Presence of neuropathy in children and adolescents with type 1 diabetes evaluated with bedside modalities.

AIMS: To investigate the prevalence of diabetic polyneuropathy (DPN), cardiac autonomic neuropathy (CAN) and sudomotor dysfunction in children and adolescents with type 1 diabetes using bedside modalities. Secondly, to evaluate the co-existence of these types of diabetes neuropathies. METHODS: Cross-sectional study including 221 children and adolescents with type 1 diabetes. DPN was assessed by vibration sensation threshold and sural nerve conductance, CAN by cardiac reflex tests and sudomotor function by electrochemical skin conductance. RESULTS: Median (interquartile range) age was 14.2 (11.9, 16.5) years, diabetes duration 4.8 (2.7, 7.7) years and Hba1c 7.1 (6.6, 7.9) %, (54: 49, 63 mmol/mol). Three had retinopathy; all had normal albuminuria. DPN was present in 40 %, early CAN in 17 %, established CAN in 3 % and sudomotor dysfunction in the feet in 5 %. Of these, 60 % had one type of neuropathy, while 35 % had two types. Only 1 participant manifested all three types of neuropathies. CONCLUSIONS: Bedside modalities demonstrated a high prevalence of neuropathy in children and adolescents with type 1 diabetes, despite good glycemic outcome, short diabetes duration and absence of complications. A lack of co-existing neuropathies was shown, underscoring the need for multiple screening modalities.

Diabetes Management Support in Preschool and Primary School: A Qualitative Ideation Study Presenting Recommendations for Improved Communicative Practice.

Diabetes care in institutional settings is a significant challenge that affects the whole family as well as care workers and teachers. The present study is the ideation part of a rigorous development process in the KIds with Diabetes in School (KIDS) project. We have previously conducted a thorough three-part needs assessment in which we explored the problem area from the viewpoints of (1) municipal administrative staff, (2) preschool and school staff and (3) families. Based on the identified needs and to a great extent on the contents and shortcomings of existing guidelines, the objective of the present study is to explore and develop possible solutions and recommendations for addressing the challenges and problems. To meet this objective, we held comprehensive multistakeholder participatory workshops in each of the five Danish regions. Five main themes with multiple subthemes were identified as areas to be addressed: (1) training and knowledge, (2) communication and collaboration, (3) the designated contact/support person, (4) national guidelines, and (5) the Diabetes Coordinator. Our findings demonstrate that communicative structures and dynamics are at the very heart of the identified problems and challenges and that the possible solutions should revolve around improving existing structures and highlighting the importance of constantly working on understanding and developing communication strategies. We propose a set of recommendations for practice based on these communicative needs.

Low birthweight is associated with a higher incidence of type 2 diabetes over two decades independent of adult BMI and genetic predisposition.

AIMS/HYPOTHESIS: Low birthweight is a risk factor for type 2 diabetes. Most previous studies are based on cross-sectional prevalence data, not designed to study the timing of onset of type 2 diabetes in relation to birthweight. We aimed to examine associations of birthweight with age-specific incidence rate of type 2 diabetes in middle-aged to older adults over two decades. METHODS: Adults aged 30-60 years enrolled in the Danish Inter99 cohort in 1999-2001 (baseline examination), with information on birthweight from original birth records from 1939-1971 and without diabetes at baseline, were eligible. Birth records were linked with individual-level data on age at diabetes diagnosis and key covariates. Incidence rates of type 2 diabetes as a function of age, sex and birthweight were modelled using Poisson regression, adjusting for prematurity status at birth, parity, polygenic scores for birthweight and type 2 diabetes, maternal and paternal diabetes history, socioeconomic status and adult BMI. RESULTS: In 4590 participants there were 492 incident type 2 diabetes cases during a mean follow-up of 19 years. Type 2 diabetes incidence rate increased with age, was higher in male participants, and decreased with increasing birthweight (incidence rate ratio [95% CI per 1 kg increase in birthweight] 0.60 [0.48, 0.75]). The inverse association of birthweight with type 2 diabetes incidence was statistically significant across all models and in sensitivity analysis. CONCLUSIONS/INTERPRETATION: A lower birthweight was associated with increased risk of developing type 2 diabetes independent of adult BMI and genetic risk of type 2 diabetes and birthweight.

