Effects of different insulin sensitisers in the management of polycystic ovary syndrome: A systematic review and meta-analysis.

OBJECTIVE: Characteristic features of polycystic ovary syndrome (PCOS) include insulin resistance and an increased risk for type 2 diabetes. To promote improved insulin sensitivity, insulin sensitisers have been used in PCOS. However, direct comparisons across these agents are limited. This study compared the effects of metformin, rosiglitazone and pioglitazone in the management of PCOS to inform the 2023 International Evidence-based PCOS Guideline. DESIGN: Systematic review and meta-analysis of the literature. PATIENTS: Women with PCOS and treatment with insulin sensitisers. MEASUREMENTS: Hormonal and clinical outcomes, as well as side effects. RESULTS: Of 1660 publications identified, 13 randomised controlled trials were included. Metformin was superior in lowering weight (mean difference [MD]: -4.39, 95% confidence interval [CI]: -7.69 to -1.08 kg), body mass index (MD: -0.95, 95% CI: -1.41 to -0.49 kg/m2 ) and testosterone (MD: -0.10, 95% CI: -0.18 to -0.03 nmol/L) versus rosiglitazone, whereas there was no difference when comparing metformin to pioglitazone. Adding rosiglitazone or pioglitazone to metformin did not improve metabolic outcomes. However, rosiglitazone seemed superior to metformin in lowering lipid concentrations. CONCLUSIONS: Metformin should remain the first-line insulin sensitising treatment in adults with PCOS for the prevention and management of weight and metabolic features. The addition of thiazolidinediones appears to offer little benefit.

Effects of an antenatal dietary intervention in women with obesity or overweight on child outcomes at 8-10 years of age: LIMIT randomised trial follow-up.

BACKGROUND: The LIMIT randomised controlled trial looked at the effect of a dietary and lifestyle intervention compared with routine antenatal care for pregnant women with overweight and obesity on pregnancy outcomes. While women in the intervention group improved diet and physical activity with a reduction of high birth weight, other outcomes were similar. We have followed the children born to women in this study at birth, 6 and 18 months and 3-5 years of age and now report follow-up of children at 8-10 years of age. METHODS: Children at 8-10 years of age who were born to women who participated in the LIMIT randomised trial, and whose mother provided consent to ongoing follow-up were eligible for inclusion. The primary study endpoint was the incidence of child BMI z-score > 85th centile for child sex and age. Secondary study outcomes included a range of anthropometric measures, neurodevelopment, child dietary intake, and physical activity. Analyses used intention to treat principles according to the treatment group allocated in pregnancy. Outcome assessors were blinded to the allocated treatment group. RESULTS: We assessed 1,015 (Lifestyle Advice n = 510; Standard Care n = 505) (48%) of the 2,121 eligible children. BMI z-score > 85th percentile was similar for children of women in the dietary Lifestyle Advice Group compared with children of women in the Standard Care Group (Lifestyle Advice 479 (45%) versus Standard Care 507 (48%); adjusted RR (aRR) 0.93; 95% CI 0.82 to 1.06; p = 0.302) as were secondary outcomes. We observed that more than 45% of all the children had a BMI z-score > 85th percentile, consistent with findings from follow-up at earlier time-points, indicating an ongoing risk of overweight and obesity. CONCLUSIONS: Dietary and lifestyle advice for women with overweight and obesity in pregnancy has not reduced the risk of childhood obesity, with children remaining at risk of adolescent and adult obesity. Other strategies are needed to address the risk of overweight and obesity in children including investigation of preconception interventions to assess whether this can modify the effects of maternal pre-pregnancy BMI. The LIMIT randomised controlled trial was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426).

Type 1 diabetes, periodontal health, and a familial history of hyperlipidaemia is associated with oral microbiota in children: a cross-sectional study.

