Search

The pathogenesis and clinical features of diabetic cardiomyopathy have been well-studied in the past decade, but effective approaches to prevent and treat this disease are limited. Diabetic cardiomyopathy occurs as a result of the dysregulated glucose and lipid metabolism associated with diabetes mellitus, which leads to increased oxidative stress and the activation of multiple inflammatory pathways that mediate cellular and extracellular injury, pathological cardiac remodelling, and diastolic and systolic dysfunction. Preclinical studies in animal models of diabetes have identified multiple intracellular pathways involved in the pathogenesis of diabetic cardiomyopathy and potential cardioprotective strategies to prevent and treat the disease, including antifibrotic agents, anti-inflammatory agents and antioxidants. Some of these interventions have been tested in clinical trials and have shown favourable initial results. In this Review, we discuss the mechanisms underlying the development of diabetic cardiomyopathy and heart failure in type 1 and type 2 diabetes mellitus, and we summarize the evidence from preclinical and clinical studies that might provide guidance for the development of targeted strategies. We also highlight some of the novel pharmacological therapeutic strategies for the treatment and prevention of diabetic cardiomyopathy.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is ubiquitously expressed in most eukaryotic cells and functions to induce a broad range of cellular defenses against exogenous and endogenous stresses, including oxidants, xenobiotics, and excessive nutrient/metabolite supply. Because the production and fate of stem cells are often modulated by cellular redox and metabolic homeostasis, important roles of Nrf2 have emerged in the regulation of stem cell quiescence, survival, self-renewal, proliferation, senescence, and differentiation. In a rapidly advancing field, this review summarizes Nrf2 signaling in the context of stem cell state and function and provides a rationale for Nrf2 as a therapeutic target in stem cell-based regenerative medicine.

Assessing maximal oxygen uptake (VO

Elderly adults are at higher risk for developing diabetic complications including diabetic nephropathy (DN), contributing to excess morbidity and mortality in elderly individuals. A non-mitogenic variant of fibroblast growth factor 1 (FGF1(ΔHBS)) was demonstrated to prevent DN in an early-stage (2-month-old) type 2 diabetes (T2D) mouse model. The present study aimed to investigate the potential therapeutic effects of FGF1(ΔHBS) against the progression of renal dysfunction in a late-stage T2D mouse model with established DN. Nine-month-old db/db mice were administered FGF1(ΔHBS) every other day for 3 months. db/db mice at 12-month-old without FGF1(ΔHBS) treatment exhibited high blood glucose level and elevated urine albumin-to-creatinine ratio. FGF1(ΔHBS) treatment effectively reversed hyperglycemia, delayed the development of renal dysfunction, and reduced kidney size and weight. Furthermore, FGF1(ΔHBS) treatment significantly prevented the progression of renal morphologic impairment. FGF1(ΔHBS) treatment demonstrated anti-inflammatory and anti-fibrotic effects, with significantly decreased protein levels of key pro-inflammatory cytokines and pro-fibrotic factors in kidney. Moreover, FGF1(ΔHBS) treatment greatly decreased apoptosis of renal tubular cells, accompanied by significant downregulation of the proapoptotic protein and upregulation of the antiapoptotic protein and peroxisome proliferator-activated receptor α (PPARα) expression in kidney. Mechanistically, FGF1(ΔHBS) treatment directly protected mouse proximal tubule cells against palmitate-induced apoptosis, which was abolished by PPARα inhibition. In conclusion, this study demonstrated that FGF1(ΔHBS) delays the progression of renal dysfunction likely through activating PPARα to prevent renal tubule cell death in late-stage T2D, exhibiting a promising translational potential in treating DN in elderly T2D individuals by ameliorating renal inflammation, fibrosis and apoptosis.

Endothelial progenitor cells (EPCs) are reduced in number and impaired in function in diabetic patients. Whether and how Nrf2 regulates the function of diabetic EPCs remains unclear. In this study, we found that the expression of Nrf2 and its downstream genes were decreased in EPCs from both diabetic patients and db/db mice. Survival ability and angiogenic function of EPCs from diabetic patients and db/db mice also were impaired. Gain- and loss-of-function studies, respectively, showed that knockdown of Nrf2 increased apoptosis and impaired tube formation in EPCs from healthy donors and wild-type mice, while Nrf2 overexpression decreased apoptosis and rescued tube formation in EPCs from diabetic patients and db/db mice. Additionally, proangiogenic function of Nrf2-manipulated mouse EPCs was validated in db/db mice with hind limb ischemia. Mechanistic studies demonstrated that diabetes induced mitochondrial fragmentation and dysfunction of EPCs by dysregulating the abundance of proteins controlling mitochondrial dynamics; upregulating Nrf2 expression attenuated diabetes-induced mitochondrial fragmentation and dysfunction and rectified the abundance of proteins controlling mitochondrial dynamics. Further RNA-sequencing analysis demonstrated that Nrf2 specifically upregulated the transcription of isocitrate dehydrogenase 2 (IDH2), a key enzyme regulating tricarboxylic acid cycle and mitochondrial function. Overexpression of IDH2 rectified Nrf2 knockdown- or diabetes-induced mitochondrial fragmentation and EPC dysfunction. In a therapeutic approach, supplementation of an Nrf2 activator sulforaphane enhanced angiogenesis and blood perfusion recovery in db/db mice with hind limb ischemia. Collectively, these findings indicate that Nrf2 is a potential therapeutic target for improving diabetic EPC function. Thus, elevating Nrf2 expression enhances EPC resistance to diabetes-induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia likely via transcriptional upregulating IDH2 expression and improving mitochondrial function of diabetic EPCs.

