A retrospective cohort study evaluating pregnancy outcomes in women with MIDD.

AIMS: The most common pathogenic mitochondrial mutation associated with mitochondrial disease is m.3243A>G. Increased obstetric complications, such as spontaneous abortion, gestational diabetes (GDM), preterm delivery, and preeclampsia, have been reported in women carrying this mutation. We aimed to determine the fetal and maternal outcomes in pregnant women with mitochondrial disease. METHODS: We retrospectively studied the obstetric and perinatal outcomes in 88 pregnancies of 26 women with genetically confirmed mitochondrial disease (m.3243A>G in the MTTL1 gene (n = 25); m.12258C>A in the MT-TS2 gene (n = 1)). Outcomes included pregnancy related complications, mode of delivery, gestational age at delivery and birthweight. RESULTS: Mean heteroplasmy rate was 18%. The miscarriage rate was higher than background at 25%. 21 pregnancies (24%) were complicated by GDM; 9 pregnancies (13.6%) had a preterm delivery and 2 of them (3%) an extreme premature delivery < 32 weeks. One woman had preeclampsia and one had a postpartum hemorrhage. The caesarean section (CS) rate was 20%. For every unit increase in maternal heteroplasmy levels there was a 26% increased risk of undergoing an assisted operative vaginal delivery (OR 1.26, 95% CI 1.04-1.53, P = 0.002, Bonferroni corrected P = 0.005) and an 18% increased risk of undergoing a CS (OR 1.18, 95% CI 1.01-1.39, P = 0.01, Bonferroni corrected P = 0.03) compared to a spontaneous vaginal delivery. There was a statistical significant correlation between maternal and offspring heteroplasmy levels. Spearman correlation rho = 0.96, 95% CI 0.78-0.99, P = 0.0002. CONCLUSION: Women with mitochondrial disease appear to have more frequent obstetric complications including miscarriage and GDM. Pre-pregnancy diagnosis of m.3243A>G will enable the counseling of women and increase awareness of possible obstetric complications.

Attitudes of women with gestational diabetes toward diet and exercise: a qualitative study.

OBJECTIVE: Gestational diabetes (GDM) refers to glucose intolerance of varying severity first occurring in pregnancy. Following a diagnosis of GDM, exercise and dietary modification has a positive effect on improving glycemic control. Lifestyle changes affected in pregnancies affected by GDM have beneficial effects on long-term health if continued following birth. In addition, the psychological impact of a diagnosis of GDM should not be overlooked. Reports of maternal stress, anxiety, and fear are commonly reported issues in the literature. Support, both socially and from health care professionals, is also linked with higher rates of success in GDM management. Research to date had focused on women's reaction to a diagnosis of GDM, their mood and quality of life following a diagnosis, and their knowledge or opinions on the management of GDM. This qualitative study explored the attitudes of women with GDM toward these lifestyle changes, specifically diet and exercise. Women were also asked to identify advice that would be useful for other women newly diagnosed with GDM. METHODS: With ethical approval a qualitative study was conducted using semi-structured interviews which were examined using Thematic Analysis. Patients were invited to participate and gave written consent after a discussion with a study researcher. The question plan for semi-structured interviews was designed with the advice of patient advocates. Recurrent themes were developed until the saturation of data. RESULTS: Thirty-two women took part in the study. Time, convenience, and lack of educational awareness were common barriers to healthy eating and physical activity plans. Enablers for change included meal planning and organization. Women regarded their diets pre-diagnosis as healthy, with small "tweaks" (such as portion control) required to comply with recommendations. Another significant facilitator to change was support from the woman's partner. This also set a benchmark for plans of diet maintenance within the family structure after pregnancy. Unlike dietary changes, a consistent theme was that exercise was considered a "chore" in managing GDM and was unlikely to be continued in the long term. Practical advice offered by participants for other women with GDM included organization, realistic approaches, and lack of self-blame. CONCLUSION: Women reported that changes in diet would be more achievable in the long term than changes in exercise patterns. Partners and the clinical team were significant sources of support. Women's views are crucial to providing clinicians with a comprehensive and holistic understanding of disease management. Involving women in self-care decisions and empowering women to manage their own health are key contributors to long-term behavior change as well as service provision and policy implementation.