Management of Diabetes during School Hours: A Cross-Sectional Questionnaire Study in Denmark.

Managing diabetes is complicated for many children. It often requires support from an adult during the school day. In Denmark, most children spend 30-35 h a week at school. Nevertheless, diabetes management in schools remains largely uninvestigated. This study aimed to examine the characteristics and organization of diabetes management in Danish primary schools from the personnel's perspective. All primary schools in Denmark were invited to participate in the study (n = 2129), and 525 schools were included. A questionnaire was constructed and sent by email. Questionnaire data are presented in the descriptive statistics and compared with the ISPAD guidelines. According to 77.2% of respondents, school personnel had received training in diabetes management, and 78.5% of the schools had at least one person available for diabetes support every day. Respondents felt prepared to help the students with counting carbohydrates (38.9%), dosing insulin (39.1%), and helping the students during high (52.1%) or low (60.3%) blood sugar levels, insulin chock (35.2%), or during activities (36.3%). Yet, diabetes management was a challenging task. Only 61.7% had an action plan for diabetes management, 37.4% had face-to-face information meetings with the parents, and 55.1% of respondents reported having sufficient time to cooperate with the parents.

Municipal Support of Diabetes Management in Daycare, Kindergarten and School: A Qualitative Study of Differences, Challenges and Potentials.

Diabetes care during institutional hours is a major challenge affecting the whole family. The aim of this study was to highlight challenges and potentials regarding municipal support in relation to diabetes care of children in school, kindergarten, and daycare. The dataset consists of 80 semi-structured online interviews with 121 municipal employees from 74 (of 98) municipalities in Denmark. Data were analysed using qualitative content analysis. The analysis produced four main themes: (1) Institutional staff initially feel insecure about diabetes care responsibilities, (2) There is a high degree of parental involvement and responsibilities during institutional hours, (3) The roles of health employees vary, and (4) Fluctuating allocation of special needs assistants (SNAs) creates challenges. The findings of this nationwide qualitative study show that, even though Denmark guarantees, by law, the child's right to support in diabetes self-care in school and childcare institutions, diabetes management in Denmark still needs to be improved, with a view to ensuring equal support for all children with diabetes.

The metabolic syndrome is frequent in children and adolescents with type 1 diabetes compared to healthy controls.

OBJECTIVE: There is a rise in overweight and obesity among children and adolescents with type 1 diabetes (T1D) in parallel with the rise in the metabolic syndrome (MetS) among children and adolescents. The aim of the study was to describe the prevalence and characteristics of MetS in children and adolescents with T1D compared to their healthy counterparts. RESEARCH DESIGN AND METHODS: The study includes two Danish cohorts; (i) the Copenhagen cross sectional cohort 2016 of 277 children and adolescents with T1D that attend the pediatric outpatient clinic at a large hospital in greater Copenhagen and (ii) the CHAMPS-study DK which is a population-based cohort study of Danish children and adolescents (control cohort). Participants were categorized to have MetS if at least two of the following criteria were met: (i) systolic and/or diastolic blood pressure ≥ 90th percentile, (ii) waist circumference ≥90th percentile, and (iii) triglyceride ≥90th percentile and/or HDL ≤10th percentile. RESULTS: The prevalence of children with Mets in the T1D cohort was higher than in the control cohort (p = 0.002). Moreover, participants with T1D had MetS at a lower level of BMI (p < 0.001) and waist circumference (p < 0.001) than participants with MetS from the control cohort (z-scores = 0.90 and 1.51). Participants with MetS were younger than the other T1D participants (median 12.8 [9.9,14.8] vs. median 14.6 [11.2,16.9] years, p = 0.006). CONCLUSIONS: Children and adolescents with T1D have an increased risk of MetS compared to healthy controls and clinicians and caretakers should consider early prevention and health promotion strategies.

