Effect of spontaneous gestational diabetes on fetal and postnatal hepatic insulin resistance in Lepr(db/+) mice

Infant macrosomia is a classic feature of a gestational diabetes mellitus (GDM) pregnancy and is associated with increased risk of adult obesity and type II diabetes mellitus, however mechanisms linking GDM and later disease remain poorly understood. The heterozygous leptin receptor-deficient (Lepr(db/+)) mouse develops spontaneous GDM and the fetuses display characteristics similar to infants of GDM mothers. We examined the effects of GDM on maternal insulin resistance, fetal growth, and postnatal development of hepatic insulin resistance. Fetal body weight on d 18 of gestation was 6.5% greater (p < 0.05) in pups from ad libitum-fed db/+ mothers compared with wild-type (WT) controls. Pair-feeding db/+ mothers to the intake of WT mothers normalized fetal weight despite less than normal maternal insulin sensitivity. More stringent caloric restriction reduced insulin and glucose levels below WT controls and resulted in fetal intrauterine growth restriction. The level of hepatic insulin receptor protein was decreased by 28% to 31% in both intrauterine growth restriction and fetuses from ad libitum-fed GDM mothers compared with offspring from WT mothers. In 24-wk-old adult offspring from GDM mothers, body weight was similar to WT offspring, however, the females from GDM mothers were fatter and hyperinsulinemic compared with offspring from WT mothers. Insulin-stimulated phosphorylation of Akt, a key intermediate in insulin signaling, was severely decreased in the livers of adult GDM offspring. Hepatic glucose-6-phosphatase activity was also inappropriately increased in the adult offspring from GDM mothers. These results suggest that spontaneous GDM in the pregnant Lepr(db/+) mouse is triggered by overfeeding, and this effect results in obesity and insulin resistance in the livers of the adult offspring. The specific decrease in Akt phosphorylation in livers of adult offspring suggests that this may be a mechanism for reduced insulin-dependent physiologic events, such as suppression of hepatic glucose production, a defect associated with susceptibility to type II diabetes mellitus.     

Long-term effects of diabetes during pregnancy on the offspring

Background: Many epidemiological and experimental studies have proven that some adult diseases might have their origin in fetal life. It has been also hypothesized that intra-uterine environment in pregnancy complicated with diabetes might influence the development of obesity, type 2 diabetes, and cardiovascular diseases in the offspring.
Objectives: To assess glucose metabolism, insulin secretion, and prevalence of obesity in the offspring of mothers with pregestational diabetes mellitus (PGDM) and gestational diabetes mellitus (GDM) and to evaluate the relationship between maternal metabolic control during pregnancy and metabolic disturbances in children.
Subjects: Children of mothers with PGDM (n = 43) and GDM (n = 34) were examined at 4–9 yr of age and compared with the control group (n = 108; metabolic parameters available for n = 29).
Methods: The incidence of overweight and obesity, impaired glucose tolerance, and insulin resistance were analyzed based on anthropometric and biochemical measurements. Statistical analysis was performed with statistica package.
Results: In children of GDM mothers, body mass index z-score (0.81 ± 1.01 vs. −0.04 ± 1.42 PGDM vs. 0.07 ± 1.28 control group) and insulin resistance indices (homeostasis model assessment index – insulin resistance 1.112 vs. 0.943 PGDM vs. 0.749 control group) were significantly higher than in other groups. Obesity and insulin resistance were also most frequent in GDM group [not significant (NS)]. In addition, we observed the relationship between maternal hemoglobin A1c and mean glycemia in perinatal period and insulin resistance in children. There was not such correlation for the class of maternal diabetes.
Conclusion: Children born to mothers with gestational diabetes seem to be at risk for obesity and metabolic disturbances.     

Glucose tolerance status in 510 children and adolescents attending an obesity clinic in Central Italy