Associations between sleep duration and sleep debt with insulin sensitivity and insulin secretion in the EGIR-RISC Study.

AIM: Extremes in sleep duration play an important role in the development of type 2 diabetes. We examined the associations between sleep duration and sleep debt with estimates of insulin sensitivity and insulin secretion. METHODS: Data were derived from the European multi-centre EGIR-RISC study. Sleep duration and sleep debt were derived from a sleep questionnaire asking about sleeping time during the week and during the weekend. Insulin sensitivity and insulin secretion were estimated from a 2-hour Oral Glucose Tolerance Test, with samples every 30 minutes. Associations between sleep duration and sleep debt with insulin sensitivity and insulin secretion, were analysed by multiple linear regression models corrected for possible confounders. RESULTS: Sleep data were available in 1002 participants, 46% men, mean age 48 ± 8 years, who had an average sleep duration of 7 ± 1 hours [range 3-14] and an average sleep debt (absolute difference hours sleep weekend days minus weekdays) of 1 ± 1 hour [range 0-8]. With regard to insulin sensitivity, we observed an inverted U-shaped association between sleep duration and the Stumvoll MCR in (mL/kg/min), with a corrected ß (95% CI) of 2.05 (0.8; 3.3) and for the quadratic term -0.2 (-0.3; -0.1). Similarly, a U-shaped association between sleep duration and log HOMA-IR in (µU/mL), with a corrected ßs of -0.83 (-1.4; -0.24) and 0.06 (0.02; 0.10) for the quadratic term. Confounders showed an attenuating effect on the associations, while BMI mediated 60 to 91% of the association between sleep duration and insulin sensitivity. No significant associations were observed between sleep duration with insulin secretion or between sleep debt with either insulin sensitivity or insulin secretion. CONCLUSIONS: Short and long sleep duration are associated with a lower insulin sensitivity, suggesting that sleep plays an important role in insulin resistance and may provide the link with development of type 2 diabetes.

Assessment of the effectiveness of group education on knowledge for women with newly diagnosed gestational diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) is identified in pregnancy and resolves following delivery. It increases maternal and foetal morbidity and may increase risk of future type 2 diabetes. Women diagnosed with GDM need high-quality multidisciplinary education in order to apply necessary changes to their diet and lifestyle. There is a paucity of information on the effectiveness of group education for women with GDM. AIMS: The aim of this study was to assess the effect of a multidisciplinary group intervention delivered by a specialist midwife and dietitian on women's knowledge of GDM. METHODS: All women with a diagnosis of GDM were invited to attend a multidisciplinary group educational session on lifestyle and GDM management. Participants were invited to complete a questionnaire before and after the educational intervention; only individuals who completed both questionnaires were included. The questionnaire reviewed knowledge of suitable diet, implications of GDM diagnosis and management of GDM. RESULTS: A total of 716 women completed both questionnaires; mean age of the participants was 34 years. Just under half of women (46.9%, n = 333) were primiparous. The majority of the women (62.5%, n = 439) were Irish; 53.4% (n = 382) had a family history of diabetes. There was a significant increase in median score for knowledge following the educational intervention (pre-intervention score 8 (-2-12); post-intervention score 12 (1-12); p < 0.001). CONCLUSIONS: This study demonstrates the benefit of a multidisciplinary group educational session delivered by a specialized midwife and a dietitian on pregnant women's knowledge and understanding of GDM.

Potential impact of cycle of care on Diabetes services in secondary care.

Diabetes Cycle of Care is a new initiative recently introduced by the Health Service Executive (HSE). In this review we found that a quarter of patients attending a secondary care diabetes outpatient clinic in a large teaching hospital could potentially be managed in primary care upon implementation of Diabetes Cycle of Care.