Current technology commonly utilized in diabetes care includes continuous glucose monitors (CGMs) and insulin pumps. One often overlooked critical component to the human glucose response is daily physical activity habits. Consumer-based activity monitors may be a valid way for clinics to collect physical activity data, but whether or not children with type 1 diabetes (T1D) would wear them or use the associated mobile application is unknown. Therefore, the purpose of this study was to test the feasibility of implementing a consumer-based accelerometer directly into ongoing care for adolescents managing T1D. Methods: Adolescents with T1D were invited to participate in this study and instructed to wear a mobile physical activity monitor while also completing a diet log for a minimum of 3 days. Clinical compliance was defined as the number of participants who were compliant with all measures while also having adequate glucose recordings using either a CGM, insulin pump, or on the diet log. Feasibility was defined as &gt, 50% of the total sample reaching clinical compliance. Results: A total of 57 children and teenagers between the ages of 7 and 19 agreed to participate in this study and were included in the final analysis. Chi-square results indicated significant compliance for activity tracking (p &lt, 0.001), diet logs (p = 0.04), and overall clinical compliance (p = 0.04). Conclusion: More than half the children in this study were compliant for both activity monitoring and diet logs. This indicates that it is feasible for children with T1D to wear a consumer-based activity monitor while also recording their diet for a minimum of three days.

OBJECTIVE This study evaluated the effects of continuous glucose monitoring (CGM) combined with family behavioral intervention (CGM+FBI) and CGM alone (Standard-CGM) on glycemic outcomes and parental quality of life compared with blood glucose monitoring (BGM) in children ages 2 to RESEARCH DESIGN AND METHODS This was a multicenter (N = 14), 6-month, randomized controlled trial including 143 youth 2 to RESULTS Approximately 90% of participants in the CGM groups used CGM ≥6 days/week at 6 months. Between-group TIR comparisons showed no significant changes: CGM+FBI vs. BGM 3.2% (95% CI −0.5, 7.0), Standard-CGM vs. BGM 0.5% (−2.6 to 3.6), CGM+FBI vs. Standard-CGM 2.7% (−0.6, 6.1). Mean time with glucose level CONCLUSIONS CGM used consistently over a 6-month period in young children with type 1 diabetes did not improve TIR but did significantly reduce time in hypoglycemia. The FBI benefited parental well-being.

Adolescents with diabetes are at increased risk for depression and anxiety, which when untreated negatively affects diabetes control. During a 6-month period, the Patient Health Questionnaire for Depression and Anxiety (PHQ-4) screening tool was utilized. Those with a positive screen then completed the Patient Health Questionnaire for Adolescents (PHQ-A) and the Generalized Anxiety Disorder 7-item (GAD-7) scale. In this article, we report on the correlations in outcomes between the PHQ-4 and the PHQ-A and GAD-7 and its clinical utility for determining the need for standard versus acute behavioral health care. Over 6 months, 77 patients aged 10 to 18 years screened positive on the PHQ-4. Thirty-two patients had positive screening with the PHQ-A and/or the GAD-7. Thoughts of self-harm were reported by 13 (40%), with 1 experiencing current/active symptoms. The PHQ-4 as a screening tool was able to identify adolescents with symptoms of depression and/or anxiety who would benefit from further evaluation by a behavioral health provider.

