Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal ...folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (-3.2 SD score vs. -2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
OBJECTIVE:--Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by FOXP3 mutations. We aimed to determine the prevalence, genetics, and clinical phenotype of ...FOXP3 mutations in a large cohort with permanent neonatal diabetes (PNDM). RESEARCH DESIGN AND METHODS--The 11 coding exons and the polyadenylation region of FOXP3 were sequenced in 26 male subjects with diabetes diagnosed before 6 months of age in whom common genetic causes of PNDM had been excluded. Ten subjects had at least one additional immune-related disorder, and the remaining 16 had isolated diabetes. RESULTS:--We identified four hemizygous FOXP3 mutations in 6 of 10 patients with associated immune-related disorders and in 0 of 16 patients with isolated diabetes (P = 0.002). Three patients with two novel mutations (R337Q and P339A) and the previously reported L76QfsX53 developed classic IPEX syndrome and died within the first 13 months. The novel mutation V408M was found in three patients from two unrelated families and had a mild phenotype with hypothyroidism and autoimmune enteropathy (n = 2) or nephrotic syndrome (n = 1) and survival to 12-15 years. CONCLUSIONS:--FOXP3 mutations result in ~4% of cases of male patients with permanent diabetes diagnosed before 6 months. Patients not only have classic IPEX syndrome but, unexpectedly, may have a more benign phenotype. FOXP3 sequencing should be performed in any male patient with the diagnosis of diabetes in the first 6 months who develops other possible autoimmune-associated conditions, even in the absence of full IPEX syndrome.
Aims: HNF1B-maturity-onset diabetes of the young is caused by abnormalities in the HNF1B gene encoding the transcription factor HNF-1β. We aimed to investigate detailed clinical features and the type ...of HNF1B gene anomaly in five pediatric cases with HNF1B-MODY.
Methods: From a cohort of 995 children and adolescents with diabetes, we analyzed the most frequent maturity-onset diabetes of the young genes (GCK, HNF1A, HNF4A) including HNF1B sequencing and deletion analysis by quantitative Multiplex-PCR of Short Fluorescent Fragments (QMPSF) if patients were islet autoantibody-negative and had one parent with diabetes or associated extrapancreatic features or detectable C-peptide outside honeymoon phase. Presence and size of disease-causing chromosomal rearrangements detected by QMPSF were further analyzed by array comparative genomic hybridization.
Results: Overall, five patients had a heterozygous HNF1B deletion, presenting renal disease, elevated liver enzymes, and diabetes. Diabetes was characterized by insulin resistance and adolescent onset of hyperglycemia. Additionally, clinical features in some patients were pancreas dysplasia and exocrine insufficiency (two of five patients), genital defects (three of five), mental retardation (two of five), and eye abnormalities (coloboma, cataract in two of five). One case also had severe growth deficit combined with congenital cholestasis, and another case had common variable immune deficiency. All patients reported here had monoallelic loss of the entire HNF1B gene. Whole genome array comparative genomic hybridization confirmed a precurrent genomic deletion of approximately 1.3–1.7 Mb in size.
Conclusion: The clinical data of our cases enlarge the wide spectrum of patients with HNF1B anomaly. The underlying molecular defect in all cases was a 1.3- to 1.7-Mb deletion, and paired, segmental duplications along with breakpoints were most likely involved in this recurrent chromosomal microdeletion.
HNF1B-Maturity-onset diabetes of youth (MODY) has a broad clinical spectrum and heterozygous contiguous gene deletions, including HNF1B and 18 other known genes.
