Becoming pregnant: exploring the perspectives of women living with diabetes

Background The risk of adverse pregnancy outcome for women with type 1 diabetes is reduced through tight diabetes control. Most women enter pregnancy with inadequate blood glucose control. Interview studies with women suggest the concept of ‘planned’ and ‘unplanned’ pregnancies is unhelpful. Aim To explore women's accounts of their journeys to becoming pregnant while living with type 1 diabetes. Design of study Semi-structured interviews with 15 women living with pre-gestational type 1 diabetes, between 20 and 30 weeks gestation and with a normal pregnancy ultrasound scan. Setting Four UK specialist diabetes antenatal clinics. Method Interviews explored women's journeys to becoming pregnant and the impact of health care. Analysis involved comparison of women's accounts of each pregnancy and a thematic analysis. Results Women's experiences of becoming pregnant were diverse. Of the 40 pregnancies described, at least one positive step towards becoming pregnant was taken by 11 women in 23 pregnancies but not in the remaining 17 pregnancies, with variation between pregnancies. Prior to and in early pregnancy, some women described themselves as experts in their diabetes but most described seeking and/or receiving advice from their usual health professionals. Three women described pre-conception counselling and the anxiety this provoked. Conclusion For women living with type 1 diabetes each pregnancy is different. The concept of planned and unplanned pregnancy is unhelpful for designing health care. Formal preconception counselling can have unintended consequences. Those providing usual care to women are well positioned to provide advice and support to women about becoming pregnant, tailoring it to the changing needs and situation of each woman.

Ocular and systemic markers for vascular function in those at risk of type 2 diabetes mellitus and cardiovascular disease

The devastating impact of Type 2 Diabetes Mellitus (T2DM) -related morbidity and mortality on global healthcare is escalating with higher prevalences of obesity, poor diet, and sedentary lifestyles. Therefore, the clinical need for early diagnosis and prevention in groups of high-risk individuals is necessary. The purpose of this thesis was to investigate the use of surrogate markers, namely retinal vascular function, to determine future vascular endothelial dysfunction, atherosclerosis, large vessel disease and cardiovascular risk in certain groups. This namely covered normoglycaemic and normotensive South Asians (SAs), those with Impaired-Glucose Tolerance (IGT) and individuals with a familial history (FH) of T2DM. Additionally the effect of overweight and obesity was studied. The techniques and modified protocols adopted for this thesis involved the investigation of endothelial function by means of vascular reactivity at the ocular and systemic level. Furthermore, the relationships between retinal and systemic function with circulating markers for endothelial cell function and cardiovascular risk markers were explored. The principal studies and findings of the research were: Vascular Function in Normoglycaemic Individuals with and without a FH of T2DM WE FH individuals exhibited higher levels of total cholesterol levels that correlated well with the retinal arterial dilation amplitude to flicker light stimulus. However this did not extend to noticeable differences in markers for endothelial cell damage and impaired retinal and systemic function. Vascular Function in Normoglycaemic South-Asians vs. White-Europeans without a FH and Vascular Disturbances Compared to healthy WEs (normo -glycaemic and -tensive), SA participants exhibited levels of dyslipidaemia and a state of oxidative stress that extended to impaired vascular function as detected by reduced brachial artery flow-mediated dilation, slower retinal arterial vessel dilation reaction times (Appendix 3) and steeper constriction profiles. Furthermore, gender sub-group analysis presented in a sub-chapter shows that SA males demonstrated 24-hour systemic blood pressure (BP) and heart rate variability (HRV) abnormalities and heightened cardiovascular disease (CVD) risk. Vascular Function in Individuals Newly Diagnosed with IGT as compared to Normoglycaemic Healthy Controls Newly-diagnosed WE and SA IGT patients showed a greater risk for CVD and T2DM progression by means of 24-hour BP abnormalities, dyslipidaemia, increased carotid artery intimal-media thickness (c-IMT), Framingham scores and cholesterol ratios. Additionally, pre-clinical markers for oxidative stress and endothelial dysfunction, as evident by significantly lower levels of plasma glutathione and increased levels of von-Willebrand factor in IGT individuals, extended to impaired vascular systemic and retinal function compared to normal controls. This originally shows retinal, systemic and biochemical disturbances in newly-diagnosed IGT not previously reported before. Vascular Function in Normal, Overweight and Obese Individuals of SA and WE Ethnicity In addition to the intended study chapters, the thesis also investigated the influence of obesity and overweight on vascular function. Most importantly, it was found for the first time that compared to lean individuals it was overweight and not obese individuals that exhibited signs of vascular systemic and ocular dysfunction that was evident alongside markers of atherosclerosis, CVD risk and endothelial damage.

