Search

BACKGROUND: Homeostasis model assessment (HOMA) and quantitative insulin-sensitivity check index (QUICKI) are measures of insulin resistance and insulin sensitivity derived from fasting glucose (FG) and insulin levels. They thus should reflect, in principle, insulin action on both the liver and the periphery. METHODS: Twenty-three prepubertal and early pubertal adolescents were studied at baseline and after 6 months, using the frequently sampled intravenous glucose tolerance test (IVGTT) with labeled glucose. Total body insulin sensitivity (SI) was calculated using the minimal model and total glucose concentrations. Peripheral insulin sensitivity (SI*) was calculated from labeled glucose concentrations. Hepatic insulin resistance (HIR) was calculated by multiplying glucose production over the last hour by the average insulin level. HOMA and QUICKI were calculated from the fasting glucose and insulin values. RESULTS: HOMA, QUICKI fasting insulin, and glucose to insulin ratio were all significantly related to SI (p <0.05) but were not independently related to SI* or HIR. Multiple linear regression analysis revealed that both SI* and HIR independently predicted HOMA and fasting glucose (p <0.1). QUICKI, fasting insulin, and glucose to insulin ratio were not independently related to SI, SI*, or HIR. CONCLUSIONS: HOMA and fasting insulin reflect total body insulin sensitivity and HIR but not peripheral insulin sensitivity in prepubertal and early pubertal adolescents. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether perioperative calcium and 1,25 OH vitamin D supplementation (PCDS) influences the rates of postoperative hypocalcemia and length of stay (LOS) following pediatric thyroidectomy., Study Design: Retrospective Cohort Review., Setting: Tertiary children's hospital., Methods: 94 patients who underwent completion or total thyroidectomy with or without concomitant neck dissection from 2010 to 2020 at a single institution were included. Patients with pre-existing hypocalcemia or preoperative vitamin D insufficiency were excluded. Rates of postoperative hypocalcemia and LOS were compared for patients receiving PCDS to those receiving no supplementation., Results: Thirty percent of patients with PCDS had documented postoperative hypocalcemia compared to 64% of patients without PCDS (p = 0.01). Patients with PCDS had a median LOS of 30 h compared to 36 h (p = 0.002). Multivariable analyses confirmed that patients with PCDS had lower odds of postoperative hypocalcemia (OR: 0.32, CI: 0.11, 0.89) and shorter LOS by 17 h (SE: 8, p = 0.04) after adjustment for confounders., Conclusion: PCDS is associated with significantly lower risk of hypocalcemia and shorter LOS. Standardizing preoperative care for pediatric patients undergoing thyroidectomy may decrease variability and improve outcomes following surgery., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study explored the frequency of adolescents with diabetes who endorse suicidality on the Patient Health Questionnaire (PHQ-9) with varying degrees of depression scores. Additionally, compared whether diabetes distress levels from the Problem Areas in Diabetes-Teen (PAID-T) assessment tool is associated with and without suicidal ideation. Χ 2 analysis was used to assess differences in subjects with or without suicidal ideation based on depression severity. Since all the data were nonparametrically distributed (Shapiro-Wilk test, p  < .05), Kruskal-Wallis test assessed differences in continuous variables. Overall, 27 of 355 adolescents screened endorsed suicidal ideation. Both PHQ-9 [13 (9-17.8) vs 1 (0-4.5)] and PAID-T [88 (61.8-104.5) vs 40 (30-58.8)] scores were significantly higher in patients with suicidal ideation. The frequency of suicidal ideation increased with the severity of depression. The frequency of severe depression was higher in adolescents with type 2 diabetes ( n  = 48) than in type 1, but there was no difference in suicidality. Adolescents with no demonstrable or minimal depression can still have potential suicidal ideation. Suicidality is a separate construct that should be screened routinely and apart from any measures screening for distress or adjustment disorders associated with adolescents experiencing life-long chronic conditions in a healthcare follow-up setting.

