Naomi Weintrob

Short- and long-range complications in offspring of diabetic mothers

The perinatal mortality rate of infants of diabetic mothers (IDMs) has declined dramatically from 250 per 1000 live births in the 1960s to a near-normal 20 per 1000 live births in the 1980s. Five to 8% of all IDMs suffer from major congenital malformations, and it is the latter that are responsible for 50% of these perinatal deaths. It has been shown that tight glycemic control prior to conception and during pregnancy can prevent an excess rate of congenital malformations, fetal macrosomia, birth trauma, and neonatal respiratory distress syndrome. We briefly review the short- and long-range complications that occur in offspring of diabetic mothers (ODMs) from gestation through young adulthood. Short-term neonatal complications, such as hypoglycemia, hypocalcemia, hypomagnesemia, hyperbilirubinemia, and polycythemia, are related mainly to fetal hyperinsulinemia, hypoxemia, and prematurity. They are readily controllable within the setup of modern neonatal intensive care units. Long-range complications include an increased rate of childhood and adolescent obesity, impaired glucose tolerance or diabetes mellitus, and subtle neuropsychological dysfunctions. These may be related to the severity of the maternal hyperglycemia during pregnancy, the consequent fetal hyperinsulinemia, and third trimester maternal lipid metabolism disturbances. Today we have at hand the knowledge and tools to properly treat both pregestational and gestational diabetes. Increased education of the general practitioner and the target population regarding early referral of pregestational diabetic mothers and the implementation of screening programs for gestational diabetes will further reduce diabetic pregnancy-related morbidity.

Insulin pump therapy in youth with type 1 diabetes: a retrospective paired study.

OBJECTIVE. To compare by age and glycemic control continuous subcutaneous insulin infusion with multiple daily injections in youth with type 1 diabetes. METHODS. The files of 279 patients who had type 1 diabetes and switched from multiple daily injections to continuous subcutaneous insulin infusion between 1998 and 2003 were reviewed for glycemic control, body mass index standard deviation score, and adverse events. Patients were divided by age as follows: 23 prepubertal (median age: 5.4; range: 1.6–8.6 years), 127 adolescent (median age: 13.7; range 9–17 years), and 129 young adult (median age: 22.8; range: 17–40 years). The data were compared between the 12 months of multiple daily injections that preceded continuous subcutaneous insulin infusion and the period after the start of continuous subcutaneous insulin infusion for the whole cohort and by age group. RESULTS. A significant decrease in hemoglobin A1c was demonstrated after the start of continuous subcutaneous insulin infusion use for the entire cohort (−0.51%) and for the prepubertal (−0.48%), adolescent (−0.26%), and young adult (−0.76%) groups. There was a significant interaction between the change in hemoglobin A1c level and hemoglobin A1c value at initiation of pump therapy (−1.7% for patients with hemoglobin A1c ≥10%; 0.2% for patients with hemoglobin A1c ≤7%). The rate of severe hypoglycemic episodes decreased significantly in the adolescent group, from 36.5 to 11.1 events per 100 patient-years, and in the young adult group, from 58.1 to 23.3. There was no significant change in the rate of diabetic ketoacidosis between the 2 periods. The young adults showed a significant decrease in body mass index standard deviation scores (−0.08 ± 0.37). CONCLUSIONS. Continuous subcutaneous insulin infusion improves glycemic control in youth with type 1 diabetes, especially in those with a history of poor glycemic control. This improvement is associated with a decrease in the rate of severe hypoglycemia in the absence of weight gain.

Heat-shock protein peptide DiaPep277 treatment in children with newly diagnosed type 1 diabetes: a randomised, double-blind phase II study.

Type 1 diabetes mellitus (T1DM) is a T‐cell‐mediated autoimmune disease that leads to the destruction of insulin‐producing beta cells. Treatment with DiaPep277, a peptide derived from heat‐shock protein 60 (hsp60), has been found to slow the deterioration of beta‐cell function after clinical onset of diabetes in NOD mice and human adults. Our aim was to evaluate the efficacy and safety of DiaPep277 treatment in attenuating beta‐cell destruction in children with recent‐onset T1DM.