A collaborative comparison of international pediatric diabetes registries.

BACKGROUND: An estimated 1.1 million children and adolescents aged under 20 years have type 1 diabetes worldwide. Principal investigators from seven well-established longitudinal pediatric diabetes registries and the SWEET initiative have come together to provide an international collaborative perspective and comparison of the registries. WORK FLOW: Information and data including registry characteristics, pediatric participant clinical characteristics, data availability and data completeness from the Australasian Diabetes Data Network (ADDN), Danish Registry of Childhood and Adolescent Diabetes (DanDiabKids), Diabetes prospective follow-up registry (DPV), Norwegian Childhood Diabetes Registry (NCDR), National Paediatric Diabetes Audit (NPDA), Swedish Childhood Diabetes Registry (Swediabkids), T1D Exchange Quality Improvement Collaborative (T1DX-QI), and the SWEET initiative was extracted up until 31 December 2020. REGISTRY OBJECTIVES AND OUTCOMES: The seven diabetes registries and the SWEET initiative collectively show data of more than 900 centers and around 100,000 pediatric patients, the majority with type 1 diabetes. All share the common objectives of monitoring treatment and longitudinal outcomes, promoting quality improvement and equality in diabetes care and enabling clinical research. All generate regular benchmark reports. Main differences were observed in the definition of the pediatric population, the inclusion of adults, documentation of CGM metrics and collection of raw data files as well as linkage to other data sources. The open benchmarking and access to regularly updated data may prove to be the most important contribution from registries. This study describes aspects of the registries to enable future collaborations and to encourage the development of new registries where they do not exist.

Communication and Social Relations: A Qualitative Study of Families' Experience with Their Outpatient Pediatric Diabetes Visits.

Clinical outpatient visits comprise a relatively small part of the lives of children with diabetes and their families, but there is evidence that these visits have a strong impact on the long-term management of diabetes. Because children with diabetes are looking at frequent hospital visits for the rest of their lives, it is important to explore their experiences to ensure visits meet their needs. This study aimed to investigate families' experiences with outpatient visits at a pediatric diabetes clinic. Thirteen semi-structured family interviews were conducted. Systematic text condensation was used to analyze the data. With an analytical focus on communication and social relations, nine themes were identified: 1. Discrepancies in perception of diabetes tasks, 2. Talking about adult things, but the children listen, 3. The importance of spoken and written words, 4. Confusion about division of responsibilities, 5. Relief when someone eases the burden, 6. Courtesy when visiting the clinic, 7. Understanding of the family context, 8. Importance of continuous personal relations, and 9. Need for a facilitated peer network. The findings encourage reflection on how to improve communication and underline the importance of establishing a continuous and personal relation between families and health care professionals to improve families' experience with pediatric outpatient visits.

Differences in insulin sensitivity in the partial remission phase of childhood type 1 diabetes; a longitudinal cohort study.