Background: Atherosclerosis is a chronic inflammatory disease that has its origins in childhood. The goal of this study was to explore the relationships of hematologic inflammatory markers to body mass, biochemical inflammatory markers and cardiometabolic risk factors., Methods: Healthy, white, non-Hispanic identifying adolescents (n = 75, age 12 to 18 years) were enrolled. Measures studied included body mass index percentile (BMI%), neutrophil and platelet to lymphocyte ratio (NLR, PLR), pan immune inflammation value (PIV), lipids, augmentation index, reactive hyperemia, inflammatory markers (interleukin 6: IL6, c-reactive protein: CRP), complement (C3, C3a, C4, C4a, C5a) insulin secretion and insulin sensitivity (oral glucose tolerance test: Matusda index, and disposition index (DI))., Results: NLR (r S  = 0.31, p < 0.01), PLR (r S  = 0.32, p < 0.01), PIV (r S  = 0.32, p < 0.01) and CRP (r S  = 0.51, p < 0.001) all positively correlated with BMI% but IL-6 did not. NLR, PLR and PIV all positively correlated with each other. NLR correlated with the reactive hyperemia response (r S  = 0.29, p < 0.02) but this relationship was lost when BMI% was included. NLR positively correlated with C3a, C4, CRP and IL6 even when BMI% was included., Conclusion: In healthy adolescents hematologic markers of inflammation increase with increasing body mass and neutrocyte to lymphocyte ratio is associated with increased complement and inflammatory markers independent of obesity., Impact Statement: Hematologic and biochemical markers of inflammation increase with increased body mass in healthy adolescents. Hematologic and biochemical markers of inflammation are positively related independent of body mass in healthy adolescents. Hematologic inflammatory markers are not related to markers of cardiometabolic risk in healthy adolescents., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Genetic deficiencies of early components of the classical complement activation pathway (especially C1q, r, s, and C4) are the strongest monogenic causal factors for the prototypic autoimmune disease systemic lupus erythematosus (SLE), but their prevalence is extremely rare. In contrast, isotype genetic deficiency of C4A and acquired deficiency of C1q by autoantibodies are frequent among patients with SLE. Here we review the genetic basis of complement deficiencies in autoimmune disease, discuss the complex genetic diversity seen in complement C4 and its association with autoimmune disease, provide guidance as to when clinicians should suspect and test for complement deficiencies, and outline the current understanding of the mechanisms relating complement deficiencies to autoimmunity. We focus primarily on SLE, as the role of complement in SLE is well-established, but will also discuss other informative diseases such as inflammatory arthritis and myositis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: To determine (1) differences in depression and distress scores between adolescents with type 1 (T1D) and type 2 diabetes (T2D), (2) how socioeconomic factors, obesity, race, and treatment regimen affect depression and diabetes distress in adolescent T2D, (3) the relationships between depression and diabetes distress scores in adolescents with T2D, and (4) how depression and diabetes distress scores relate to current and future glycemic control in adolescents with T2D., Background: Diabetes distress is a negative emotional reaction to diabetes complications, self-management demands, unresponsive providers, poor interpersonal relationships, and to diabetes itself. It is frequently mistaken for depression and the two are interrelated. Increases in both predict poor glycemic control in adolescents with T1D., Method: Depression (PHQ-9) and diabetes distress (PAID-T) scores from self-administered tests were studied in 364 patients with diabetes between the ages of 13-17. Kruskal-Wallis test was used to assess differences between types of diabetes, sexes, races, and insurance status. Spearman correlations, and robust rank order multivariable regression analysis were used to assess relationships. Medical records were reviewed for follow-up hemoglobin A1c (HbA1c) levels over 3 years., Results: HbA1c was significantly lower in females with T2D than with T1D (p  =  0.019) but not in males. It, also, did not differ between females and males with T2D. Median PHQ-9 score in females with T2D was significantly greater than in females with T1D (p = 0.007) but did not differ between females and males with T2D. PHQ-9 scores did not differ between males with T2D and T1D. PAID-T scores, however, were higher in males with T2D than in males with T1D but did not differ between females. PHQ-9 scores and PAID-T scores were significantly related in T2D (r s  = 0.65, p < 0.001). Neither was related to HbA1c in T2D., Conclusions: As in adolescents with T1D, depression and diabetes distress screening scores are closely related in adolescent T2D. However, unlike T1D, they are not related to glycemic control in T2D. Depression and diabetes distress may be more closely related to weight and lifestyle concerns., (© 2022. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Insulin is primarily considered for its glycemic effects in patients with diabetes. There are, however, non-glycemic adverse effects of insulin that may significantly impact patient health and interfere with glycemic control. Insulinogenic edema primarily occurs with rapid improvement in glycemic control either in patients with newly discovered diabetes or in patients with poorly-controlled diabetes. Insulin-induced sympathetic activation, vasodilation, changes in vascular permeability, and most importantly, sodium retention play significant etiologic roles in the development of edema. Clinically, it is usually self-limited, but significant complications can develop. Allergic reactions to all insulin preparations and various compounds used in insulin formulations with a wide range of severity have been reported. Frequently, changing the type of insulin or delivery method is sufficient, but more advanced treatments such as insulin desensitization and anti-IgE antibody treatment may be needed. Lipohypertrophy and lipoatrophy frequently develop with the overuse of injection sites. Lipohypertrophy can affect tissue insulin absorption and glycemic control., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: To determine whether diabetes distress or depression screening better predict increased hemoglobin A1c (HbA1c) and to assess interactions with age, sex, race, obesity, and insurance status., Background: Diabetes distress is a negative emotional reaction to diabetes, diabetes complications, self-management demands, unresponsive providers, and/or poor interpersonal relationships. Guidelines recommend annual depression screening, however diabetes distress may be mistaken for depression., Method: Depression (PHQ-9) and diabetes distress (PAID-T) scores from self-administered tests were studied in 313 patients with type 1 diabetes (T1D) between the ages of 13-17. Spearman correlations and robust rank order multivariable regression analysis were used to assess relationships to age, duration, HbA1c. Kruskal-Wallis test was used to assess differences between sexes, races, and insurance status. Receiver operator curves (ROC) were constructed to see whether PAID-T or PHQ-9 scores more closely predicted HbA1c greater than 9%., Results: HbA1c was more strongly correlated with PAID-T (r s  = 0.37, p < 0.01), than PHQ-9 (r s  = 0.27, p < 0.01) scores. Area under ROC curve for poor HbA1c was 0.75 for PAID and 0.64 for PHQ-9. PAID-T and PHQ-9 scores were increased in females and subjects with public insurance and both were significantly related to HbA1c even when accounting for age, sex, race obesity, and insurance status. PHQ-9 and PAID-T scores correlated with BMI-Z scores in Blacks, but not Whites., Conclusions: Both depression and diabetes distress are associated with increased HbA1c in adolescents with T1D, though distress is more so. Diabetes distress and depression should be routinely assessed in T1D adolescents, particularly those with public insurance., (© 2021. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Objective: Only 17% of adolescents with type 1 diabetes (T1D) are currently meeting their glycemic targets despite advances in diabetes technologies. Self-management behaviors and challenges specific to use of diabetes technologies are insufficiently studied in adolescents. We aimed to describe the experience of diabetes technology self-management, including facilitators and barriers, among preteens/adolescents with low and high A1C., Research Design and Methods: Youth (10-18 years of age) with T1D who use insulin pump therapy were recruited from the larger quantitative cohort of a mixed methods study for participation in semi-structured qualitative interviews. Maximum variability sampling was used to recruit youth with A1C <7.5% (n = 5) and A1C >9% (n = 5). Participants' personal insulin pump and continuous glucose monitoring data were downloaded and served as a visual reference. Interviews were analyzed using a qualitative descriptive approach., Results: Participants were 50% female with a median age of 14.9 years and 80% used CGM. The sample was predominantly white (90.0%). Analysis produced four major themes, Bad Day, Expect the Unexpected, Nighttime Dependence, and Unpredictability, It's Really a Team and interconnecting subthemes. Youth characterized ''Bad Days'' as those requiring increased diabetes focus and self-management effort. The unpredictability (''Expect the Unexpected'') of glucose outcomes despite attention to self-management behaviors was considerable frustration., Conclusions: Diabetes devices such as insulin pumps are complex machines that rely heavily on individual proficiency, surveillance, and self-management behaviors to achieve clinical benefit. Our findings highlight the dynamic nature of self-management and the multitude of factors that feed youths' self-management behaviors., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Human complement C4 is one of the most diverse but heritable effectors for humoral immunity. To help understand the roles of C4 in the defense and pathogenesis of autoimmune and inflammatory diseases, we determined the bases of polymorphisms including the frequent genetic deficiency of C4A and/or C4B isotypes. We demonstrated the diversities of C4A and C4B proteins and their gene copy number variations (CNVs) in healthy subjects and patients with autoimmune disease, such as type 1 diabetes, systemic lupus erythematosus (SLE) and encephalitis. We identified subjects with (a) the fastest migrating C4B allotype, B7, or (b) a deficiency of C4B protein caused by genetic mutation in addition to gene copy-number variation. Those variants and mutants were characterized, sequenced and specific techniques for detection developed. Novel findings were made in four case series. First, the amino acid sequence determinant for C4B7 was likely the R729Q variation at the anaphylatoxin-like region. Second, in healthy White subject MS630, a C-nucleotide deletion at codon-755 led to frameshift mutations in his single C4B gene, which was a private mutation. Third, in European family E94 with multiplex lupus-related mortality and low serum C4 levels, the culprit was a recurrent haplotype with HLA-A30, B18 and DR7 that segregated with two defective C4B genes and identical mutations at the donor splice site of intron-28. Fourth, in East-Asian subject E133P with anti-NMDA receptor encephalitis, the C4B gene had a mutation that changed tryptophan-660 to a stop-codon (W660x), which was present in a haplotype with HLA-DRB1*04:06 and B*15:27 . The W660x mutation is recurrent among East-Asians with a frequency of 1.5% but not detectable among patients with SLE. A meticulous annotation of C4 sequences revealed clusters of variations proximal to sites for protein processing, activation and inactivation, and binding of interacting molecules., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhou, Rudnicki, Chua, Lawrance, Zhou, Drew, Barbar-Smiley, Armstrong, Hilt, Birmingham, Passler, Auletta, Bowden, Hoffman, Wu, Jarjour, Mok, Ardoin, Lau and Yu.)