BACKGROUND: Hyperlipidaemia may play a significant role in the interrelationship between type 1 diabetes (T1D) and periodontal disease. A potential mechanism that links these three aspects together is the oral microbiota. We wanted to determine if there is an association between hyperlipidaemia, periodontal disease, and the oral microbiota of children with T1D, as this has not yet been explored. METHODS: In a post-hoc, cross-sectional study using 16S rRNA gene sequencing, we explored links between oral bacterial diversity and composition of gingival swab samples from 72 children with T1D to periodontal risk factors and hyperlipidaemia status of first-degree relatives. While multiple periodontal risk factors were assessed, we used periodontal pocket depth of 3 mm to characterise periodontal risk. As periodontal pocket depth confounded the analysis of familial history of hyperlipidaemia, a multivariate analyses were performed (i.e., no periodontal risk markers in children with or without a family history of hyperlipidaemia were compared to counterparts who did not have periodontal risk markers) to examine linkages between these factors and diversity and composition of the microbiome. RESULTS: In participants with no periodontitis risk, children with a family history of dyslipidemia had different bacterial diversity and composition compared to those without a familar hisitory. In contrast, such differences did not exist in the children with periodontal risk, whether or not they had a family history of hyperlipidaemia. Co-occurrence networks showed that these differences in children with no periodontists risk were linked to the presence of fewer oral microbial networks, but more microbes linked to mature plaque structures. In contrast, children with periodontal risk markers, regardless of family history of hyperlipidaemia, contained co-occurrence networks that were associated with microbes linked to periodontal disease. CONCLUSIONS: In children diagnosed with T1D, our findings support an association between oral microbiota and two different exposure variables: familial history of hyperlipidaemia and periodontal risk factors.

Diagnosis experiences of adolescents with polycystic ovary syndrome: Cross-sectional study.

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) report delayed diagnosis of the condition and receiving inadequate information at diagnosis. No studies have investigated the diagnosis experiences of adolescents with PCOS. Our objective was to investigate the adolescents' experiences of PCOS diagnosis and their concerns about the condition. DESIGN: Cross-sectional study. PATIENT(S): Eighty-six adolescents (aged 13-19 years) were diagnosed with PCOS by a medical practitioner. Adolescents were recruited consecutively from paediatric and women's outpatient hospital clinics in South Australia and online PCOS support organisations in Australia and the United Kingdom (May 2017-June 2019). MEASUREMENTS: PCOS diagnosis experience and information received at the time of diagnosis were evaluated using a validated questionnaire. RESULTS: The majority of the adolescents (n = 67, 78%) were diagnosed with PCOS in less than 1 year from their first doctor's visit but 11 (13%) were diagnosed more than 2 years from that visit. Fifty-three adolescents (66%) saw 1-2 health professionals before the diagnosis was made. Forty-nine adolescents (57%) were satisfied with the overall diagnosis experience but adolescents were either dissatisfied or reported that the information was not mentioned after diagnosis in relation to lifestyle management (n = 47, 55%), long-term complications (n = 53, 62%) and emotional support and counselling (n = 65, 76%). CONCLUSIONS: The majority of adolescent girls with PCOS are receiving a timely diagnosis, but delayed diagnosis still occurs in a minority of adolescents. Current information provided at diagnosis is not meeting the needs of adolescents and is a lost opportunity for preventive healthcare at a critical transition to adult care period.

ISPAD Clinical Practice Consensus Guidelines 2022: Type 2 diabetes in children and adolescents.

Since the 2018 ISPAD guidelines on this topic, follow-up of large cohorts from around the globe have continued informing the current incidence and prevalence of co-morbidities and complications in young adults with youth-onset type 2 diabetes (T2D). This chapter focuses on the risk factors, diagnosis and presentation of youth-onset T2D, the initial and subsequent management of youth-onset T2D, and management of co-morbidities and complications. We include key updates from the observational phase of the multi-center Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial, the SEARCH for Diabetes in Youth (SEARCH) study and new data from the Restoring Insulin Secretion (RISE) study, a head-to-head comparison of youth onset vs adult-onset T2D. We also include an expanded section on risk factors associated with T2D, algorithms and tables for treatment, management, and assessment of co-morbidities and complications, and sections on recently approved pharmacologic therapies for the treatment of youth-onset T2D, social determinants of health, and settings of care given COVID-19 pandemic.