AIMS: Studies suggest that type 1 diabetes (T1D) contributes to impaired insulin sensitivity (IS). Most children with T1D experience partial remission but the knowledge regarding the magnitude and implications of impaired IS in this phase is limited. Therefore, we investigate the impact of IS on the partial remission phase. METHODS: In a longitudinal study of children and adolescents, participants were seen at three clinical visits during the first 14.5 months after diagnosis of T1D. Partial remission was defined as IDAA1c (HbA1c (%) + 4*daily insulin dose) ≤ 9. Beta-cell function was considered significant by a stimulated c-peptide > 300 pmol/L. Participants were characterized by (i) remission or non-remission and (ii) stimulated c-peptide levels above or below 300 pmol/L. IS, body mass index (BMI), total body fat, sex, age, pubertal status and ketoacidosis at onset were compared. RESULTS: Seventy-eight children and adolescents aged 3.3-17.7 years were included. At 14.5 months post-diagnosis, 54.5% of the participants with stimulated c-peptide > 300 pmol/L were not in partial remission. Participants not in remission had significant lower IS 2.5 (p = 0.032), and 14.5 (p = 0.022) months after diagnosis compared to participants in partial remission with similar c-peptide levels. IS did not fluctuate during the remission phase. CONCLUSIONS: A number of children and adolescents have impaired IS in the remission phase of paediatric T1D and are not in remission 14.5 months after diagnosis despite stimulated c-peptide > 300 pmol/L.

Episodes of severe hypoglycemia is associated with a progressive increase in hemoglobin A1c in children and adolescents with type 1 diabetes.

OBJECTIVE: To investigate the trajectory in glycemic control following episodes of severe hypoglycemia (SH) among children and adolescents with type 1 diabetes (T1D). METHODS: A Danish national population-based study comprising data from 2008-17. SH was defined according to the 2014 ISPAD guidelines. A mixed model was applied with HbA1c as outcome and SH episodes and time since first episode as explanatory variables. Data were adjusted for age, gender and diabetes duration. RESULTS: A total of 4244 children (51.6% boys) with 18 793 annual outpatient visits were included. Mean (SD) age at diabetes onset was 9.0 (4.1) years. Median diabetes duration at inclusion in the study was 1.2 (Q1 = 0.9, Q3 = 3.0) years, and median diabetes duration at last visit was 5.0 (Q1 = 2.7, Q3 = 8.1) years. A total of 506 children experienced at least one episode of SH during the nine-year follow-up; 294 children experienced one episode, 115 two episodes and 97 three or more episodes of SH. HbA1c increased with episodes of SH and in the years following the first episode. The glycemic trajectory peaked 2 to 3 years after an SH episode. The accumulated deterioration in glycemic control was in the range of 5% in patients with two or more episodes equivalent to an increase in HbA1c of 4 mmol/mol (HbA1c ~0.4%). CONCLUSION: SH was followed by a progressive and lasting increase in HbA1c among Danish children and adolescents with T1D. Thus, in addition to the known risk of new episodes of hypoglycemia and cognitive impairment, SH contributes to long-term diabetes complications.

Screening for retinopathy in children with type 1 diabetes in Denmark.

BACKGROUND/OBJECTIVE: Children with type 1 diabetes (T1D) are screened regularly for retinopathy with fundus photography to prevent visual impairment. According to Danish national guidelines, screening should take place at age 12, 15, and 18 years after minimum 3 years of diabetes. As glycemic control has improved, prevalence of retinopathy is expected to be decreased. The aim of this study is to investigate the prevalence, degree, and progression of retinopathy in children with T1D and to explore if screening at 12 years is currently indicated in Denmark. METHODS: Data on all Danish children with onset of T1D from 2003 to 2013 (n = 2943) were collected from the "DanDiabKids" registry. For children with registered screenings (n = 2382), prevalence of retinopathy at 12, 15, and 18 years was determined. In children with retinopathy, subsequent screenings were studied to reveal if retinopathy was persistent or temporary. RESULTS: Prevalence of retinopathy at 12, 15, and 18 years was 0.9%, 2.3%, and 3.1%, respectively. Minimal background retinopathy was seen in over 90% and 100% at 12 years. In available re-screenings, retinopathy resolved spontaneously in 87.5% of all cases and 100% of cases at 12 years. CONCLUSIONS: The prevalence of retinopathy in Danish children with T1D was low. At 12 years, prevalence was 0.9% and exclusively minimal background retinopathy with 100% remission in re-screenings. Thus, screening at this age does not seem to have significant clinical relevance. We propose more individualized screening selection before the age of 15.