Exercise With and Without an Insulin Pump Among Children and Adolescents With Type 1 Diabetes Mellitus

Background. The use of insulin pumps is becoming a popular technique for insulin delivery among patients with type 1 diabetes mellitus (T1DM), but there is no consensus regarding the guidelines for proper pump use during exercise. Objective. To investigate the physiologic responses and risk of hypoglycemia among children and adolescents with T1DM when exercising with the pump on (PO) (50% of the basal rate) or pump off (PF). Methods. Ten subjects with T1DM (6 female subjects and 4 male subjects), 10 to 19 years of age, performed prolonged exercise (40–45 minutes) on a cycle ergometer ∼2 hours after a standard breakfast and an insulin (Lispro) bolus. Complex carbohydrates (20 g) were provided before and after the exercise. Each patient exercised once with PO and once with PF, in a randomized, crossover (single-blind) manner. During exercise and 45 minutes of recovery, subjects were monitored for cardiorespiratory, metabolic, and hormonal responses. Blood glucose concentrations were recorded for 24 hours after exercise, with a continuous glucose monitoring system, to document late hypoglycemic events. Results. During exercise, blood glucose concentrations decreased by 59 ± 58 mg/dL (mean ± SD: 29 ± 24%) with PF and by 74 ± 51 mg/dL (35.5 ± 18%) with PO (not significant). No significant differences were found in cortisol, growth hormone, or noradrenaline levels between PO and PF. There were no differences in cardiorespiratory parameters, blood lactate concentrations, or free fatty acids concentrations between pump modes. Hypoglycemic events during exercise were asymptomatic and occurred for 2 subjects with PO and 2 with PF. Nine subjects had late hypoglycemia after PO, compared with 6 after PF (not significant). Conclusions. We found no advantage for subjects with either PO or PF during exercise, and we noted that late hypoglycemia was more common than hypoglycemia during exercise. However, PO was associated with a trend of increased risk for late hypoglycemia. We recommend that the pump be removed or turned off during prolonged exercise and that blood glucose concentrations be monitored for several hours after exercise, regardless of the pump mode.

Serum ferritin level as a predictor of impaired growth and puberty in thalassemia major patients.

Abstract:  Objective: Previous studies suggested that in patients with thalassemia major, initiating deferoxamine (DFO) therapy before puberty can prevent iron‐induced failure of growth and puberty. However, early initiation of chelation has also been associated with DFO toxicity. The aim of this retrospective study was to determine the prevalence rates of endocrine complications and DFO bone toxicity in our thalassemia major patients and to correlate them with the degree of iron chelation. Methods: Thirty‐nine patients with thalassemia major were followed for a median of 16.3 yr (range 2–28). Individual mean serum ferritin level during the study period was calculated using repeated annual measurements. Bone DFO toxicity was assessed by wrist and spine radiographs; endocrine dysfunction by anthropometric measurements and pubertal stage; and hypogonadotropic hypogonadism by lack of luteinizing hormone response to gonadotropin‐releasing hormone. Results: Chelation therapy was initiated at median age 4.9 yr. Mean serum ferritin level during the study period was 2698 ± 1444 ng/mL. Hypogonadism was noted in 59% of the patients who reached pubertal age, and short stature was found in 36% of patients who reached final height. Mean ferritin level of 2500 ng/mL during puberty was the cut‐off for hypogonadism, and ferritin level of 3000 ng/mL during prepuberty was the cut‐off for final short stature. None of the patients who attained final height had signs of DFO bone toxicity. Conclusions: High serum ferritin levels during puberty are a risk factor for hypogonadism, and high serum ferritin levels during the first decade of life predict final short stature. It remains to be determined whether improving chelation by earlier initiation of DFO or by the combined use of DFO and deferiprone will lead to better growth and sexual development without DFO toxicity.

Clinical and genetic heterogeneity of congenital adrenal hypoplasia due to NR0B1 gene mutations.

Introduction  X‐linked adrenal hypoplasia congenita (AHC) is a rare disorder caused by mutations or complete deletion of the NR0B1 gene that encodes the DAX‐1 protein, an orphan member of the nuclear receptor superfamily. AHC is characterized by adrenal insufficiency in infancy and early childhood. Later, hypogonadotropic hypogonadism (HH) manifests as pubertal failure.

