Charlotte M. Boney

Severe endocrine and nonendocrine manifestations of the McCune-Albright syndrome associated with activating mutations of stimulatory G protein Gs**

McCune-Albright syndrome (MCAS) is a sporadic disease classically including polyostotic fibrous dysplasia, café au lait spots, sexual precocity, and other hyperfunctional endocrinopathies. An activating missense mutation in the gene for the alpha subunit of GS, the G protein that stimulates cyclic adenosine monophosphate formation, has been reported to be present in these patients. The mutation is found in variable abundance in different affected endocrine and nonendocrine tissues, consistent with the mosaic distribution of abnormal cells generated by a somatic cell mutation early in embryogenesis. We describe three patients with MCAS who had profound endocrine and nonendocrine disease and who died in childhood. Two of the patients were severely ill neonates whose complex symptoms did not immediately suggest MCAS. A mutation of residue Arg201 of GS alpha was found in affected tissues from all three children. A review of the literature and unpublished case histories emphasizes the existence of other patients with severe and unusual clinical manifestations. We conclude that the manifestations of MCAS are more extensive than is generally appreciated, and may include hepatobiliary disease, cardiac disease, other nonendocrine abnormalities, and sudden or premature death.

Gestational diabetes: The forerunner for the development of maternal and childhood obesity and metabolic syndrome?

Objective. To examine the risk of obesity and metabolic syndrome in women with a history of gestational diabetes mellitus and in offspring born to mothers with gestational diabetes mellitus. Methods. A review of studies examining the development of obesity, hypertension, metabolic abnormalities, metabolic syndrome, and type II diabetes in mothers with a history of gestational diabetes mellitus and control mothers, and offspring of mothers with a history of gestational diabetes and control mothers. Results. Longitudinal studies demonstrate that women with a prior history of gestational diabetes mellitus and obesity are at significantly greater risk of developing metabolic syndrome than mothers with no history of gestational diabetes or obesity. The development of metabolic syndrome in children with increasing age is related to maternal gestational diabetes mellitus, maternal glycemia in the 3rd trimester, maternal obesity, neonatal macrosomia, and childhood obesity. Conclusions. The current prevalence of obesity in both adults and children and associated disorders of blood pressure and lipid metabolism, suggest a perpetuating cycle of increasing obesity, insulin resistance, and abnormal lipid metabolism, which has ominous consequences for future generations.

Brain growth retardation due to the expression of human insulin like growth factor binding protein-1 in transgenic mice: an in vivo model for the analysis of igf function in the brain

Three lines of transgenic (Tg) mice carrying a fusion gene linking the mouse metallothionein-I promoter to a cDNA encoding human insulin-like growth factor binding protein-1 (hIGFBP-1) were found to express the transgene in brain. As judged by comparing Tg brain weights to those of non-transgenic littermates, adult hemizygotic Tg mice of each line exhibited brain growth retardation (16.2%, 14.4% and 8.1% reductions in weight, respectively in each line). In two lines, total brain DNA and protein content were decreased. Further analysis indicated that the brain growth retardation was manifested in the second week of postnatal life. Given that the insulin-like growth factors (IGFs) stimulate cell proliferation and/or survival in neural cultures and that hIGFBP-1, when present in a molar excess, inhibits IGF interactions with their cell surface receptors, the brain growth retardation in hIGFBP-1 Tg mice likely results from hIGFBP-1 inhibition of IGF-stimulated growth-promoting actions. These hIGFBP-1 Tg mice should prove useful in defining IGF actions during postnatal brain maturation.

IGF-I Activation of the AKT Pathway Is Impaired in Visceral But Not Subcutaneous Preadipocytes from Obese Subjects

Obesity morbidity is associated with excess visceral adiposity, whereas sc adipose tissue is much less metabolically hazardous. Human abdominal sc preadipocytes have greater capacity for proliferation, differentiation, and survival than omental preadipocytes. IGF-I is a critical mediator of preadipocyte proliferation, differentiation, and survival through multiple signaling pathways. We investigated IGF-I action in primary cultures of human preadipocytes isolated from sc and omental adipose tissue of obese subjects. IGF-I-stimulated DNA synthesis was significantly lower in omental compared with sc preadipocytes. IGF-I phosphorylation of the IGF-I receptor and the ERK pathway was comparable in sc and omental cells. However, omental preadipocytes had decreased insulin receptor substrate (IRS)-1 protein associated with increased IRS-1-serine(636/639) phosphorylation and degradation. IGF-I-stimulated phosphorylation of AKT on serine(473) but not threonine(308) was decreased in omental cells, and activation of downstream targets, including S6Kinase, glycogen synthase kinase-3, and Forkhead box O1 was also impaired. CyclinD1 abundance was decreased in omental cells due to increased degradation. Over-expression of IRS-1 by lentivirus in omental preadipocytes increased IGF-I-stimulated AKT-serine(473) phosphorylation. The mammalian target of rapamycin (mTOR)-Rictor complex regulates phosphorylation of AKT-serine(473) in 3T3-L1 adipocytes, but knockdown of Rictor by lentivirus-delivered short hairpin RNA in sc preadipocytes did not affect AKT-serine(473) phosphorylation by IGF-I. These data reveal an intrinsic defect in IGF-I activation of the AKT pathway in omental preadipocytes from obese subjects that involves IRS-1 but probably not mTOR-Rictor complex. We conclude that impaired cell cycle regulation by AKT contributes to the distinct growth phenotype of preadipocytes in visceral fat of obese subjects.