Early markers of periodontal disease and altered oral microbiota are associated with glycemic control in children with type 1 diabetes.

OBJECTIVES: To determine the relationship between periodontal disease and glycemic control in children with type 1 diabetes and to characterize the diversity and composition of their oral microbiota. METHODS: Cross-sectional study including children with type 1 diabetes recruited from clinics at the Women's and Children's Hospital (Australia). Participants had a comprehensive dental assessment, periodontal examination, and buccal and gingival samples collected for 16S rRNA sequencing. RESULTS: Seventy-seven participants (age 13.3 ± 2.6 years, 38 males, BMI z-score 0.81 ± 0.75) had a diabetes duration of 5.6 ± 3.9 years and median HbA1c of 8.5% (range 5.8-13.3), 69.4 mmol/mol (range 39.9-121.9). Thirty-eight (49%) had early markers of periodontal disease. HbA1c was positively correlated with plaque index (Rho = 0.34, P = 0.002), gingival index (Rho = 0.30, P = 0.009), bleeding on probing (Rho = 0.44, P = 0.0001) and periodontal pocket depth >3 mm (Rho = 0.21, P = 0.06). A 1% increase in HbA1c was independently associated with an average increase in bleeding on probing of 25% (P = 0.002) and with an increase in the rate of sites with pocket depth >3 mm of 54% (P = 0.003). Higher HbA1c was independently related to increased phylogenetic alpha diversity (P = 0.008) and increased compositional variation (beta diversity P = 0.02) in gingival, but not buccal, microbiota. Brushing frequency, plaque index, and gingival index had a significant effect on microbiota composition, independent of HbA1c. CONCLUSIONS: Children with type 1 diabetes showed a continuous relationship between less favorable glycemic control and increased early markers of periodontal disease. Glycemic control was also related to the complexity and richness of the plaque microbiota, with diversity increasing as HbA1c levels increase.

Role of meditation to improve children's health: Time to look at other strategies.

In the United States, it is reported that up to 7 million of the population practice some form of meditation with the main purpose of improving emotional wellbeing and reducing stress. As the prevalence of mental health conditions continues to climb, other forms of health management strategies, including meditation practices, are increasingly used in adults. The evidence continues to emerge for the use of meditation as a way of managing health conditions in adults as demonstrated in systematic reviews and randomised controlled trials. There is also growing evidence evaluating the use of meditation practices and their potential benefits for child and adolescent health. Studies have identified improvements in mood and mental health conditions, school attendance and attention in the classroom in children and adolescents. This article aims to provide a perspective on commonly evaluated meditation types, such as Transcendental Meditation and mindfulness-based stress reduction. The article also aims to discuss the available evidence for the use of meditation to improve health and general wellbeing of children, including the use of meditation programs in schools, the current downfalls and limitations to the existing literature around meditation, and important points that healthcare practitioners need to consider when discussing the use of meditation as an additional strategy to manage and improve health and wellbeing in children and adolescents.

Temporal trends in diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes between 2006 and 2016: results from 13 countries in three continents.

