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Type 2 diabetes (T2D) is associated with loss of transcription factors (TFs) from a subset of failing β-cells. Among these TFs is Pdx1, which controls the expression of numerous genes involved in maintaining β-cell function and identity. Pdx1 activity is modulated by transcriptional coregulators and has recently been shown, through an unbiased screen, to interact with the Chd4 ATPase subunit of the nucleosome remodeling and deacetylase complex. Chd4 contributes to the maintenance of cellular identity and functional status of numerous different cell types. Here, we demonstrated that Pdx1 dynamically interacts with Chd4 under physiological and stimulatory conditions within islet β-cells and established a fundamental role for Chd4 in regulating insulin secretion and modulating numerous Pdx1-bound genes in vitro, including the MafA TF, where we discovered Chd4 is bound to the MafA region 3 enhancer. Furthermore, we found that Pdx1:Chd4 interactions are significantly compromised in islet β-cells under metabolically induced stress in vivo and in human donor tissues with T2D. Our findings establish a fundamental role for Chd4 in regulating insulin secretion and modulating Pdx1-bound genes in vitro, and disruption of Pdx1:Chd4 interactions coincides with β-cell dysfunction associated with T2D.

Classifying diabetes at diagnosis is crucial for disease management but increasingly difficult due to overlaps in characteristics between the commonly encountered diabetes types. We evaluated the prevalence and characteristics of youth with diabetes type that was unknown at diagnosis or was revised over time. We studied 2073 youth with new-onset diabetes (median age [IQR]=11.4 [6.2] years; 50% male; 75% White, 21% Black, 4% other race; overall, 37% Hispanic) and compared youth with unknown versus known diabetes type, per pediatric endocrinologist diagnosis. In a longitudinal subcohort of patients with data for ≥3 years post-diabetes diagnosis (n=1019), we compared youth with unchanged versus changed diabetes classification. In the entire cohort, after adjustment for confounders, diabetes type was unknown in 62 youth (3%), associated with older age, negative IA-2 autoantibody, lower C-peptide, and no diabetic ketoacidosis (all, p

Objective To describe a 4-year-old girl with Graves disease and methimazole allergy who underwent desensitization, allowing continued methimazole use when other treatments were contraindicated. Methods We formulated a desensitization plan utilizing cetirizine and prednisone for a patient with previously diagnosed Graves disease who developed urticaria and arthralgias from methimazole. She was admitted for monitoring of rash, urticaria, angioedema, and anaphylaxis. Her methimazole dose was increased as tolerated and then titrated as an outpatient. Results A 4-year-old girl presented with a heart rate of 195 beats/minute, blood pressure of 145/108, and subsequent labs of undetectable thyroid stimulating hormone (TSH), free T4 5.8 ng/dL, thyroid peroxidase antibody 11.5 IU/ml, and TSH receptor antibody 39.03 IU/L, consistent with Graves disease. She developed urticaria and arthralgias after 2.5 weeks on methimazole, which resolved with drug cessation. Because of her age, the risks of radioactive iodine ablation and surgery were concerning; therefore, methimazole desensitization was attempted. Prednisone (1 mg/kg/day) and cetirizine (5 mg/day) were started prior to low-dose methimazole reintroduction and continued for 7 days. Methimazole was then gradually increased to a final dose of 15 mg daily (0.8 mg/kg/day). Free T4 normalized within a month (1.12 ng/dL), and her TSH normalized within 10 months (4.61 mcU/mL). Except for 2 possible breakthrough allergic responses that resolved with pulse steroids, she continues to tolerate methimazole. Conclusion We describe a case of methimazole desensitization. In this patient, pretreatment with prednisone, coupled with daily cetirizine, successfully induced methimazole tolerance when other treatment modalities were contraindicated.

* Abbreviation: ADHD — : attention-deficit/hyperactivity disorder Hyperthyroidism (particularly Graves’ disease) affects people of all ages, with symptomatology including restlessness and inability to focus, anxiety, weight loss, tachycardia, heat intolerance, diaphoresis, and diarrhea. The conventional wisdom is that symptoms resolve once the hyperthyroidism is adequately treated. However, authors of some reports suggest that with respect to mental health, this may not be the case. In this issue, Zader et al1 investigate this question and conclude that children with hyperthyroidism have a higher prevalence of attention-deficit/hyperactivity disorder (ADHD), adjustment disorder, anxiety, bipolar disorder, depression, and suicidality. The authors used the Military Health System Data Repository to identify children aged 10 to 18 years in the military system for ≥1 month who had International Classification of Diseases, Ninth Revision or International Classification of Diseases, 10th Revision codes for hyperthyroidism and the aforementioned mental health conditions. The Military Health System Data Repository included >2.5 million children, with a total of nearly 2500 children with hyperthyroidism during a 9-year interval. Compared with children without hyperthyroidism, the prevalence ratios of mental health conditions in those with hyperthyroidism ranged from … Address correspondence to Rebecca Schneider Aguirre, MD, PhD, Division of Pediatric Endocrinology, Riley Hospital for Children, 705 Riley Hospital Dr, Room 5960, Indianapolis, IN 46202. E-mail: rsaguirr{at}iupui.edu