High frequencies of dermatological complications in children using insulin pumps or sensors.

BACKGROUND: Dermatological complications in children and adolescents that are related to continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) have not been well-characterized. This study examined the prevalence and characteristics of different types of dermatological complications. METHODS: Online questionnaires regarding dermatological complications related to CSII and/or CGM were returned from a total of 144 children and adolescents, aged 2 to 20 years. Both previous and current skin problems were reported along with their clinical characteristics. Descriptive statistics, χ2 tests, and multivariate analyses were used to evaluate the data. RESULTS: Of 143 patients using CSII, 90% had previous and 63% reported current dermatological complications. Non-specific eczema was most frequently reported and was currently present in 25.7% of the patients. These results were independent of age and current CGM use. Among the 76 patients using CGM, 46% reported current dermatological complications. A history of atopy was associated with dermatological complications in individuals using CSII, but not CGM. The patients rated CGM-related dermal issues as significantly worse than those associated with CSII (P < .05). CONCLUSIONS: Dermatological complications can be a serious problem in treating pediatric and adolescent patients of all ages with CSII and/or CGM. Only a few clinical characteristics associated with these complications were identified in this study, highlighting the need for prospective studies that might lead to improvements in the prevention and treatment of dermatological problems.

Hypoglycemia-Associated EEG Changes in Prepubertal Children With Type 1 Diabetes.

BACKGROUND: The purpose of this study was to explore the possible difference in the electroencephalogram (EEG) pattern between euglycemia and hypoglycemia in children with type 1 diabetes (T1D) during daytime and during sleep. The aim is to develop a hypoglycemia alarm based on continuous EEG measurement and real-time signal processing. METHOD: Eight T1D patients aged 6-12 years were included. A hyperinsulinemic hypoglycemic clamp was performed to induce hypoglycemia both during daytime and during sleep. Continuous EEG monitoring was performed. For each patient, quantitative EEG (qEEG) measures were calculated. A within-patient analysis was conducted comparing hypoglycemia versus euglycemia changes in the qEEG. The nonparametric Wilcoxon signed rank test was performed. A real-time analyzing algorithm developed for adults was applied. RESULTS: The qEEG showed significant differences in specific bands comparing hypoglycemia to euglycemia both during daytime and during sleep. In daytime the EEG-based algorithm identified hypoglycemia in all children on average at a blood glucose (BG) level of 2.5 ± 0.5 mmol/l and 18.4 (ranging from 0 to 55) minutes prior to blood glucose nadir. During sleep the nighttime algorithm did not perform. CONCLUSIONS: We found significant differences in the qEEG in euglycemia and hypoglycemia both during daytime and during sleep. The algorithm developed for adults detected hypoglycemia in all children during daytime. The algorithm had too many false alarms during the night because it was more sensitive to deep sleep EEG patterns than hypoglycemia-related EEG changes. An algorithm for nighttime EEG is needed for accurate detection of nocturnal hypoglycemic episodes in children. This study indicates that a hypoglycemia alarm may be developed using real-time continuous EEG monitoring.

Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB.

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the proatherogenic cytokine osteopontin (OPN) in mouse arteries via local release of endothelin-1 and activation of CREB. Infusion of GIP increases plasma OPN concentrations in healthy individuals. Plasma endothelin-1 and OPN concentrations are positively correlated in patients with critical limb ischemia. Fasting GIP concentrations are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared with control subjects. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients, and expression associates with parameters that are characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration, and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from humans, mice, rats, and pigs, remarkable upregulation is observed in endothelial and smooth muscle cells upon culture conditions, yielding a "vascular disease-like" phenotype. Moreover, the common variant rs10423928 in the GIPR gene is associated with increased risk of stroke in patients with type 2 diabetes.

Link between GIP and osteopontin in adipose tissue and insulin resistance.