AIMS/HYPOTHESIS: The aim of this work was to evaluate geographical variability and trends in the prevalence of diabetic ketoacidosis (DKA), between 2006 and 2016, at the diagnosis of childhood-onset type 1 diabetes in 13 countries over three continents. METHODS: An international retrospective study on DKA at diagnosis of diabetes was conducted. Data on age, sex, date of diabetes diagnosis, ethnic minority status and presence of DKA at diabetes onset were obtained from Australia, Austria, Czechia, Denmark, Germany, Italy, Luxembourg, New Zealand, Norway, Slovenia, Sweden, USA and the UK (Wales). Mean prevalence was estimated for the entire period, both overall and by country, adjusted for sex and age group. Temporal trends in annual prevalence of DKA were estimated using logistic regression analysis for each country, before and after adjustment for sex, age group and ethnic minority status. RESULTS: During the study period, new-onset type 1 diabetes was diagnosed in 59,000 children (median age [interquartile range], 9.0 years [5.5-11.7]; male sex, 52.9%). The overall adjusted DKA prevalence was 29.9%, with the lowest prevalence in Sweden and Denmark and the highest in Luxembourg and Italy. The adjusted DKA prevalence significantly increased over time in Australia, Germany and the USA while it decreased in Italy. Preschool children, adolescents and children from ethnic minority groups were at highest risk of DKA at diabetes diagnosis in most countries. A significantly higher risk was also found for females in Denmark, Germany and Slovenia. CONCLUSIONS/INTERPRETATION: DKA prevalence at type 1 diabetes diagnosis varied considerably across countries, albeit it was generally high and showed a slight increase between 2006 and 2016. Increased awareness of symptoms to prevent delay in diagnosis is warranted, especially in preschool children, adolescents and children from ethnic minority groups.

Adolescent polycystic ovary syndrome according to the international evidence-based guideline.

BACKGROUND: Diagnosing polycystic ovary syndrome (PCOS) during adolescence is challenging because features of normal pubertal development overlap with adult diagnostic criteria. The international evidence-based PCOS Guideline aimed to promote accurate and timely diagnosis, to optimise consistent care, and to improve health outcomes for adolescents and women with PCOS. METHODS: International healthcare professionals, evidence synthesis teams and consumers informed the priorities, reviewed published data and synthesised the recommendations for the Guideline. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied to appraise the evidence quality and the feasibility, acceptability, cost, implementation and strength of the recommendations. RESULTS: This paper focuses on the specific adolescent PCOS Guideline recommendations. Specific criteria to improve diagnostic accuracy and avoid over diagnosis include: (1) irregular menstrual cycles defined according to years post-menarche; > 90 days for any one cycle (> 1 year post-menarche), cycles< 21 or > 45 days (> 1 to < 3 years post-menarche); cycles < 21 or > 35 days (> 3 years post-menarche) and primary amenorrhea by age 15 or > 3 years post-thelarche. Irregular menstrual cycles (< 1 year post-menarche) represent normal pubertal transition. (2) Hyperandrogenism defined as hirsutism, severe acne and/or biochemical hyperandrogenaemia confirmed using validated high-quality assays. (3) Pelvic ultrasound not recommended for diagnosis of PCOS within 8 years post menarche. (4) Anti-Müllerian hormone levels not recommended for PCOS diagnosis; and (5) exclusion of other disorders that mimic PCOS. For adolescents who have features of PCOS but do not meet diagnostic criteria an 'at risk' label can be considered with appropriate symptomatic treatment and regular re-evaluations. Menstrual cycle re-evaluation can occur over 3 years post menarche and where only menstrual irregularity or hyperandrogenism are present initially, evaluation with ultrasound can occur after 8 years post menarche. Screening for anxiety and depression is required and assessment of eating disorders warrants consideration. Available data endorse the benefits of healthy lifestyle interventions to prevent excess weight gain and should be recommended. For symptom management, the combined oral contraceptive pill and/or metformin may be beneficial. CONCLUSIONS: Extensive international engagement accompanied by rigorous processes honed both diagnostic criteria and treatment recommendations for PCOS during adolescence.

Curtailing PCOS.