Background/purpose: Thyroid Imaging Reporting and Data System (TI-RADS) is validated in adults but not yet in children. The purpose of this study was to determine the sensitivity, specificity, and accuracy of TI-RADS in predicting thyroid malignancy for pediatric nodules, and to compare the diagnostic accuracy to the current American Thyroid Association (ATA) guidelines., Methods: A single institution retrospective review was performed of patients younger than 21 years who underwent thyroid nodule fine needle aspiration biopsy (FNAB). Two radiologists were blinded to the pathology and independently classified all biopsied thyroid nodules based on TI-RADS. ATA and TI-RADS guidelines were analyzed to determine the diagnostic sensitivity and specificity of both scoring systems., Results: 115 patients (median age 15.5 years, 90 females) with 138 nodules were scored using TI-RADS. There was moderate inter-rater agreement between radiologists (Kappa = 0.51; p < 0.0001). Evaluating several potential TI-RADS criteria, 23.2%-68.1% of nodules were recommended for FNAB, compared to 82.6% of nodules using ATA guidelines. Using TI-RADS ≥ 3 (without size cutoff) as an indication for FNAB had 100% sensitivity with no missed suspicious or malignant nodules on cytology or pathology., Conclusions: Using TI-RADS for diagnostic management of pediatric thyroid nodules improves accuracy in predicting malignancy., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: In obese adults the shape of the glucose response curve during an oral glucose tolerance test (OGTT) predicts future type 2 diabetes. Patients with an incessant increase or monophasic curves have increased risk compared to those with biphasic curves. Since type 2 diabetes is associated with increased cardiometabolic risk, we studied whether differences in OGTT response curve are associated with differences in cardiometabolic risk factors in healthy adolescents across a wide body mass index (BMI) range., Methods: Sixty-nine (33F/36M), white adolescents (age: 15.2 ± 1.7 years; BMI: 21.5 ± 4.7 kg/m 2 ; mean ± SD) were studied. Risk factors measured included percent body fat, blood pressure, lipids, augmentation index, reactive hyperemia, endothelin 1, plasminogen activator 1, inflammatory markers (interleukin 6, c-reactive protein), insulin secretion, insulin sensitivity (Matusda index), and disposition index (DI)., Results: Thirty-two subjects had biphasic responses; 35 subjects had monophasic responses and two females had incessant increases. Sex did not affect the frequency of responses. Glucose area under the curve during OGTT was greater in those with a mono vs. biphasic curves (p=0.01). Disposition index was markedly lower in subjects with a monophasic curve than in those with a biphasic curve (3.6 [2.3-5.0] vs. 5.8 [3.8-7.6], median [25th, 75th%] p=0.003). Triglyceride to high-density lipoprotein cholesterol (HDL) ratio was higher in subjects with a monophasic curve (p=0.046)., Conclusions: The decreased disposition index indicates that in healthy adolescents a monophasic response to OGTT is due to decreased insulin secretion relative to the degree of insulin resistance present. This was not associated with differences in most other cardiometabolic risk markers., Trial Registration: Clinical Trials.gov, NCT02821104., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Objective: Despite increased diabetes device use, few adolescents with type 1 diabetes (T1D) meet glycemic targets. We examine associations between utilization of insulin pumps and continuous glucose monitoring (CGM) and glycemic control., Research Design and Methods: This prospective cohort study included 80 youths (10-18 years of age) with T1D. Multiple linear regression and linear mixed models (LMM) were used to estimate the effects of device self-management on HbA1c and daily time in range (70-180 mg/dL), respectively., Results: Every blood glucose (BG) input/day was associated with a 0.2% decrease in HbA1c (95% CI: -0.297, -0.013), each bolus/day was associated with a 0.2% decrease (-0.327, -0.057), and use of CGM was associated with a 0.5% decrease (-1.00, -0.075). Among CGM users (n = 45) every 10% increase in CGM use was associated with a 0.3% decrease in HbA1c (-0.390, -0.180). In LMM accounting for within subject and between subject variability, there was a negative association between BG input/day frequency (coefficient = -1.880, [-2.640, -1.117]) and time in range. Residual random effects for CGM users were large showing time in range varied between youth with a SD of 15.0% (3 hours and 36 minutes) (SE 2.029, [11.484, 19.530]). Time in range varied significantly from day-to-day with SD of 18.6% (4 hours and 40 minutes) (SE0.455, [17.690, 19.473])., Conclusions: Device self-management behaviors among youth are significantly associated with both HbA1c and time in range. Our findings showing an association between reduced time in range and increased self-management behaviors is novel and deserves further investigation., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Background: Complement promotes inflammatory and immune responses and may affect cardiometabolic risk. This study was designed to investigate the effect of complement components C3 and C4 on cardiometabolic risk in healthy non-Hispanic white adolescents., Methods: Body mass index (BMI), BMI percentile, waist circumference, and percent body fat were assessed in 75 adolescents. Arterial stiffness was assessed using arterial tomography and endothelial function using reactive hyperemia. Fasting lipids, inflammatory markers, and complement levels were measured and oral glucose tolerance test was performed. A single C3 polymorphism and C4 gene copy number variations were assessed., Results: C3 plasma levels increased with measures of obesity. Endothelial function worsened with increased C3 and C4 levels. Triglycerides and low-density lipoprotein increased and high-density lipoprotein (HDL) and insulin sensitivity decreased with increasing C3 levels, but the relationships were lost when body habitus was included in the model. C4 negatively related to HDL and positively to inflammatory markers. Subjects with at least one C3F allele had increased BMI and fat mass index. HDL was significantly related to C4L, C4S, C4A, and C4B gene copy number variation., Conclusions: C3 levels increase with increasing body mass and increased C4 levels and copy number are associated with increased cardiometabolic risk in healthy adolescents.

Background: Cardiovascular disease has its origins in adolescents. Endothelial dysfunction, arterial stiffness, and decreased endocardial oxygen supply: demand ratios are early functional markers of cardiovascular risk. The goal of this study was to determine the relationships of these markers to physical, inflammatory, and metabolic markers in healthy non-Hispanic, white adolescents., Methods: Thirty-four of the 75 subjects were female. Mean age was 15.0 ± 1.7 years and mean body mass index (BMI) was 22.0 ± 5.8 kg/m 2 (mean ± SD). Reactive hyperemia was measured using venous occlusion plethysmography. Arterial tonometry was used to measure the augmentation index (AIx 75 ) and the Buckberg subendocardial viability ratio. Blood samples were taken to measure inflammatory and lipid markers and oral glucose tolerance test was used to assess insulin sensitivity., Results: Reactive hyperemia decreased as body mass and fat mass increased. It also decreased with increasing neutrophil count. The Buckberg index was higher in males and was positively related to insulin sensitivity even when accounting for age, sex, and resting heart rate. AIx 75 was not related to any of the other variables., Conclusions: These results demonstrate that increased fat mass and decreased insulin sensitivity are related to poorer vascular function and cardiac risk in adolescents before the development of actual cardiovascular disease., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Increased systemic inflammation plays a significant role in the development of adult cardiometabolic diseases such as insulin resistance, dyslipidemia, atherosclerosis, and hypertension. The complement system is a part of the innate immune system and plays a key role in the regulation of inflammation. Of particular importance is the activation of complement components C3 and C4. C3 is produced primarily by the liver but is also produced in adipocytes, macrophages and endothelial cells, all of which are present in adipose tissues. Dietary fat and chylomicrons stimulate C3 production. Adipocytes in addition to producing C3 also have receptors for activated C3 and other complement components and thus also respond to as well as produce a target for complement. C3adesArg, also known as acylation stimulation factor, increases adipocyte triglyceride synthesis and release. These physiological effects play a significant role in the development of metabolic syndrome. Epidemiologically, obese adults and non-obese adults with cardiometabolic disease who are not obese have been shown to have increased complement levels. C4 levels also correlate with body mass index. Genetically, specific C3 polymorphisms have been shown to predict future cardiovascular events and. D decreased C4 long gene copy number is associated with increased longevity., Conclusion: Future research is clearly needed to clarify the role of complement in the development of cardiovascular disease and mechanisms for its action. The complement system may provide a new area for intervention in the prevention of cardiometabolic diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background Individuals with Prader-Willi syndrome (PWS) have hypothalamic dysfunction and may have central adrenal insufficiency (CAI). The prevalence of CAI in PWS remains unknown. Methods Twenty-one subjects with PWS aged 4-53 years underwent a low dose adrenocorticotropic hormone (ACTH) stimulation test (LDAST) (1 μg/m2, maximum 1 μg) followed by an overnight metyrapone test (OMT). Metyrapone (30 mg/kg, maximum 3 g) was administered at 2400 h. Cortisol, 11-deoxycortisol (11-DOC) and ACTH levels were collected the following morning at 0800 h. OMT was the standard test for comparison. Peak cortisol ≥15.5 μg/dL (427.6 nmol/L) on LDAST and 0800 h 11-DOC ≥7 μg/dL (200 nmol/L) on OMT were classified as adrenal sufficiency. Results Twenty subjects had 0800 h 11-DOC values ≥7 μg/dL on OMT indicating adrenal sufficiency. One subject had an inconclusive OMT result. Six of the 21 (29%) subjects had peak cortisol <15.5 μg/dL on LDAST. Conclusions We found no evidence of CAI based on OMT, yet 29% of our PWS population failed the LDAST. This suggests that the LDAST may have a high false positive rate in diagnosing CAI in individuals with PWS. OMT may be the preferred method of assessment for CAI in patients with PWS.

