stomach. Respondents, however, counteracted side effects by turning to alternative medications which were perceived to facilitate flow within the circulatory and digestive system. Thus, in spite of the difficulties that Indians and Pakistanis experienced in following biomedical recommendations for diabetes control, they still actively engaged in searching and using different treatments available to them in order to control the disease.

Introduction. Pima Indians living in the United States (U.S.) have the highest prevalence of type 2 diabetes mellitus in the world. Their Mexican counterparts, living a traditional lifestyle in the mountain of Sonora, Mexico, have at least five times less diabetes than the U.S. Pima Indians. The effects of a traditional lifestyle in reducing type 2 diabetes risk factors and the association of factors to type 2 diabetes were evaluated in a sample of 1211 genetically related Pima Indians living different lifestyles (224 from Mexico and 887 from U.S.). Subsets of these populations were used to address specific questions. First, differences in insulin resistance between subjects with normal glucose tolerance (194 Mexican versus 449 U.S. Pima) were evaluated. Second, the effect of physical activity and obesity explaining differences in metabolic syndrome prevalence were evaluated in 224 and 447 Mexican and U.S. Pima Indians. Third, factors associated with type 2 diabetes were evaluated in each Pima Indian population (224 from Mexico and 887 from U.S.).Methods. Demographic, physical, biochemical, and lifestyle factors were measured in 1996 in a cross-sectional study of Pima Indians 20 years of age or older living in Maycoba, Sonora Mexico and contrasted to results from a sample of U.S. Pima Indians participating in an ongoing epidemiological study that used similar methods and selection criteria. Insulin resistance was estimated by both fasting insulin and homeostasis model assessment-insulin resistance (HOMA-IR). Metabolic syndrome was defined using the Third Report of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP III) criteria. Body mass index (BMI) was calculated by dividing weigh in kilograms by the square of height in meters (Kg/m2). Physical activity was measured using a questionnaire developed for the U.S. Pima Indians and adapted to the Mexican Pima Indian population. Type 2 diabetes was defined according to the 1999 WHO criteria after an oral glucose tolerance test. Multiple linear regression analysis was used to answer the first question (related to differences in insulin resistance) and multiple logistic regressions analysis to answer the second (related with differences in metabolic syndrome) and third questions (related to factors associated with type 2 diabetes).Results. Insulin resistance was much lower in the Mexican Pima Indians than in genetically related U.S. counterparts, even after controlling for differences in obesity, age and sex. In addition, the unadjusted prevalence of metabolic syndrome was 24.1% and 56.6 % in the Mexican and U.S. Pima Indians, respectively. However, most of the difference in metabolic syndrome prevalence was explained by differences in obesity and physical activity. Furthermore, in Mexican Pima Indians, type 2 diabetes was independently associated with age, fasting insulin, and waist circumference. In the U.S. Pima Indians, type 2 diabetes was associated with with age, sex, fasting insulin, total cholesterol, blood pressure and physical activity.Conclusion. The findings underscore the importance of lifestyle in the prevention of type 2 diabetes risk factors, such as insulin resistance and metabolic syndrome, even in individuals with high propensity to develop diabetes.

Background and Methods: The involvement of iron in the risk for, and complications of, type 2 diabetes has generated substantial interest over the past 15 years, initially sparked by an association with raised serum ferritin, and the observation that people with iron overload diseases frequently develop diabetes. Considerable advances have since been made in understanding the effect glucose has on molecules, cells, and tissues; and the role that oxidative stress plays in the development of the pathologies of long-term diabetes. Poorly liganded iron is potentially both a contributor to, and consequence of, these complications. In vitro experiments with glucose-incubated transferrin by earlier workers have demonstrated loss of function with increasing glycation, leading to the suggestion that the failure of this key iron-binding protein may contribute to diabetic pathology, via the presence of redox active non-transferrin-bound iron (NTBI). In vitro glycated transferrin is examined here by ultrafiltration, to assess loss of function and possible oxidative fragmentation. Mass spectrometry is used to identify a range of amino acid glycation sites on in vitro glycated transferrin for the first time. Finally, several groups have previously measured NTBI in people with diabetes, finding little agreement in results. NTBI is measured here in a cohort of people with type 2 diabetes, using a new adaptation of earlier NTBI assays. NTBI is also assessed in pre-dialysis chronic kidney disease (CKD) stages I to III for the first time. Results and Conclusions: Experiments with glycated transferrin in vitro demonstrate oxidative fragmentation, explaining the loss of function reported by earlier groups. In vitro glycated transferrin examined by mass spectrometry reveals a substantial number and range of amino acids subject to glycation. Comparison with in vivo glycated transferrin suggests that many of the in vitro glycation sites are not glycated in vivo, and that there are many oxidized methionine residues which are potential artefacts, or likely to be repaired by methionine sulphoxide reductases in vivo. A study of people with type 2 diabetes finds no direct association between NTBI and protein glycation. Unexpected correlations between NTBI and LDL, and LDL and haemoglobin with increasing protein glycation, are reported for the first time. NTBI is suggested to be iron sourced from haemoglobin or haem, from erythrocyte haemolysis prior to sample collection. In people with pre-dialysis CKD stages I to III no significant difference in NTBI level compared to controls is seen, or correlations with markers of renal function. No link between NTBI and kidney function at this stage of disease is indicated.