Kineret Mazor-Aronovitch

Treatment of Congenital Hyperinsulinism with Lanreotide Acetate (Somatuline Autogel)

CONTEXT Congenital hyperinsulinism (CH) may be treated conservatively in many children with octreotide given by multiple sc injections or via an insulin pump. OBJECTIVE We describe two children treated with a once-monthly injection of a long-acting somatostatin analog. PATIENTS AND METHODS Both patients presented with hypoglycemia 30 min after birth and were subsequently diagnosed with CH. Patients were initially treated with diazoxide, hydrochlorothiazide, frequent feedings, and octreotide via an insulin pump. With this therapy, they were normoglycemic with a good growth rate, normal weight gain, and excellent neurodevelopment. Treatment with the long-acting somatostatin analog lanreotide acetate (Somatuline Autogel), administered by deep sc injection of 30 mg once a month, was started at the ages of 4½ and 4 yr, respectively. Octreotide infusion was gradually weaned over 1 month. Continuous glucose monitoring after discontinuation of pump therapy showed normoglycemia. The first patient has now been treated with the lanreotide acetate for over 5 yr, and the second for 3 yr. Treatment is well-tolerated, and both the patients and their parents are satisfied with the transition from pump therapy to once-a-month injection and prefer it to pump therapy. CONCLUSION Lanreotide acetate may be a safe and effective alternative to octreotide pump therapy in patients with CH, offering an improved quality of life. Longer follow-up of a larger patient group is needed.

Long-term neurodevelopmental outcome in conservatively treated congenital hyperinsulinism

BACKGROUND Congenital hyperinsulinism (CH) is treated surgically in many centers (near-total and partial pancreatectomy for diffuse and focal disease respectively). Most patients treated with near-total pancreatectomy developed diabetes during childhood/puberty. CH patients are at increased risk of neurodevelopmental disorders, some being severe, which are reported to occur in 14-44% of patients from highly heterogenous cohorts. Over the last few decades, we have treated children with CH conservatively without surgery. The aim of this study was to assess the neurodevelopmental outcome of these patients. DESIGN AND METHODS The study included 21 Ashkenazi CH medically treated patients: 11 homozygotes (diffuse disease) and 9 heterozygotes with mutations on the paternal allele (presumed focal disease). The mean age was 13.7 years (range 8-23). Neurodevelopmental outcomes were assessed by telephone interviews of parents, using a standard questionnaire. Closest age siblings of CH patients served as controls. RESULTS Ten CH patients had perinatal seizures of short duration. Four had post-neonatal seizures, which remitted entirely. During early childhood, four patients (19%) had hypotonia, eight (38%) had fine motor problems, seven (33%) had gross motor problems (clumsiness), and one had mild cerebral palsy. Three patients (14%) had speech problems. Eight patients required developmental therapy, compared to one in the control group. Most of these problems were resolved by age 4-5 years. At school age, all were enrolled in regular education, some excelled in their studies, 6 out of 21 patients (29%) had learning problems (2 out of 21 controls). None had overt diabetes. CONCLUSIONS Good neurodevelopmental outcome was observed in our conservatively treated CH patients, with no diabetes as reported in patients undergoing pancreatectomy.

The effectiveness of Internet-based blood glucose monitoring system on improving diabetes control in adolescents with type 1 diabetes.

Landau Z, Mazor‐Aronovitch K, Boaz M, Blaychfeld‐Magnazi M, Graph‐Barel C, Levek‐Motola N, Pinhas‐Hamiel O. The effectiveness of Internet‐based blood glucose monitoring system on improving diabetes control in adolescents with type 1 diabetes.

Prevalence of overweight, obesity and metabolic syndrome components in children, adolescents and young adults with type 1 diabetes mellitus

We aimed to determine the prevalence of overweight and obesity among children, adolescents and young adults with type 1 diabetes mellitus (T1DM), and to assess the prevalence of the metabolic syndrome and its components.

Type 1 diabetes in pre-school children – long-term metabolic control, associated autoimmunity and complications

Diabet. Med. 29, 1291–1296 (2012)

ABCC8 mutation allele frequency in the Ashkenazi Jewish population and risk of focal hyperinsulinemic hypoglycemia

Purpose: Congenital hyperinsulinism of infancy (OMIM# 256450) is a devastating disease most commonly caused by dominant or recessive mutations in either ABCC8 or KCNJ11, the genes that encode for the β-cell adenosine triphosphate-regulated potassium channel. A unique combination of a paternally inherited germline mutation and somatic loss-of-heterozygosity causes the focal form of the disease (Focal-congenital hyperinsulinism of infancy [Focal-CHI]), the incidence of which in genetically susceptible individuals is not known.Methods: We genotyped 21,122 Ashkenazi Jewish individuals for two previously identified ABCC8 founder mutations and utilized a clinical database of 61 unrelated Ashkenazi patients with congenital hyperinsulinism of infancy to obtain an estimate of the risk of Focal-CHI in a genetically susceptible fetus.Results: The combined mutation carrier rate in Ashkenazi Jews was 1:52, giving an estimated frequency of homozygosity or compound heterozygosity of 1:10,816 in this population. The risk of Focal-CHI is 1:540 per pregnancy in offspring of carrier fathers.Conclusion: We recommend that these mutations be included in the genetic screening program for the Ashkenazi Jewish population. As the risk of Focal-CHI is not expected to be mutation specific, the data reported in this study are useful for counseling all families in which the father was found to carry a recessive ABCC8 or KCNJ11 mutation.