Background: This study was designed to determine the effects of diabetes type and gender on depression risk determined by a highly sensitive screening questionnaire in adolescents. Glycemic control and counseling affect were also studied., Methods: A retrospective chart review of patients seen between 2013 and 2015 was performed. Five hundred and thirty adolescents with type 1 (T1DM) or 2 (T2DM) diabetes mellitus completed the Patient Health Questionnaire-9 (PHQ-9) to identify depressive symptoms. Hemoglobin A1c (HbA1c) was measured when the PHQ-9 was given, and at 1 year. Patients with increased depression risk were referred for counseling and comparisons were made between those who did and did not attend., Results: Females with T2DM, but not males, had increased depression compared to T1DM. Females had increased depression compared to males in T1DM (p = 0.046) and a near significant increase in T2DM (p = 0.069). In T1DM, but not T2DM, HbA1c levels were increased in high and moderate, compared to low, risk depression risk groups (p = 0.007). Follow-up HbA1c was unchanged 1 year later and there were no differences between those involved in counseling and those who refused to attend. Sex and type of diabetes had no effect on response to counseling., Conclusions: These results demonstrate increased depression in adolescents with T2DM compared to T1DM and in females compared to controls. Glycemic control did not change in adolescents who reported moderate to severe symptoms of depression and received counseling intervention compared to adolescents who declined counseling.

Type 1 diabetes mellitus is a chronic state of insulin deficiency which results from destruction of beta cells by the immune system. The long term microvascular and macrovascular complications can be devastating. Since the discovery of insulin almost 100 years ago new medical therapies have improved the long-term survival for people with type 1 diabetes. Each year we come closer to discovering a cure but much work still needs to be done to eliminate this disease., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Extremely young children aged ≤6 years old represent a unique population among patients with type 1 diabetes in terms of glycemic variation, diabetes management and complications., Objective: We describe distinct features of diabetes care and outcomes in preschool age children., Methods: We searched PubMed, Google Scholar, and authors' bibliographies in order to extract articles specific to type 1 diabetes in preschool age children., Findings: The preschool age group is beset by many challenges to diabetes care, including more frequent hypo- and hyperglycemia, hypoglycemia unawareness, decreased residual beta cell function, and greater long-term neurocognitive effects from severe hypoglycemia and chronic hyperglycemia. Randomized controlled trials show that equally good metabolic control can be obtained with multiple daily injections or an insulin pump. Several non-randomized trials, including an 8 year longitudinal study, show lower hemoglobin A1C and decreased hypoglycemia on insulin pumps. Sensor augmented pump therapy resulted in superior A1C as long as sensors were used regularly. In contrast to adults, continuous glucose monitoring has little to no impact on A1C, although parents appreciate the improved monitoring for hypoglycemia. Children with onset of diabetes prior to age 5 are at risk for younger onset of microalbuminuria, however do not develop earlier onset retinopathy than children diagnosed after 5 years. Both severe hypoglycemia and chronic hyperglycemia have negative impact on neurocognition., Conclusion: Special knowledge about this young population is helpful for practitioners and parents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Schizophrenia is a chronic and debilitating brain disorder. It is associated with increased mortality, primarily due to elevated cardio-metabolic risk. Affected patients have higher rates of obesity, metabolic syndrome and diabetes [1]. Intrinsic factors contributing to this increased risk include a shared underlying pathophysiology between schizophrenia and diabetes mellitus involving stress, inflammation and genetics. Extrinsic contributing factors include diet, lifestyle, health care access, low socioeconomic status and overburden of traditional diabetes risk factors. Antipsychotics are associated with an increased risk of obesity, metabolic syndrome and diabetes mellitus [1]. Appetite-regulating hormones, pharmacodynamics and alterations in glucose metabolism may underlie the negative effect of these medications. Reduction in diabetes risk is achieved by mitigating traditional risk factors. Non-pharmacologic and pharmacologic approaches to cardio-metabolic risk reduction may be helpful in these patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

If we are to gain a full and complete understanding of mechanisms of cardiovascular risk factors in adolescent type 1 diabetes mechanistic risk markers must be developed that predict risk accurately and which can be used as endpoints for short or intermediate term intervention studies aimed at reducing risk. A variety of biochemical and vascular markers have potential to meet these requirements. Biochemical markers include markers of inflammation, oxidation, and endothelial damage. Vascular markers include static and dynamic measures of arterial function. Adolescents with type 1 diabetes demonstrate alterations in many of these markers. For many of the biochemical markers precise cut-off points with high sensitivity and specificity are not available and many of the vascular measures require specific equipment and are operator dependent.

Background: Adolescents with type 1 diabetes (T1D) have increased risk of cardiovascular disease as well as elevations in biomarkers of systemic inflammation, plasma protein oxidation and vascular endothelial injury. It is unclear whether hyperglycemia itself, or variations in blood glucose are predictors of these abnormalities., Methods: This study was designed to determine the relationship of inflammatory (C-reactive protein, CRP), oxidative (total anti-oxidative capacity, TAOC) and endothelial injury (soluble intracellular adhesion molecule 1, sICAM1) markers to glycemic control measures from 3 days of continuous glucose monitoring (CGM) and to hemoglobin A1c (HbA1c), and HbA1c×duration area under the curve (A1cDur)., Results: Seventeen adolescents (8 F/9M; age, 13.1±1.6 years (mean±SD); duration, 4.8±3.8 years, BMI, 20.3±3.1 kg/m2; A1c, 8.3±1.2%) were studied. Log CRP but was not related to age, duration, body mass index (BMI), HbA1c, or A1cDUR. TAOC increased as logA1cDUR increased (n=13, r=0.61, p=0.028). CRP and sICAM were not related to CGM average glucose but log CRP increased as 3 day glucose standard deviation increased (r=0.66, p=0.006). TAOC increased as glucose standard deviation increased (r=0.63, p=0.028)., Conclusions: Increased glucose variability is associated with increased inflammation in adolescents withT1D. Increased TAOC with increasing variability may be an effort to compensate for the ongoing oxidative stress.