Low-grade inflammation in obesity is associated with accumulation of the macrophage-derived cytokine osteopontin (OPN) in adipose tissue and induction of local as well as systemic insulin resistance. Since glucose-dependent insulinotropic polypeptide (GIP) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate OPN expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13 ± 0.04 vs. 0.04 ± 0.01, P < 0.05) and correlated inversely with measures of insulin sensitivity (r = -0.24, P = 0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with a lower amount of the exon 9-containing isoform required for transmembrane activity. Carriers of the A allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of the GIPR rs10423928 A allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions.

The birth weight lowering C-allele of rs900400 near LEKR1 and CCNL1 associates with elevated insulin release following an oral glucose challenge.

BACKGROUND AND AIM: The first genome-wide association study on birth weight was recently published and the most significant associated birth weight lowering variant was the rs900400 C-allele located near LEKR1 and CCNL1. We aimed to replicate the association with birth weight in the Danish Inter99 study and furthermore to evaluate associations between rs900400 and indices of insulin secretion and insulin sensitivity obtained by oral glucose tolerance tests in adults from the Danish Inter99 study and the Finnish, Metabolic Syndrome in Men (METSIM) sample. METHODS: For 4,744 of 6,784 Inter99 participants, midwife journals were traced through the Danish State Archives and association of rs900400 with birth weight was examined. Associations between rs900400 and fasting serum insulin, fasting plasma glucose, insulinogenic index, homeostasis model assessment of insulin resistance (HOMA-IR) and disposition index were studied in 5,484 Danish and 6,915 Finnish non-diabetic individuals and combined in meta-analyses. RESULTS: The C-allele of rs900400 was associated with a 22.1 g lower birth weight ([-41.3;-3.0], P = 0.024) per allele. Moreover, in combined analyses of the Danish Inter99 study and the Finnish METSIM study we found that the birth weight lowering allele was associated with increased insulin release measured by the insulinogenic index (ß = 2.25% [0.59; 3.91], P = 0.008) and with an increased disposition index (ß = 1.76% [0.04; 3.49], P = 0.05). CONCLUSION: The birth weight lowering effect of the C-allele of rs900400 located near LEKR1 and CCNL1 was replicated in the Danish population. Furthermore the C-allele was associated with increased insulin response following oral glucose stimulation in a meta-analysis based on Danish and Finnish non-diabetic individuals.

Pleiotropic effects of GIP on islet function involve osteopontin.

OBJECTIVE: The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic ß-cell function by potentiating insulin secretion and ß-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function. RESEARCH DESIGN AND METHODS: Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies. Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of ß-cell viability and proliferation. RESULTS: The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells. CONCLUSIONS: These findings support ß-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional ß-cell mass in humans.

Differential nongenetic impact of birth weight versus third-trimester growth velocity on glucose metabolism and magnetic resonance imaging abdominal obesity in young healthy twins.

CONTEXT: Low birth weight is associated with type 2 diabetes, which to some extent may be mediated via abdominal adiposity and insulin resistance. Fetal growth velocity is high during the third trimester, constituting a potential critical window for organ programming. Intra-pair differences among monozygotic twins are instrumental in determining nongenetic associations between early environment and adult metabolic phenotype. OBJECTIVE: Our objective was to investigate the relationship between size at birth and third-trimester growth velocity on adult body composition and glucose metabolism using intra-pair differences in young healthy twins. METHODS: Fifty-eight healthy twins (42 monozygotic/16 dizygotic) aged 18-24 yr participated. Insulin sensitivity was assessed using hyperinsulinemic-euglycemic clamps. Whole-body fat was assessed by dual-energy x-ray absorptiometry scan, whereas abdominal visceral and sc fat (L1-L4) were assessed by magnetic resonance imaging. Third-trimester growth velocity was determined by repeated ultrasound examinations. RESULTS: Size at birth was nongenetically inversely associated with adult visceral and sc fat accumulation but unrelated to adult insulin action. In contrast, fetal growth velocity during third trimester was not associated with adult visceral or sc fat accumulation. Interestingly, third-trimester growth was associated with insulin action in a paradoxical inverse manner. CONCLUSIONS: Abdominal adiposity including accumulation of both sc and visceral fat may constitute primary nongenetic factors associated with low birth weight and reduced fetal growth before the third trimester. Reduced fetal growth during vs. before the third trimester may define distinct adult trajectories of metabolic and anthropometric characteristics influencing risk of developing type 2 diabetes.