Background: Diabetic ketoacidosis and significant hyperglycemia are associated with known electrolyte derangements in sodium, potassium, and phosphorus. Hypocalcemia and hypoparathyroidism occurring in uncontrolled diabetes are rare. We present a case of new-onset diabetes with severe hypocalcemia. Case: A 15-year-old obese Caucasian male with ADHD and autism presented to the Emergency room due to hyperglycemia found on laboratory evaluation for hypertension. Serum glucose was 563 mg/dL, serum bicarbonate 24 meq/L (21 - 31 meq/L), and HgbA1C 11.4% (4.0 - 5.6%). He was admitted to initiate insulin and for diabetes education. On admission, hypocalcemia was noted: serum calcium 6.6 mg/dL (8.5 - 10.5 mg/dL), alkaline phosphatase 352 units/L (48 - 277 units/L), and albumin 4.6 g/dL (3.5 - 5.0 g/dL). Repeat testing revealed serum calcium 5.1 mg/dL, phosphorus 4.3 mg/dL (2.5 - 4.5 mg/dL), and magnesium 1.7 mg/dL (1.6 - 2.9 mg/dL). He endorsed a 2 month history of tetany, paresthesia, and muscle weakness. Due to food aversions, his dietary intake of calcium and vitamin D was minimal. He had limited sun exposure. Subsequent PTH was 40 pg/mL (10 - 65 pg/mL) with concurrent serum calcium of 6.5 mg/dL. QTc was prolonged [529 msec ( Conclusion: This teen presented with new-onset type 2 diabetes and symptomatic hypocalcemia, an atypical feature of new-onset diabetes. This patient’s hypocalcemia was likely due to both vitamin D deficiency and hypoparathyroidism. He had a low vitamin D level and poor calcium intake with elevated alkaline phosphatase; however, his high normal serum phosphorus and inappropriately normal PTH (instead of elevated in the setting of severe hypocalcemia) indicated a component of hypoparathyroidism. Calcium normalized with detectable 25-OH Vitamin D levels but PTH remained low. Our case highlights the importance of recognizing both that electrolyte abnormalities at diabetes onset may not be directly attributable to diabetes/hyperglycemia and that vitamin D deficiency and hypoparathyroidism may co-exist.

Reliable clinical indicators of near-term risk of worsening glycemia in type 2 diabetes (T2D) could help guide individual-level interventions. Here we analyzed data from the Early Diabetes Intervention Program (EDIP) to identify predictors of near-term glycemic progression. EDIP evaluated progression of fasting blood glucose (FBG) above 140 mg/dl on consecutive quarterly measurements in individuals with screen-detected T2D and FBG below 140 at study entry (age 52.6 + 11.5 years, 41.9% male, mean entry FBG 121±14 mg/dL; mean 2-hour OGTT glucose 236±30; mean HbA1C 6.4+0.57%). We investigated accessible clinical parameters (weight, glycemia, lipids, and insulin levels) as potential near-term predictors of progression, evaluating absolute levels and yearly changes preceding progression. Variables were evaluated individually in age/sex/race-adjusted analyses and in combination in multivariable Cox progression models. Change over the preceding 1 year in fasting glucose, but not in weight or insulin levels, was predictive of glycemic progression in the subsequent year in adjusted univariate analyses (p Disclosure R.S. Aguirre: None. T.S. Hannon: Advisory Panel; Self; Eli Lilly and Company. R. Considine: None. M. Kirkman: Research Support; Self; Bayer AG, Novo Nordisk A/S, Theracos, Inc. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk A/S, Sanofi.