Background: Black adolescents are at increased risk of cardiometabolic disease but have lower fasting triglyceride, which is usually associated with decreased risk. No one has studied racial differences in triglycerides or free fatty acids (FFAs) after a high-fat meal., Methods: Oral glucose tolerance testing was used to assess insulin secretion, sensitivity, and disposition index (DI). Endothelial function, triglycerides, FFA, c-reactive protein, interleukin 6 (IL6), and adiponectin were measured both pre- and 3 hr postprandially (McDonald's Big Breakfast(®) and 12 ounce Sprite(®)) in obese adolescents (10-13 years, 9 black and 7 white). Endothelial function was assessed using reactive hyperemic changes in forearm vascular resistance (FVR)., Results: Oral glucose tolerance test (OGTT) showed no difference in insulin sensitivity, but blacks tended to have (P = 0.08) higher insulin secretion and had increased DI (P = 0.003). After a high-fat meal, triglycerides increased in both groups (P < 0.001), tended to be lower in blacks compared with whites preprandially (64 ± 33 mg/dL vs 110 ± 80, P = 0.064), and was lower postprandially (112 ± 63 vs 188 ± 112, P = 0.039). Pre- and postprandial FFA (Black: 0.58 ± 0.15 and 0.39 ± 0.18 vs. white: 0.44 ± 0.14 and 0.26 ± 0.06, P = 0.020) and adiponectin (P = 0.002) were increased in blacks. FFA decreased in both groups postprandially (P = 0.002). IL6 increased after the meal (P = 0.022). Endothelial function decreased postprandially (P < 0.02), but this was due to a decrease in preocclusion FVR., Conclusions: These results indicate that differences in fat metabolism are present in both black and white obese adolescents. How these differences explain higher rates of cardiometabolic disease in blacks is unclear.

Aim: The prevalence of cardiovascular risk factors in children with type 1 diabetes and elevated BMI in the USA is poorly defined. We aimed to test the hypothesis that children with type 1 diabetes who are overweight or obese have increased frequencies of hypertension, dyslipidemia, and micro-/macroalbuminuria compared to their healthy weight peers., Methods: We studied 11,348 children 2 to <18 years of age enrolled in T1D Exchange between September 2010 and August 2012 with type 1 diabetes for ≥1 year and BMI ≥ 5th age-/sex-adjusted percentile (mean age 12 years, 49 % female, 78 % non-Hispanic White). Overweight and obesity were defined based on Centers for Disease Control and Prevention criteria. Diagnoses of hypertension, dyslipidemia, and micro-/macroalbuminuria were obtained from medical records. Logistic and linear regression models were used to assess factors associated with weight status., Results: Of the 11,348 participants, 22 % were overweight and 14 % obese. Hypertension and dyslipidemia were diagnosed in 1.0 % and 3.8 % of participants, respectively; micro-/macroalbuminuria was diagnosed in 3.8 % of participants with available data (n = 7,401). The odds of either hypertension or dyslipidemia were higher in obese than healthy weight participants [OR 3.5, 99 % confidence interval (CI) 2.0-6.1 and 2.2, 99 % CI 1.6-3.1, respectively]. Obese participants tended to be diagnosed with micro-/macroalbuminuria less often than healthy weight participants (OR 0.6, 99 % CI 0.4-1.0)., Conclusions: Obese children with type 1 diabetes have a higher prevalence of hypertension and dyslipidemia than healthy weight children with type 1 diabetes. The possible association of obesity with lower micro-/macroalbuminuria rates warrants further investigation.

Background/objectives: Endothelial dysfunction due to hyperglycemia-induced oxidative damage is an important predictor of future cardiovascular risk in patients with type 1 diabetes mellitus (T1DM) and is present in adolescent T1DM. We hypothesized that combined treatment with the antioxidant vitamins C and E might improve endothelial function (EF) and other biochemical risk factors in adolescents with T1DM., Subjects/methods: Open-label antioxidant supplementation was given for six weeks with endpoint measurements collected at baseline and study completion. Endpoints measured included EF and plasma measurements of biochemical endothelial risk., Results: Two males and 7 females were studied. Mean age was 12.9 ± 0.9 yrs; mean T1DM duration was 5.5 ± 2.5 yrs; mean BMI was 22.1 ± 3.8 kg/m(2); and mean hemoglobin A1c was 9.3 ± 1.1%. No differences were found for EF, high sensitivity CRP, total antioxidant capacity, adiponectin, or endothelial progenitor cells (EPCs) between before and after combined vitamin C and E therapy., Conclusions: Our negative study results do not support previous findings of decreased oxidative damage, improved endothelial function, and increased vascular repair capacity with antioxidant therapy. Longer term studies may be needed to determine the effects, if any, of combined antioxidant therapy on EPCs, EF, and markers of micro- and macrovascular complications in T1DM.

Cardiovascular disease is the major cause of death in patients with type 1 diabetes. Vascular endothelial dysfunction is an early pathophysiological precursor of cardiovascular disease. There is extensive evidence that hyperglycemia causes acute perturbations in endothelial function likely due to increases in oxidative damage. Interestingly, oscillating hyperglycemia may cause more damage than persistent hyperglycemia. Many, but not all, studies indicate that vascular endothelial dysfunction occurs early in the course of type 1 diabetes and is present even in adolescents. Ascorbic acid has been shown to diminish the acute effects of hyperglycemia on endothelial function in type 1 diabetes and in conjunction with euglycemia to restore endothelial function to normal values in adults with well-controlled diabetes. In vitro and in vivo animal evidence suggests potential benefit from two other small molecule antioxidants, nicotinamide and taurine. Early studies suggested that folate supplementation may improve endothelial function in adolescents with type 1 diabetes but this has not been confirmed by more recent studies. Epidemiological evidence suggests a possible role for vitamin D therapy although intervention studies in type 2 diabetes have yielded varying results and have not been done in type 1 diabetes. Further exploration of these and other compounds is clearly appropriate if we are to reduce cardiovascular risk in type 1 diabetes.

Background. Endothelial dysfunction and increased inflammation are precursors of cardiovascular disease in type 1 diabetes (T1D) and occur even in adolescents with T1D. The goal of this study was to determine the relationship of endothelial dysfunction to various measures of glycemia. Research Design and Methods. Forearm blood flow (FBF, venous occlusion plethysmography) was measured before and after 5 min of upper arm vascular occlusion in 17 adolescents with uncomplicated type 1 diabetes. Endothelial function was assessed as postocclusion FBF and forearm vascular resistance (FVR, mean arterial pressure/FBF). Fasting glucose, 72 hour mean glucose and standard deviation from continuous glucose monitoring, hemoglobin A1c, and hemoglobin A1c by duration area under the curve were used to assess immediate, short-term, and intermediate- and long-term glycemia. Results. Postocclusion FBF (r = -0.53, P = 0.030) negatively correlated and postocclusion FVR positively correlated (r = 0.52, P = 0.031) with hemoglobin A1c levels. FVR was positively associated with log 3 day mean glucose (r = 0.55, P = 0.027). Postocclusion FBF (2.8 ± 1.1 versus 3.4 ± 0.5 mL/dL/min, mean ± SE, P = 0.084) tended to be lower and FVR (31.4 ± 10.4 versus 23.9 ± 4.4 mmHg dL min/mL, P = 0.015) was significantly higher in subjects with hemoglobin A1c above the median (8.3%) compared to those with lower hemoglobin A1c levels. Conclusions. These results demonstrate that poor intermediate-term glycemic control is associated with impaired endothelial function.

