The relation between glucose homeostasis and outcome in hypoxic-ischemic encephalopathy (HIE) is unclear. To investigate whether glucose abnormalities assessed by using continuous interstitial ...glucose monitoring (CGM) correlate with later neurological outcomes in HIE.
Prospective cohort study recruiting full-term neonates who received therapeutic hypothermia for HIE. CGM devices were placed soon after birth and recorded glucose profile for 3 days. The association between hypoglycemia (≤50 mg/dL), hyperglycemia (>144 mg/dL) and primary outcome defined as death or moderate or severe disability was examined with generalized estimating equations adjusted for Apgar scores, umbilical artery pH and base deficit. Neurodevelopmental outcome was assessed between 18 and 24 months.
Fifty-four neonates had outcome data available for the analysis; 19 of them (35%) had adverse outcome. Longer duration of hypoglycemia (OR 7.1, 95% CI 1.8-20.3, P < 0.001) and hyperglycemia (OR 5.4, 95% CI 1.6-15.7, P < 0.001), a greater area under the hypoglycemic (OR 2.6, 95% CI 1.4-4.6, P = 0.04) and hyperglycemic (OR 6.4, 95% CI 1.9-16.3, P < 0.001) curve were significantly associated with adverse outcomes.
Both hyper and hypoglycemia may be associated with adverse outcome in neonates with HIE. Future studies are needed to assess their prognostic association with neurological outcome.
Glucose abnormalities during therapeutic hypothermia are associated with later neurological outcomes.Increased glucose variability correlates to the neurological outcome between 18 and 24 months.This study provides the first data on the continuous glucose profile in a group of HIE infants followed up to 2 years of age.Glucose homeostasis represents a key point in the management of HIE patients.Further research is needed to find the appropriate glycemic target in this population.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In pediatric diabetology, a precise diagnosis is very important because it allows early and correct clinical management of the patient. Monogenic diabetes (MD), which accounts for 1-6% of all ...pediatric-adolescent diabetes cases, is the most relevant example of precision medicine. The definitive diagnosis of MD, possible only by genetic testing, allows us to direct patients to more appropriate therapy in relation to the identified mutation. In some cases, MD patients can avoid insulin and be treated with oral hypoglycemic drugs with a perceptible impact on both the quality of life and the healthcare costs. However, the genetic and phenotypic heterogeneity of MD and the overlapping clinical characteristics between different forms, can complicate the diagnostic process. In recent years, the development of Next-Generation Sequencing (NGS) methodology, which allows the simultaneous analysis of multiple genes, has revolutionized molecular diagnostics, becoming the cornerstone of MD precision diagnosis. We report two cases of patients with clinical suspects of MD in which a genetic test was carried out, using a NGS multigenic panel, and it clarified the correct pathogenesis of diabetes, allowing us to better manage the disease both in probands and other affected family members.
The Pediatric Artificial Pancreas (PedArPan) project tested a children-specific version of the modular model predictive control (MMPC) algorithm in 5- to 9-year-old children during a camp.
A total of ...30 children, 5- to 9-years old, with type 1 diabetes completed an outpatient, open-label, randomized, crossover trial. Three days with an artificial pancreas (AP) were compared with three days of parent-managed sensor-augmented pump (SAP).
Overnight time-in-hypoglycemia was reduced with the AP versus SAP, median (25(th)-75(th) percentiles): 0.0% (0.0-2.2) vs. 2.2% (0.0-12.3) (P = 0.002), without a significant change of time-in-target, mean: 56.0% (SD 22.5) vs. 59.7% (21.2) (P = 0.430), but with increased mean glucose 173 mg/dL (36) vs. 150 mg/dL (39) (P = 0.002). Overall, the AP granted a threefold reduction of time-in-hypoglycemia (P < 0.001) at the cost of decreased time-in-target, 56.8% (13.5) vs. 63.1% (11.0) (P = 0.022) and increased mean glucose 169 mg/dL (23) vs. 147 mg/dL (23) (P < 0.001).
This trial, the first outpatient single-hormone AP trial in a population of this age, shows feasibility and safety of MMPC in young children. Algorithm retuning will be performed to improve efficacy.
To examine body image problems and their associations with disordered eating behavior in adolescents with type 1 diabetes and well-matched healthy peers.