Polycystic ovary syndrome (PCOS), characterized by hormonal imbalance and ovarian dysfunction, often starts during adolescence. Inconsistent diagnostic criteria, variable provider knowledge, and lack of consensus pose specific challenges for the care of women with PCOS. These factors encourage inaccurate diagnosis with both under and overdiagnosis. This unfavorable diagnostic experience exasperates affected women and limits timely opportunities for intervention to minimize associated comorbidities, especially during the transition from pediatric to adult care. Recognition of these issues in the care of adolescents and women with PCOS inspired the development of the International Evidence-Based PCOS Guidelines, which emphasize the prevention, screening, and treatment of PCOS across the reproductive lifespan. The Guidelines and accompanying meta-analyses focus on three major categories of associated comorbidities: (1) reproductive; (2) metabolic; and (3) psychological. With the exception of infertility, this article considers common manifestations and comorbidities associated with PCOS throughout the lifecycle. Healthy lifestyle interventions with prevention of excess weight gain comprise the primary intervention for all comorbidities. Hence, early identification of girls "at risk" for PCOS and those with PCOS is a priority. Extensive guidelines for provider and patient education aim to decrease the medical, psychosocial, and economic burdens attributable to PCOS and its associated comorbidities.

Screening, assessment and management of type 2 diabetes mellitus in children and adolescents: Australasian Paediatric Endocrine Group guidelines.

INTRODUCTION: The incidence of type 2 diabetes mellitus has increased in children and adolescents due largely to the obesity epidemic, particularly in high risk ethnic groups. ß-Cell function declines faster and diabetes complications develop earlier in paediatric type 2 diabetes compared with adult-onset type 2 diabetes. There are no consensus guidelines in Australasia for assessment and management of type 2 diabetes in paediatric populations and health professionals have had to refer to adult guidelines. Recent international paediatric guidelines did not address adaptations to care for patients from Indigenous backgrounds. MAIN RECOMMENDATIONS: This guideline provides advice on paediatric type 2 diabetes in relation to screening, diagnosis, diabetes education, monitoring including targets, multicomponent healthy lifestyle, pharmacotherapy, assessment and management of complications and comorbidities, and transition. There is also a dedicated section on considerations of care for children and adolescents from Indigenous background in Australia and New Zealand. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINES: Published international guidelines currently exist, but the challenges and specifics to care for children and adolescents with type 2 diabetes which should apply to Australasia have not been addressed to date. These include: recommendations regarding care of children and adolescents from Indigenous backgrounds in Australia and New Zealand including screening and management; tighter diabetes targets (glycated haemoglobin, ≤ 48 mmol/mol [≤ 6.5%]) for all children and adolescents; considering the use of newer medications approved for adults with type 2 diabetes under the guidance of a paediatric endocrinologist; and the need to transition adolescents with type 2 diabetes to a diabetes multidisciplinary care team including an adult endocrinologist for their ongoing care.

Quality of life in adolescent girls with polycystic ovary syndrome.

Quality of life (QoL) is an important aspect of health and well-being. QoL is reduced in women with polycystic ovary syndrome (PCOS), but there is limited data in adolescents. This review aimed to assess studies regarding the QoL of adolescent girls with PCOS. Five databases were searched for relevant studies. Studies were included if they were conducted in adolescent girls with PCOS, aged 12-22 years old, and used a questionnaire to measure QoL. The search identified a total of 254 studies, and after exclusions, 11 relevant studies were included in the review. Most studies had a relatively small sample size, but overall included a total of 512 adolescents with PCOS. In most cases, adolescent girls with PCOS have reduced QoL when compared to healthy girls, and PCOS symptoms/excess weight impact on their QoL. Further research is required due to limited data on QoL in adolescents with PCOS of normal weight.

Australian children with type 1 diabetes consume high sodium and high saturated fat diets: Comparison with national and international guidelines.