Insulin resistance and ß-cell function in smokers: results from the EGIR-RISC European multicentre study.

AIMS: Tobacco smoking is known to increase the long-term risk of developing Type 2 diabetes mellitus, but the mechanisms involved are poorly understood. This observational, cross-sectional study aims to compare measures of insulin sensitivity and ß-cell function in current, ex- and never-smokers. METHODS: The study population included 1246 people without diabetes (mean age 44 years, 55% women) from the EGIR-RISC population, a large European multicentre cohort. Insulin sensitivity was measured using a hyperinsulinaemic, euglycaemic clamp and the homeostatic model assessment - insulin resistance (HOMA-IR) index. Two ß-cell function parameters were derived from measures during an oral glucose tolerance test: the early insulin response index and ß-cell glucose sensitivity. Additionally, the areas under the curve during the oral glucose tolerance test were calculated for glucose, insulin and C-peptide. RESULTS: According to smoking habits, there were differences in insulin sensitivity, which was lower in women who smoked, and in ß-cell glucose sensitivity, which was lower in men who smoked, but these associations lost significance after adjustment. However, after adjustment, the areas under the glucose and the C-peptide curves during the oral glucose tolerance test were significantly higher in men who smoked. CONCLUSIONS: Smoking habits were not independently associated with insulin sensitivity or ß-cell function in a healthy middle-aged European population. Health-selection bias, methodological shortcomings or a true lack of causal links between smoking and impaired insulin sensitivity/secretion are possible explanations. The mechanisms behind the observed increased glucose and C-peptide areas under the curve during the oral glucose tolerance test in male smokers need to be further evaluated.

Pomalidomide-induced hypothyroidism.

Hypothyroidism is a recognized side effect of thalidomide drugs. We herein report a case of 83-year-old Irish female with a diagnosis of multiple myeloma and a background history of type 2 diabetes mellitus and hypertension. Our patient received pomalidomide and multiple courses of chemotherapy and achieved very good initial response for her multiple myeloma but subsequently she relapsed. She did not have any past history of thyroid disease or family history of thyroid disorders. Prior to treatment with pomalidomide, her thyroid function test was completely normal. She was commenced on pomalidomide in February 2017. Four weeks post treatment, she presented with worsening fatigue, and as a part of her workup, a thyroid function test was performed. Her free T4 was low at 7.2 pmol/L (reference range: 9.0-20.0) while her TSH was elevated at 44.7 mIU/L (reference range: 0.35-4.94). Pomalidomide treatment was terminated, and she was commenced on thyroid hormonal therapy replacement therapy with thyroxine with good clinical and biochemical response. Practitioners prescribing pomalidomide should be aware of this potential complication and patients who are receiving immunomodulatory drugs like pomalidomide should undergo regular thyroid hormone levels screen. LEARNING POINTS: Overt hypothyroidism is a side effect of pomalidomide.Thyroid function test should be included as a screening test with regular review in patients receiving pomalidomide.Unexplained worsening fatigue in patients receiving pomalidomide should raise the possibility of overt hypothyroidism.

Obesity and carotid artery remodeling.