Treating type 2 diabetes through insulin resistance

Type 2 diabetes is an insidious disorder, with micro and/or macrovascular and nervous damage occurring in many patients before diagnosis. This damage is caused by hyperglycaemia and the diverse effects of insulin resistance. Obesity, in particular central obesity, is a strong pre-disposing factor for type 2 diabetes. Skeletal muscle is the main site of insulin-stimulated glucose disposal and appears to be the first organ that becomes insulin resistant in the diabetic state, with later involvement of adipose tissue and the liver. This study has investigated the use of novel agents to ameliorate insulin-resistance in skeletal muscle as a means of identifying intervention sites against insulin resistance and of improving glucose uptake and metabolism by skeletal muscle. Glucose uptake was measured in vitro by cultured L6 myocytes and isolated muscles from normal and obese diabetic ob/ob mice, using either the tritiated non-metabolised glucose analogue 2-deoxy-D-glucose or by glucose disposal. Agents studied included lipoic acid, isoferulic acid, bradykinin, lipid mobilising factor (provisionally synonymous with Zinca2 glycoprotein) and the trace elements lithium, selenium and chromium. The putative role of TNFa in insulin resistance was also investigated. Lipoic acid improved insulin-stimulated glucose uptake in normal and insulin resistance murine muscles, as well as cultured myocytes. Isoferulic acid, bradykinin and LMF also produced a transient increase in glucose uptake in cultured myocytes. Physiological concentrations of TNFa were found to cause insulin resistance in cultured, but no in excised murine muscles. The effect of the M2 metabolite of the satiety-inducing agent sibutramine on lipolysis in excised murine and human adipocytes was also investigated. M2 increased lipolysis from normal lean and obese ob/ob mouse adipocytes. Arguably the most important observation was that M2 also increased the lipolytic rate in adipocytes from catecholamine resistant obese subjects. The studies reported in this thesis indicate that a diversity of agents can improve glucose uptake and ameliorate insulin resistance. It is likely that these agents are acting via different pathways. This thesis has also shown that M2 can induce lipolysis in both rodent and human adipocytes. M2 hence has potential to directly reduce adiposity, in addition to well documented effects via the central nervous system.

The role of adipokines in beta-cell failure of type 2 diabetes

Beta-cell failure coupled with insulin resistance is a key factor in the development of type 2 diabetes. Changes in circulating levels of adipokines, factors released from adipose tissue, form a significant link between excessive adiposity in obesity and both aforementioned factors. In this review we consider the published evidence for the role of individual adipokines on the function, proliferation, death and failure of beta-cells, focusing on those reported to have the most significant effects (leptin, adiponectin, TNFa, resistin, visfatin, DPP-IV and apelin). It is apparent that some adipokines have beneficial effects whereas others have detrimental properties; the overall contribution to beta-cell failure of changed concentrations of adipokines in the blood of obese pre-diabetic subjects will be highly dependent on the balance between these effects and the interactions between the adipokines which act on the beta-cell via a number of intersecting intracellular signalling pathways. We emphasise the importance, and comparative dearth, of studies into the combined effects of adipokines on beta-cells.

The hypocaloric diet in type 2 diabetes - déjà vu

Dietary modification is considered a cornerstone in the management of diabetes superimposed upon which are pharmacological therapies as required. The value of hypocaloric diets in reducing and eliminating glycosuria was extolled in the pre-insulin era. A common feature of the nutrient balance of these diets was restriction in the availability of carbohydrate. Herein we review the use of diet as therapy in the past and discuss the rationale for hypocaloric dietary management of type 2 diabetes in the 21st century, drawing comparisons with bariatric surgery and considering why weight loss is particularly difficult for overweight and obese individuals with type 2 diabetes. © SAGE Publications 2012.

Pre-transplant signal induction for vascularisation in human islets

Human islet transplant success is partially impaired by slow revascularisation. Our study investigated the potential for rotational cell culture (RC) of human islets combined with thiazolidinedione (TZD) stimulation of peroxisome proliferator-activated receptor gamma (PPAR?) to upregulate vascular endothelial growth factor (VEGF) expression in the islets. Four groups of human islets were studied: static culture (SC) with and without 25 mmol/L TZD and RC with and without 25 mmol/L TZD. These were assessed for insulin secretion and soluble VEGF-A release. Both proteins were quantified by enzyme-linked immunosorbent assay (ELISA), supported with qualitative immunofluorescence staining. RC + TZD increased insulin secretion by >20% (p <0.05-0.001) in response to 16.7 mmol/L glucose and 16.7 mmol/L glucose + 10 mmol/L theophylline (G + T). This effect was seen at all time intervals compared with SC and without addition of TZD. Soluble VEGF-A release was significantly augmented by RC and TZD exposure with an increased effect of >30% (p <0.001) at 72 h under both SC and RC conditions. RC supplemented with a TZD enhances and prolongs the release of insulin and soluble VEGF-A by isolated human islets. © 2013 The Author(s).

