Regular physical activity among children with Type 1 Diabetes Mellitus (T1DM) can help optimise long-term health outcomes. This thesis explores the experience of physical activity among children aged 9-11 years with T1DM and their parents, develops a physical activity intervention and evaluates its feasibility. Social cognitive theories have been drawn upon to develop our understanding and inform theoretically-driven behaviour change strategies. First, a systematic review with meta-analysis evaluates existing physical activity interventions for children with T1DM. The findings confirm the health benefits associated with regular physical activity, including improved glycaemic control and lipid profile. Gaps in the existing literature are identified, such as the need for theoretically-driven interventions. Second, the experience of physical activity for children with T1DM from the perspective of i) parents and ii) paediatric diabetes healthcare professionals are explored. Qualitative research findings highlight the challenges faced, as well as the methods used by families to overcome obstacles to physical activity. Healthcare professionals recognise their role in promoting physical activity, but perceive barriers to the successful fulfilment of this role. Third, the feasibility and acceptability of wrist-worn ActiGraph GT3X+ accelerometers in children with T1DM is explored. The findings demonstrate that the accelerometer is feasible, acceptable, sensitive to change and objective data correlates with self-reported physical activity. Fourth, correlates of physical activity are explored alongside children’s values, beliefs and expectations. The findings suggest that self-efficacy and enjoyment have a role in physical activity and children perceive few diabetes-related barriers to participation. Finally, the feasibility and acceptability of the Steps To Active Kids-Diabetes (STAK-D) programme for children with T1DM is explored using mixed-methods. The capacity to detect change over time in selected health outcomes is also explored (e.g., physical activity level, self-efficacy and parental fear of hypoglycaemia) All findings are discussed in terms of their implications for knowledge and understanding, a future definitive trial and clinical practice.

Background: The practice of diabetes self-care plays an important role in glycaemic control. However, not all patients with insulin-treated diabetes engage in their self-care activities. Although there is evidence that self-care practices in patients with insulin-treated diabetes can be understood and predicted by health beliefs proposed by Health Belief Model (HBM), little is known about adult patients due to several methodological weaknesses of previous studies. Furthermore, knowledge is lacking about adults with insulin-treated diabetes in Malaysia. Aim: To examine whether health beliefs suggested by the HBM can predict self-care practices in patients with insulin-treated diabetes in Malaysia. Methods: A longitudinal design was chosen to conduct this study for a six month period at three endocrinology clinics in Malaysia. Data for self-care practices (diet, insulin intake, exercise and SMBG) and health beliefs were measured using a self-reported questionnaire. In addition, participants’ glycaemic control was also examined as the objective measure for the self-care practices. These data were measured based on the participants’s glycated hemoglobin (HbA1c) results. All data were collected twice: at baseline (Time 1) and at six months follow up (Time 2). Differences in all study variables between Time 1 and Time 2 were tested using paired t-test and McNemar’s. Multiple linear regression and multiple logistic regression were used to predict the dependent variables at different points of time. Age, gender, race and diabetes-related knowledge were statistically controlled in the regression analyses. In addition, a qualitative evaluation was carried out to explore the context of the self-care practices by interviewing diabetes educators in the study setting about their diabetes education practice. Results: A total of 159 patients with insulin-treated diabetes (aged 18-40 years) participated in this study. Of these, only 108 (67.9%) completed the study. The participants were more likely to adhere to their insulin injection than to engage in good dietary habits, regular exercise and testing SMBG ≥ 3 times per day. The mean value of HbA1c was 9.8% (SD 2.61). The self-care practices and HbA1c as well as the participants’ health beliefs remained consistent at six (6) months follow up (p >.05). The HBM significantly predicted dietary self-care, insulin intake practice and HbA1c. Of the HBM costructs, perceived benefits significantly predictive of good dietary habits at Time 1 (OR 1.92) and Time 2 (OR .23) and adherence to insulin injection at Time 1 (OR 3.17) and Time 1-2 (OR 2.68). Meanwhile, except perceived severity, all other HBM contructs were predictive of HbA1c [perceived susceptibility (β .169), perceived barriers (β -.206), perceived benefits (β -.397) and cues to action (β -.233)]. The findings of the qualitative data indicate that some participants might not have been provided with diabetes education while those who did might have received inconsistent and inaccurate information regarding their self-care activities. These data were provided by 27 diabetes educators in the study settings. Conclusion: Self-care practices and glycaemic control in this study were related to health beliefs and also could be a result of limitations in the diabetes education that they had received. These findings should be given attention by diabetes educators in their efforts to improve diabetes self-care in patients with insulin-treated diabetes aged 18-40 years in Malaysia. More studies on health beliefs in diabetes self-care are needed for Malaysian patients.