Continuous Subcutaneous Insulin Infusion versus Multiple Daily Injections in Adolescents with Type I Diabetes Mellitus: A Randomized Open Crossover Trial

Intensive therapy for type 1 diabetes mellitus (DM) is usually provided by either multiple daily injections of insulin (MDI) or by insulin pump (continuous subcutaneous insulin infusion CSII). We designed an open, randomized, crossover trial to compare CSII with MDI for glycemic control, dose requirements, weight change, incidence of adverse events, quality of life and satisfaction in adolescents.

Cognitive impairment is prevalent in pseudohypoparathyroidism type Ia, but not in pseudopseudohypoparathyroidism: possible cerebral imprinting of Gsα

Objective  Pseudohypoparathyroidism type Ia (PHP‐Ia) is a hereditary disorder characterized by resistance to multiple hormones that work via cAMP such as PTH and TSH, accompanied by typical skeletal features including short stature and brachydactyly, termed Albright hereditary osteodystrophy (AHO). In affected kindreds, some members may have AHO but not hormone resistance; they are termed as pseudopseudohypoparathyroidism (PPHP). The molecular basis for the disorder is heterozygous inactivating mutation of the Gsα gene. In affected families, subjects with both PHP‐Ia and PPHP have the same Gsα mutations. The skeletal features common to PPHP and PHP‐Ia are presumably caused by tissue‐specific Gsα haploinsufficiency. Other features that distinguish between PPHP and PHP‐Ia, such as the multihormone resistance, are presumably caused by tissue‐specific paternal imprinting of Gsα. This suggests that major differences in phenotype between PHP‐Ia and PPHP point to specific tissues with Gsα imprinting. One such major difference may be cognitive function in PHP‐Ia and PPHP.

Immunogenetics of HLA class II in Israeli Ashkenazi Jewish, Israeli non-Ashkenazi Jewish, and in Israeli Arab IDDM patients

The distribution of HLA class II alleles and genotypes in IDDM patients was examined in the three main Israeli ethnic groups: Ashkenazi Jews, non-Ashkenazi Jews, and Arabs. Molecular sequence specific oligonucleotide probe analysis was performed for DRB1, DQA1, and DQB1 genes. The DRB1*03011, DQA1*05 DQB1*02/DRB1*0402, DQA1*03, DQB1*0302 genotype was found to be the main susceptibility genotype in all three groups, with differences in the degree of association. In addition to DRB1*0402 (more frequent among Ashkenazi Jews), DRB1*0405, another subtype of DRB1*04, was found to be more prevalent among non-Ashkenazi Jews and Arabs. Many alleles were found to be negatively associated with insulin dependent diabetes mellitus (IDDM). This could be a result of the high frequency of susceptible alleles, or of linkage disequilibrium to a primary negatively associated allele. The strongest negative association was observed for DQB1*0301 in all three ethnic groups. The alleles DRB1*1401, DRB1*1501, DQB1*05031, DQB1*0602, and DQB1*0609 were not detected in any of the 202 IDDM patients, and are probably either strongly protective or in linkage with such alleles. Despite the differences found between the three ethnic groups, an overall analysis shows that the DRB1*04 alleles that account for susceptibility to IDDM in the Israeli population (DRB1*0402 and *0405) are the same as those responsible for susceptibility to IDDM in a number of other Mediterranean populations. In contrast, the susceptible allele in most Caucasian populations is DRB1*0401. It is noteworthy that the susceptible alleles DRB1*0402/05 for Mediterranean and DRB1*0401 for Caucasian populations are also frequent in the respective healthy populations. These findings support the results obtained in other studies, which point to a genetic relationship between the Israeli and Mediterranean populations.

Use of GnRH agonist and human chorionic gonadotrophin tests for differentiating constitutional delayed puberty from gonadotrophin deficiency in boys.

objectives The differentiation of constitutional delayed puberty (CDP) from gonadotrophin deficiency (GD) in boys at referral poses a difficult challenge. The effectiveness of the GnRH agonist (GnRH‐a) test in distinguishing between the two conditions was evaluated and compared with findings of the GnRH and hCG stimulation tests.