A double-blind randomized study comparing the effects of continuing or not continuing rosiglitazone + metformin therapy when starting insulin therapy in people with type 2 diabetes

Aims: To compare the efficacy and safety of either continuing or discontinuing rosiglitazone + metformin fixed-dose combination when starting insulin therapy in people with Type 2 diabetes inadequately controlled on oral therapy. Methods: In this 24-week double-blind study, 324 individuals with Type 2 diabetes inadequately controlled on maximum dose rosiglitazone + metformin therapy were randomly assigned to twice-daily premix insulin therapy (target pre-breakfast and pre-evening meal glucose ≤ 6.5 mmol/l) in addition to either rosiglitazone + metformin (8/2000 mg) or placebo. Results: Insulin dose at week 24 was significantly lower with rosiglitazone + metformin (33.5 ± 1.5 U/day, mean ± se) compared with placebo [59.0 ± 3.0 U/day; model-adjusted difference -26.6 (95% CI -37.7, -15,5) U/day, P < 0.001]. Despite this, there was greater improvement in glycaemic control [HbA 1c rosiglitazone + metformin vs. placebo 6.8 ± 0.1 vs. 7.5 ± 0.1%; difference -0.7 (-0.8, -0.5)%, P < 0.001] and more individuals achieved glycaemic targets (HbA1c < 7.0% 70 vs. 34%, P < 0.001). The proportion of individuals reporting at least one hypoglycaemic event during the last 12 weeks of treatment was similar in the two groups (rosiglitazone + metformin vs. placebo 25 vs. 27%). People receiving rosiglitazone + metformin in addition to insulin reported greater treatment satisfaction than those receiving insulin alone. Both treatment regimens were well tolerated but more participants had oedema [12 (7%) vs. 4 (3%)] and there was more weight gain [3.7 vs. 2.6 kg; difference 1.1 (0.2, 2.1) kg, P = 0.02] with rosiglitazone + metformin. Conclusions: Addition of insulin to rosiglitazone + metformin enabled more people to reach glycaemic targets with less insulin, and was generally well tolerated. © 2007 The Authors.

Obstructive sleep apnoea is associated with sight threatening retinopathy and predicts the developement of preproliferative and proliferative retinopathy in patients with type 2 diabetes:a longitudinal analysis

troduct I on . An observational longitudinal study. P ur P ose . Assess the relationship between obstructive sleep apnoea (OSA) and DR cross-sectionally and longitudinally. M ethods . Adults with Type 2 diabetes mellitus (T2DM), who were re - cruited from a hospital-based diabetes clinic in the UK. Patients with pre-existing OSA, end-stage renal disease and non-diabetic retinopa - thy were excluded. OSA (apnoea hypopnea index ≥ 5 events/hour) was assessed by a single overnight home-based cardio-respiratory study (Alice PDX, Philips Respironics, USA). DR was assessed us - ing retinal images between 2007 and 2012. Sight threatening diabetic retinopathy (STDR) was defined as presence of pre-proliferative or proliferative DR, maculopathy or photocoagulation. Advanced DR was defined as pre-proliferative or proliferative DR. r esults . 199 patients were included (57.3% (n=114) men, 47.7% (n=95) White Europeans). STDR and OSA prevalence were 38.7% (n=77) and 62.8% respectively. A t b A sel I ne . STR prevalence was higher in patients with OSA (OSA+) compared to those without OSA (OSA-) [48.8% n=61 vs. 21.6% n=16, p<0.001]. After adjustment for confounders, OSA remained independently associated with STR (OR 3.7, 95% CI 1.6-8.9, p=0.006), maculopathy (OR 4.5, 95% CI 1.8-11.4, p=0.002) and advanced DR (OR 3.9, 95% CI 1.02-15.3, p=0.047). Mild and moderate to severe OSA were independently associated with STR and maculopathy and only moderate to severe OSA was associated with advanced DR following adjustment for con - founders. l ong I tud I n A lly . Over the follow-up period of (4.4±1 years), more OSA+ patients progressed from no or background DR to advanced DR (15.3% (n=17) vs. 3% (n=2), p=0.01). OSA was an independent pre - dictor of advanced DR development after adjustment for confounders (OR 6.6, 95% CI 1.2-35.1, p=0.03). OSA did not predict the develop - ment of maculopathy. c onclus I ons . OSA is independently associated with STR and predicts the development of preproliferative and proliferative DR. Intervention - al studies are needed to assess the impact of OSA treatment on DR.