Aims Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by sulforaphane (SFN) protects from, and deletion of the Nrf2 gene exaggerates, diabetic cardiomyopathy. Angiotensin II (Ang II) plays a critical role in the development of diabetic cardiomyopathy. Therefore, whether SFN prevents Ang II-induced cardiomyopathy through activation of Nrf2 was examined using wild-type, global deletion of Nrf2 gene (Nrf2-KO) and cardiomyocyte-specific overexpression of Nrf2 gene (Nrf2-TG) mice. Methods and results Administration of a subpressor dose of Ang II to wild-type mice induced cardiac oxidative stress, inflammation, remodeling and dysfunction, all of which could be prevented by SFN treatment with Nrf2 up-regulation and activation. Nrf2-KO mice are susceptible, and Nrf2-TG mice are resistant, respectively, to Ang II-induced cardiomyopathy. Meanwhile, the ability of SFN to protect against Ang II-induced cardiac damage was lost in Nrf2-KO mice. Up-regulation and activation of Nrf2 by SFN is accompanied by activation of Akt, inhibition of glycogen synthase kinase (GSK)-3β, and accumulation of Fyn in nuclei. In vitro up-regulation of Nrf2 by SFN was abolished and nuclear Fyn accumulation was increased when cardiac cells were exposed to a PI3K inhibitor or GSK-3β-specific activator. Conclusion These results suggest that Nrf2 plays a central role in the prevention of Ang II-induced cardiomyopathy, and SFN prevents Ang II-induced cardiomyopathy partially via the Akt/GSK-3β/Fyn-mediated Nrf2 activation., Graphical abstract fx1, Highlights • Sulforaphane (SFN) can prevent angiotensin II (AngII) -induced cardiomyopathy. • SFN prevents AngII-induced cardiomyopathy via up-regulating and activating Nrf2. • Cardiac overexpression of Nrf2 prevents Ang II-induced cardiomyopathy. • Up-regulation and activation of Nrf2 by SFN is achieved through the Akt/GSK-3β/Fyn pathway.

Purpose: To determine associations between physical activity (PA) and sport participation on HbA1c levels in children with type 1 diabetes (T1D). Method: Pediatric patients with T1D were invited to complete a PA and sport participation survey. Data were linked to their medical records for demographic characteristics, diabetes treatment and monitoring plans, and HbA1c levels. Results: Participants consisted of 71 females and 81 males, were 13 ± 3 years old with an average HbA1c level of 8.75 ± 1.81. Children accumulating 60 min of activity 3 days or more a week had significantly lower HbA1c compared to those who accumulated less than 3 days (p &lt, 0.01) of 60 min of activity. However, there was no significant difference in HbA1c values based on sport participation groups. A multiple linear regression model indicated that PA, race, age, duration of diagnosis, and CGM use all significantly predicted HbA1c (p &lt, 0.05). Conclusion: This study demonstrated the significant relationship between daily PA and HbA1c. Those in this sample presented with lower HbA1c values even if accumulating less than the recommended number of days of activity. Further, it was shown that sport participation alone may not be adequate enough to impact HbA1c in a similar manner.

For someone managing type 1 diabetes, understanding their body's glucose response to physical activity could aid in effectively addressing nocturnal hypoglycemia. The purpose of this investigation was to examine the acute temporal associations between blood glucose and measures of moderate-vigorous physical activity (MVPA) through an accelerometer. Ten adolescent athletes with type 1 diabetes wore an accelerometer and continuous glucose monitor (CGM) consecutively for a minimum of 2 weeks. Physical activity was analyzed according to intensity indicating time spent in light, moderate, and vigorous intensities. Hypoglycemic episodes were defined as two successive CGM readings70 mg/dL, at 5-min intervals, with an episode ending with at least two CGM readings70 mg/dL. Incidence of nocturnal hypoglycemia occurred during 29% of the nights measured with an average duration of 52.33 ± 41.04 min. When combining total minutes of moderate and vigorous intensities a significant difference was observed between combined MVPA and number of nocturnal hypoglycemic episodes (62.92 min vs. 49 episodes

Context Treatment-induced neuropathy of diabetes (TIND) is a rarely reported but important consideration in patients presenting with an acute onset of neuropathic symptoms following rapid correction of hyperglycemia in diabetes. Although it has been reported in children, the preponderance of literature focuses on adults with TIND. Case Description We report an 18-year-old male with this condition and his clinical course. We then discuss the proposed pathophysiology of TIND and review the literature. We also provide a standard workup for the diagnosis of TIND. Conclusion In both pediatric and adult populations, TIND should be considered in diabetic patients who develop neuropathy acutely following rapid correction of hyperglycemia. Because the pathophysiology of TIND remains poorly understood, there is insufficient information regarding how to target susceptible individuals and prevent the development of TIND.

The transcription factor nuclear factor erythroid 2‐like 2 (NFE2L2) is essential for preventing type 2 diabetes mellitus (T2DM)‐induced complications in animal models. This case and control study assessed genetic variants of NFE2L2 for associations with T2DM and its complications in Han Chinese volunteers. T2DM patients with (n = 214) or without (n = 236) complications, or healthy controls (n = 359), were genotyped for six NFE2L2 single nucleotide polymorphisms (SNPs: rs2364723, rs13001694, rs10497511, rs1806649, rs1962142 and rs6726395) with TaqMan Pre‐Designed SNP Genotyping and Sequence System. Serum levels of heme oxygenase‐1 (HMOX1) were determined through enzyme‐linked immunosorbent assay. Informative data were obtained for 341 cases and 266 controls. Between T2DM patients and controls, the genotypic and allelic frequencies and haplotypes of the SNPs were similar. However, there was a significant difference in genotypic and allelic frequencies of rs2364723, rs10497511, rs1962142 and rs6726395 between T2DM patients with and without complications, including peripheral neuropathy, nephropathy, retinopathy, foot ulcers and microangiopathy. Furthermore, HMOX1 levels were significantly higher in T2DM patients with complications than in controls. Multiple logistic regression analysis, however, showed that only rs2364723 significantly reduced levels of serum HMOX1 in T2DM patients for the GG genotype carriers compared with participants with CG+CC genotype. The data suggest that although NFE2L2 rs2364723, rs10497511, rs1962142 and rs6726395 were not associated with T2DM risk, they were significantly associated with complications of T2DM. In addition, only for rs2364723 higher serum HMOX1 levels were found in the T2DM patients with CG+CC than those with GG genotype.

