Mark A. Sperling

Measurement of “True” Glucose Production Rates in Infancy and Childhood with 6,6-Dideuteroglucose

“New” glucose production has been measured in 54 infants and children for the first time by continuous three-to-four-hour infusion of the safe, nonradioactive tracer 6,6-dideuterogiucose. The use of combined gas chromatography-mass spectrometry with monitoring of selected ions allowed deuterium enrichment in blood glucose to be measured on microliter samples with an error of less than 2 per cent. In the young child, glucose production increased in a slightly curvilinear manner from 1 kg. to 25 kg. body weight, when it reached 140 mg. per minute, almost the adult value of 173 mg. per minute (2.28 ± 0.23 mg./kg. ·min., mean ± S.E.). Normalized for weight, glucose production in premature infants was 5.46 ± 0.31 mg./kg. ·min., in term neonates averaged 6.07 ± 0.46 mg./kg. · min., in children below the age of six years was 7.1 ± 0.27 mg./kg.· min., and in late childhood averaged 5.4 ± 0.28 mg./ kg.· min. Relative to estimated brain weight, however, glucose production was essentially linear from the 1-kg. premature infant to the 80-kg. adult. These data, the first measurements of “new” glucose production in childhood, suggest that brain size may be a principal determinant of those factors that regulate hepatic glucose output throughout life.

ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents

Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (TIDM). Mortality is predominantly related to the occurrence of cerebral oedema; only a minority of deaths in DKA are attributed to other causes. Cerebral oedema occurs in about 0.3–1% of all episodes of DKA, and its aetiology, pathophysiology, and ideal method of treatment are poorly understood. There is debate as to whether physicians treating DKA can prevent or predict the occurrence of cerebral oedema, and the appropriate site(s) for children with DKA to be managed. There is agreement that prevention of DKA and reduction of its incidence should be a goal in managing children with diabetes.

Diabetic ketoacidosis in children and adolescents with diabetes

aDivision of Endocrinology, Children’s Hospital Boston, MA, USA; bSchool of Women’s and Children’s Health, University of New South Wales, Sydney, Australia; cUniversity of Toronto, The Hospital for Sick Children, Toronto, Canada; dDepartment of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK; eDepartment of Paediatrics, John Radcliffe Hospital, Oxford, UK; fEndocrinology Service Department of Paediatric Medicine, KK Children’s Hospital, Singapore; gDivision of Endocrinology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; hDepartment of Pediatric Endocrinology, Children’s Hospital, University of Pittsburgh, PA, USA; iDepartment of Pediatrics, Uddevalla Hospital, Uddevalla, Sweden

Diabetic Ketoacidosis in Infants, Children, and Adolescents

The adage “A child is not a miniature adult” is most appropriate when considering diabetic ketoacidosis (DKA). The fundamental pathophysiology of this potentially life-threatening complication is the same as in adults. However, the child differs from the adult in a number of characteristics. 1 ) The younger the child, the more difficult it is to obtain the classical history of polyuria, polydipsia, and weight loss. Infants and toddlers in DKA may be misdiagnosed as having pneumonia, reactive airways disease (asthma), or bronchiolitis and therefore treated with glucocorticoids and/or sympathomimetic agents that only compound and exacerbate the metabolic derangements. Because the diagnosis of diabetes is not suspected as it evolves, the duration of symptoms may be longer, leading to more severe dehydration and acidosis and ultimately to obtundation and coma. Even in developed countries, some 15–70% of all newly diagnosed infants and children with diabetes present with DKA (1–8). Generally, the rates of DKA are inversely proportional to rates of diabetes in that community, but throughout the U.S., the overall rates of DKA at diagnosis have remained fairly constant at ∼25% (6). DKA, defined by blood bicarbonate 14 years but did not differ significantly by sex or ethnicity (6). 2 ) The higher basal metabolic rate and large surface area relative to total body mass in children requires greater precision in delivering fluids and electrolytes. The degree of dehydration is expressed as a function of body weight, i.e., 10% dehydration implies 10% loss of total body weight as water. However, the calculation of basal requirements, although a constant per unit …