BACKGROUND/OBJECTIVE: The present study tested the hypothesis that obesity-related changes in carotid intima-media thickness (IMT) might represent not only preclinical atherosclerosis but an adaptive remodeling meant to preserve circumferential wall stress (CWS) in altered hemodynamic conditions characterized by body size-dependent increase in stroke volume (SV) and blood pressure (BP). SUBJECTS/METHODS: Common carotid artery (CCA) luminal diameter (LD), IMT and CWS were measured in three different populations in order to study: (A) cross-sectional associations between SV, BP, anthropometric parameters and CCA LD (266 healthy subjects with wide range of body weight (24-159 kg)); (B) longitudinal associations between CCA LD and 3-year IMT progression rate (ΔIMT; 571 healthy non-obese subjects without increased cardiovascular (CV) risk); (C) the impact of obesity on CCA geometry and CWS (88 obese subjects without CV complications and 88 non-obese subjects matched for gender and age). RESULTS: CCA LD was independently associated with SV that was determined by body size. In the longitudinal study, baseline LD was an independent determinant of ΔIMT, and ΔIMT of subjects in the highest LD quartile was significantly higher (28±3 µm) as compared with those in the lower quartiles (8±3, 16±4 and 16±3 µm, P=0.001, P<0.05 and P=0.01, respectively). In addition, CCA CWS decreased during the observational period in the highest LD quartile (from 54.2±8.6 to 51.6±7.4 kPa, P<0.0001). As compared with gender- and age-matched lean individuals, obese subjects had highly increased CCA LD and BP (P<0.0001 for both), but only slightly higher CWS (P=0.05) due to a significant increase in IMT (P=0.005 after adjustment for confounders). CONCLUSIONS: Our findings suggest that in obese subjects, the CCA wall thickens to compensate the luminal enlargement caused by body size-induced increase in SV, and therefore, to normalize the wall stress. CCA diameter in obesity could represent an additional biomarker, depicting the impact of altered hemodynamics on arterial wall.

Hypoglycaemia-induced myocardial infarction as a result of sulphonylurea misuse.

BACKGROUND: Recent large-scale randomized trials of intensive therapy in Type 2 diabetes have reported increased cardiovascular morbidity and mortality in patient populations who experience a high frequency of hypoglycaemic events. However, there are few descriptions of hypoglycaemia leading directly to a myocardial infarction (MI) in the medical literature to date. CASE REPORT: In this article we describe the case of a 76-year-old woman without diabetes who presented with symptoms, left bundle branch block and raised troponin, indicative of an MI. She was also noted to be hypoglycaemic with a plasma glucose level of 2.5 mmol/l. It was subsequently discovered that she had mistakenly been dispensed glibenclamide, a long-acting sulphonylurea, in the preceding weeks. Her cardiac symptoms resolved completely upon treatment of her hypoglycaemia and she had no significant coronary artery disease on angiography. CONCLUSION: This is the first case of sulphonylurea-induced MI in a patient without diabetes and illustrates the adverse effects of acute hypoglycaemia upon the cardiovascular system.

The Leu262Val polymorphism of presenilin associated rhomboid like protein (PARL) is associated with earlier onset of type 2 diabetes and increased urinary microalbumin creatinine ratio in an Irish case-control population.

AIMS: Environmental and genetic factors contribute to the evolution of type 2 diabetes (T2DM). Presenilin associated rhomboid like protein (PARL) is a mitochondrial protein that has been implicated in T2DM in both the rodent Psammomys obesus and in humans. The SNP variant (Leu262Val) in PARL has been shown to be associated with hyperinsulinaemia in an age-dependent manner in a US non-diabetic, cohort. However, this finding has not been replicated in UK cohorts. We studied Leu262Val associations in an Irish Caucasian T2DM case-control population. METHODS: An RFLP-PCR assay using BstN I was used to assess Leu262Val genotype in a total of 613 subjects, 421 with T2DM and 192 controls. RESULTS: In the control group genotype frequencies were as follows 27.37% (GG), 51.58% (CG) and 21.05% (CC), while in the group with T2DM 30.64% (GG), 47.74% (CG) and 21.62% (CC). We observed no association between Leu262Val variant and T2DM nor was there an association with plasma insulin concentrations or BMI. There was no interaction between age and fasting plasma insulin concentration. However, in the group with T2DM the C allele was associated with higher urinary albumin to creatinine ratio while the GG genotype was associated with an earlier age of onset of T2DM. CONCLUSION: The Leu262Val polymorphism of PARL is not associated with markers of insulin resistance. However, in subjects with T2DM, genetic variation at this locus may indicate earlier onset of T2DM and increased susceptibility to nephropathy and cardiovascular complications.