Background/Objectives: Growth hormone (GH) treatment of idiopathic short stature (ISS) received US Food and Drug Administration approval in 2003. We assessed height gain and safety in 2,450 children with ISS treated with GH in US clinical practice. Methods: Short-term height gain, near-adult height (NAH), and safety outcomes were investigated using Genetics and Neuroendocrinology of Short Stature International Study data. Results: Compared to children with isolated idiopathic GH deficiency (IGHD), those with ISS were shorter at baseline but had similar age and GH dose. Mean ± SD height SD score (SDS) increase was similar for ISS and IGHD, with 0.6 ± 0.3 (first), 0.4 ± 0.3 (second), 0.3 ± 0.3 (third), and 0.1 ± 0.3 (fourth year) for ISS. Girls with ISS (27% of subjects) were younger and shorter than boys but had similar height gain over time. At NAH in the ISS group (n = 467), mean ± SD age, GH duration, and height SDS were 17.3 ± 2.3 years, 4.6 ± 2.7 years, and –1.2 ± 0.9, respectively. Height gain from baseline was 1.1 ± 1.0 SDS and was greater for boys than girls (1.2 ± 1.0 vs. 0.9 ± 0.9), but boys were treated longer (5.1 ± 2.8 vs. 3.6 ± 2.5 years). Adverse events were reported for 24% with ISS versus 20% with IGHD – most were common childhood conditions or previously reported in GH-treated patients. Conclusions: GH-treated children with ISS achieved substantial height gain, similar to patients with IGHD. Fewer GH-treated girls were enrolled than boys, but with similar height SDS gain over time. No ISS-specific safety issues were identified. Thus, GH treatment of ISS appears to have a safety/effectiveness profile similar to that of IGHD.

Rationale: Endothelial progenitor cells (EPCs) respond to stromal cell–derived factor 1 (SDF-1) through chemokine receptors CXCR7 and CXCR4. Whether SDF-1 receptors involves in diabetes mellitus–induced EPCs dysfunction remains unknown. Objective: To determine the role of SDF-1 receptors in diabetic EPCs dysfunction. Methods and Results: CXCR7 expression, but not CXCR4 was reduced in EPCs from db/db mice, which coincided with impaired tube formation. Knockdown of CXCR7 impaired tube formation of EPCs from normal mice, whereas upregulation of CXCR7 rescued angiogenic function of EPCs from db/db mice. In normal EPCs treated with oxidized low-density lipoprotein or high glucose also reduced CXCR7 expression, impaired tube formation, and increased oxidative stress and apoptosis. The damaging effects of oxidized low-density lipoprotein or high glucose were markedly reduced by SDF-1 pretreatment in EPCs transduced with CXCR7 lentivirus but not in EPCs transduced with control lentivirus. Most importantly, EPCs transduced with CXCR7 lentivirus were superior to EPCs transduced with control lentivirus for therapy of ischemic limbs in db/db mice. Mechanistic studies demonstrated that oxidized low-density lipoprotein or high glucose inhibited protein kinase B and glycogen synthase kinase-3β phosphorylation, nuclear export of Fyn and nuclear localization of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), blunting Nrf2 downstream target genes heme oxygenase-1, NAD(P)H dehydrogenase (quinone 1) and catalase, and inducing an increase in EPC oxidative stress. This destructive cascade was blocked by SDF-1 treatment in EPCs transduced with CXCR7 lentivirus. Furthermore, inhibition of phosphatidylinositol 3-kinase/protein kinase B prevented SDF-1/CXCR7-mediated Nrf2 activation and blocked angiogenic repair. Moreover, Nrf2 knockdown almost completely abolished the protective effects of SDF-1/CXCR7 on EPC function in vitro and in vivo. Conclusions: Elevated expression of CXCR7 enhances EPC resistance to diabetes mellitus–induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia. The benefits of CXCR7 are mediated predominantly by a protein kinase B/glycogen synthase kinase-3β/Fyn pathway via increased activity of Nrf2.