Brufani C, Ciampalini P, Grossi A, Fiori R, Fintini D, Tozzi A, Cappa M, Barbetti F. Glucose tolerance status in 510 children and adolescents attending an obesity clinic in Central Italy. Childhood obesity is epidemic in developed countries and is accompanied by an increase in the prevalence of type 2 diabetes (T2DM). Aims: Establish prevalence of glucose metabolism alterations in a large sample of overweight/obese children and adolescents from Central Italy. Methods: The study group included 510 overweight/obese subjects (3–18 yr). Oral glucose tolerance test (OGTT) was performed with glucose and insulin determination. Homeostatic model assessment of insulin resistance (HOMA‐IR) and insulin sensitivity index (ISI) were derived from fasting and OGTT measurements. Beta‐cell function was estimated by insulinogenic index. Fat mass was measured by dual‐energy x‐ray absorptiometry. Results: Glucose metabolism alterations were detected in 12.4% of patients. Impaired glucose tolerance (IGT) was the most frequent alteration (11.2%), with a higher prevalence in adolescents than in children (14.8 vs. 4.1%, p < 0.001); silent T2DM was identified in two adolescents (0.4%). HOMA‐IR and glucose‐stimulated insulin levels were higher in patients with IGT than individuals with normal glucose tolerance (HOMA‐IR = 4.4 ± 2.5 vs. 3.4 ± 2.3, p = 0.001). Fat mass percentage and insulinogenic index were not different between the two groups. In multivariate analysis, age, fasting glucose, and insulin resistance influenced independently plasma glucose at 120 min of OGTT. Individuals with combined impaired fasting glucose/IGT (IFG/IGT) and T2DM were older and had reduced plasma insulin values at OGTT when compared to patients with simple IGT. Conclusions: Glucose metabolism alterations are frequently found among children and adolescents with overweight/obesity from Central Italy. Age, fasting glucose, and insulin resistance are main predictors of IGT. We suggest the use of OGTT as a screening tool in obese European adolescents.     

The prevalence of impaired fasting glucose and type 2 diabetes in a population‐based sample of overweight/obese children in the Middle East

Moadab MH, Kelishadi R, Hashemipour M, Amini M, Poursafa P. The prevalence of impaired fasting glucose and type 2 diabetes in a population‐based sample of overweight/obese children in the Middle East. Background: Type 2 diabetes mellitus (T2DM) and impaired fasting glucose (IFG) are increasing in young population who are facing an escalating trend of overweight. The aim of this study was to determine the prevalence of IFG and T2DM for the first time in a population‐based sample of Iranian obese children. Methods: This cross‐sectional, population‐based study was conducted in Isfahan, the second large city of Iran. Overall, 672 overweight and obese school students, selected from 7554 students, aged 6–19 yr, were screened for IFG and T2DM. Fasting plasma glucose (FPG) and lipid profile were measured in all participants. Oral glucose tolerance test and insulin level were measured in those children with IFG. Insulin resistance was defined as homeostasis model assessment for insulin resistance (HOMA‐IR) > 3.10. Results: Among the7554 students (48.7% boys and 51.3% girls) studied, 9.34% (n = 706) were overweight and 5.3% (n = 403) were obese. A number of 672 overweight and obese students including 302 (44.9%) boys and 370 (55.1%) girls, with a mean age of 12.8 ± 3.10 yr underwent biochemical work up. Overall, the prevalence of IFG was 4.61% (n = 31), the corresponding figure was 2% (n = 4) in the 6–10 yr age group, and 5% (n = 27) in those aged 10.1–19 yr. The prevalence of T2DM was 0.1% (n = 1; age, 18.00 yr). Impaired glucose tolerance and insulin resistance were detected in three and six participants with IFG, who consisted 0.4 and 0.8% of total obese and overweight students, respectively. Conclusions: Although the prevalence of T2DM is low in Iranian obese children, IFG is not uncommon. Preventive measures and screening of FPG should be considered for these children.     

Impaired β‐cell sensitivity to glucose and maximal insulin secretory capacity in adolescents with type 2 diabetes

Elder DA, Woo JG, D’Alessio DA. Impaired β‐cell sensitivity to glucose and maximal insulin secretory capacity in adolescents with type 2 diabetes. Background: Adults with type 2 diabetes mellitus (T2DM) have broad impairments in β‐cell function, including severe attenuation of the first‐phase insulin response to glucose, and reduced β‐cell mass. In adolescents with T2DM, there is some evidence that β‐cell dysfunction may be less severe. Our objective was to determine β‐cell sensitivity to glucose and maximal insulin secretory capacity (AIR_max) in teenagers with T2DM. Methods: Fifteen adolescents with T2DM [11 F/4 M, age 18.4 ± 0.3 yr, body mass index (BMI) 39.8 ± 2.2 kg/m²] and 10 non‐diabetic control subjects (7 F/3 M, age 17.4 ± 0.5 yr, BMI 41.5 ± 2.2 kg/m²) were studied. T2DM subjects had a mean duration of diabetes of 48.8 ± 6.4 months, were treated with conventional therapies, and had good metabolic control [hemoglobin A1c (HbA1c) 6.7 ± 1.2%]. Insulin and C‐peptide were determined before and after a graded glucose infusion and after intravenous arginine at a whole blood glucose level of ≥22 mM. Results: The insulin response to increasing plasma glucose concentrations was blunted in the diabetic compared with control subjects (34.8 ± 11.9 vs. 280.5 ± 57.8 pmol/mmol; p < 0.0001), and AIR_max was also significantly reduced in the diabetic group (1868 ± 330 vs. 4445 ± 606; p = 0.0005). Conclusion: Even adolescents with well‐controlled T2DM have severe impairments of insulin secretion. These data support β‐cell dysfunction as central in the pathogenesis of T2DM in young people, and indicate that these abnormalities can develop over a period of just several years.     