Cognitive and developmental outcome of conservatively treated children with congenital hyperinsulinism.

Abstract Background: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants. Its management can be extremely complicated, and may involve medical therapy and surgery. The mainstay of the treatment is to maintain normoglycemia, since hypoglycemia during infancy can have severe neurological consequences. Objective: To assess the cognitive and developmental levels and the adaptive skills achieved by children with CHI who were treated medically over the past decade. Subjects and methods: Fourteen children with CHI, under the age of 10 years, who received medical treatment only, underwent a physical and neurological examination and standardized assessments that included the Bayley Scale of Infant and Toddler Development, 3rd Edition, or Kaufman Assessment Battery for Children, the Vineland Adaptive Behavior Scales and the Achenbach Child Behavior Checklist (CBCL) parent questionnaire form. Results: Twelve children (86%) achieved normal range scores in the cognitive and development assessments (Bayley Scale of Infant and Toddler Development or Kaufman Assessment Battery for Children). Only two showed cognitive achievements below the normal range. The Vineland questionnaire, which was based on parental report, showed below normal adaptive skills in eight patients (57%). Conclusions: In contrast to previous studies showing a high prevalence of neurodevelopmental difficulties in children with congenital hyperinsulinism, our study showed normal cognitive achievements in most children. This may be attributed to the earlier recognition and better management of the disease in the past decade.

Benefits of Continuous Subcutaneous Insulin Infusion (CSII) Therapy in Preschool Children

OBJECTIVE The incidence of type 1 diabetes mellitus (T1DM) in young children has increased considerably over recent years. The purpose was to examine the effectiveness and safety of continuous subcutaneous insulin infusion (CSII) therapy in preschool children with T1DM. METHODS A retrospective chart review of 113 children diagnosed with T1DM while younger than age 6 years. Mean age at diagnosis was 3.5±1.5 years and mean duration of follow 9.7±7.0 years. Patients were divided into 3 groups. Group1 initiated CSII therapy before the age of 6 years (n=26), Group 2 was treated with multiple daily injections (MDI) throughout follow-up (n=34), and Group 3 initiated CSII after age 6 (n=53). Metabolic control was assessed by HbA1C levels and safety by rates of severe hypoglycemia and diabetic ketoacidosis (DKA) events. RESULTS In Group 1, the highest mean HbA1C value (8.5%) was observed 1-2 years prior to CSII initiation. During the 5 year period following CSII initiation, mean HbA1C levels ranged between 7.4 and 8.0%. Throughout the entire follow-up period, mean HbA1C levels were lower for Group 1 than Group 2 (p=0.05). In Group 3, mean HbA1C level decreased from 8.7% pre-CSII to 8.3% post-CSII (p<0.001). Nevertheless HbA1C levels remained higher than for those who started pump therapy before age 6 (p=0.02). CONCLUSIONS Our study demonstrated better metabolic control in pre-school children treated with CSII compared to those treated with MDI. This benefit sustained for 5 years after CSII initiation and was not accompanied by increased risk of severe hypoglycemia or DKA events.

Klotho response to treatment with growth hormone and the role of IGF-I as a mediator

CONTEXT Klotho is an aging-modulating protein expressed mainly in the kidneys, which can be cleaved and shed to act as a circulating hormone. Several lines of evidence suggest a tight interaction between klotho and the GH-IGF-I axis. We showed previously that klotho levels are decreased in pediatric patients with growth hormone deficiency (GHD). Our aim now is to investigate the effect of GH therapy on klotho levels in these patients and to elucidate the role of IGF-1 in mediating secretion of klotho. BASIC PROCEDURES Klotho levels were measured in 29 GHD pediatric patients (males=15, aged 12.2±3.3years), treated with GH for 2.5±2.8years; nineteen patients had samples obtained both before and during treatment. The effect of IGF-I and its downstream effectors on secretion of klotho to media was studied in COS-7 cells overexpressing klotho. MAIN FINDINGS Klotho levels increased under GH treatment (from 1321±691pg/ml to 3380±2120pg/ml, p<0.001), and were higher compared to controls (1645±778pg/ml, p<0.001), resulting in supraphysiological levels. Fold-increase in klotho correlated with fold-increase in IGF-I (r=0.63, p=0.004). Studies in COS-7 cells overexpressing klotho revealed mTOR-dependent induction of klotho shedding by IGF-I. PRINCIPAL CONCLUSIONS Klotho levels increased during GH treatment of pediatric GHD patients. This increase was associated with an increase in IGF-I levels. Furthermore, we showed, for the first time, a direct role of IGF-I in the regulation of klothos shedding which depends on activation of the AKT-mTOR pathway. Our findings add further support for the close association between klotho and the GH/IGF-I axis.

Increased prevalence of disordered eating in the dual diagnosis of type 1 diabetes mellitus and celiac disease

Disordered eating behaviors (DEBs) may lead to full blown eating disorders. Both type 1 diabetes mellitus (T1DM) and celiac disease (CD) have been linked to DEBs.