AIM: We aimed to evaluate the diets of children with type 1 diabetes (T1D) against recommended Australian dietary intakes and international T1D guidelines and compare them to children without T1D. METHODS: A cross-sectional analysis in 143 children (103 children aged 8-18 years with T1D and 40 age- and gender-matched controls) and longitudinal analysis at 0, 3, 6 and 12 months in 90 T1D children were conducted. Diet was assessed using an Australian validated food frequency questionnaire. Diet quality was assessed against recommended servings and nutrient intakes from Australian Dietary Guidelines and International Society for Pediatric and Adolescent Diabetes (ISPAD) Nutritional Guidelines. RESULTS: Diet was evaluated in 478 questionnaires. Diet composition did not differ between T1D and controls, and both groups did not meet the majority of the Australian Dietary Guidelines, except for fruit intake. The majority of T1D children and controls (80-83%) were overconsuming sodium (2837 ± 848 mg/day), discretionary foods (5.9 ± 2.5 serves/day) and saturated fat and trans fatty acids (13.1 ± 2.7% of total daily energy intake) in comparison with Australian and ISPAD guidelines. A total of 84% of T1D children and controls achieved the recommended intake of fibre (34.4 ± 11.0 g/day). Longitudinal analysis in children with T1D showed that total daily energy, macronutrient, micronutrient and food group servings intake did not change over the 12 months. Overconsumption of sodium, discretionary foods and saturated fat persisted over the 12-month study period. CONCLUSIONS: The majority of Australian children, with and without T1D, is not meeting recommended dietary guidelines. Significant overconsumption of sodium, saturated fat and discretionary foods attracts the most concern.

Dietary sodium intake relates to vascular health in children with type 1 diabetes.

BACKGROUND AND OBJECTIVE: Children with type 1 diabetes (T1D) have vascular dysfunction and frequently struggle to adhere to dietary recommendations. Limited data exist for the vascular consequences of poor diet quality in children. We aimed to evaluate the association between dietary components and vascular function in children with T1D. METHODS: Cross-sectional study including 90 children (13.6 [3.5] years, 41 boys) with T1D. They had evaluation of dietary micro and macronutrients (Australian Child and Adolescent Eating Survey), vascular endothelial and smooth muscle function (flow-mediated dilatation and glyceryl trinitrate mediated dilatation [GTN], respectively), clinical and biochemical variables. RESULTS: Children had a sodium intake of 3.013 (0.76) (mean [SD]) g/day. Vascular smooth muscle dysfunction, as measured by GTN, related to higher daily sodium intake (r = -0.31, P = .003), independent of the inverse relationships between GTN and total energy (r = -0.30, P = .005) and fat intake (r = -0.28, P = .007). Multiregression model showed that an increase in 1 g of daily sodium intake was independently associated with a deterioration of 3 percentage units in GTN (95% CI -4.3, -0.9; P = .003). There was an association between sodium intake and systolic blood pressure after adjustment for age and gender (regression coefficient 2.4; 95% CI 0.5, 4.3; P = .01). CONCLUSIONS: High dietary sodium intake in children with T1D is common and relates to vascular dysfunction, independently of other dietary intake, blood pressure, and glycemic control.

Early atherosclerosis is associated with retinal microvascular changes in adolescents with type 1 diabetes.

BACKGROUND/OBJECTIVE: Adolescents with type 1 diabetes have early macrovascular changes (increased intima-media thickness [IMT]) and early retinal changes that predict clinical disease in adulthood. We hypothesized that early changes in the macrovascular and retinal microvascular beds develop in parallel before retinopathy develops. We therefore aimed to investigate the relationship between changes in atherosclerosis (carotid and aortic IMT) and retinal vascular geometry cross-sectionally and longitudinally in adolescents with type 1 diabetes. METHODS: Ninety adolescents with type 1 diabetes (41 boys, aged 13.6 ± 3.5 years) who were enrolled in a randomized controlled trial had evaluations at baseline; 41 randomized to placebo were also investigated at 12 months for carotid and aortic IMT using ultrasound and retinal vascular geometry was measured from retinal photographs. RESULTS: There were significant associations between thicker mean/maximum carotid IMT and wider retinal arteriolar and venular calibers; for every 0.1 mm increase in mean carotid IMT, retinal arteriolar caliber increased by 7.90 µm (95% confidence interval [CI] 4.50, 11.30, P < 0.0001) and venular caliber by 9.61 µm (95% CI 4.16, 15.06, P = 0.0008). Increased mean aortic IMT was associated with increased arteriolar tortuosity (2.61, 95% CI 0.50, 4.71, P = 0.02). CONCLUSIONS: The early changes of atherosclerosis are associated with retinal microvascular changes in adolescents with type 1 diabetes. This supports parallel adverse changes in the macro and microvascular circulations from early adolescence in type 1 diabetes, and highlights the importance of early intervention.

