George S. Jeha

The nuclear orphan receptor COUP-TFII plays an essential role in adipogenesis, glucose homeostasis, and energy metabolism.

Adipose tissue development and function play a central role in the pathogenesis and pathophysiology of metabolic syndromes. Here, we show that chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) plays a pivotal role in adipogenesis and energy homeostasis. COUP-TFII is expressed in the early stages of white adipocyte development. COUP-TFII heterozygous mice (COUP-TFII(+/-)) have much less white adipose tissue (WAT) than wild-type mice (COUP-TFII(+/+)). COUP-TFII(+/-) mice display a decreased expression of key regulators for WAT development. Knockdown COUP-TFII in 3T3-L1 cells resulted in an increased expression of Wnt10b, while chromatin immunoprecipitation analysis revealed that Wnt10b is a direct target of COUP-TFII. Moreover, COUP-TFII(+/-) mice have increased mitochondrial biogenesis in WAT, and COUP-TFII(+/-) mice have improved glucose homeostasis and increased energy expenditure. Thus, COUP-TFII regulates adipogenesis by regulating the key molecules in adipocyte development and can serve as a target for regulating energy metabolism.

Activation of Cyclic AMP Signaling Leads to Different Pathway Alterations in Lesions of the Adrenal Cortex Caused by Germline PRKAR1A Defects versus Those due to Somatic GNAS Mutations

CONTEXT The overwhelming majority of benign lesions of the adrenal cortex leading to Cushing syndrome are linked to one or another abnormality of the cAMP or protein kinase pathway. PRKAR1A-inactivating mutations are responsible for primary pigmented nodular adrenocortical disease, whereas somatic GNAS activating mutations cause macronodular disease in the context of McCune-Albright syndrome, ACTH-independent macronodular hyperplasia, and, rarely, cortisol-producing adenomas. OBJECTIVE AND DESIGN The whole-genome expression profile (WGEP) of normal (pooled) adrenals, PRKAR1A- (3) and GNAS-mutant (3) was studied. Quantitative RT-PCR and Western blot were used to validate WGEP findings. RESULTS MAPK and p53 signaling pathways were highly overexpressed in all lesions against normal tissue. GNAS-mutant tissues were significantly enriched for extracellular matrix receptor interaction and focal adhesion pathways when compared with PRKAR1A-mutant (fold enrichment 3.5, P < 0.0001 and 2.1, P < 0.002, respectively). NFKB, NFKBIA, and TNFRSF1A were higher in GNAS-mutant tumors (P < 0.05). Genes related to the Wnt signaling pathway (CCND1, CTNNB1, LEF1, LRP5, WISP1, and WNT3) were overexpressed in PRKAR1A-mutant lesions. CONCLUSION WGEP analysis revealed that not all cAMP activation is the same: adrenal lesions harboring PRKAR1A or GNAS mutations share the downstream activation of certain oncogenic signals (such as MAPK and some cell cycle genes) but differ substantially in their effects on others.

Newer therapeutic options for children with diabetes mellitus: theoretical and practical considerations

Abstract:  Recent studies in adult patients with type 1 diabetes mellitus (T1DM) and T2DM have examined the potential utility, benefits, and side effects of agents that augment insulin secretion after oral ingestion of nutrients in comparison with intravenous nutrient delivery, the so‐called incretins. Two families of incretin‐like substances are now approved for use in adults. Glucagon‐like peptide‐1 (GLP‐1) or agents that bind to its receptor (exenatide, Byetta®) or agents that inhibit its destruction [dipeptidyl peptidase‐IV (DPP‐IV) inhibitors, Vildagliptin] improve insulin secretion, delay gastric emptying, and suppress glucagon secretion while decreasing food intake without increasing hypoglycemia. Pramlintide, a synthetic amylin analog, also decreases glucagon secretion and delays gastric emptying, improves hemoglobin A1c (HbA1C), and facilitates weight reduction without causing hypoglycemia. We review the historical discovery of these agents, their physiology applications, and their current applications. Remarkably, only one or two studies have been reported in children. Pediatricians caring for children with T1DM and T2DM should become familiar with these agents and investigate their applicability, as they seem likely to enhance our therapeutic armamentarium to treat children with diabetes mellitus.

Neonatal Diabetes Mellitus: Patient Reports and Review of Current Knowledge and Clinical Practice

Neonatal diabetes mellitus (NDM) is a rare disease reported to have an incidence of one in 400,000 to 500,000 live births. The disorder may be more common as it is not routinely considered a diagnostic possibility by many neonatologists who may routinely use insulin to treat neonatal hyperglycemia. NDM can be grouped into two distinct clinical entities--transient and permanent--based on certain features detailed herein; however, distinction between the two categories can only be definitely made in hindsight. Treatment is with insulin; however, determining the correct dose and method of delivery is often challenging, given the sensitivity of neonates to insulin and the risk of hypoglycemia. We report the successful use of Glargine insulin in the treatment of three infants with NDM, review the recent discoveries, and discuss guidelines for the care of newborns with NDM.

Congenital hypothyroidism in association with Caroli's disease and autosomal recessive polycystic kidney disease: patient report.

Autosomal recessive polycystic kidney disease (ARPKD) is an important renal disease of childhood. Congenital hypothyroidism has been associated with glomerulocystic kidney disease, but to date no association has been made with ARPKD. To our knowledge this is the first reported case of congenital hypothyroidism in an infant with ARPKD.

Total parenteral nutrition associated with severe insulin resistance following hematopoietic stem cell transplantation in patients with hemophagocytic syndrome: report on two cases

Suresh D, Athanassaki I, Jeha GS, Heptulla RA. Total parenteral nutrition associated with severe insulin resistance following hematopoietic stem cell transplantation in patients with hemophagocytic syndrome: report on two cases.

Persistent Diabetes Mellitus Postadrenalectomy in Neonatal McCune-Albright Syndrome:

Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits noncommercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Brief Report

X-linked Hypophosphatemic Rickets Associated With Respiratory Failure

We report a 5-year-old girl who presented to our emergency room with respiratory arrest and limb deformities and was subsequently diagnosed with X-linked hypophosphatemic rickets. On normalization of the serum phosphorus concentration, her respiratory distress resolved, illustrating that untreated X-linked hypophosphatemic rickets can lead to life-threatening respiratory distress.