A Comparison of Postprandial and Preprandial Administration of Insulin Aspart in Children and Adolescents With Type 1 Diabetes
Thomas Danne , MD 1 ,
Jan Aman , MD 2 ,
Edith Schober , MD 3 ,
Dorothee ...Deiss , MD 4 ,
Judith L. Jacobsen , MSC 5 ,
Hans Henrik Friberg , MSC 5 ,
Lars Hein Jensen , MSC PHARM 5 and
the ANA 1200 Study Group
1 Kinderkrankenhaus auf der Bult, Diabetes-Zentrum für Kinder und Jugendliche, Hannover, Germany
2 Department of Paediatrics, (Barn och Ungdomskliniken), Regional Hospital, Örebro, Sweden
3 Universitätsklinik für Kinder- und Jugendheilkunde, Wien, Austria
4 Klinik für Allgemeine Pädiatrie, Charité, Campus Virchow-Klinikum, Berlin, Germany
5 Novo Nordisk A/S, Bagsvaerd, Denmark
Address correspondence and reprint requests to Thomas Danne, MD, Kinderkrankenhaus auf der Bult, Diabetes-Zentrum für Kinder
und Jugendliche, Janusz-Korczak-Allee 12, 30173 Hannover, Germany. E-mail: danne{at}hka.de
Abstract
OBJECTIVE —The aim of this study was to compare the glycemic control of preprandial versus postprandial injections of the new rapid-acting
insulin analogue aspart in children and adolescents with type 1 diabetes.
RESEARCH DESIGN AND METHODS —Forty-two children (aged 6–12 years) and 34 adolescents (13–17 years) were randomized to preprandial (immediately before
meal start) and postprandial (immediately after a meal or a maximum of 30 min after meal start) treatment with insulin aspart
(at least thrice daily) as part of a basal/bolus regimen in a multicenter study with an open labeled, two-period cross-over
design (6-week periods). Of this group, 49% were boys, 55% were aged ≤13 years, and duration of diabetes was 4.4 years (range
1.0–9.4).
RESULTS —Glycemic control for postprandial treatment was not worse than preprandial treatment as assessed by fructosamine week 0 vs.
6 (mean ± SD, preprandial 367 ± 74 vs. 378 ± 90 μmol/l; postprandial 383 ± 83 vs. 385 ± 77 μmol/l) and HbA 1c (preprandial 7.9 ± 1.3 vs. 8.0 ± 1.5%; postprandial 8.0 ± 1.4 vs. 8.3 ± 1.5%, P = 0.14). The only statistically significant finding from the seven-point blood glucose profiles and derived parameters between
preprandial and postprandial treatment was a lower postprandial glucose level 120 min after breakfast (mean ± SEM, −2.08 ±
0.74 mmol/l, P = 0.016). The relative risk of hypoglycemia (blood glucose <3.9 mmol/l) preprandially to postprandially was not significantly
different (mean 1.1; 95% CI 0.91–1.35; P = 0.31). Overall treatment satisfaction was equally high for both regimens with both patients and parents.
CONCLUSIONS —Although preprandial administration of insulin aspart is generally preferable, this study shows that in children and adolescents,
postprandial administration of insulin aspart is a safe and effective alternative.
AE, adverse event
DTSQ, Diabetes Treatment Satisfaction Questionnaire
IAsp post, postprandial administration of insulin aspart
IAsp pre, preprandial administration of insulin aspart
PP, per protocol
Footnotes
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
T.D. has received honoraria for speaking engagements from several companies involved in the diabetes field and has received
grant support from Abbott MediSense, Aventis, Bayer, Disetronic, Lifescan, Lilly, Medtronic Minimed, Menarini, NovoNordisk,
and Pharmacia for research or scientific meetings; E.S. received a consultation fee from NovoNordisk for each participating
patient; J.L.J., H.H.F., and L.H.J. are employed by Novo Nordisk A/S, who manufactures and markets pharmaceuticals related
to the treatment of diabetes and its complications; and J.L.J. and H.H.F. personally or an immediate family member holds stock
in Novo Nordisk A/S.
Accepted May 1, 2003.
Received September 18, 2002.
DIABETES CARE
Continuous glucose monitoring (CGM) systems use trend arrows to accurately display the anticipated glucose curve for the user. These are used for both “real-time” glucose monitoring and for ...intermittent scanning glucose monitoring. Trend arrow data are used by people with diabetes to make corrections to their glucose control. It is essential that they are correctly interpreted when adjusting insulin doses and to ensure that appropriate treatment decisions are made. The aim of this article is to provide general treatment guidance for diabetes teams and for people with diabetes using CGM in the context of trend arrows. This is based on previous recommendations for interpreting trend arrows without losing sight of the need for individual therapy adjustment.