Hypoparathyroidism-sensorineural Deafness-Renal dysgenesis (HDR, or Barakat) syndrome is an uncommon cause of hypoparathyroidism, representing fewer than 200 documented cases in the literature worldwide. Individuals with HDR have variable penetrance and a range of phenotypes. While basal ganglia calcifications are known to occur with chronic hypoparathyroidism, they are less common in children and intracranial calcifications outside the basal ganglia, to our knowledge, have not been documented in HDR syndrome. Case presentation: A 10 year-old boy with a history of sensorineural deafness and attention deficit hyperactivity disorder presented after a new-onset seizure during a basketball game. His initial total serum calcium level of 5.9 mg/dl with an albumin level of 4.4 mg/dl, serum phosphorus was 7.0 mg/dl, and normal creatinine for age. PTH level was 2 pg/ml. He was started on calcitriol and calcium supplementation. There was no prior personal nor family history of hypocalcemia, nephrolithiasis, deafness nor renal problems. A head CT showed calcifications in the basal ganglia as well as at the temporal and frontoparietal gray-white matter junction and thalamus. Parathyroid antibody testing was negative. Subsequent genetic analysis of the GATA3 gene indicated heterozygosity for c.790T>C causing a missense mutation (p.Cys264Arg), that has been reported to cause HDR due to altered DNA binding affinity of the zinc finger component of GATA3. On renal ultrasound kidneys were in the 8th-13th percentile for size, raising the possibility of mild hypoplasia. Post-treatment urine Calcium-to-Creatinine ratio was 0.105. We describe a case of HDR in childhood who presented with seizures and very rare pediatric finding of calcifications in the basal ganglia as well as additional intracranial calcification in the thalamus and temporal and frontoparietal gray-white matter junction, which to our knowledge have not previously been described with HDR Syndrome. This case highlights important features of this disorder including severe intracranial calcifications and morphologic renal anomalies. HDR patients are at high risk for renal impairment, which is a key prognostic factor. Thus, careful monitoring of renal function, avoidance of nephrotoxins and of excessive calciuria during hypoparathyroidism management are necessary.

Central precocious puberty (CPP) results from early activation of the hypothalamic - pituitary -gonadal (HPG) axis and follows the same sequence as normal puberty. While many factors involved in pubertal initiation remain poorly understood, the kisspeptin system is known to play a key role. Currently, mutations in the kisspeptin system, MKRN3, and DLK1 have been identified in sporadic and familial cases of CPP. The diagnosis is based on physical exam findings indicating advancing puberty and on laboratory tests confirming central HPG axis activation. GnRH analogs are the mainstay of treatment and are used with the goal of height preservation. Newer extended release formulations continue to be developed. Currently there is no evidence of long-term complications associated with treatment. However, many areas remain to be explored such as targeted therapies and aspects of clinical management. Further investigation into psychological effects and additional data regarding long-term outcomes, particularly in males, is needed.

The oral glucose tolerance test (OGTT) is used both in clinical practice and research to assess glucose tolerance. In addition, the OGTT is utilized for surrogate measures of insulin sensitivity and the insulin response to enteral glucose and has been widely applied in the evaluation of β-cell dysfunction in obesity, prediabetes, and type 2 diabetes. Here we review the use of the OGTT and the OGTT-derived indices for measurement of risk markers for type 2 diabetes in youth. Advantages of using the OGTT for measures of diabetes risk include its accessibility and the incorporation of physiological contributions of the gut-pancreas axis in the measures of insulin response to glucose. Mathematical modeling expands the potential gains from the OGTT in physiology and clinical research. Disadvantages include individual differences in the rate of glucose absorption that modify insulin responses, imperfect control of the glycemic stimulus, and poor intraindividual reproducibility. Available research suggests the OGTT provides valuable information about the development of impaired glycemic control and β-cell function in obese youth along the spectrum of glucose tolerance.

Retinoid X receptor α [RXRα; nuclear receptor (NR)2B1] is a crucial regulator in the expression of a broad array of hepatic genes under both normal and pathologic conditions. During inflammation, RXRα undergoes rapid post-translational modifications, including c-Jun N-terminal kinase (JNK)-mediated phosphorylation, which correlates with a reduction in RXRα function. A small ubiquitin-like modifier (SUMO) acceptor site was recently described in human RXRα, yet the contributors, regulators, and consequences of SUMO-RXRα are not well understood. Inflammation and other stressors alter nuclear receptor function in liver and induce SUMOylation of several NRs as part of proinflammatory gene regulation, but linkages between these two pathways in liver, or for RXRα directly, remain unexplored. We sought to determine if inflammation induces SUMOylation of RXRα in human liver-derived (HuH-7) cells. Lipopolysaccharide, interleukin-1β, and tumor necrosis factor α (TNFα) rapidly and substantially stimulated SUMOylation of RXRα. Two RXRα ligands, 9-cis retinoic acid (9cRA) and LG268, induced SUMOylation of RXRα, whereas both inflammation- and ligand-induced SUMOylation of RXRα require the K108 residue. Pretreatment with 1,9-pyrazoloanthrone (SP600125), a potent JNK inhibitor, abrogates TNFα- and 9cRA-stimulated RXRα SUMOylation. Pretreatment with SUMOylation inhibitors markedly augmented basal expression of several RXRα-regulated hepatobiliary genes. These results indicate that inflammatory signaling pathways rapidly induce SUMOylation of RXRα, adding to the repertoire of RXRα molecular species in the hepatocyte that respond to inflammation. SUMOylation, a newly described post-translational modification of RXRα, appears to contribute to the inflammation-induced reduction of RXRα-regulated gene expression in the liver that affects core hepatic functions, including hepatobiliary transport.