Obstructive sleep apnoea predicts the development of preproliferative and proliferative retinopathy in patients with type 2 diabetes:a longitudinal analysis

Background and aims: Diabetic Retinopathy (DR) is a leading cause of blindness. OSA is associated with increased oxidative and nitrosative stress and endothelial dysfunction in patients with type 2 diabetes (T2DM). Hence, it is plausible that OSA can promote the development and progression of DR. Materials and methods: An observational longitudinal study in adults with T2DM. Patients with pre-existing OSA, end-stage renal disease and non-diabetic retinopathy were excluded. OSA (apnoea hypopnea index ≥ 5 events/hour) was assessed by a single overnight home-based cardio-respiratory monitoring (Alice PDX, etc.). DR was assesses using retinal images between 2007 and 2012. Sight threatening retinopathy (STR) was defined as pre-proliferative or proliferative DR, maculopathy or photocoagulation. Advanced DR was defined as pre-proliferative or proliferative DR. Results: 199 patients were included (57.3% men, 47.7% White Europeans). STR and OSA prevalence were 38.7 % and 62.8% respectively. STR preva-lence was higher in patients with OSA (OSA+) compared to those with-out (OSA-) [48.8% vs. 21.6%, p <0.001]. After adjustment for confounders, OSA remained independently associated with STR (OR 3.7, 95%CI 1.6-8.9, p=0.006, maculopathy (OR 4.5, 1.8-11.4, p=0.002) and advanced DR (OR 3.9, 1.02-15.3, p=0.047). Over 4.4±1 years, more OSA+ patients progressed from no or background DR to advanced DR (15.3% vs. 3%, p=0.01). OSA was an independent predictor of advanced DR development after adjustment (OR 6.6, 95%CI 1.2-35.1, p=0.03). OSA did not predict the development of maculopathy. Patients received continuous positive airway pressure treatment were less likely to develop advanced DR. Conclusion: OSA is independently associated with STR and predicts the development of preproliferative and proliferative DR. Interventional studies are needed to assess the impact of OSA treatment on DR.Supported by: NIHR (UK) and The UK Novo Nordisk Research Foundation.

Natural history of retinopathy in children and young people with type 1 diabetes

Purpose: To describe the prevalence and natural history of retinopathy in a cohort of children and young people with type 1 diabetes attending a tertiary hospital diabetes clinic. Methods: We analysed retinopathy screening data from 2008 to 2010 on all eligible children using the 'Twinkle' diabetes database and the regional retinal screening database. Results: A total of 88% (149/169) of eligible children were screened in 2008, median age 14 years, 52% male. The prevalence of retinopathy was 19.5% (30/149). All children had background retinopathy grade R1. There was significant difference in median (range) duration of diabetes, 7.7 years (0.6–13.7) vs 5 years (0.2–12.5) (P<0.001) and median (range) HbA1C, 9.1% (7.2–14) vs 8.6% (5.6–13.1) (P=0.02), between the groups with and without retinopathy. At 2- years follow-up, 12/30 (40%) had unchanged retinopathy grade R1, 10/30 (33.3%) showed resolution of changes (R0), 1/30 progressed to maculopathy, and 7/30 had no follow-up data. Median (range) HbA1C in 2008 and 2010 for the groups with stable vs resolved changes was similar, 9.1% (7.2–14.0) and 9.2% (7–14.0) vs 9.5% (7.8–14.0) and 9.2% (8.7–14.0). Of the 119 without retinopathy in 2008, 27 (22.5%) had developed retinopathy within 2 years, including 1 with pre-proliferative retinopathy and 1 with maculopathy. There was no significant difference in HbA1c between those who progressed to retinopathy (8.7% (7.1–13.1)) (8.7% (7.1–13.1)), and those who did not (8.6% (6.3–12.2)). Conclusions: Prevalence of background retinopathy in our cohort was comparable to the previously published reports, with higher HbA1c and longer duration of diabetes being significant risk factors. On short-term follow-up, Grade 1 retinopathy is likely to resolve in a third of patients and remain unchanged in just over a third.