African-Americans have more hypertension, stroke, and type 2 diabetes than do Caucasians. Endothelial dysfunction and insulin resistance are precursors for each. Since these diseases have origins in pediatrics and are associated with obesity, this study was designed to determine if obesity has different effects on endothelial function, insulin sensitivity, and secretion in African-American and Caucasian adolescents. Thirty-three Caucasian and 25 African-Americans (10-18 years old) were subdivided by BMI into lean, overweight, and obesity groups. Endothelial function was measured as forearm vascular resistance (FVR) over 1 min following 5 min of upper arm vascular occlusion. Insulin sensitivity and secretion were measured using intravenous glucose tolerance test and minimal model. Postocclusive FVR was significantly increased in obese African-Americans. Insulin sensitivity was reduced in obese subjects but did not differ by race. Insulin secretion was increased in African-Americans but did not differ by obesity. Subjects were subdivided into risk groups based on 20th percentile for postocclusion FVR response in lean. Seven of nine obese African-Americans were in the high risk group compared to 0 of 5 obese Caucasians. These results demonstrate that obesity significantly impairs endothelial function in African-Americans. Endothelial dysfunction likely predisposes to future cardiometabolic disease in obese African-American adolescents.

Objective: To determine whether acute ascorbic acid infusions alter the effect of hyperglycemia on endothelial function in adolescents with type 1 diabetes., Research Design and Methods: The forearm blood flow (FBF) reactive hyperemic response to 5 min of upper arm occlusion was studied in eight adolescents with type 1 diabetes during euglycemic and hyperglycemic insulin clamp (40 mU/m2/min) with and without ascorbic acid infusion (3 mg/min)., Results: The ratio of post- to preocclusion FBF decreased during hyperglycemia without ascorbic acid (p = 0.013), but did not change during hyperglycemia with ascorbic acid. The changes during hyperglycemia were different between the two studies (p = 0.038). Similar results were found when the percent change in forearm vascular resistance following occlusion was assessed., Conclusions: These results indicate that antioxidant treatment with ascorbic acid blocks acute hyperglycemic impairment of endothelial function in adolescents with type 1 diabetes., (© 2012 John Wiley & Sons A/S.)

Objective: To determine the roles of complement C4A and C4B gene copy-number variations and their plasma protein concentrations in residual insulin secretion and loss of pancreatic β-cell function in new-onset type 1 diabetes (T1D) patients., Methods: We studied 34 patients of European ancestry with new-onset T1D, aged between 3 and 17 yr (10.7 ± 3.45), at Nationwide Children's Hospital in Columbus, Ohio. Gene copy-number and size variations of complement C4A and C4B were determined by genomic Southern blot analyses. C4A and C4B protein phenotypes were elucidated by immunofixation and radial immunodiffusion. Two-digit human leukocyte antigen (HLA)-DRB1 genotypes were determined by sequence-specific polymerase chain reaction. At 1- and 9-month post diagnosis, stimulated C-peptide levels were measured after a standardized mixed-meal tolerance test., Results: The diploid gene copy-numbers of C4A varied from 0 to 4, and those of C4B from 0 to 3. Patients with higher copy-number of C4A or higher C4A plasma protein concentrations at diagnosis had higher C-peptide levels at 1-month post diagnosis (p = 0.008; p = 0.008). When controlled by the Z-score of body mass index, C4A copy-numbers, C4A protein concentrations, the age of disease onset, and the number of HLA-DR3 but not DR4 alleles were significant parameters in determining C-peptide levels. At 9-month post diagnosis, 42.3% of patients remained in partial remission, and these patients were characterized by lower total C4B copy-numbers or lower C4B protein concentrations (p = 0.02; p = 0.0004)., Conclusions: C4A appears to associate with the protection of residual β-cell function in new-onset T1D; C4B is correlated with the end of disease remission at 9-month post diagnosis., (© 2011 John Wiley & Sons A/S.)

Alterations of blood flow and endothelial function precede development of complications in type 1 diabetes. The effects of hyperglycemia on vascular function in early type 1 diabetes are poorly understood. To investigate the effect of hyperglycemia on forearm vascular resistance (FVR) and endothelial function in adolescents with type 1 diabetes, FVR was measured before and after 5 minutes of upper arm arterial occlusion using venous occlusion plethysmography in (1) fasted state, (2) euglycemic state (~90 mg/dL; using 40 mU/m(2)/min insulin infusion), and (3) hyperglycemic state (~200 mg/dL) in 11 adolescents with type 1 diabetes. Endothelial function was assessed by the change in FVR following occlusion. Seven subjects returned for a repeat study with hyperglycemia replaced by euglycemia. Preocclusion FVR decreased from euglycemia to hyperglycemia (P = 0.003). Postocclusion fall in FVR during hyperglycemia was less than during euglycemia (P = 0.002). These findings were not reproduced when hyperglycemia was replaced with a second euglycemia. These results demonstrate that acute hyperglycemia causes vasodilation and alters endothelial function in adolescents with type 1 diabetes. In addition they have implications for future studies of endothelial function in type 1 diabetes and provide insight into the etiology of macrovascular and microvascular complications of type 1 diabetes.

Objectives: Type 2 diabetes mellitus is a growing problem in pediatrics and there is no consensus on the best treatment. We conducted this chart review on newly diagnosed pediatric patients with type 2 diabetes mellitus to compare the effect of treatment regimen on body mass index (BMI) and hemoglobin A1c over a 6-month period., Methods: We conducted a retrospective chart review on patients with type 2 DM who presented to Nationwide Children's Hospital. Data were collected on therapy type, BMI, and hemoglobin A1c over a 6-month follow-up. Therapy type was divided into metformin, insulin, or combination insulin and metformin. 1,997 charts were reviewed for inclusion based on ICD-9 codes consistent with a diagnosis of diabetes, abnormal oral glucose tolerance test, or insulin resistance., Results: Of the 47 charts eligible for the review, 26 subjects were treated with metformin 1000-1500 mg daily, 14 patients were treated with insulin therapy, and 7 patients were treated with a combination of insulin and metformin therapy. At baseline, the only significant difference among groups was A1c (P = 0.012). In regression analysis with baseline A1c as a covariate, the only predictor of change in A1c over time was the A1c at onset (P < 0.001). Therapy type was not predictive of change (P = 0.905). Regression analysis showed a greater BMI at onset predicted a greater decrease in BMI (P = 0.006), but therapy type did not predict a change (P = 0.517)., Conclusion: Metformin may be as effective as insulin or combination therapy for treatment of diabetes from onset to 6-month follow-up.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Objective: A mechanistic, physiologically-based pharmacokinetic (PK/PD) model was developed to describe the biphasic insulin release and evaluate the racial effects on the glucose-insulin kinetics in response to intravenous glucose., Methods: Fifteen African-American and 18 Caucasian children and adolescents between 8 and 18 years of age were enrolled in the study. Intravenous bolus of glucose (250 mg/kg) was administered and blood samples collected at frequent intervals for three hours following the glucose injection. A nonlinear mixed-effect population kinetic analysis with covariate structure was performed using Monolix., Results: A significantly higher initial insulin secretion from a readily releasable pool, which is responsible for the first-phase insulin secretion, was detected in African-Americans compared to Caucasians (p<0.05)., Conclusions: The proposed kinetic model is able to describe the glucose-stimulated insulin response, account for the first-phase insulin release and identify a racially-based pharmacokinetic difference in insulin's biphasic secretion behavior. It is hypothesized that the first-phase insulin component may play an important role in the development of type 2 diabetes. The proposed mechanistic model provides a quantitative analysis of the biphasic insulin release that may be useful in the early detection of diabetes., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Most studies of primary antiretroviral (ARV) resistance have been conducted in large metropolitan areas with reported rates of 8% to 25%. We collected data on 99 HIV-1-infected antiretroviral-naive patients from several sites in Springfield, MA, who underwent genotypic resistance assay between 2004 and 2008. Only major resistance mutations per International AIDS Society-USA (IAS-USA) drug resistance mutations list were considered. The prevalence of resistance was 5% (5 of 99). Three patients had one nonnucleoside reverse transcriptase inhibitor (NNRTI) mutation: 103N, 103N, and 190A, 1 patient had a protease inhibitor (PI) mutation: 90M; and 1 patient had 3-class resistance with NNRTI: 181C, 190A, PI: 90M, and nucleoside analogue reverse transcriptase inhibitor (NRTI): 41L, 210W. Mean time from HIV diagnosis to resistance testing was shorter in patients with resistance versus those without: 9 (range 0.3-42 months) versus 27 (range 0.1-418 months), P = .11. There was a trend to lower mean CD4 count in those with resistance, 170 versus 318 cells/mm(3), P = .06. No differences were noted in gender, age, HIV risk category, or HIV RNA level. The low prevalence of primary resistance may be explained by differences in demographic and risk factors or may reflect the time from infection to resistance testing. Our findings emphasize the importance of continued resistance surveillance.

