[Transition in diabetology]. / Transition en diabétologie.

For patients with type I diabetes, transition from pediatric to adult care is a challenge due to complex treatment requirements and the physical, psychological and social changes of adolescence. Members of the care team must recognize that while these emerging adults need to develop self-management skills, this may conflict at times with the developmentally appropriate desire for increasing autonomy. The role of nursing in coordinating a successful transition is critical for maintaining continuity of patient-centered care that responds to the specific needs of these young adults.

Widespread intracranial calcifications in the follow-up of a patient with cartilage-hair hypoplasia--anauxetic dysplasia spectrum disorder: a coincidental finding?

BACKGROUND/PURPOSE: Intracranial calcifications have been identified in many neurological disorders. To our knowledge, however, such findings have not been described in cartilage-hair hypoplasia - anauxetic dysplasia spectrum disorders (CHH-AD), a group of conditions characterized by a wide spectrum of clinical manifestations. METHODS/RESULTS: We report a 22-year old female patient, diagnosed with this disorder during her first year of life, and in whom bilateral intracranial calcifications (frontal lobes, basal ganglia, cerebellar dentate nuclei) were discovered by brain MRI at the age of 17 years. CONCLUSION: The etiology of this finding remains unclear. Some causes of such deposits can be of a reversible nature, thus prompting early recognition although their consequences on clinical outcome remain mostly unknown.

Decreased bone turnover in children and adolescents with well controlled type 1 diabetes.

AIM: Osteoporosis is a common long-term complication of type 1 diabetes (T1DM). We aimed to determine whether bone mineral density (BMD) and turnover are already altered during childhood. PATIENTS AND METHODS: We recruited 27 T1DM children and 32 controls (age 10.5 +/- 2.5 yr.) and measured BMD (dual-energy x-ray absorptiometry); bone biomarkers levels (osteocalcin: OC; procollagen type 1 propeptides amino-terminal: PINP; crosslinking telopeptides of type 1 collagen C-terminal: CTX), glycated hemoglobin (HbA1c), dietary intake and physical activity. RESULTS: Patients with T1DM had lower levels of OC (70.3 +/- 3.3 vs 105.3 +/- 6.8), PINP (556.4 +/- 47.6 vs 716.3 +/- 53.8), CTX(0.97 +/- 0.07 vs 1.20 +/- 0.08), physical activity, and calcium intake. Biomarkers were negatively correlated with HbA1c. Though, BMD was similar among groups and not related to HbA1c, disease duration, physical activity or dietary intakes. CONCLUSIONS: Bone turnover is altered in T1DM children, whereas BMD remains normal during growth. Physical activity and optimal calcium intakes may improve bone metabolism and delay osteoporosis.

Modeling intrauterine growth retardation in rodents: Impact on pancreas development and glucose homeostasis.

Fetal adverse environment, such as insufficient maternal nutrition, placental insufficiency and stress, alters organ development and leads to poor fetal growth, also called intrauterine growth retardation (IUGR). IUGR is associated with an increased risk of perinatal mortality and morbidity as well as late-onset metabolic diseases, such as obesity, diabetes and hypertension in adulthood. In the rodent model, IUGR can be induced by fetal caloric restriction, fetal protein restriction, by exposure to high levels of glucocorticoids or by restricted placental blood supply. Such experimental IUGR models show a decreased beta cell mass and lower pancreatic insulin content. Recent research has provided an insight into the mechanisms responsible for the loss of beta cells. Here we review models that give further details about the molecular determinants of fetal and postnatal pancreatic islet development that are required to understand the consequences of fetal insults.

[The diabetic child and the specifics of insulin therapy]. / L'enfant diabétique et les spécificités de son traitement insulinique.