Approximately 3 million people throughout the UK suffer with Type 2 diabetes mellitus (T2DM), and are 32% more likely to die early. There remains a lack of evidence for the long-term effectiveness and safety of anti-diabetic drugs in preventing diabetes-related complications, making it unclear how to optimally manage diabetes. Work to date includes observational studies subject to bias, and randomised controlled trials (RCTs), which may not reflect the ‘real world’ situation. The aim of this thesis is to combine such findings via systematic reviews, meta-analyses and retrospective cohort studies to provide more water-tight evidence of the effectiveness and safety of glucose-lowering therapies (GLT) in the long term. Firstly, a systematic review of observational studies was performed, identifying and providing a simple description of the types of biases and control measures employed in retrospective cohort studies on treatment outcomes of GLTs. Secondly, retrospective cohort studies were conducted to strengthen the evidence of the clinical effectiveness of DPP-4 inhibitors, compare their durability when combined with other anti-diabetic drugs and assess their cardiovascular safety when used in patients with T2DM, using data from The Health Improvement Network (THIN) database. Linear and logistic regression, Cox proportional hazard regression models and propensity score techniques were used to analyse routine clinical data. Thirdly, a meta-analysis was conducted on RCTs investigating the risk of bone fracture following the administration of DPP-4 inhibitor, based on data from an extensive literature search. Conducting this research has led to a better understanding of how biases may have influenced retrospective cohort studies on oral anti-diabetic drugs. An algorithm was developed to illustrate strategies for addressing biases. Potential clinical factors associated with ‘response’ to DPP-4 inhibitor treatment were found to include the addition of DPP-4 inhibitor to ongoing metformin (MET), or MET plus sulphonylurea (SU) therapy. High HbA1c at the time of treatment intensification and longer duration of diabetes were associated with the lack of HbA1c target attainment. In terms of the durability of second-line glucose-lowering agents, the co-administration of thiazolidinedione with MET was associated with the most durable glycaemic response, followed by a SU and then a DPP-4 inhibitor. Compared with a SU, adding a DPP-4 inhibitor to MET was associated with an increased need for earlier treatment intensification with a third agent. The use of statins, being a female, a smoker, having longer duration of diabetes and higher HbA1c at baseline were identified to be associated with earlier dual therapy failure. In terms of cardiovascular safety, routine clinical data showed patients who intensified MET + SU dual therapy with a DPP-4 inhibitor were associated with a decreased risk of a composite of non-fatal cardiovascular outcomes and all-cause mortality compared to those who added insulin. Furthermore, the results from meta-analysis showed DPP-4 inhibitors are not associated with increased bone fracture risks in patients with T2DM. This research is valuable in informing the choices of healthcare professionals in prescribing treatments for T2DM. For the users of this treatment, it is good news that DPP-4 inhibitors are not generally associated with fracture incidence, and that findings support the use of DPP-4 inhibitors as a second line therapeutic option, especially among non-obese patients whose glucose control remains suboptimal following MET treatment. It is recommended that treatment should be characterised on an individual basis. There remains a need for robust RCTs to investigate the influence of obesity and longer treatment durations on the efficacy of co-administering DPP-4 inhibitors to patients who are unresponsive to other oral GLTs.