Liver-specific Deletion of the Growth Hormone Receptor Reveals Essential Role of Growth Hormone Signaling in Hepatic Lipid Metabolism

Growth hormone (GH) plays a pivotal role in growth and metabolism, with growth promotion mostly attributed to generation of insulin-like growth factor I (IGF-I) in liver or at local sites of GH action, whereas the metabolic effects of GH are considered to be intrinsic to GH itself. To distinguish the effects of GH from those of IGF-I, we developed a Cre-lox-mediated model of tissue-specific deletion of the growth hormone receptor (GHR). Near total deletion of the GHR in liver (GHRLD) had no effect on total body or bone linear growth despite a >90% suppression of circulating IGF-I; however, total bone density was significantly reduced. Circulating GH was increased 4-fold, and GHRLD displayed insulin resistance, glucose intolerance, and increased circulating free fatty acids. Livers displayed marked steatosis, the result of increased triglyceride synthesis and decreased efflux; reconstitution of hepatic GHR signaling via adenoviral expression of GHR restored triglyceride output to normal, whereas IGF-I infusion did not correct steatosis despite restoration of circulating GH to normal. Thus, with near total absence of circulating IGF-I, GH action at the growth plate, directly and via locally generated IGF-I, can regulate bone growth, but at the expense of diabetogenic, lipolytic, and hepatosteatotic consequences. Our results indicate that IGF-I is essential for bone mineral density, whereas hepatic GH signaling is essential to regulate intrahepatic lipid metabolism. We propose that circulating IGF-I serves to amplify the growth-promoting effects of GH, while simultaneously dampening the catabolic effects of GH.

Diabetic ketoacidosis and hyperglycemic hyperosmolar state

aDivision of Endocrinology, Boston Children’s Hospital, Boston, MA, USA; bBarts Health NHS Trust, Royal London Hospital, London, UK; cInstitute of Endocrinology and Diabetes, The Children’s Hospital at Westmead; School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia; dOxfordshire Children’s Diabetes Service, Oxford Children’s Hospital, Oxford, UK; eSection of Endocrinology, University of California, Davis School of Medicine, Sacramento, CA, USA; fPediatric Endocrinology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India; gEndocrinology Service, Department of Paediatrics, KK Women’s and Children’s Hospital, Singapore; hDepartment of Paediatrics and Child Health, University of Nairobi, Nairobi, Kenya ; iDepartment of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; jDivision of Endocrinology, Diabetes and Metabolism, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA and kDepartment of Pediatrics, NU Hospital Group, Uddevalla and Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden

Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice

Skeletal muscle development, nutrient uptake, and nutrient utilization is largely coordinated by growth hormone (GH) and its downstream effectors, in particular, IGF-1. However, it is not clear which effects of GH on skeletal muscle are direct and which are secondary to GH-induced IGF-1 expression. Thus, we generated mice lacking either GH receptor (GHR) or IGF-1 receptor (IGF-1R) specifically in skeletal muscle. Both exhibited impaired skeletal muscle development characterized by reductions in myofiber number and area as well as accompanying deficiencies in functional performance. Defective skeletal muscle development, in both GHR and IGF-1R mutants, was attributable to diminished myoblast fusion and associated with compromised nuclear factor of activated T cells import and activity. Strikingly, mice lacking GHR developed metabolic features that were not observed in the IGF-1R mutants, including marked peripheral adiposity, insulin resistance, and glucose intolerance. Insulin resistance in GHR-deficient myotubes derived from reduced IR protein abundance and increased inhibitory phosphorylation of IRS-1 on Ser 1101. These results identify distinct signaling pathways through which GHR regulates skeletal muscle development and modulates nutrient metabolism.