The Region 4 Midwest Genetics Collaborative, made up of seven regional states (Illinois, Indiana, Kentucky, Michigan, Minnesota, Ohio, and Wisconsin), brought together pediatric endocrinologists, state laboratory experts, public health follow-up specialists, and parents of children with congenital hypothyroidism (CH) to identify the three-year follow-up management and education patterns of primary care clinicians and pediatric endocrinologists in the care of children diagnosed with CH by state newborn screening (NBS) programs. Among a number of challenges, each state had different NBS methods, data systems, public health laws, and institutional review board (IRB) requirements. Furthermore, the diagnosis of CH was complicated by the timing of the NBS sample, the gestational age, weight, and co-morbidities at delivery. There were 409 children with CH identified through NBS in 2007 in the seven state region. The clinician of record and the parents of these children were invited to participate in a voluntary survey. Approximately 64 % of clinician surveys were collected with responses to questions relating to treatment, monitoring practices, educational resources, genetic counseling, and services provided to children with confirmed CH and their families. Nearly one-quarter (24 %) of parents surveyed responded to questions relating to treatment, education, genetic counseling, resources, and services they received or would like to receive. De-identified data from six of the seven states were compiled for analysis, with one state being unable to obtain IRB approval within the study timeline. The data from this collaborative effort will improve state follow-up programs and aid in developing three-year follow-up guidelines for children diagnosed with CH. To aid in the facilitation of similar public health studies, this manuscript highlights the challenges faced, and focuses on the pathway to a successful multi-state public health endeavor.

Fractures are common injuries caused by child abuse. Although the consequences of failing to diagnose an abusive injury in a child can be grave, incorrectly diagnosing child abuse in a child whose fractures have another etiology can be distressing for a family. The aim of this report is to review recent advances in the understanding of fracture specificity, the mechanism of fractures, and other medical diseases that predispose to fractures in infants and children. This clinical report will aid physicians in developing an evidence-based differential diagnosis and performing the appropriate evaluation when assessing a child with fractures.

To develop a clinic-relevant protocol for systemic up-regulation of NFE2-related factor 2 (Nrf2) to prevent diabetic cardiomyopathy (DCM), male db/db and age-matched wild-type (WT) mice were given sulforaphane (SFN, an Nrf2 activator) and its natural source, broccoli sprout extract (BSE) by gavage every other day for 3 months, with four groups: vehicle (0.1 ml/10 g), BSE-low dose (estimated SFN availability at 0.5 mg/kg), BSE-high dose (estimated SFN availability at 1.0 mg/kg) and SFN (0.5 mg/kg). Cardiac function and pathological changes (hypertrophy, fibrosis, inflammation and oxidative damage) were assessed by echocardiography and histopathological examination along with Western blot and real-time PCR, respectively. Both BSE and SFN significantly prevented diabetes-induced cardiac dysfunction, hypertrophy and fibrosis. Mechanistically, BSE, like SFN, significantly up-regulated Nrf2 transcriptional activity, evidenced by the increased Nrf2 nuclear accumulation and its downstream gene expression. This resulted in a significant prevention of cardiac oxidative damage and inflammation. For all these preventive effects, BSE at high dose provided a similar effect as did SFN. These results indicated that BSE at high dose prevents DCM in a manner congruent with SFN treatment. Therefore, it suggests that BSE could potentially be used as a natural and safe treatment against DCM via Nrf2 activation.

1. William T. Myers, MD* 2. Kupper A. Wintergerst, MD* 3. Suzanne E. Kingery, MD* 4. Michael B. Foster, MD* 1. *Department of Pediatrics University of Louisville, Louisville, KY. A 15-year-old girl with a history of poorly controlled type 1 diabetes mellitus presents to the emergency department with a 4-day history of generalized swelling. She initially noticed bilateral lower extremity edema and right-sided facial swelling that subsequently progressed to include both sides of her face, her abdomen, pelvis, and labia. She also reports a 9-lb (3.54-kg) weight gain. She denies pain, fever, vomiting, loose stools, chest pain, or shortness of breath. Current medications include insulin glargine and insulin aspart. She has only become compliant with this therapy in the past week. On physical examination, the teen’s weight is 51 kg (41st percentile), height is 155 cm (13th percentile), and body mass index is 20.1 (54th percentile). Her vital signs are within normal limits. She is in no acute distress. She has mild facial edema, moderate abdominal distention without …