Limitations of first-phase insulin response to evaluate insulin secretion in children

The first-phase insulin response (FPIR) is a widely used method to evaluate beta-cell function during the prediabetic phase of evolving type 1 diabetes mellitus (DM). The aim of the present study was to evaluate the influence of clinical and methodological variables on FPIR in normal children and adolescents. Children and adolescents who were first-degree relatives of those with type 1 DM and healthy young adults were studied. All subjects were islet cell antibody-negative. A FPIR test was performed on all subjects while fasting. Insulin samples were drawn at 0, 1, 2, 3, 4, 5, 6, 8, and 10 min after 0.3 g/kg of dextrose. FPIR(1–10) was calculated as the area under the FPIR curve corrected for baseline. Eighty-five subjects aged 4–22 yr were studied, 43 of whom were pre-pubertal, 24 pubertal, and 18 post-pubertal. FPIR(1–10) values were lower in the pre-pubertal group when compared to either the pubertal and post-pubertal groups (415 [179–965, 2SD], 756 [256–2 223] and 684 [235–1 180] mU/L, respectively; p<0.05). Obese subjects had a higher FPIR than non-obese subjects (856 vs. 520 mU/L; p<0.005). Despite correcting for the influence of puberty and obesity, there remained considerable unaccounted variability in FPIR(1–10) (R=0.46). Further variables found to influence FPIR(1–10) were: fasting insulin level (r²=0.49); weight for length index (r²=0.38); peak blood glucose level (r²=0.38, all p<0.001); and pre-pubertal age (r²=0.20, p<0.05). Conclusion: FPIR exhibited wide inter-subject variability and was influenced by a number of clinical and methodological factors that make interpretation more difficult without more specifically defined standards.     

Maternal overnutrition impairs offspring's insulin sensitivity: A systematic review and meta‐analysis

This systematic review and meta‐analysis aimed to investigate the association between maternal overnutrition and offspring's insulin sensitivity—following the Preferred Reporting Items for Systematic Reviews and Meta‐analyses statement. Studies published in English before April 22, 2019, were identified through searches of four medical databases. After selection, 15 studies aiming to explore the association between prepregnancy body mass index (ppBMI) or gestational weight gain (GWG) of non‐diabetic mothers and their offspring's insulin sensitivity (fasting insulin or glucose level and Homeostatic Measurement Assessment for Insulin Resistance [HOMA‐IR]) were included in the meta‐analysis. Associations of ppBMI and GWG with offspring's insulin sensitivity were analysed by pooling regression coefficients or standardized differences in means with 95% confidence intervals (CIs). Maternal ppBMI showed significant positive correlations with the level of both fasting insulin and HOMA‐IR in offspring (standardized regression coefficient for fasting insulin: 0.107, CI [0.053, 0.160], p < 0.001 and that for HOMA‐IR: 0.063, CI [0.006, 0.121], p = 0.031). However, the result of the analysis on coefficients adjusted for offspring's actual anthropometry (BMI and adiposity) was not significant. Independent from ppBMI, GWG tended to show a positive correlation with insulin level, but not after adjustment for offspring's anthropometry. Offspring of mothers with excessive GWG showed significantly higher HOMA‐IR than those of mothers with optimal GWG (p = 0.004). Our results demonstrate that both higher ppBMI and GWG increase the risk of offspring's insulin resistance, but the effect of ppBMI on insulin sensitivity in offspring may develop as consequence of their adiposity.     