What is adolescent polycystic ovary syndrome?

The diagnostic criteria for adolescent polycystic ovary syndrome (PCOS) has been derived from adult criteria, which makes diagnosis challenging as criteria include normal physiological events that occur during puberty such as acne, hirsutism, menstrual irregularities, high androgen levels and polycystic ovarian morphology on pelvic ultrasound. The only criteria that applies from the adult criteria is exclusion of other conditions that mimic PCOS. Clinical findings consistent with hyperandrogenaemia during adolescence include inflammatory acne, hirsutism, alopecia and/or menstrual irregularities, which are severe and present 2 years after menarche. The measurement of androgen levels during adolescence should take into account age, puberty, type of androgen measured, assay used and diurnal rhythm. Multiple measurements are useful to demonstrate hyperandrogenaemia. The combination, severity and persistence of the hyperandrogenic symptoms and hyperandrogenaemia in girls 2 years or more post-menarche support the diagnosis of adolescent PCOS. Adolescent girls with these findings should be followed up into adulthood.

Lack of evidence for progression of atherosclerosis during puberty in type 1 diabetes.

OBJECTIVES: Children with type 1 diabetes have early changes in vascular structure with increased aortic intima-media thickness (aIMT) or carotid IMT (cIMT). aIMT may be an earlier, more sensitive marker; however, longitudinal data in type 1 diabetes are lacking. This study will aim to evaluate changes in vascular structure (aIMT and cIMT) over 2 yr during puberty in children with type 1 diabetes and compare them with those in healthy children. RESEARCH DESIGN AND METHODS: A total of 110 children (aged 10-18 yr, 55 males) participated in a prospective cohort study, including 77 children with type 1 diabetes and 33 age- and sex-matched healthy children. Ultrasound assessments of aIMT and cIMT; and clinical and biochemical data were collected at baseline and 2 yr later. RESULTS: Mean and maximal aIMT or cIMT did not worsen over time in children with type 1 diabetes compared with healthy children. Longer duration of diabetes related to an increase in aIMT. Improvement in HDL cholesterol and leptin related to a decrease in aIMT. Higher baseline IMT related to an improvement in IMT in children with type 1 diabetes (mean and maximal aIMT: ß = -0.52, p < 0.001; ß = -0.49, p = 0.001, and mean and maximal cIMT: ß = -0.36, p = 0.003; ß = -0.40, p = 0.001), independent of cardiovascular risk factors. CONCLUSIONS: Aortic and carotid IMT does not deteriorate during puberty in children with type 1 diabetes. This has implications for the design of interventional studies in this important age group.

A NOS3 polymorphism determines endothelial response to folate in children with type 1 diabetes or obesity.

OBJECTIVE: To determine the effect of polymorphisms in NOS3 and folate pathway enzymes on vascular function and folate status and endothelial response to folate in children with diabetes or obesity. STUDY DESIGN: A total of 244 subjects (age 13.8 ± 2.8 years, 125 males) were studied for NOS3 and/or folate pathway polymorphisms using polymerase chain reaction/restriction fragment length polymorphism, including at baseline: 139 with type 1 diabetes; 58 with obesity; and 47 controls. The effect of NOS3 genotype on endothelial response to folate (5 mg) was assessed in 85 subjects with diabetes and 28 obese subjects who received active treatment during intervention trials. Vascular function (flow-mediated dilatation [FMD] and glyceryl trinitrate-mediated dilatation), clinical, and biochemical measurements were assessed at baseline and 8 weeks in folate intervention studies. RESULTS: Folate pathway enzyme and NOS3 polymorphisms did not significantly affect baseline vascular function. The polymorphism in intron 4 of endothelial nitric oxide synthase altered endothelial response to folate significantly: in subjects with diabetes FMD improved by 6.4 ± 5% (insertion carriers) vs 2.3 ± 6.6% (deletion carriers), P = .01; in obese subjects FMD improved by 1.8 ± 5.4% (insertion carriers) and deteriorated by -3.2 ± 7.2% (deletion carriers), P = .05. More subjects carrying the insertion normalized FMD after folate supplementation (insertion 64% vs deletion 28%, χ(2) = 10.14, P = .001). CONCLUSIONS: A NOS3 polymorphism predicts endothelial response to folate in children with diabetes or obesity, with implications for vascular risk and folate intervention studies.