Introduction New onset hyperandrogenism in postmenopausal female is a rare occurrence, presenting with hirsutism or signs and symptoms of virilization. The causes of hyperandrogenism in postmenopausal female can be categorized into tumorous (androgen-secreting ovarian or adrenal tumors) and non-tumorous in origin (Hyperthecosis, Cushing’s syndrome, Acromegaly, Congenital Adrenal Hyperplasia, and iatrogenic). Here we present a case of severe hyperandrogenism of ovarian origin in a postmenopausal female where definite etiology could not be ascertained either by imaging or pathology. Case A 72-year-old female was referred to endocrinology clinic for complaints of worsening alopecia and hirsutism for the past 4 years. History was positive for weight gain of 80 lbs in the last ten years, menstrual irregularities since menarche, and recent deepening of voice. She denied exposure to exogenous androgenic steroid. Physical examination was remarkable for android obesity, severe male pattern alopecia, hirsutism involving face and deepening of voice, no clitoromegaly was noted. Lab evaluation showed elevated total testosterone level 261 ng/dl (normal value: 2-45 ng/dL) and free testosterone 14.1 pg/mL (normal value: 0.2-3.7 pg/mL ). Estradiol level was elevated and FSH and LH were low for a post-menopausal state. 17 hydroxy progesterone, TSH, and 1 mg overnight dexamethasone suppression test were normal ruling out congenital adrenal hyperplasia, thyroid dysfunction and Cushing’s syndrome. IGF-1 was not elevated ruling out acromegaly. DHEAS level was normal and CT abdomen and pelvis showed no evidence of an adrenal tumor, excluding adrenal source of androgen excess. Transvaginal Ultrasound showed normal volume of the ovaries, thickened endometrium and uterine myomas. Given markedly elevated testosterone levels and exclusion of adrenal tumor, suspicion for an ovarian source remained high. An MRI of the pelvis was done that showed 1.9 cm left adnexal cyst. She was then referred to Gynecology and underwent total hysterectomy with bilateral salpingo-oophorectomy. Interestingly surgical pathology was negative for tumor, showed unremarkable ovaries and right fallopian tube, left fallopian tube with hydrosalpinx, and showed atypical hyperplasia of the endometrium. However, testosterone levels decreased to normal two months after surgery; Free testosterone 1.8 pg/ml (normal values: 0.2-3.7 pg/mL), total testosterone 31 ng/dl (normal value: 2-45 ng/dL) indicating removal of ovarian source of testosterone production. Discussion Although relatively rare, severe hyperandrogenism (total testosterone >150 ng/dL, DHEAS >700 mcg/dL, signs of virilization) in postmenopausal women is caused either by adrenal or ovarian androgen secreting tumor or ovarian hyperthecosis, which is characterized by a hyperplastic ovarian stroma. Severity of symptoms, degree of androgen excess followed by imaging studies lead to identification of source of excessive androgen secretion in most cases. Diagnosis of ovarian virilizing tumors can be difficult since size of such tumors is often too small to allow detection on imaging studies, but are generally detected on surgical pathology and therefore bilateral salpingo-oophorectomy is recommended after exclusion of adrenal cause. However, rarely etiology may remain undetermined in some cases with conventional histology as in our patient.

It is estimated that 366 million people were living with diabetes in 2011, and this is predicted to rise to 522 million by 2030. One of the most common complications of diabetes is diabetic neuropathy, where patients experience various symptoms of neuropathic pain including mechanical allodynia. Using a high fat diet (HFD) in combination with streptozotocin (STZ) produces a model of diabetes which mimics aspects of type 2 diabetes. The aim of this thesis was to characterise pain responses in the HFD/STZ model and to explore some of the peripheral and spinal mechanisms associated with the changes in somatosensory processing. The effectiveness of a variety of drugs in alleviating/preventing neuropathic pain was also investigated in this model. The effects of the HFD/STZ model on mechanical sensitivity, and changes in metabolic parameters were investigated, and it was found to cause a robust development of mechanical hypersensitivity and a large increase in plasma glucose and a contrasting decrease in plasma insulin. The impacts of the HFD/STZ model on peripheral nerve function and pathology, and spinal mechanisms of central sensitisation, were explored to help identify the mechanisms underpinning the behavioural pain phenotype in these rats. No neuronal degeneration was detected in DRGs or the spinal cord at the timepoints investigated, and a decrease in microglial activation and GFAP immunoreactivity was observed at later timepoints (day 50). Changes in neuronal responses in the dorsal horn of the spinal cord were then investigated, and there was a trend towards a decrease in mechanically evoked responses of spinal neurones in the HFD/STZ group, but no changes in the threshold for electrical activation of C-fibres, nor any significant changes to electrically evoked responses, were observed. There was no change in spontaneous firing, possibly due to the search criteria used. The effects of different types of interventions on aberrant pain responses were also investigated. As neuropathic pain often proves intractable, one of the key objectives is to develop new drugs, or to find alternative uses of current drugs, that are able to provide symptomatic relief of pain. The gold standard treatment for pain in diabetic neuropathy, pregabalin (10mgkg-1, p.o.), was effective at alleviating established mechanical hypersensitivity at day 37 in the HFD/STZ model. A novel MAGL inhibitor, MJN110 (5mgkg-1, i.p.), was found to be as effective as pregabalin in this model, highlighting a possible role for endocannabinoid modulators in providing pain relief in diabetes. The antidiabetic pioglitazone (10mgkg-1, p.o.), however, was unable to alleviate mechanical hypersensitivity when administered at day 21 for 28 days. Two other antidiabetic drugs, linagliptin (3mgkg-1, p.o.) and metformin (200mgkg-1, p.o.), did show promise in preventing the development of mechanical hypersensitivity in this model when administered from day 4, independent of glycemic control. It is worth investigating these findings further since both of these drugs are already licensed and have undergone all necessary safety testing, and so could rapidly be put to use if effective. In conclusion, this thesis has highlighted the role that the HFD/STZ model can play in investigating underlying mechanisms of diabetic peripheral neuropathic pain, and its use in exploring potential new therapeutic options for alleviating this pain.