Cardiac septal hypertrophy in hyperinsulinemic infants

One infant with nesidioblastosis, and five of 18 infants of diabetic mothers had echocardiographically determined septal hypertrophy (greater than or equal to 6 mm). No correlation was found between the septal hypertrophy and the presence of hypocalcemia, polycythemia, birth asphyxia, or other observed clinical findings. All of the infants with septal hypertrophy, however, had profound hypoglycemia shortly after birth in contrast to those infants without septal hypertrophy. Macrosomic IDM have intrauterine hyperglycemia and hyperinsulinemia. The presence of profound neonatal hypoglycemia is consistent with the metabolic effects of significant neonatal hyperinsulinemia which is also present in the fetus. Infants with nesidioblastosis also have fetal hyperinsulinemia. Recent investigations have suggested an important role for insulin in the developing heart since it is rich in insulin receptors and contains marked insulin degrading capacity. Although fetal hyperglycemia has been suggested as the cause of septal hypertrophy in IDM, we hypothesize that fetal hyperinsulinemia contributes directly to the spinal hypertrophy.

Spontaneous and Amino Acid-Stimulated Glucagon Secretion in the Immediate Postnatal Period: RELATION TO GLUCOSE AND INSULIN

The extent and significance of spontaneous glucagon secretion in the immediate postnatal period were investigated in groups of normal infants studied cross-sectionally and longitudinally. Arginine-and alanine-stimulated glucagon secretion was also studied. Plasma glucagon concentrations were correlated with prevailing glucose and insulin concentrations. The characteristic fall in blood glucose, reaching a nadir within hours of birth, was associated with a significant increase in glucagon concentration. Despite persistence of relative glucopenia, glucagon did not change appreciably between 2 and 24 h of life. A further significant elevation in glucagon concentration occurred from day 1 to day 3 of life associated with a return of glucose to euglycemic levels. In contrast to the sluggishness of pancreatic glucagon release, glucagon-like immunoreactivity rose markedly to mean levels of approximately 2,000 pg/ml after introduction of formula feeding. No significant changes in insulin levels were observed in these studies. Arginine infusion via an umbilical vein catheter into six infants within 6 h of birth elicited a brisk, almost threefold increment in glucagon concentration (from 339+/-85 to 940+/-254 pg/ml) in blood obtained from, or close to, the portal circulation. Bolus injection of alanine (1 mmol/kg) into a peripheral vein to six infants resulted in significant increments in glucagon (mean maximal, 128 pg/ml) as well as glucose and insulin. The observations suggest that spontaneous glucagon secretion may be an important factor in neonatal glucose homeostasis. Secretion seems more brisk in response to amino acid stimulation than to a falling glucose concentration.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation presenting in childhood

OBJECTIVE. The goal was to characterize the phenotype and potential candidate genes responsible for the syndrome of late-onset central hypoventilation with hypothalamic dysfunction. METHODS. Individuals with late-onset central hypoventilation with hypothalamic dysfunction who were referred to Rush University Medical Center for clinical or genetic assessment in the past 3 years were identified, and medical charts were reviewed to determine shared characteristics of the affected subjects. Blood was collected for genetic testing of candidate genes (PHOX2B, TRKB, and BDNF) and for high-resolution conventional G-banding, subtelomeric fluorescent in situ hybridization, and comparative genomic hybridization analysis. A subset of these children were studied in the Pediatric Respiratory Physiology Laboratory at Rush University Medical Center. RESULTS. Twenty-three children with what we are now naming rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation were identified. Comprehensive medical charts and blood for genetic testing were available for 15 children; respiratory physiology studies were performed at Rush University Medical Center on 9 children. The most characteristic manifestations were the presentation of rapid-onset obesity in the first 10 years of life (median age at onset: 3 years), followed by hypothalamic dysfunction and then onset of symptoms of autonomic dysregulation (median age at onset: 3.6 years) with later onset of alveolar hypoventilation (median age at onset: 6.2 years). Testing of candidate genes (PHOX2B, TRKB, and BDNF) revealed no mutations or rare variants. High-resolution chromosome analysis, comparative genomic hybridization, and subtelomeric fluorescent in situ hybridization results were negative for the 2 patients selected for those analyses. CONCLUSIONS. We provide a comprehensive description of the clinical spectrum of rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation in terms of timing and scope of symptoms, study of candidate genes, and screening for chromosomal deletions and duplications. Negative PHOX2B sequencing results demonstrate that this entity is distinct from congenital central hypoventilation syndrome.