Prevalence of metabolic markers of insulin resistance in offspring of gestational diabetes pregnancies

In utero hyperglycemia has been associated with insulin resistance (IR) in children; however, there are limited data in low-risk populations. The purpose of this study was to describe the prevalence of metabolic markers of IR in a primarily Caucasian cohort of gestational diabetes mellitus (GDM) offspring aged 7-11 yr (mean 9.1) and to correlate offspring with maternal indexes. Sixty-eight children were recruited through a follow-up study of women who participated in a randomized controlled trial of minimal intervention vs. tight glycemic control for GDM. All participants had a fasting plasma glucose (FPG), insulin, total cholesterol, high-density lipoprotein cholesterol (HDL-chol), triglyceride (TG) level, and a 2-h oral glucose tolerance test. We calculated homeostasis model assessment (HOMA) and recorded body mass index and waist circumference (WC). Criteria for metabolic syndrome for children included: FPG > 6.0 mmol/L, HDL-chol < 1.03 mmol/L, TG > 1.24 mmol/L, WC > 90% for age and gender, and 2-h glucose > 7.8 mmol/L. Among these children, 45 (66%), 17 (25%), 5 (7%), and 1 (1.5%) had zero, one, two, or three metabolic markers of IR, respectively. Hypertriglyceridemia (21%) was most prevalent, with no child having an elevated FPG. WC (p = 0.018) and TG (p = 0.005) were strong predictors of IR in the offspring after adjustment for age, gender, birthweight, family history, and maternal IR. Maternal and offspring HDL-chol, TG, WC, and HOMA but not fasting or 2-h glucose levels were significantly correlated. We conclude that metabolic markers of IR in children exposed to GDM may be present in the absence of abnormal fasting or 2-h glucose values. Screening strategies that focus on glucose levels may need to be reconsidered to institute early intervention with lifestyle changes for children at risk.     

Variables associated with severe hypoglycemia in children and adolescents with type 1 diabetes: a population‐based study

Blasetti A, Di Giulio C, Tocco AM, Verrotti A, Tumini S, Chiarelli F, Altobelli E. Variables associated with severe hypoglycemia in children and adolescents with type 1 diabetes: a population‐based study. Objective: Hypoglycemia remains a central problem in the management of type 1 diabetes mellitus (T1DM) and limits the achievement of good or normal glycemic control. The Diabetes Control and Complication Trial showed that intensive treatment of T1DM increased the risk of severe hypoglycemia (SH) when compared to conventional therapy. The aim of our study was to determine the incidence of SH and associated variables in a population of children and adolescents with T1DM. Research design and methods: We performed a 7.5‐yr prospective study enrolling 195 patients aged 13.9 ± 6.6 yr. The study was carried out by referring to the T1DM population‐based register in the Abruzzo region of Italy. The incidence of SH, defined as blood glucose levels <50 mg/dL (<2.77 mmol/L) associated with altered states of consciousness (including confusional state, seizures, and coma) was recorded. Glycated hemoglobin (HbA1c) percentage, insulin dose, insulin regimen, time since diagnosis, and age at onset were also recorded. Results: One hundred and thirty‐three severe hypoglycemic events occurred during the study period; the overall incidence was 9.4 episodes per 100 patient‐years. Significant predictors of hypoglycemia were diabetes duration >10 yr (p = 0.01), basal/bolus insulin ratio (ratio of daily basal insulin units to daily bolus insulin units) >0.8 (p = 0.01). No relationship was found between hypoglycemic episodes and HbA1c levels, daily insulin requirements, or insulin regimen. Conclusions: In these patients, a relatively low incidence of SH was recorded, without pronounced association with lower HbA1c or multiple daily injection insulin therapy. SH seems to be mainly related to management of diabetes. We believe that the main path to SH prevention is through patient and family education in the management of T1DM.     

Insulin resistance at diagnosis in Japanese children with type 2 diabetes mellitus

Background: Insulin resistance at diagnosis was investigated in Japanese children with type 2 diabetes mellitus (T2DM). Methods: A total of 160 children with T2DM were divided into groups on the basis of percent overweight at time of diagnosis: group A (n= 28), <20%; group B (n= 55), 20–39%; group C (n= 37), 40–59%; group D (n= 40), ≥60%. Indicators of insulin resistance at diagnosis were compared among the four patient groups, and also between the children with T2DM and the 201 age‐matched normal Japanese children. Results: There were no significant differences in plasma glucose (PG) levels among the four patient groups. The mean concentration of fasting plasma immunoreactive insulin (IRI) was significantly higher in group D than in groups A and B (39.2 µU/mL vs 16.2 µU/mL and 24.1 µU/mL, P < 0.05, respectively). The mean homeostasis model assessment (HOMA‐R) was significantly higher in group D than in all the other three groups (17.6 vs 7.8, 10.8 and 12.7, P < 0.05, respectively). The indicators HOMA‐R and fasting IRI were significantly higher in each diabetes group, even in non‐obese group A, than in normal children (P < 0.01, respectively). Conclusions: Japanese children with T2DM had insulin resistance at diagnosis regardless of percent overweight, and the degree of insulin resistance gradually increased with rise in percent overweight.     