Elevated blood pressure in overweight and obese Irish children.

BACKGROUND: The Irish childhood obesity epidemic, one of the highest ranking internationally, represents a major threat to public health. We sought to perform a retrospective observational study of a clinic based cohort of obese Irish children. METHODS: Clinical data relating to gender, age, height, weight, body mass index and blood pressure were analysed, from 206 children referred to a paediatric endocrine referral centre over a 15-year period for assessment of obesity. RESULTS: Younger patients tended to have a higher standardised body mass index at initial presentation; 92% of boys and 96% of girls referred were obese (age-related BMI >/= 95th percentile). Boys (51%) and girls (49%) had initial blood pressure measurements in the hypertensive range. There was a correlation between the degree of obesity and systolic blood pressure, particularly in boys. CONCLUSIONS: Obese Irish children present with significant long-term health risks, including hypertension at baseline.

Adverse metabolic profiles in a cohort of obese Irish children.

BACKGROUND: The metabolic characteristics of obese Irish children are not well defined. We prospectively examined the relationship between the degree of obesity and glucose metabolism, insulin sensitivity and suspected non-alcoholic steatohepatosis (NASH) in a pilot study of obese Irish children. METHODS: We measured height, weight, body mass index (BMI), blood pressure, waist and hip circumference in 18 participants (mean age 15.5 years). Fasting blood glucose, insulin, lipid profile and alanine aminotransferase (ALT) concentrations were also measured. A standard 75 g oral glucose tolerance test was performed and insulin sensitivity was derived from this using a mathematical model--oral glucose insulin sensitivity. RESULTS: There were significant associations between the degree of obesity, insulin sensitivity and markers of liver steatosis. For example, when adjusted for pubertal status, there were significant associations between standardized BMI and insulin sensitivity (regression coefficient, beta = -70.1, P = 0.018) and ALT (beta = 20.7, P = 0.007). CONCLUSION: This study suggests that the degree of obesity is associated with lower insulin sensitivity and possible NASH in obese Irish children.

Early-onset type 2 diabetes in obese white subjects is characterised by a marked defect in beta cell insulin secretion, severe insulin resistance and a lack of response to aerobic exercise training.

AIMS/HYPOTHESIS: Early-onset type 2 diabetes is associated with marked visceral obesity and extreme insulin resistance, but its pathogenesis and response to treatment are not completely understood. We studied physical fitness, whole-body and hepatic glucose turnover, and insulin secretion in young obese Irish subjects before and after 3 months of aerobic exercise training. We hypothesised that exercise alone, with stable diet, should improve insulin sensitivity. MATERIALS AND METHODS: Anthropometric parameters and maximum volume of oxygen utilisation (VO(2max)) were measured in 13 subjects with type 2 diabetes and 18 non-diabetic control subjects, matched for age and BMI. Insulin sensitivity and hepatic glucose turnover were measured using the hyperinsulinaemic-euglycaemic clamp. Insulin secretion was assessed from an OGTT and a modified intravenous glucose tolerance test. Some subjects (seven type 2 diabetic, 14 non-diabetic control subjects) then completed a 12-week supervised aerobic exercise programme. All measurements were repeated on completion of the exercise programme. RESULTS: Type 2 diabetic subjects had higher WHR, systolic blood pressure and triacylglycerols than non-diabetic control subjects. They were significantly more insulin-resistant as measured both by the clamp and oral glucose insulin sensitivity. They also displayed marked defects in insulin secretion in response to oral and intravenous glucose challenges. Exercise intervention had no significant effect on whole-body or hepatic insulin sensitivity or insulin secretion. VO(2max) increased significantly in the non-diabetic control subjects, but not in the type 2 diabetic subjects after exercise training. CONCLUSIONS/INTERPRETATION: Young obese subjects with type 2 diabetes are severely insulin-resistant with marked loss of beta cell function compared with control subjects matched for age and obesity. Neither group responded metabolically to aerobic exercise intervention.