Background: HIV-1 genotypic resistance testing is not routinely recommended for patients who have been off antiretroviral therapy (ART) for longer than 4 weeks. We assessed the results and use of resistance testing in patients off ART., Methods: All HIV resistance genotypes from November 2003 through April 2008 were reviewed from one large teaching hospital and two private HIV practices. Inclusion criterion was having a genotypic resistance test after an ART interruption of at least 2 months. Medical records were reviewed using a standardized data collection sheet., Results: Sixty-two of 304 treatment-experienced patients with HIV genotypes met the inclusion criteria. Prior cumulative ART class exposure included nucleoside reverse transcriptase inhibitors in 54 patients, nonnucleoside reverse transcriptase inhibitors in 32 patients, and protease inhibitors in 30 patients. Resistance testing was performed at a mean of 12 months (range, 2.5-48 months) after ART interruption. The mean time between ART interruption and resistance testing did not differ for patients with mutations and those without mutations detected. Seventeen of 62 (27.4%) patients were found to have resistance mutations. Eleven patients were found to have mutations to nonnucleoside reverse transcriptase inhibitors, four patients had mutations to nucleoside reverse transcriptase inhibitors, and two patients had protease inhibitor-associated mutations. No patient had multiclass resistance. Among the 17 patients with mutations after treatment interruption, 15 had mutations that were either not present on a prior genotype (n = 2) or did not have a prior genotype (n = 13)., Conclusions: HIV genotypic resistance assays may identify mutations even when performed after a prolonged treatment interruption and may offer clinically significant information. Current guidelines that discourage resistance testing after treatment interruptions of longer than 4 weeks should be re-evaluated.

The metabolic syndrome consists of obesity, insulin resistance, dyslipidemia, atherosclerosis, and hypertension. Its clinical outcomes are stroke, myocardial infarction, and type 2 diabetes. Each of these is more frequent in African-Americans than in Caucasians. This is surprising since most studies indicate that the incidence of the metabolic syndrome is lower in African-American than Caucasian adults. There is growing evidence that adult cardiovascular disease has its origin in childhood and adolescents. Thus, it is important that we understand differences in the pathophysiological precursors to metabolic and cardiovascular disease in this age group. Many studies, but not all, have demonstrated that African-American children and adolescents are insulin resistant compared to similar age Caucasians. The increased insulin resistance occurs in spite of lower triglyceride levels. Low triglyceride levels are usually associated with increased insulin sensitivity. There is evidence that the relationship between triglycerides and insulin sensitivity differs between the two races. African-Americans compensate for the increased insulin resistance by increasing insulin secretion and insulin clearance. Interestingly, those studies that have not found increased insulin resistance in African-Americans have found increased insulin secretion suggesting the increased secretion may precede the insulin resistance. Hyperinsulinism and insulin resistance are linked to endothelial dysfunction in adults and African-American adolescents have poorer endothelial function than do Caucasians. In African-American adolescents, endothelial function decreases as insulin secretion increases. It is likely that the hyperinsulinism, insulin resistance and endothelial dysfunction in adolescent African-American adolescents play an important role in the increased rates of cardiovascular disease and type 2 diabetes. Future research should focus on the mechanisms of these abnormalities and ways to prevent their development in this age group.

The objective of this study was to examine the differences in glucose and insulin responses between African-American and Caucasian youths and to determine the associations of between-group differences with sex, body mass index (BMI) and pubertal status using a noncompartmental pharmacokinetic approach. Sixteen African-American and 22 Caucasian healthy adolescents were tested using the frequently sampled intravenous glucose tolerance test. Longitudinal t-tests across each observation revealed that (1) African-American youths have higher insulin concentrations between 4 to 19 min; (2) insulin levels remained similar as subjects were grouped according to sex and pubertal status; (3) for glucose, the only difference was found as it approached steady-state basal level (>100 min) between groups with different BMIs. Linear regression showed that insulin concentrations between 4 to 19 min are associated with BMI in Caucasians. African-American youths were found to have higher insulin responses after glucose stimulation and the insulin concentrations were more related to BMI in Caucasians compared with African-Americans. BMI also has a significant effect on the glucose steady state basal level. The acute insulin response to glucose (AIR(g)) extended to 20 min resulted in a more significant racial difference (p<0.0006) compared with the calculation done over 10 min suggested in the past (p<0.001).

Insulin stimulates muscle glucose uptake and inhibits hepatic glucose production. Measures of insulin sensitivity or insulin resistance must take both of these actions into account. Homeostatic model assessment of insulin resistance (HOMA(IR)) and quantitative insulin sensitivity check index (QUICKI) are two simple measures of insulin resistance and insulin sensitivity that are derived from fasting glucose and insulin levels as such it is likely that they reflect primary hepatic insulin action and not muscular effects. To prove this hypothesis, the relationships of HOMA(IR) and QUICKI to peripheral insulin sensitivity (S(I)(*)) and hepatic insulin resistance (HIR) were assessed in 34 adolescents (age 13.5 +/- 2.9 yr, body mass index 23.0 +/- 5.7, mean +/- SD; 16 Caucasian and 14 African-American). S(I)(*) and HIR were determined using the stable-labeled, frequently sampled intravenous glucose tolerance test (250 mg total glucose/kg, 13% [6,6]-D(2)-glucose). The former was calculated using the one-compartment minimal model and stable glucose concentration (S(I)(*)), and the latter was determined over the last hour of the study by multiplying hepatic glucose production (Steele's equation) by mean plasma insulin concentration. As expected, HOMA(IR) and QUICKI were significantly related to HIR (log HOMA(IR) and log HIR, r = 0.73, p < 0.001; QUICKI and log HIR, r = -0.69, p < 0.001) but not S(I)(*). When both S(I)(*) and HIR were included in the equations, only the relationships to log HIR were significant (log HOMA(IR), p < 0.001; QUICKI, p < 0.001). The relationships were similar in African-American and Caucasian subjects. These results demonstrate that in adolescents, HOMA(IR) and QUICKI assess hepatic but not peripheral insulin action.

Objective: To determine whether there are different rates of partial remission in preschool, school-age children, and adolescents with type 1 diabetes mellitus (T1DM) and to identify clinical characteristics that are associated with increased rate of partial remission., Design/methods: A total of 152 consecutive patients with newly diagnosed T1DM in 2004 were studied. Clinical characteristics at diagnosis, hemoglobin A1C (HbA1C), and total daily insulin dose (TDD) at 3-month interval follow-up for 1 yr were analyzed in each age-group (group 1, aged <5 yr; group 2, aged 5-12 yr; and group 3, aged >12 yr). Partial remission was defined as TDD <0.5 units/kg/d with HbA1C <8% assessed at 6 months after diagnosis., Results: Young children (group 1, 26.8%) and adolescents (group 3, 29%) had low rates of partial remission compared with school-age children (group 2, 56%, p = 0.002). There were no differences in the rates of diabetic ketoacidosis (DKA), autoantibody frequency, and HbA1C at diagnosis between age-groups. DKA at diagnosis was associated with less likelihood of having partial remission (p < 0.001). There were no associations between gender, autoantibodies, and HbA1C at diagnosis and the rate of partial remission., Conclusions: Young children and adolescent children with T1DM had a low rate of partial remission. Metabolic control was poorest in young children, whereas higher dose insulin in adolescents because of insulin resistance contributes to less likelihood of having partial remission. DKA at diagnosis was associated with low rate of partial remission. It is possible that the low frequency of honeymoon phase in young children reflects more aggressive beta-cell destruction in young children.

