The mechanism of insulin dysregulation in children with hyperinsulinism associated with inactivating mutations of short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) was examined in mice with a knock-out of the hadh gene (hadh ؊/؊ ). Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infants and children (1). Six genetic loci have been associated with the disorder. The most common of these disorders are due to inactivating mutations of the sulfonylurea receptor 1 (SUR1) 2 and Kir6.2 subunits of the ␤-cell ATP-dependent potassium (K ATP ) channel or to activating mutations of glutamate dehydrogenase (GDH) and glucokinase. Recently, several children have been described with a recessively inherited form of hyperinsulinism that is associated with deficiency of a mitochondrial fatty acid ␤-oxidation enzyme, short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) encoded by the HADH gene on 4q (2-4). SCHAD catalyzes the third step in the ␤-oxidation cycle for medium and short-chain 3-hydroxy fatty acyl-CoAs. Children afflicted with SCHAD deficiency have recurrent episodes of hypoglycemia that can be prevented by treatment with diazoxide (2, 3) and also have characteristic accumulations of fatty acid metabolites, including plasma 3-hydroxybutyrylcarnitine and urinary 3-hydroxyglutaric acid (2, 3). This form of abnormal insulin regulation is unique, because other genetic disorders of mitochondrial fatty acid oxidation do not cause hyperinsulinism (5). In addition, the genetic defect in SCHAD deficiency is expected to impair, rather than increase, the production of ATP, which normally serves as the triggering signal for insulin release. An important clue to the mechanism of insulin dysregulation in SCHAD deficiency has been recently provided by the report * This work was supported, in whole or in part, by National Institutes of Health Grants DK53012 (to C. A. S.), DK22122 (to F. M. M.), DK 53761 (to I. N.), HL075421 (to A. W. S.). This work was also supported by a fellowship award from Society for Inherited Metabolic Disorders (to A. P.

Background: ␤-Cells regulate ␣-cells via paracrine mechanisms. Results: A GABA shunt defect impairs glucose suppression of glucagon secretion in diabetic human islets. Glucagon secretion is inhibited by ␥-hydroxybutyrate produced by ␤-cells but is stimulated by glycine via plasma membrane receptors. Conclusion: ␥-Hydroxybutyrate and glycine serve as counterbalancing receptor-based regulators of glucagon secretion. Significance: Amino acids and their metabolites are central regulators of ␣-cell function.

Greater PTH and 1,25(OH)₂D and lower calcium concentrations were independently associated with baseline and progressive cortical deficits in childhood CKD. Lower CortBMD Z-score was associated with increased fracture risk.

Background/Aims: In a family with congenital hyperinsulinism (HI), first described in the 1950s by McQuarrie, we examined the genetic locus and clinical phenotype of a novel form of dominant HI. Methods: We surveyed 25 affected individuals, 7 of whom participated in tests of insulin dysregulation (24-hour fasting, oral glucose and protein tolerance tests). To identify the disease locus and potential disease-associated mutations we performed linkage analysis, whole transcriptome sequencing, whole genome sequencing, gene capture, and next generation sequencing. Results: Most affecteds were diagnosed with HI before age one and 40% presented with a seizure. All affecteds responded well to diazoxide. Affecteds failed to adequately suppress insulin secretion following oral glucose tolerance test or prolonged fasting; none had protein-sensitive hypoglycemia. Linkage analysis mapped the HI locus to Chr10q21-22, a region containing 48 genes. Three novel noncoding variants were found in hexokinase 1 (HK1) and one missense variant in the coding region of DNA2. Conclusion: Dominant, diazoxide-responsive HI in this family maps to a novel locus on Chr10q21-22. HK1 is the more attractive disease gene candidate since a mutation interfering with the normal suppression of HK1 expression in beta-cells could readily explain the hypoglycemia phenotype of this pedigree.

Background Vitamin D-binding protein (DBP) and catabolism have not been examined in childhood chronic kidney disease (CKD). Methods Serum vitamin D [25(OH)D, 1,25(OH)2D, 24,25(OH)2D], DBP, intact parathyroid hormone (iPTH), and fibroblast growth factor-23 (FGF23) concentrations were measured in 148 participants with CKD stages 2–5D secondary to congenital anomalies of the kidney/urinary tract (CAKUT), glomerulonephritis (GN), or focal segmental glomerulosclerosis (FSGS). Free and bioavailable 25(OH)D were calculated using total 25(OH)D, albumin and DBP. Results All vitamin D metabolites were lower with more advanced CKD (p<0.001) and glomerular diagnoses (p≤0.002). Among non-dialysis participants, DBP was lower in FSGS vs. other diagnoses (FSGS-dialysis interaction p=0.02). Winter season, older age, FSGS and GN, and higher FGF23 were independently associated with lower free and bioavailable 25(OH)D. Black race was associated with lower total 25(OH)D and DBP, but not free or bioavailable 25(OH)D. 24,25(OH)2D was the vitamin D metabolite most strongly associated with iPTH. Lower 25(OH)D, black race, greater CKD severity, and higher iPTH were independently associated with lower 24,25(OH)2D, while higher FGF23 and GN were associated with greater 24,25(OH)2D. Conclusions Children with CKD exhibit altered catabolism and concentrations of DBP and free and bioavailable 25(OH)D, and there is an important impact of their underlying disease.