Type 2 diabetes mellitus is a chronic condition caused by a deficiency in the secretion of insulin from the islets of Langerhans and/or impaired insulin signalling, resulting in hyperglycaemia. The role of the endocannabinoid system is well-recognised in the CNS and immune system, but its role in glucose homeostasis is poorly understood. The aim of this study was to define the roles of cannabinoids in insulin secretion, to provide insights into their therapeutic potential (or limitation) in the treatment of type 2 diabetes. Isolated islets were used, from Wistar rats, in static incubation studies measuring changes in insulin secretion rates. The endocannabinoid anandamide (AEA) was found to inhibit insulin secretion in a glucose- and concentration-dependent manner, with an IC50 of 1.6μM (95% CI: 227nM to 4.0μM; n= 10). Upon further analysis of the concentration-response data islet sensitivity to AEA appeared to vary, with islets either appearing to be sensative (IC50 220nM; 95% CI: 21.9nM to 2.2μM; n= 5) or less sensative (IC50 12.3μM; 95% CI: 6.8μM to 19.4μM; n= 5) to AEA. Pre-incubation of islets with a fatty acid amide hydrolase inhibitor did not affect islet responsiveness to AEA. AEA-mediated inhibition of insulin secretion was not consistently affected by cannabinoid receptor 1 (CB1) or CB2 antagonism. Surprisingly, the CB1 receptor antagonist AM251 was found to inhibit insulin secretion in a glucose- and concentration-dependent (IC50 1.6μM; 95% CI: 507nM to 3.3μM; n= 6) manner. Results from this study suggest that differences in CB-receptor signalling pathways, rather than endocannabinoid metabolism, could be responsible for the variations in the potency of AEA between islet preparations. Characterisation of cannabinoid signalling in islets was hindered as the CB receptor antagonists used in this study also affected insulin secretion. This study highlights the dynamics of endocannabinoid signalling in islets, which may be linked to their physiological function.

Thesis (doctoral)--Universität der Bundeswehr München, 1995. / Includes bibliographical references.

Thesis (doctoral)--Universität der Bundeswehr München, 1995. / Includes bibliographical references.