The incidence of diabetes type I has increased considerably in young children with an annual increase in Switzerland of 23,8% over the last ten years. The development of rapid acting and long acting analogues allowed a significant progress in treatment. Multiple daily insulin injections together with carbohydrate counting as well as continuous subcutaneous insulin infusion (CSII) improved the quality of life and led to an increased daily flexibility. The incidence of severe hypoglycaemic events has decreased at the same time metabolic control improved. The development of interstitial glucose measurement (online) coupled to the insulin pump represents a step further towards the artificial pancreas. The new therapeutic strategies of immunomodulation will hopefully lead to secondary and tertiary prevention of diabetes.

[Epigenetic origin of diabetes and growth disorders]. / Rô1e de l'epigenetique dans le diabète et la croissance.

The understanding of genomic imprinting has made us realize that maternal and paternal contributions to the embryo are different. Disturbances during the imprinting process may lead to different pathologies due to an imbalance of gene expression either maternally or paternally derived. Known epigenetic diseases such as neonatal diabetes, growth retardation or overgrowth syndromes as well as cancer are better understood. It has become clear that environmental factors can be at the origin of such epigenetic changes. Careful analysis and diagnosis of epigenetic diseases are important for patient treatment and outcome.

[Growth hormone treatment: pediatric to adult clinic transition]. / Traitement par hormone de croissance: phase de transition de l'enfance à l'âge adulte.

The diagnosis of GH deficiency is difficult to establish: clinical, radiological and hormonal data are combined to suspect the disease. GH stimulation tests are an essential part of the evaluation, although the cut-off values are determined arbitrarily. There are different stimulation tests. Their use depends on the patient's age. Once the diagnosis is ascertained, the treatment is started and maintened until the end of statural growth. The persistence of GH deficiency needs to be confirmed during the transition phase. If required, GH treatment can be continued until the achievement of peak bone mass. Thereafter the benefit of continuing GH treatment are mainly related to the quality of life. The long term effects on cardiovascular morbidity/mortality are not demonstrated.

Programming of the pancreas.

The pancreas, as most of the digestive tract, derives from the endoderm. Differentiation of these early gut endoderm cells into the endocrine cells forming the pancreatic islets of Langerhans depends on a cascade of gene activation events. These are controlled by different classes of transcription factors including the homeodomain, the basic helix-loop-helix (bHLH) and the winged helix proteins. Recently, considerable progress has been made delineating this cascade. The present review focuses on the role of the different transcription factors during pancreas development, with a particular emphasis on the newly identified bHLH transcription factor neurogenin3.

Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas.

Most insulin-producing beta-cells in the fetal mouse pancreas arise during the secondary transition, a wave of differentiation starting at embryonic day 13. Here, we show that disruption of homeobox gene Nkx6.1 in mice leads to loss of beta-cell precursors and blocks beta-cell neogenesis specifically during the secondary transition. In contrast, islet development in Nkx6. 1/Nkx2.2 double mutant embryos is identical to Nkx2.2 single mutant islet development: beta-cell precursors survive but fail to differentiate into beta-cells throughout development. Together, these experiments reveal two independently controlled pathways for beta-cell differentiation, and place Nkx6.1 downstream of Nkx2.2 in the major pathway of beta-cell differentiation.

beta-cell transcription factors and diabetes: no evidence for diabetes-associated mutations in the gene encoding the basic helix-loop-helix transcription factor neurogenic differentiation 4 (NEUROD4) in Japanese patients with MODY.

The basic helix-loop-helix (bHLH) family of transcription factors plays an important role in the normal development and function of the endocrine pancreas. Heterozygous mutations in the gene encoding one member of this family, NeuroD1/BETA2, are associated with a monogenic form of diabetes that resembles maturity-onset diabetes of the young (MODY) in many respects. This result prompted us to screen the genes encoding related bHLH transcription factors that are also expressed in pancreatic islets for diabetes-associated mutations. We have screened 57 unrelated Japanese subjects with a clinical diagnosis of MODY for mutations in the NeuroD4/Math-3/ATH-3 gene (NEUROD4). This analysis revealed seven frequent polymorphisms that were not associated with MODY, including five in the 5'-untranslated region (UTR) (-477G/A, -436delA, -324delT, -107insTTTT, and -104T/C [cDNA sequences]) and two in the 3'-UTR (1027C/T and 1076C/A). A missense mutation, K68T (203A/C), was found in a heterozygous state in one MODY subject and two nondiabetic subjects. The results of our study suggest that genetic variation in NEUROD4 is not a common cause of MODY in Japanese.