Which obese youth are at increased risk for type 2 diabetes? Latent class analysis and comparison with diabetic youth

Greig F, Hyman S, Wallach E, Hildebrandt T, Rapaport R. Which obese youth are at increased risk for type 2 diabetes? Latent class analysis and comparison with diabetic youth. Purpose: Most obese youth screened for diabetes have normal fasting glucose levels. Identification of youth with increased risk for type 2 diabetes (T2D) is needed within this large population to guide further management. Methods: Retrospective chart review was performed for obese youth, 8–20 yr old, who met American Diabetes Association criteria for screening (OB) or had T2D (D). Measures included body mass index z‐score (BMIz) and homeostasis model assessment of insulin resistance (HOMA‐IR) by fasting plasma glucose (FPG) and insulin. Statistics compared OB with D and further examined OB by latent class analysis (LCA). Results: Normal FPG was found in 91.5% of all obese youth (OBt n = 94) Comparison of OB with normal FPG (OBng; n = 86) and D (n = 44) was significant for family history of T2D (p = 0.008) without other associations. Evaluation of OBng by LCA showed three classes with increasing BMIz and HOMA‐IR. Class 3 (32.5%; BMIz 2.66 ± 0.38; HOMA‐IR 6.72 ± 2.29) differed from classes 1 and 2 (p < 0.05), and was associated with family history of T2D. Conclusion: Currently recommended screening of obese youth by FPG is normal in 91.5%, but lacks further information to detect increased risk for youth‐onset T2D. Evaluation of obese youth by LCA identified one third (class 3) in whom the combination of higher levels of BMIz, HOMA‐IR, and family history suggests the greatest risk for T2D and targets them for further evaluation and intensive preventative management.     

Former small for gestational age (SGA) status is associated to changes of insulin resistance in obese children during weight loss

Reinehr T, Kleber M, Toschke AM. Former small for gestational age (SGA) status is associated to changes of insulin resistance in obese children during weight loss. Objective: Former small for gestational age (SGA) children are at risk of both obesity and insulin resistance. Longitudinal studies are required to assess a possible relationship between former SGA status and insulin resistance independent of weight status. We hypothesized that obese children with former appropriate for gestational age (AGA) status improve their insulin resistance during weight loss more effectively compared to obese children with former SGA status. Methods: A 1‐yr longitudinal follow‐up study design was adopted in the primary care setting and 341 obese children [8% SGA, mean age 10.5 ± 0.1 yr, body mass index (BMI) 27.7 ± 0.2, BMI‐standard deviation score (SDS) 2.47 ± 0.02] were taken for the study. Outpatient 1‐yr intervention was based on exercise, behavior and nutrition therapy. We measured insulin resistance index following the Homeostasis model assessment model (HOMA), blood pressure, lipids, glucose, and insulin in all children before and after the 1‐yr intervention. Results: In a multiple linear regression analysis adjusted for age, gender, and pubertal stage, changes of HOMA were significantly related to changes of BMI‐SDS (?2.55 per loss of 1 BMI‐SDS unit; p < 0.001) and SGA status (+2.05 for SGA children; p < 0.001). Changes of BMI‐SDS together with gender and age explained 10% of the variance of changes of HOMA, while SGA status explained an additional 4%. After adjustment for age, sex, pubertal stage, and BMI‐SDS, former SGA status was not significantly related to any other considered cardiovascular risk factor. Conclusions: Change of weight status predicted change of HOMA in obese children participating in a lifestyle intervention. Changes of HOMA were also predicted by former SGA status supporting that former SGA status influences insulin resistance.     

Relationship of maternal weight status and weight gain rate during pregnancy to the development of advanced beta cell autoimmunity in the offspring: a prospective birth cohort study