The impact of family composition on glycemic control in children with type 1 diabetes remains unclear. We sought to evaluate the relationship between health insurance coverage, family composition, and insulin management, and assess their impact on glycemic control in a pediatric type 1 diabetes population.A retrospective chart review was completed for patients seen in the Pediatric Endocrinology Clinic at the University of Louisville in 2012.The analysis included 729 patients with type 1 diabetes; 268 (37%) had public insurance while 461(63%) had private insurance. Compared with publicly insured patients, privately insured patients had higher rates of intensive insulin management with multiple daily injections (MDI) plans or pump devices (88 vs. 83.2%, p = 0.066) and lower HbA1c levels [8.57 vs. 9.39% (70 vs. 79 mmol/mol), p 0.001]. Of the 729 patients, 243 were in single-adult homes (33%). Single-adult homes had higher HbA1c levels than two-adult homes, [9.3 vs. 8.6% (78 vs. 70 mmol/mol), p 0.001]. Among publicly insured, there was no difference in HbA1c levels for single-adult vs. two-adult homes [9.4 (79 mmol/mol), p = 0.868]. For privately insured, patients in single-adult homes had higher HbA1c levels than peers in two-adult homes [9.2 vs. 8.4% (77 vs. 68), p 0.001].Insurance type and family composition have significant associative effects on glycemic control and insulin management that may be mitigated by insulin pump therapy. Identifying and addressing factors such as availability of resources, family education, and adult support and supervision, may help improve glycemic control in high-risk pediatric diabetes patients.

Concerns about possible early pubertal development are a common cause for referral to pediatric medical subspecialists. Several recent studies have suggested that onset of breast and/or pubic hair development may be occurring earlier than in the past. Although there is a chance of finding pathology in girls with signs of puberty before 8 years of age and in boys before 9 years of age, the vast majority of these children with signs of apparent puberty have variations of normal growth and physical development and do not require laboratory testing, bone age radiographs, or intervention. The most common of these signs of early puberty are premature adrenarche (early onset of pubic hair and/or body odor), premature thelarche (nonprogressive breast development, usually occurring before 2 years of age), and lipomastia, in which girls have apparent breast development which, on careful palpation, is determined to be adipose tissue. Indicators that the signs of sexual maturation may represent true, central precocious puberty include progressive breast development over a 4- to 6-month period of observation or progressive penis and testicular enlargement, especially if accompanied by rapid linear growth. Children exhibiting these true indicators of early puberty need prompt evaluation by the appropriate pediatric medical subspecialist. Therapy with a gonadotropin-releasing hormone agonist may be indicated, as discussed in this report.

Background The two major obstacles in the successful transplantation of islets for diabetes treatment are inadequate supply of insulin-producing tissue and immune rejection. Induction of the differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs) into insulin-producing cells (IPCs) for autologous transplantation may alleviate those limitations. Methods hMSCs were isolated and induced to differentiate into IPCs through a three-stage differentiation protocol in a defined media with high glucose, nicotinamide, and exendin-4. The physiological characteristics and functions of IPCs were then evaluated. Next, about 3 × 106 differentiated cells were transplanted into the renal sub-capsular space of streptozotocin (STZ)-induced diabetic nude mice. Graft survival and function were assessed by immunohistochemistry, TUNEL staining and measurements of blood glucose levels in the mice. Results The differentiated IPCs were characterized by Dithizone (DTZ) positive staining, expression of pancreatic β-cell markers, and human insulin secretion in response to glucose stimulation. Moreover, 43% of the IPCs showed L-type Ca2+ channel activity and similar changes in intracellular Ca2+ in response to glucose stimulation as that seen in pancreatic β-cells in the process of glucose-stimulated insulin secretion. Transplantation of functional IPCs into the renal subcapsular space of STZ-induced diabetic nude mice ameliorated the hyperglycemia. Immunofluorescence staining revealed that transplanted IPCs sustainably expressed insulin, c-peptide, and PDX-1 without apparent apoptosis in vivo. Conclusions IPCs derived from hMSCs in vitro can ameliorate STZ-induced diabetic hyperglycemia, which indicates that these hMSCs may be a promising approach to overcome the limitations of islet transplantation.

Objective To study Ferriman-Gallwey (FG) scoring in adolescents with an aim to correlate these scores with serum androgens and mullerian inhibiting substance (MIS). Design Cross sectional study. Setting Pediatric and Adolescent Gynecology Clinic of a university hospital. Patients Twenty-four hirsute adolescent girls age 12-19 with a FG score of 6 or greater. Interventions FG examination and collection of serum levels of MIS, total testosterone, free testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, cortisol, and androstenedione. Main Outcome Measures Correlation between FG scores in adolescents and serum androgens and MIS. Results Weak correlations were seen between FG score and FSH, free-testosterone, total testosterone, and cortisol. Increasing FG scores correlated with an increase in cortisol. As FG score increased, FSH, free-testosterone, and total testosterone decreased. There was no statistical relationship between FG score and LH, androstenedione, prolactin, and MIS. There were weak positive correlations between MIS levels and FSH, total testosterone, and androstenedione. There was no evidence for a linear relationship between MIS levels and LH, free testosterone, cortisol, prolactin, and FG score. Conclusions The utility of FG scoring in adolescents is unknown. There were no direct correlations found with MIS levels and FG score. MIS was not found to be a predictor of hirsutism. A larger study is needed to assess the clinical relevance of FG scoring and presence of underlying causes of hirsutism in adolescents.