Vascular function and glucose variability improve transiently following initiation of continuous subcutaneous insulin infusion in children with type 1 diabetes.

OBJECTIVE: The effect of continuous subcutaneous insulin infusion (CSII) and glucose variability on vascular health in type 1 diabetes (T1D) is not known. We aimed to determine whether initiation of CSII improves vascular function and reduces glucose variability, independent of changes in HbA1c. METHODS: Twenty-two children with T1D (12.5 ± 2.9 yr) were reviewed immediately prior, 3 wk, and 12 months after initiation of CSII. Vascular function [flow-mediated dilatation (FMD), glyceryl trinitrate-mediated dilatation (GTN)], glucose variability [mean of daily differences (MODD), mean amplitude of glycaemic excursions (MAGE) and continuous overlapping net glycaemic action (CONGA)], and clinical and biochemical data were measured at each visit. Results for the first two visits were compared to a previously studied cohort of 31 children with T1D who remained on multiple daily injections (MDI). RESULTS: FMD, GTN, blood pressure, HbA1c, fructosamine, and glucose variability significantly improved 3 wk after CSII commencement (all p < 0.05), but there was no change in the MDI control group. At 3 wk, vascular function related to glucose variability [(FMD: MODD, r = -0.62, p = 0.002) and (GTN: MAGE, r = -0.59, p = 0.004; CONGA-4, r = -0.51, p = 0.01; MODD, r = -0.62, p = 0.002)] but not to blood pressure, HbA1c, or fructosamine. At 12 months, FMD, GTN, blood pressure, and glucose variability returned to baseline levels, while HbA1c deteriorated. Carotid intima media thickness was unchanged over 12 months. CONCLUSIONS: Initiation of CSII rapidly improves vascular function in association with decreased glucose variability; however, the effects are not sustained with deterioration of metabolic control and glucose variability.

Does metformin improve vascular health in children with type 1 diabetes? Protocol for a one year, double blind, randomised, placebo controlled trial.

BACKGROUND: Cardiovascular disease is the leading cause of mortality in Type 1 diabetes (T1D). Vascular dysfunction is an early and critical event in the development of cardiovascular disease. Children with T1D have vascular dysfunction therefore early interventions to improve vascular health are essential to reduce cardiovascular mortality in T1D. Metformin is an insulin sensitising agent which is known to improve vascular health outcomes in type 2 diabetes (T2D) and other individuals with insulin resistance. It has been used safely in children and adolescents with T2D for over 10 years. This study aims to assess the effect of metformin on vascular health in children with T1D. METHODS/DESIGN: This study is a 12 month, double blind, randomised, placebo controlled trial to determine the effect of metformin on vascular health in children (age 8-18) with T1D. The sample size is 76 with 38 children in the metformin group and 38 children in the placebo group. Vascular health and biochemical markers will be measured at baseline, 3, 6 and 12 months. Vascular function will be measured using flow mediated dilatation and glyceryl trinitrate mediated dilatation of the brachial artery and vascular structure will be measured with carotid and aortic intima media thickness, using standardised protocols. DISCUSSION: This study will be the first to investigate the effect of metformin on vascular health in children with T1D. It will provide important information on a potential intervention to improve cardiovascular morbidity and mortality in this population at high risk from cardiovascular disease. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12611000148976.