The studies presented in this thesis aimed to investigate the effects of nutritional modulation and age-associated changes on insulin sensitivity. Four separate studies were performed; three of these had insulin sensitivity as the primary outcome. Existing studies show that ageing is associated with insulin resistance, but data may be confounded by several factors that also occur with increasing age, such as increased adiposity, skeletal muscle lipid accumulation and reduced physical activity. To elucidate this further the first study compared body composition, skeletal muscle lipid content, fat metabolism during light-intensity exercise and whole-body and skeletal muscle insulin sensitivity between 7 healthy young and 14 older males. Ageing and insulin resistance are also associated with impaired skeletal muscle protein synthesis, however the effects of insulin resistance per se on amino acid metabolism and associated insulin signalling pathways are not really known. The second study involved 8 young healthy males and aimed to explore the effect of insulin resistance on the protein synthetic response to amino acid ingestion and muscle protein signalling pathway in humans. Dietary intake has been shown to affect insulin sensitivity; however it is unclear if diet composition affects liver fat content independent of energy balance. Therefore the third study aimed to investigate the effects of hyperenergetic diets high in fat or carbohydrate on liver fat and insulin sensitivity. The study involved 23 healthy but overweight and obese males who initially consumed an isoenergetic diet for one week, and then were randomised to 2 weeks of either hyperenergetic (+25% excess) high fat or high carbohydrate diets. Liver fat content, abdominal visceral fat, skeletal muscle fat content, hepatic lipid metabolism and insulin sensitivity were assessed before and after the 2 week intervention period. Whilst dietary excess can exacerbate insulin resistance, certain micronutrients may improve insulin sensitivity. Carnitine has shown encouraging outcomes in relation to promoting fatty acid oxidation, metabolism and modulating body composition in healthy young volunteers. However the effects on older people have never been explored. This formed the basis of the fourth study that investigated the effects of 6 months of oral carnitine supplementation or placebo in 14 older (≥65 years of age) healthy males in relation to fatty acid metabolism, skeletal muscle lipid and insulin sensitivity. The main findings are summarised. Irrespective of age, adiposity and physical activity are associated with impaired fatty acid oxidation, greater skeletal muscle lipid accumulation and reduced insulin sensitivity. However ageing per se appears to increase the sympathetic response to exercise and enhance systemic fatty acid delivery and adipose tissue lipolysis. Insulin resistance induced by acute elevation of lipid was found to affect the skeletal muscle protein synthetic response to amino acid ingestion, and this impairment appeared to occur downstream from the Akt insulin signalling pathway. Energy excess per se increases liver fat content and affects liver metabolism but there were no differential effects of carbohydrate or fat on hepatic insulin sensitivity and liver fat content. Finally, oral carnitine ingestion for 6 months successfully increased skeletal muscle total carnitine content of older healthy people and resulted in increased fatty acid oxidation and intramyocellular lipid (IMCL) utilisation during light-intensity exercise, but no effect on skeletal muscle insulin sensitivity was seen. These studies have increased mechanistic insight into the associations between ageing, nutrients and insulin sensitivity, paving the way to further research.

Background: Hypoglycemia is a commonly encountered metabolic state in the patient population. It can be medically defined as a blood sugar <70mg/dL in a diabetic patient or <50mg/dL in a non-diabetic patient. It is less frequently seen in non-diabetics due to the body’s ability to autoregulate insulin administration. Common symptoms are sweating, tremors, palpitations, dizziness, drowsiness, and confusion. If left untreated, these symptoms can progress to seizures, arrythmias, or other complications that ultimately lead to death. Objective: To highlight the possible causes of hypoglycemia and the appropriate work-up for normally euglycemic patients. Case Description: We herein report a case of hypoglycemia in a 36-year-old female with Lupus related end-stage renal disease on hemodialysis via Ash-catheter who presented with peritonitis due to a defunct peritoneal dialysis catheter. The patient was found to be bacteremic; therefore both catheters were removed and antibiotics were started. Repeat blood cultures showed no growth for 48 hours, so the patient was held fasting at midnight for placement of a new catheter. On the day of surgery, she registered multiple blood sugar readings as low as 15mg/dL. Her symptoms were limited to drowsiness and shortness of breath. She was given four D50 boluses, glucagon IV, and a D5 drip that was adjusted to a D15 drip to stabilize her blood sugar. It was discovered that at an admission two months ago, the patient had a few readings in the 30s. She denied any recollection of this and claimed to have been asymptomatic. She also denied a history of low blood sugars and a diagnosis of diabetes. In surgery that day, the patient went into cardiac arrest on the operating table after being sedated. She was resuscitated after one round of chest compressions, and her catheter was placed. During the episodes of low blood sugar, specific labs were drawn for the work-up of hypoglycemia (glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, insulin antibodies, and sulfonylurea/meglitinide screen), but results yielded inconclusive values that prevented a diagnosis. The patient’s blood sugars became steady once her diet was restarted, and she was discharged in stable condition to a rehab facility after cautionary counseling was given. Discussion: This case highlights an optimal way to work-up a patient with new onset hypoglycemia, focusing on patient history and drawing the appropriate labs during hypoglycemic episodes. The specific labs listed above can be used to differentiate between various causes of hypoglycemia (exogenous insulin administration, an insulin secreting tumor [insulinoma], insulin antibodies, insufficient cortisol or glucagon levels, or improper sulfonylurea/meglitinide use) by comparing them to standards. If labs are unable to be obtained, a 72-Hour Fast can be conducted to create a controlled environment, and a Glucagon Tolerance Test can further explore if the cause of hypoglycemia is insulin related. The goal of all of this testing is to be able to identify and treat the underlying cause of the hypoglycemia and prevent future episodes and the complications that accompany it.