Do gene variants influencing adult adiposity affect birth weight? A population-based study of 24 loci in 4,744 Danish individuals.

BACKGROUND: Several obesity risk alleles affecting adult adiposity have been identified by the recent wave of genome wide association studies. We aimed to examine the potential effect of these variants on fetal body composition by investigating the variants in relation to birth weight and ponderal index of the newborn. METHODOLOGY/PRINCIPAL FINDINGS: Midwife records from the Danish State Archives provided information on mother's age, parity, as well as birth weight, birth length and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. Twenty-four risk alleles showing genome-wide associations with adult BMI and/or waist circumference were genotyped. None of the 24 risk variants tested showed an association with birth weight or ponderal index after correction for multiple testing. Birth weight was divided into three categories low (≤10(th) percentile), normal (10(th)-90(th) percentile) and high birth weight (≥90th percentile) to allow for non-linear associations. There was no difference in the number of risk alleles between the groups (p = 0.57). No interactions between each risk allele and birth weight in the prediction of adult BMI were observed. An obesity risk score was created by summing up risk alleles. The risk score did not associate with fetal body composition. Moreover there was no interaction between the risk score and birth weight/ponderal index in the prediction of adult BMI. CONCLUSION: 24 common variants associated with adult adiposity did not affect or interact with birth weight among Danes suggesting that the effects of these variants predominantly arise in the post-natal life.

Increased risk of type 2 diabetes in elderly twins.

OBJECTIVE: Genetic susceptibility, low birth weight (LBW), and aging are key etiological factors in the development of type 2 diabetes. LBW is common among twins. It is unknown whether twin status per se is associated with risk of type 2 diabetes, and valid concordance rates of type 2 diabetes in twins on a lifetime perspective are lacking. RESEARCH DESIGN AND METHODS: A clinical study was done on a population-based cohort of same-sex elderly monozygotic (MZ) and dizygotic (DZ) twins (n = 297) and singleton control subjects (C) (n = 71) including measures of anthropometry and glucose tolerance. In addition, type 2 diabetes incidence cases in twins (n = 626) and singletons (n = 553) were identified through the National Diabetes Register. RESULTS: Twins were more abdominally obese, insulin resistant, and glucose intolerant, as evidenced by a higher A1C (%) (means +/- SD) (MZ: 6.0 +/- 1.0, DZ: 5.8 +/- 0.7, C: 5.6 +/- 0.3, P = 0.004) and 120-min post-oral glucose tolerance test plasma glucose levels (in mmol/l) (MZ: 8.6 +/- 4.6, DZ: 8.4 +/- 3.9, C: 6.8 +/- 2.4, P = 0.003) compared with singletons. Importantly, twins had a higher prevalence of type 2 diabetes (MZ: 17.5% [95% CI 14.4-20.6], DZ: 15.7% [13.1-18.3], C: 5.6% [3.0-8.2], P = 0.03) together with a 60% higher incidence rate of type 2 diabetes compared with singletons. Cumulative concordance rates of type 2 diabetes to the age of 84 years were similar among elderly MZ (0.76 [0.68-0.84]) and DZ (0.71 [0.63-0.78]) twins. CONCLUSIONS: Twin status per se is associated with abdominal obesity, insulin resistance, and increased prevalence of type 2 diabetes in elderly twins. The data support a quantitatively significant impact of the fetal environment as opposed to genetics on risk of type 2 diabetes.