EGF regulates survivin stability through the Raf-1/ERK pathway in insulin-secreting pancreatic β-cells

BackgroundPostnatal expansion of the pancreatic β-cell mass is required to maintain glucose homeostasis immediately after birth. This β-cell expansion is regulated by multiple growth factors, including glucose, insulin, insulin-like growth factor (IGF-1) and epidermal growth factor (EGF). These mitogens signal through several downstream pathways (AKT, ERK, STAT3, and JNK) to regulate the survival and proliferation of β-cells. Survivin, an oncofetal protein with both pro-proliferative and anti-apoptotic properties, is a known transcriptional target of both IGF-1 and EGF in cancer cells. Here, we analyzed the effects of the β-cell mitogens IGF-1 and EGF on survivin regulation in the established pancreatic β-cell model cell lines, MIN6 and INS-1 and in primary mouse islets.ResultsIn pancreatic β-cells, treatment with glucose, insulin, or EGF increased survivin protein levels at early time points. By contrast, no significant effects on survivin were observed following IGF-1 treatment. EGF-stimulated increases in survivin protein were abrogated in the presence of downstream inhibitors of the Raf-1/MEK/ERK pathway. EGF had no significant effect on survivin transcription however it prolonged the half-life of the survivin protein and stabilized survivin protein levels by inhibiting surviving ubiquitination.ConclusionsThis study defines a novel mechanism of survivin regulation by EGF through the Raf-1/MEK/ERK pathway in pancreatic β-cells, via prolongation of survivin protein half-life and inhibition of the ubiquitin-mediated proteasomal degradation pathway. This mechanism may be important for regulating β-cell expansion after birth.

Role of epidermal growth factor and ErbB2 receptors in 3T3-L1 adipogenesis.

Objective: Epidermal growth factor (EGF) stimulates proliferation in 3T3‐L1 preadipocytes, but EGF action in differentiation is less clear. EGF promotes differentiation at concentrations <1 nM but inhibits differentiation at higher concentrations, suggesting a dual role in adipogenesis. We hypothesized that differences in EGF receptor activation and downstream signaling mediate distinct biological effects of EGF at low vs. high abundance.

Inhibition of insulin-like growth factor-I mitogenic action by zinc chelation is associated with a decreased mitogen-activated protein kinase activation in RAT-1 fibroblasts

The mechanisms responsible for the resistance to the anabolic actions of IGF‐I induced by zinc deficiency are not understood. We showed that zinc chelation by DTPA (diethylenetriaminepenta‐acetic acid) inhibits [3H]thymidine incorporation stimulated by IGF‐I in Rat‐1 fibroblasts. This inhibition was specific of zinc chelation since it was prevented by the addition of zinc to DTPA. The stimulation of MAPK, which is crucial for the [3H]thymidine incorporation induced by IGF‐I in Rat‐1 cells, was partially blunted by DTPA. Therefore, the inhibition of the mitogenic action of IGF‐I in Rat‐1 fibroblasts by DTPA is potentially caused by decreased MAPK activation by IGF‐I.

Rare complications of pediatric diabetic ketoacidosis

The incidence of type 1 diabetes (T1D) among youth is steadily increasing across the world. Up to a third of pediatric patients with T1D present with diabetic ketoacidosis, a diagnosis that continues to be the leading cause of death in this population. Cerebral edema is the most common rare complication of diabetic ketoacidosis in children. Accordingly, treatment and outcome measures of cerebral edema are vastly researched and the pathophysiology is recently the subject of much debate. Nevertheless, cerebral edema is not the only sequela of diabetic ketoacidosis that warrants close monitoring. The medical literature details various other complications in children with diabetic ketoacidosis, including hypercoagulability leading to stroke and deep vein thrombosis, rhabdomyolysis, pulmonary and gastrointestinal complications, and long-term memory dysfunction. We review the pathophysiology, reported cases, management, and outcomes of each of these rare complications in children. As the incidence of T1D continues to rise, practitioners will care for an increasing number of pediatric patients with diabetic ketoacidosis and should be aware of the various systems that may be affected in both the acute and chronic setting.

Transient adrenal insufficiency in the premature newborn.

Purpose of reviewRelative adrenal insufficiency is a controversial phenomenon described in adults and children with critical illness, especially septic shock. In the past 2 decades, relative adrenal insufficiency has also been reported in the critically ill premature as well as term newborn. The present study will review the initial and more recent studies addressing adrenal insufficiency in the premature infant. Recent findingsStudies suggest that ‘relative adrenal insufficiency’ is a contributing factor to hemodynamic instability in the sick preterm newborn. Many ill preterm newborns have inappropriately low serum cortisol concentrations and respond to steroid administration. Adrenal insufficiency is transient and likely reflects normal adrenal physiology at younger gestational ages. There is no general consensus on its diagnosis, effective minimum dose for treatment and duration of treatment. SummaryMore large scale, multicenter, randomized, double-blind studies are needed to make the diagnosis of relative adrenal insufficiency and to determine the indication, dose, complications and outcome of glucocorticoid therapy.

A novel presentation of Addison disease: Hypoglycemia unawareness in an adolescent with insulin-dependent diabetes mellitus☆☆☆★

A 16-year-old boy with insulin-dependent diabetes mellitus (IDDM) and a history of marginal glycemic control had severe hypoglycemia unawareness and a marked decrease in insulin requirement. His counterregulatory hormone response at the time of hypoglycemia suggested adrenocortical and adrenomedullary dysfunction. Further testing confirmed Addison disease. The patients hypoglycemia unawareness was reversed by glucocorticoid replacement, although the plasma epinephrine response to hypoglycemia remained undetectable.