Background: In adults with growth hormone (GH) deficiency (GHD), GH treatment restores impaired endothelial function, a precursor of cardiovascular disease. Its effect in children with GHD is unknown., Methods: Three months of GH (0.3 mg/kg/wk) were given to nine children with GHD. Endothelial function was measured via reactive hyperemic response. Forearm blood flow (FBF, strain gauge plethysmography) was measured before and after 5 min of upper arm arterial occlusion. Blood pressure and lipid, insulin and glucose levels were measured. Pretreatment endothelial function was compared to 18 previously studied control children., Results: Percent fall in forearm vascular resistance was greater in controls (81.2 +/- 1.9%) than in children with GHD (69.6 +/- 5.3%, p = 0.021) but was not affected by GH (60.6 +/- 7.5%). GH markedly increased HOMAIR (21 +/- 7 versus 43 +/- 8, p = 0.004). Plasma lipid levels did not significantly differ., Conclusion: These results indicate that endothelial function is impaired in children with GHD. GH therapy does not restore the impairment.

We report an interesting and unique case of an overweight adolescent with a novel mutation of the maturity-onset diabetes of the young (MODY)3 gene [hepatocyte nuclear factor-1 alpha (HNF-1alpha)] and positive islet cell autoantibodies. The patient is a 17-yr-old Caucasian female, who was diagnosed with type 2 diabetes mellitus, treated with metformin and glipizide, with poor control for 18 months prior to being referred to the Endocrinology clinic. Family history was strongly positive for type 2 diabetes (father, paternal aunts, uncles, and grandmother). All were diagnosed at age 40-50 and treated with oral hypoglycemic agents. The patient's body mass index was 36.4 kg/m(2). She had no acanthosis nigricans. Initial hemoglobin A1c was 11.9%, with fasting glucose of 234 mg/dL and fasting insulin 10.7 microU/mL. She was started on insulin therapy (0.6 units/kg/d), resulting in good glycemic control. Oral hypoglycemic agents were discontinued. Immunologic studies showed positive islet cell (29 U/mL, normal <1.0) and glutamic acid decarboxylase-65 (0.9 U/mL, normal <0.5) antibodies. Sequencing for HNF-1alpha gene revealed a nucleotide A to G substitution (ACC to GCC), resulting in a missense mutation, T196A. To our knowledge, T196A has not been previously reported. The coexistence of type 1 diabetes autoimmunity and a mutation in the gene responsible for MODY3 in this overweight patient is intriguing and might explain the early onset of progressive insulinopenia compared with the later age of diabetes onset of the earlier generation in the family.

In normal individuals hypoglycemic counterregulation is a multifactorial, redundant process that involves reduction of insulin secretion, increasing glucagon secretion, adrenergic activation, and increased growth hormone and cortisol secretion. Metabolically, these lead to increased glucose production, initially through glycogenolysis and later through gluconeogenesis, decreased muscle glucose oxidation and storage and increased release and use of alternative fuels, primarily free fatty acids. They also lead to hypoglycemic symptoms and hunger which increase food intake. These systems are designed to provide as much glucose as possible for brain glucose use. In patients with type 1 diabetes there are multiple impairments of these responses. Insulin does not decrease. Glucagon secretion is decreased or absent. Recovery from hypoglycemia is therefore dependent on the adrenergic response. Hypoglycemia increases plasma levels of both epinephrine and norepinephrine. These catechols are released primarily from the adrenal medulla. However, it is well documented that hypoglycemic increases muscle sympathetic nerve activity, and that both alpha and beta adrenergic activity increase. Increased beta-activity increases free fatty acid release which increase glucose production and decrease glucose utilization. The increased alpha-adrenergic activity's primary role is to counteract beta-adrenergic vasodilation. It may also reduce neurogenic and neuroglycopenic symptoms. Lastly, there is evidence that both cardiac and adrenergic sensitivity are altered in type 1 diabetes. It is hoped that this information can be used in the future to help develop ways to protect patients with type 1 diabetes from hypoglycemia and its adverse effects.

Objective: To determine whether African-American adolescents have endothelial dysfunction compared with Caucasians and whether differences are a result of differences in insulin sensitivity calculated from total glucose (S(I)) or secretion., Study Design: Thirty-three Caucasian (13.6 +/- 2.6 years of age; body mass index [BMI] 21.6 +/- 4.4 kg/m2 mean +/- SD) and 25 African-American (13.3 +/- 2.9 years of age; BMI 24.0 +/- 4.4 kg/m2) adolescents were studied. Forearm blood flow (FBF; plethysmography) was measured before and after 5 minutes of arterial occlusion. S(I) and acute insulin response to glucose (AIRG) were measured using intravenous glucose tolerance tests and minimal modeling., Results: Baseline FBF did not differ between races. Postocclusion FBF was lower in African-Americans (17.2 +/- 1.2 vs 22.6 +/- 1.2 mL/dL/minute, P = .006). AIRG was higher in African-Americans (6050 +/- 940 vs 2410 +/- 30 microU minute/mL, P = .001). Pubertal stage had no effect. S(I) did not differ by race or pubertal stage. In African-Americans, percent fall in FVR following arterial occlusion correlated (r = 0.67, P = .001) with log AIRG. No relationships were found between percent fall in FVR and S(I) in either race., Conclusion: African-American adolescents have decreased endothelial function. This may be a result of increased insulin secretion. Endothelial dysfunction in African-American adolescents may predispose to cardiovascular and type II diabetes.

The objective of this study was to analyse the PK/PD of the insulin-glucose physiology for glucose stimulated insulin secretion from beta-cells between lean and obese pre-pubertal children in an 18 month study. The subjects were divided into two groups of six children according to their body mass index (BMI). Each subject was assessed on four occasions: on admission and at 6, 12 and 18 month follow-ups. Each time, 23 blood samples were obtained from the subjects according to the frequently sampled intravenous glucose tolerance test involving a bolus of 250 mg/kg dextrose. For the obese group, a significant difference (p <0.05) was found in the rate constant for the first phase secretion of insulin between the time of admission (1.73 +/- 0.372 min(-1)) and the 18 month follow-up (3.08 +/- 0.391 min(-1)). Additionally, the lean vs obese group comparisons showed a higher first phase insulin secretion rate constant (p <0.05) in the obese group on admission (1.73 +/- 0.372 vs 1.29 +/- 0.278 min(-1)), 6 months (1.96 +/- 0.317 vs 1.32 +/- 0.444 min(-1)), 12 months (2.33 +/- 0.621 vs 1.57 +/- 0.435 min(-1)) and 18 months (3.08 +/- 0.391 vs 1.83 +/- 0.587 min(-1)). The proposed PK/PD model for the insulin secretion from beta-cells is able to identify kinetic differences in first phase insulin secretion between lean and obese non-diabetic pre-pubertal children in this 18 month follow-up study., (Copyright 2006 John Wiley & Sons, Ltd.)