Arkkola T, Kautiainen S, Takkinen H‐M, Kenward MG, Nevalainen J, Uusitalo U, Simell O, Ilonen J, Knip M, Veijola R, Virtanen SM. Relationship of maternal weight status and weight gain rate during pregnancy to the development of advanced beta cell autoimmunity in the offspring: a prospective birth cohort study. Objective: This study set out to examine how maternal initial body mass index (BMI) and weight gain during pregnancy associate with advanced beta cell autoimmunity in the offspring. Subjects: A population‐based birth cohort of 4093 children with increased human leukocyte antigen (HLA)‐conferred susceptibility to type 1 diabetes (T1D) and their mothers were recruited between 1997 and 2002 in two university hospital regions in Finland. Methods: The children were monitored for T1D‐associated autoantibodies at 3‐ to 12‐month intervals. Advanced beta cell autoimmunity was defined as repeated positivity for islet cell antibodies and at least one of the other three autoantibodies (antibodies to insulin, glutamate decarboxylase and islet antigen 2). Mothers were asked to record the results of the weight measurements during their first and last visits to the antenatal clinic. The initial BMI and weight gain rate were calculated for each woman. Results: Altogether, 175 children developed advanced beta cell autoimmunity or T1D during the follow‐up. Maternal BMI before pregnancy or weight gain during pregnancy was not associated with the end‐point. Maternal vocational education was associated with child's smaller risk of developing advanced beta cell autoimmunity.     

Sulfonylurea challenge test in subjects diagnosed with type 1 diabetes mellitus

Background: Patients with early onset diabetes because of defects in glucose‐stimulated insulin secretion (GSIS) may respond better to sulfonylureas than insulin treatment. Such patients include those with monogenic disorders, who can be differentiated from autoimmune type 1 diabetes mellitus (T1DM) by genetic testing. Genetic testing is expensive and unknown defects in GSIS would not be diagnosed. Aims: We propose a sulfonylurea challenge test to identify patients who have been clinically diagnosed with T1DM, but those who maintain a preferentially sulfonylurea‐responsive insulin secretion. Materials & Methods: A total of 3 healthy controls, 2 neonatal diabetes mellitus (NDM) subjects, 3 antibody‐positive (Ab+T1DM), and 12 antibody‐negative (Ab?T1DM) subjects with type 1 diabetes, were given an intravenous bolus of glucose followed by an oral dose of glipizide. Results: Healthy controls showed a robust C‐peptide increase after both glucose and glipizide, but NDM subjects showed a large increase in C‐peptide only following glipizide. As expected, 2 of 3 Ab+T1DM, as well as 11 of 12 Ab?T1DM showed no response to either glucose or glipizide. However, 1 Ab?T1DM and 1 Ab+T1DM showed a small C‐peptide response to glucose and a marked positive response to glipizide, suggesting defects in GSIS rather than typical autoimmune diabetes. Discussion: These data demonstrate the feasibility of the sulfonylurea challenge test, and suggest that responder individuals may be identified. Conclusions: We propose that this sulfonylurea challenge test should be explored more extensively, as it may prove useful as a clinical and scientific tool.     

Maternal food consumption during pregnancy and risk of advanced β-cell autoimmunity in the offspring

Virtanen SM, Uusitalo L, Kenward MG, Nevalainen J, Uusitalo U, Kronberg‐Kippilä C, Ovaskainen M‐L, Arkkola T, Niinistö S, Hakulinen T, Ahonen S, Simell O, Ilonen J, Veijola R, Knip M. Maternal food consumption during pregnancy and risk of advanced β‐cell autoimmunity in the offspring. Background: Evidence for a putative role of maternal diet during pregnancy in the development of β‐cell autoimmunity in the child is scarce. The authors study the association of food consumption during pregnancy and the development of β‐cell autoimmunity in the offspring. Subjects and methods: A prospective Finnish birth cohort of 4297 infants with human leukocyte antigen (HLA)‐DQB1‐conferred susceptibility to type 1 diabetes and their mothers. Blood samples were collected from the children at 3–12 months intervals to measure type 1 diabetes‐associated antibodies: antibodies against islet cells (ICA), insulin, glutamate dehydroxylase, and islet antigen 2. The mothers completed a validated food frequency questionnaire. The end‐point was repeated positivity for ICA together with at least one of the other three antibodies. Piecewise‐exponential survival models were used. The effective sample size was 3723, with 138 end‐points. The median follow‐up time was 4.4 years. Results: Maternal consumption of butter, low‐fat margarines, berries, and coffee were inversely associated with the development of advanced β‐cell autoimmunity in the offspring, adjusted for genetic risk group and familial diabetes. These associations for low‐fat margarines (use vs. non‐use HR 0.60, 95% CI: 0.38–0.93, p = 0.02), berries (continuous variable HR 0.90, 95% CI: 0.83–0.98, p = 0.02) and coffee (highest quarter vs. lowest HR 0.62, 95% CI: 0.40–0.97, p = 0.04), remained significant when adjusting for potential confounding sociodemographic, perinatal, and other dietary factors. Conclusions: In this study assessing total food consumption of the mother during pregnancy, only few among the 27 food groups tested were weakly related to the development of advanced β‐cell autoimmunity in Finnish children.     