Objective To determine whether phthalate exposure is associated with precocious puberty in girls. Study design This was a multicenter cross-sectional study in which 28 girls with central precocious puberty (CPP) and 28 age- and race-matched prepubertal females were enrolled. Nine phthalate metabolites and creatinine were measured in spot urine samples from these 56 children. Results Levels of 8 of the 9 phthalate metabolites were above the limit of detection (LOD) in all 56 subjects. Mono (2-ethylhexyl) phthalate (MEHP) was below the LOD in 25/56 samples (14 subjects with precocious puberty and 11 controls). No significant differences between the children with CPP and the controls in either absolute or creatinine-normalized concentrations of any of the 9 phthalate metabolites were measured. Conclusions Although phthalates may be associated with certain other toxicities in humans, our study suggests that their exposure is not associated with precocious puberty in female children.

We report a 9-year-old female who presented with new onset intractable seizure activity followed by a prolonged encephalopathic state. After ruling out common etiologies, Hashimoto’s encephalopathy (HE) was considered, and antibody levels to thyroid peroxidase and thyroglobulin were both markedly elevated in her serum. She was euthyroid at the time of presentation. Upon treatment with high dose methylprednisolone, the patient demonstrated a significant improvement in her encephalopathy. The diagnosis of HE requires strong clinical suspicion with evidence of antithyroid antibodies, as well as an encephalopathy not explained by another etiology. While well documented in the adult literature, only a handful of pediatric cases have been described to date. Patients with HE have a nearly universal response to high dose glucocorticoids. HE should be considered in the differential diagnosis of any patient, adult or pediatric, who displays prolonged, unexplainable encephalopathy.

OBJECTIVE. We evaluated retrospectively plasma glucose levels and the degree of hypoglycemia, hyperglycemia, and glucose variability in a PICU and then assessed their association with hospital length of stay and mortality rates. METHODS. Electronic medical records at the Packard Children's Hospital at Stanford University were reviewed retrospectively for all PICU admissions between March 1, 2003, and March 31, 2004. Patients with a known diagnosis of diabetes mellitus were excluded. The prevalence of hyperglycemia was defined with cutoff values of 110, 150, and 200 mg/dL. Hypoglycemia was defined as ≤65 mg/dL. Glucose variability was assessed with a calculated glucose variability index. RESULTS. In 13 months, 1094 eligible admissions generated 18865 glucose values (median: 107 mg/dL; range: 13–1839 mg/dL). Patients in the highest maximal glucose quintile had a significantly longer median PICU length of stay, compared with those in the lowest quintile (7.5 days vs 1 day). Mortality rates increased as patients' maximal glucose levels increased, reaching 15.2% among patients with the greatest degree of hyperglycemia. Hypoglycemia was also prevalent, with 18.6% of patients (182 of 980 patients) having minimal glucose levels of ≤65 mg/dL. There was an increased median PICU length of stay (9.5 days vs 1 day) associated with glucose values in the lowest minimal quintile, compared with those in the highest quintile. Hypoglycemia was correlated with mortality rates; 16.5% of patients with glucose levels of ≤65 mg/dL died. Glucose variability also was associated with increased length of stay and mortality rates. In multivariate logistic regression analyses, glucose variability, taken with hyperglycemia and hypoglycemia, showed the strongest association with mortality rates. CONCLUSIONS. Hyperglycemia and hypoglycemia were prevalent in the PICU. Hypoglycemia, hyperglycemia, and, in particular, increased glucose variability were associated with increased morbidity (length of stay) and mortality rates.

Diabetes mellitus among young patients in Asia is caused by a complex set of factors. Although type 1 diabetes (T1D) remains the most common form of diabetes in children, the recent unabated increase in obesity has resulted in the emergence of type 2 diabetes (T2D) as a new type of diabetes among adolescents and young adults. In addition to the typical autoimmune type 1 diabetes (T1aD) and T2D patients, there is a variable incidence of cases of non-autoimmune types of T1D associated with insulin deficiency (T1bD). Additional forms have been described, including fulminant T1D (FT1D). Although most diagnoses of T1D are classified as T1aD, fulminant T1D exists as a hyper-acute subtype of T1D that affects older children, without associated autoimmunity. Patient with this rare aetiology of diabetes showed a complete loss of β-cell secretory capacity without evidence of recovery, necessitating long-term treatment with insulin. In addition, latent autoimmune diabetes in adults is a form of autoimmune-mediated diabetes, usually diagnosed during the insulin-dependent stage that follows a non-insulin requiring phase, which can be diagnosed earlier based on anti-islet autoantibody positivity. Some reports discuss T1bD. Others are elaborating on the presence of "atypical T1b diabetes," such as Flatbush diabetes. The prevalence of diabetes mellitus in young adults continues to rise in Asian populations as T2D increases. With improved characterization of patients with diabetes, the range of diabetic subgroups will become even more diverse in the future. Distinguishing T1D, T2D, and other forms of diabetes in young patients is challenging in Asian populations, as the correct diagnosis is clinically important and has implications for prognosis and management. Despite aetiological heterogeneity in the usual clinical setting, early diagnosis and classification of patients with diabetes relying on clinical grounds as well as measuring islet autoantibodies and fasting plasma C-peptide could provide a possible viable method to minimize complications.