Using a cross-sectional design, 183 ...adolescents with type 1 diabetes (13.02-18.05 years) were recruited from diabetes centers in southern Italy and compared to healthy peers matched for age and gender. Participants completed self-report measures of disordered eating behaviors (DEPS-r and EDI-3RF) and a gender-specific body image problem questionnaire (SATAQ-4R). Socio-demographic and clinical data (zBMI, HbA1c, and disease duration) were also collected. Hierarchical multiple linear regression analyses were computed to determine the relative importance of diabetes variables and body image problems on participants' disordered eating behaviors after controlling for demographic variables.
Adolescents with type 1 diabetes showed diabetes-specific eating problems in 37.7% of cases and had more eating problem symptoms (assessed as drive for thinness and bulimia) than healthy peers. Male adolescents with type 1 diabetes did not display more body image problems (
> 0.05); females with type 1 diabetes compared to females in the control group were found to be more pressured by family (
= 0.025) but less by media (
= 0.022) to improve their appearance and attain a thin body. zBMI and body image problems contributed to a significant increase in disordered eating behavior risk both in male and female adolescents with diabetes and in healthy peers (zBMI 0.213 < β < 0.426,
< 0.05; body image 0.243 < β < 0.572,
< 0.05). None of the variables analyzed were found to significantly predict male bulimic symptoms (all β < 0.296,
> 0.05).
Since in adolescence type 1 diabetes and insulin therapy may increase the risk of weight gain and promote focus and attention on the body and thus contribute to the development of body image problems and disordered eating behaviors, continuity of medical, nutritional, and psychological care is needed.
Zonulin Upregulation Is Associated With Increased Gut Permeability in Subjects With Type 1 Diabetes and Their Relatives
Anna Sapone 1 2 ,
Laura de Magistris 2 ,
Michelle Pietzak 3 ,
Maria G. Clemente ...1 ,
Amit Tripathi 1 ,
Francesco Cucca 4 ,
Rosanna Lampis 4 ,
Deborah Kryszak 1 ,
Maria Cartenì 2 ,
Maddalena Generoso 2 ,
Dario Iafusco 2 ,
Francesco Prisco 2 ,
Francesca Laghi 2 ,
Gabriele Riegler 2 ,
Romano Carratu 2 ,
Debra Counts 5 and
Alessio Fasano 1
1 Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, Maryland
2 Department Magrassi-Lanzara, Gastroenterology Unit, II University of Naples, Naples, Italy
3 University of Southern California Keck School of Medicine and the Division of Gastroenterology and Nutrition, Children’s Hospital
Los Angeles, Los Angeles, California
4 Department of Biomedical Science and Biotechnology, University of Cagliari, Cagliari, Italy
5 Division of Pediatric Endocrinology, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
Address correspondence and reprint requests to Alessio Fasano, MD, Mucosal Biology Research Center, University of Maryland
School of Medicine, 20 Penn St., Room 345, Baltimore, MD 21201. E-mail: afasano{at}mbrc.umaryland.edu
Abstract
Zonulin, a protein that modulates intestinal permeability, is upregulated in several autoimmune diseases and is involved in
the pathogenesis of autoimmune diabetes in the BB/Wor animal model of the disease. To verify the association between serum
zonulin levels and in vivo intestinal permeability in patients with type 1 diabetes, both parameters were investigated in
different stages of the autoimmune process. Forty-two percent (141 of 339) of the patients had abnormal serum zonulin levels,
as compared with age-matched control subjects. The increased zonulin levels correlated with increased intestinal permeability
in vivo and changes in claudin-1, claudin-2, and myosin IXB genes expression, while no changes were detected in ZO1 and occludin
genes expression. When tested in serum samples collected during the pre–type 1 diabetes phase, elevated serum zonulin was
detected in 70% of subjects and preceded by 3.5 ± 0.9 years the onset of the disease in those patients who went on to develop
type 1 diabetes. Combined, these results suggest that zonulin upregulation is associated with increased intestinal permeability
in a subgroup of type 1 diabetic patients. Zonulin upregulation seems to precede the onset of the disease, providing a possible
link between increased intestinal permeability, environmental exposure to non–self antigens, and the development of autoimmunity
in genetically susceptible individuals.
ELISA, enzyme-linked immunosorbent assay
GALT, gut-associated lymphoid tissue
ICA, islet cell antibody
IA-2, insulinoma-associated protein 2
LA/MA, lactulose/mannitol
MAdCAM-1, mucosal vascular addressin cell adhesion molecule 1
TBS-T, Tris-buffered saline 0.05% Tween 20
TJ, tight junction
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted February 13, 2006.
Received December 8, 2005.
DIABETES
Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases ...documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic beta cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.
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