First-phase insulin release during the intravenous glucose tolerance test as a risk factor for type 1 diabetes

OBJECTIVE: To determine the relationship between first-phase (1 minute + 3 minutes) insulin production during the intravenous glucose tolerance test (IV-GTT) and risk factors for developing type 1 diabetes. STUDY DESIGN: Relatives of persons with type 1 diabetes (n = 59,600) were screened for islet cell antibodies (ICAs). Subjects who had positive screening results underwent IV-GTT (> or =2 times), repeat ICA screening, insulin autoantibody (IAA) screening twice, and an oral glucose tolerance test. RESULTS: Of the 59,600 subjects in the study, 2199 (3.69%) had positive findings on initial ICA test. IV-GTTs were performed in 1622 subjects, with children <8 years having the lowest first-phase insulin release (FPIR) and subjects 8 to 20 years of age having the highest FPIR. The FPIR was lower for subjects with a confirmed positive ICA test result or a positive IAA test result, subjects with higher titers of ICA or IAA, and subjects who had an abnormal (impaired or diabetic) oral glucose tolerance test result. CONCLUSION: FPIR in the IV-GTT correlates strongly with risk factors for development of type 1 diabetes.     

Significance of acanthosis nigricans in childhood obesity

Aim: Acanthosis nigricans (AN) is among the most common dermatologic manifestations of obesity and hyperinsulinism. In this study, we aimed to find the clinical and laboratory differences in obese children with AN and without AN (non‐AN). Methods: In total, 160 obese children were included in the study. The duration of obesity, body mass index (BMI), BMI z‐scores, birth weight, parental BMI, lipid profile, fasting and post‐meal (PM) glucose and insulin levels were compared in 67 obese with AN and 93 obese without AN. Results: Age was similar in both groups. AN group had higher male to female ratio (42/25 in AN, 43/50 in non‐AN; P = 0.03), higher BMI (30.3 ± 6.1 in AN, 26.4 ± 3.6 in non‐AN; P < 0.001) and weight for height (162.6 ± 28.8 in AN, 144.6 ± 15.8 in non‐AN; P < 0.001) than non‐AN group. There were no significant differences between the groups in birth weight, parental BMI and blood pressure. AN group had higher fasting (19.9 ± 16.2 mU/L in AN, 10.4 ± 7.6 mU/L in non‐AN; P < 0.001) and PM insulin (88.6 ± 87.3 mU/L in AN, 51.1 ± 42.0 mU/L in non‐AN; P = 0.01) and homeostasis model assessment for insulin resistance (HOMA‐IR) (4.0 ± 2.5 in AN, 2.2 ± 1.8 in non‐AN; P < 0.001) than non‐AN group. However, fasting and PM glucose, triglyceride, low‐density lipoprotein‐, high‐density lipoprotein‐ and total cholesterol levels were similar in both groups. BMI was correlated with HOMA‐IR in both groups (r = 0.40 for AN, r = 0.28 for non‐AN). PM glucose and PM insulin were correlated in both groups (r = 0.56 for AN, r = 0.39 for non‐AN). However, fasting glucose and fasting insulin were correlated in only non‐AN (r = 0.25), but not in AN group. Conclusions: Obese children with AN show higher insulin levels and HOMA‐IR. AN is an important predictor of the insulin resistance in childhood obesity. Insulin secretory dynamics seem to be disrupted in fasting state initially, which is reflected as the loss of fasting insulin–glucose correlation in AN group.     

Type 1 diabetes patients born to immigrants to Sweden increase their native diabetes risk and differ from Swedish patients in HLA types and islet autoantibodies