Background: Studies of pediatric intensive care unit (PICU) patients have shown a significant association of morbidity and mortality with hyperglycemia. We retrospectively evaluated the degree of hyperglycemia as well as its correlation with glucocorticoid and insulin use and assessed its association with hospital length of stay (LOS) and mortality. This study preceded the initiation of a standard glycemic control protocol. Methods: We examined medical records at Kosair Children's Hospital for all PICU admissions from 2008 of patients without diabetes mellitus. Critical illness hyperglycemia (CIH) was defined by having three or more peak glucose values greater than thresholds of 110, 140, 180, and 200 mg/dl. These patients were evaluated for glucocorticoid, insulin use, and outcome measures. Results: We evaluated the eligible 1173 admissions, where 10.5% of these patients reached the highest threshold (200 mg/dl) of CIH. Glucocorticoids were used in 43% of these patients, with dexamethasone being the most common (58%). There was a significant correlation between glucocorticoids and higher peak glucose values, where 81% of the patients who were above the 200 mg/dl cutoff level were treated with glucocorticoids. Only 36.8% in that group were also treated with insulin. Patients at the 200 mg/dl cutoff had the highest median PICU and total hospital length of stays (4 and 10 days, respectfully). Mortality was associated with increasing glucose levels, reaching 18.7% among patients above the 200 mg/dl cutoff. Conclusion: Hyperglycemia was prevalent in the PICU and was associated with increased morbidity, as characterized by increased LOS and increased mortality. Glucocorticoid use was prevalent among patients exhibiting hyperglycemia. Insulin use was uncommon.

A 15-year-old female presented to a pediatric emergency department with glycosuria, ketonuria, and hyperglycemia and was admitted with a presumed diagnosis of diabetes mellitus. The patient required no insulin therapy and only minor dietary modification to maintain euglycemia. Clinical examination and laboratory findings revealed a primary diagnosis of Graves' hyperthyroidism with associated impaired glucose tolerance. Here, we review the mechanisms of thyrotoxicosis resulting in impaired glucose metabolism.

Aims: To examine the association between health insurance coverage, insulin management plans, and their impact on diabetes control in a pediatric type 1 diabetes mellitus clinic population. Methods: Retrospective cohort design drawn from the medical records of the Pediatric Endocrinology Clinic at the University of Louisville, Kentucky. Results: Out of 701 patients, 223 had public insurance, and 478 had private insurance. 77% of publically insured used two or three injections per day vs. 40% private. Conversely, 58% of privately insured used a multiple daily injection (MDI) plan or insulin pump (vs. 21%). 84% of MDI patients had private insurance with 93% using insulin pens compared with 38% of publically insured. Mean HbA1c was 8.6% for privately insured vs. 9.8% public, p < 0.0001. Privately insured MDI and pump patients had the lowest HbA1cs. Conclusions: Insurance type had a significant effect on the insulin management plan used and was the most significant factor in overall diabetes control. Limitations on insulin pen use and number of glucose test strips may play a role in the decreased use of MDI/insulin pumps by publicly insured patients. Addressing factors related to insurance type, including availability of resources, could substantially improve diabetes control in those with public insurance.

Control of hyperglycemia in adult medical and surgical intensive care units (ICUs) has been shown to dramatically decrease morbidity and mortality. Algorithms to achieve glycemic control in the ICU setting are evolving. We have evaluated the use of a discrete proportional-integral-derivative (PID) algorithm to control hyperglycemia in pediatric ICU (PICU) patients both with and without diabetes.Six PICU patients [four with diabetic ketoacidosis (DKA) and two with glucocorticoid-induced hyperglycemia] with glucose values150 mg/dL were enrolled. Their hyperglycemia was managed with a PID algorithm that provided recommendations for both changes in the intravenous insulin infusion rate and the time to obtain the next discrete glucose value. Glucose targets were adjusted based on clinical circumstances.Patients (mean age 9.2 years; range 1.8-14 years) utilized the algorithm for a total of 454.4 h. Mean time to the initial glucose target was 8.7 h (range 1.3-15.1 h) in five patients. One subject with hyperosmolar DKA did not achieve target before discharge from the PICU, and another was at target when the algorithm was initiated. After the glucose target was achieved, the mean SD was 23.5 mg/dL, and glucose values were40 mg/dL above target 13% of the time and40 mg/dL below target 1% of the time. There were no glucose values55 mg/dL.The PID algorithm safely and effectively controlled hyperglycemia in a PICU, despite multiple changes in intravenous fluids, steroid doses (including high-dose pulses), and hemodialysis.