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Background: Prior investigations regarding glucose variability in nondiabetic subjects measured by continuous glucose monitoring (CGM) have been limited to only few weeks. Little is known about what ...defines healthy or pathologic glycemic variability. This study investigated “normal glycemia” under daily conditions using a long-term implantable CGM system in nondiabetic adults for 90 days.
Methods: 25 adult nondiabetic participants (10 Male, 15 Female, 17 participants >45 years old) were inserted with the Eversense® CGM System (Senseonics Inc, MD). Participants were instructed to continuously wear the CGM system during the 90 day period and calibrate the system when prompted. Analysis was performed to estimate standardized measures of euglycemia (70-180 mg/dL), hypoglycemia (<54, <70 mg/dL), hyperglycemia (>180, >200 mg/dL) and glucose variability (Mean, SD, CV).
Results: Out of 25 participants, 5 had inadequate data for inclusion. Analysis showed the average glucose value of the nondiabetic participants was 102 mg/dL (SD=18 and CV=0.17). Average percent time spent in hypoglycemia <54mg/dL was 0.14% and <70mg/dL was 1.5%. Time spent in euglycemia 70-180 mg/dL was 98%. Time spent in hyperglycemia >180 and >200 mg/dL was 0.17% and 0.05%, respectively. 17 participants had at least one value < 54mg/dL and 18 participants had glucose values >180mg/dL with 11 subjects with glucose values > 200mg/dL.
Conclusions: Glycemic variability recorded over extended period of time in participants without a diagnosis of diabetes showed similar results as observed by previous researchers over short duration with tight glycemic control. However, hypo- and hyperglycemic excursions are in some normoglycemic regarded individuals more frequent than suggested without CGM. Further analysis including meal challenge and fasting levels may provide guidance regarding expected values for persons without a diagnosis of diabetes and to set realistic target ranges for those with diabetes.
Disclosure
D. Deiss: Consultant; Self; Senseonics. Advisory Panel; Self; Abbott. Consultant; Self; Roche Diabetes Care Health and Digital Solutions. Advisory Panel; Self; Becton, Dickinson and Company. T. Abtahi: Other Relationship; Self; Senseonics. R. Rastogi: Employee; Self; Senseonics. E.L. Kelley: Employee; Self; Senseonics.
The use of real-time continuous glucose monitoring (rtCGM) systems has proved to positively impact the management of type 1 diabetes with the potential to lower HbA1c, reduce frequency and time spent ...in hypoglycemia, and lower glycemic variability. Nevertheless, the acceptance of rtCGM remains below expectations and the dropout rate within the first year has been reported to be 27%. Besides financial reasons due to limited reimbursement, reasons include the need for frequent sensor replacement, the discomfort of wearing a sensor, the presence of adverse skin reactions, or privacy. Thus, novel approaches to rtCGM are desired to overcome these barriers. The first long-term implantable rtCGM system diversifies the field of glucose monitoring further. However, due to its novelty, there are no published clinical practice guidelines available.
The aim of this article is to set the foundation for a best clinical practice for the everyday clinical care using a long-term implantable CGM system.
An international expert panel for the long-term implantable CGM system developed this best practice guidance. All participants were certified and experienced in the use of the Eversense
long-term implantable CGM system. The workflows from the respective clinics were presented, discussed and are summarized in an ideal care workflow outlined in these practice recommendations.
The participants agreed on the following aspects: definition of the patient population that will benefit from a long-term implantable CGM device; real-world experience on safety and accuracy of a long-term CGM; definition of the ideal sensor position; description of the optimal process for sensor insertion, removal, and replacement.
All had adhered to intensified insulin treatment (continuous subcutaneous insulin infusion, n = 78; multiple daily injection, n = 84) but had HbA1c (A1C) levels ≥8.1%. Thus, intermittent corrective ...adjustments of insulin administration, such as the number of boluses or the basal-to-total dose ratio, and food intake adjustments based on the real-time glucose display and alarm functions may have been carried out on an individual basis.
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