Delli AJ, Lindblad B, Carlsson A, Forsander G, Ivarsson S‐A, Ludvigsson J, Marcus C, Lernmark Å; for the Better Diabetes Diagnosis (BDD) Study Group. Type 1 diabetes patients born to immigrants to Sweden increase their native diabetes risk and differ from Swedish patients in HLA types and islet autoantibodies. Aim: To determine whether type 1 diabetes mellitus (T1DM) patients, having parents who immigrated to Sweden, have increased T1DM risk before 18 yr compared with countries of origin. We also determined whether they have different human leukocyte antigen (HLA) genetic markers and islet autoantibodies at diagnosis compared with Swedish patients. Methods: A total of 1988 (53% males) newly diagnosed and confirmed T1DM patients <18 yr registered within the Better Diabetes Diagnosis (BDD) study (May 2005 to September 2008) were included. Participants were classified into three groups: Swedish, non‐Swedish, and Mixed‐origin patients according to country of origin of two generations (parents and grandparents). These groups were compared with respect to T1DM HLA markers and islet autoantibodies [glutamic acid decarboxylase autoantibodies (GAD65Ab), insulin autoantibodies (IAA), and islet antigen‐2 autoantibodies (IA‐2Ab)]. Results: Only 30 (1.5%) patients were born outside Sweden. Swedish patients constituted 66%, non‐Swedish patients 8%, Mixed origins 17%, and 9% were of uncertain origin. Confirmed T1DM in patients within the study was 22 (95% CI: 21–23) patients/10⁵/yr rate for Swedish patients compared with 14 (95% CI: 13–15) among non‐Swedish patients. The HLA‐DQ8 haplotype (p < 0.0001) and DQ2/8 genotype (p < 0.02) predominated among Swedish compared with non‐Swedish patients. In contrast, DQ2 was the most frequent haplotype among non‐Swedish patients [OR = 1.5 (95% CI: 1.0–2.0), p < 0.04]. Multiple (≥2) autoantibodies (p < 0.04) and specifically IA‐2Ab (p < 0.001) were most prevalent among the Swedish patients. Multiple autoantibodies were associated with DQ8 among the Swedish patients only (p < 0.001). Conclusion: Patients born to parents who had immigrated to the high T1DM incidence environment of Sweden have, compared with Swedish patients, more frequent HLA‐DQ2 genetic markers and are diagnosed more often with GAD65Ab.     

Neonatal and infant beta cell hormone concentrations in relation to type 1 diabetes risk

Type 1 diabetes is preceded by the appearance of islet autoantibodies. Seroconversion to islet autoantibodies is greatest around 1 yr of age and is more frequent in children born to fathers with type 1 diabetes as compared to children born to mothers with type 1 diabetes. Here we asked whether changes in beta‐cell function in the neonate and infant reflect variations in the incidence of islet autoantibody seroconversion. Insulin, proinsulin, and c‐peptide concentrations were measured in sequential samples taken from birth to age 2 yr in 103 children who had a first degree relative with type 1 diabetes and who had been followed for islet autoantibody seroconversion. Serum insulin and proinsulin concentrations were highest at birth declining by age 3 months and stable thereafter until age 2 yr. C‐peptide concentrations, proinsulin/insulin, and proinsulin/c‐peptide ratios were stable from age 3 months. No differences were observed between children who developed islet autoantibodies and children who remained islet autoantibody negative. Children born to a mother with type 1 diabetes had higher birth concentrations of insulin (p = 0.005) and proinsulin (p = 0.014) as compared with children of non‐diabetic mothers. Increased insulin concentrations in children of type 1 diabetes mothers persisted until age 6 months. In conclusion, we could not relate excursions in beta‐cell hormones to autoantibody development, but suggest that the higher exposure to insulin and proinsulin in neonates born to mothers with type 1 diabetes may be linked to the relative protection against islet autoantibody seroconversion observed in these children.     

Use of continuous glucose monitoring in young children with type 1 diabetes: implications for behavioral research

Patton SR, Williams LB, Eder SJ, Crawford MJ, Dolan L, Powers SW. Use of continuous glucose monitoring in young children with type 1 diabetes: implications for behavioral research. Objective: This study presents data on the use of continuous glucose monitoring (CGM) in young children with type 1 diabetes mellitus (T1DM). CGM provides moment‐to‐moment tracking of glucose concentrations and measures of intra‐ and interday variability, which are particularly salient measures in young children with T1DM. Methods: Thirty‐one children (mean age = 5.0 yr ) with T1DM wore the Medtronic Minimed CGM for a mean of 66.8 h. The CGM was inserted in diabetes clinics, and parents were provided brief training. Results: Few difficulties were experienced and families cited the acceptability of CGM. Participants' CGM data are compared with self‐monitoring blood glucose (SMBG) data as well as data from older children with T1DM to illustrate differences in methodology and variability present in this population. CGM data are used to calculate glucose variability, which is found to be related to diabetes variables such as history of hypoglycemic seizures. Conclusions: CGM is an acceptable research tool for obtaining glucose data in young children with T1DM and has been used previously in older children and adults. CGM may be particularly useful in young children who often experience more glucose variability. Data obtained via CGM are richer and more detailed than traditional SMBG data and allow for analyses to link blood glucose with behavior.