Expression of neurogenin3 reveals an islet cell precursor population in the pancreas.

Differentiation of early gut endoderm cells into the endocrine cells forming the pancreatic islets of Langerhans depends on a cascade of gene activation events controlled by transcription factors including the basic helix-loop-helix (bHLH) proteins. To delineate this cascade, we began by establishing the position of neurogenin3, a bHLH factor found in the pancreas during fetal development. We detect neurogenin3 immunoreactivity transiently in scattered ductal cells in the fetal mouse pancreas, peaking at embryonic day 15.5. Although not detected in cells expressing islet hormones or the islet transcription factors Isl1, Brn4, Pax6 or PDX1, neurogenin3 is detected along with early islet differentiation factors Nkx6.1 and Nkx2.2, establishing that it is expressed in immature cells in the islet lineage. Analysis of transcription factor-deficient mice demonstrates that neurogenin3 expression is not dependent on neuroD1/BETA2, Mash1, Nkx2.2, Nkx6.1, or Pax6. Furthermore, early expression of neurogenin3 under control of the Pdx1 promoter is alone sufficient to drive early and ectopic differentiation of islet cells, a capability shared by the pancreatic bHLH factor, neuroD1/BETA2, but not by the muscle bHLH factor, MyoD. However, the islet cells produced in these transgenic experiments are overwhelmingly (alpha) cells, suggesting that factors other than the bHLH factors are required to deviate from a default * cell fate. These data support a model in which neurogenin3 acts upstream of other islet differentiation factors, initiating the differentiation of endocrine cells, but switching off prior to final differentiation. The ability to uniquely identify islet cell precursors by neurogenin3 expression allows us to determine the position of other islet transcription factors in the differentiation cascade and to propose a map for the islet cell differentiation pathway.

Normal female infants born of mothers with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, especially those patients with the salt-losing form, have decreased fertility rates. Pregnancy experience in this population is limited. We report the pregnancy outcomes and serial measurements of maternal serum steroid levels in four women with classic 21-hydroxylase deficiency, three of whom were female pseudohermaphrodites with the salt-losing form. These glucocorticoid-treated women gave birth to four healthy female newborns with normal female external genitalia, none of whom were affected with 21-hydroxylase deficiency. In three women, circulating androgen levels increased during gestation, but remained within the normal range for pregnancy during glucocorticoid therapy. In the fourth patient, androgen levels were strikingly elevated during gestation despite increasing the dose of oral prednisone from 5 to 15 mg/day (two divided doses). Notwithstanding the high maternal serum concentration of androgens, however, placental aromatase activity was sufficient to prevent masculinization of the external genitalia of the female fetus and quite likely the fetal brain, consistent with the idea that placental aromatization of androgens to estrogens is the principal mechanism that protects the female fetus from the masculinizing effects of maternal hyperandrogenism. These four patients highlight key issues in the management of pregnancy in women with 21-hydroxylase deficiency, particularly the use of endocrine monitoring to assess adrenal androgen suppression in the mother, especially when the fetus is female. Recommendations for the management of pregnancy and delivery in these patients are discussed.

Neonatal hyperinsulinism.

Hyperinsulinism is the most frequent cause of severe, persistent hypoglycemia in neonates and young infants. Timely diagnosis and aggressive treatment are necessary to prevent long-term neurologic sequelae. This article explores the latest advances in the understanding of the pathophysiology of this disorder at the molecular and cellular level. The clinical features, hallmarks for diagnosis, and various treatment options are discussed.