Diabetes In Infancy Research Articles

Safe and effective use of a hybrid closed‐loop system from diagnosis in children under 18 months with type 1 diabetes

The management of type 1 diabetes in infancy presents significant challenges. Hybrid closed loop systems have been shown to be effective in a research setting and are now available for clinical use. There are relatively little reported data regarding their safety and efficacy in a real world clinical setting. We report two cases of very young children diagnosed with type 1 diabetes at ages 18 (Case 1) and 7 months (Case 2), who were commenced on hybrid closed-loop insulin delivery using the CamAPS FX™ system from diagnosis. At diagnosis, total daily dose (TDD) was 6 and 3.3 units for Case 1 and 2, respectively. Closed loop was started during the inpatient stay and weekly follow up was provided via video call on discharge. Seven months from diagnosis, Case 1 has an HbA1C of 49 mmol/mol, 61% time in range (TIR, 3.9-10 mmol/L) with 2% time in hypoglycemia (<3.9 mmol/L) with no incidents of very low blood glucose (BG; <3 mmol/L, 54 mg/dL) over 6 months. Given the extremely small TDD of insulin in Case 2, we elected to use diluted insulin (insulin aspart injection, NovoLog, Novo Nordisk Inc., Plainsboro, NJ, Diluting Medium for NovoLog®). Six months from diagnosis, the estimated HbA1c is 50 mmol/mol, TIR 76% with 1% hypoglycemia and no incidents of very low BG (<3 mmol/L, 54 mg/dL) over 6 months. We conclude that the use hybrid closed-loop can be safe and effective from diagnosis in children under 2 years of age with type 1 diabetes.

Is the relationship between vitamin D deficiency and type 1 diabetes in children an accident or a pattern?

The results of numerous studies confirm the link between type 1 diabetes mellitus and vitamin D. In humans, the main circulating form of vitamin D is 25 (OH) D3, which is considered to predict the level of vitamin D. Children with type 1 diabetes have lower concentrations of 25 (OH) D and a greater prevalence of vitamin D deficiency and insufficiency compared to healthy peers. Although the problem of vitamin D deficiency in patients with type 1 diabetes is known, it has not been established whether low vitamin D level is a trigger of type 1 diabetes or a consequence of the disease. Literature data suggest both possibilities. In addition, the relationship between vitamin D and type 1 diabetes risk depends not only on nutrition and exposure to sunlight, but also on the polymorphisms of genes involved in the vitamin D metabolic pathway. The degree of vitamin D influence on the risk of type 1 diabetes is not the same in different periods of life. Vitamin D sufficiency has the most significant effect on the risk of type 1 diabetes in infancy. The article presents the effects of calcitriol on immune cells. Vitamin D receptors are present in almost all immune cells. That indicates its effect on the immune system. Vitamin D is involved in innate and adaptive immunity. The main immunomodulatory effects of vitamin D include regulation of the expression of genes involved in cell proliferation, differentiation and function. A number of immunomodulatory effects of calcitriol determines the therapeutic potential of vitamin D in autoimmune diseases, including type 1 diabetes. Adequate levels of vitamin D play an important role in reducing the risk of type 1 diabetes and slowing the progression of islet cell death. Currently, recommendations for people with a high genetic predisposition to type 1 diabetes should include prevention of vitamin d deficiency.

161-LB: Neurodevelopmental Outcomes of Infancy-Onset Diabetes

Background: Infancy-onset diabetes is largely monogenic before 6 months of age, whereas autoimmune type 1 diabetes is more likely from 6-12 months of age. As the most common neonatal diabetes, patients with KATP channel mutations exhibit a spectrum of neurodevelopmental disability that is largely related to brain expression of mutated channels. It is not known how glycemic dysregulation of any type of early-onset diabetes may affect brain development. Methods: Subjects included from UChicago Monogenic Diabetes Registry with diabetes diagnosed under a year of age currently aged 4-20 years and unaffected sibling controls. Known KATP channel mutations or other rare causes affecting brain development were excluded. Measures of intellectual function (IF), executive function (EF), visual motor integration (VMI) and academic achievement (AA) were utilized (Table 1). A two-sample t-test was conducted comparing each group assuming unequal variance. Results: Comprehensive testing was completed for those with infancy-onset diabetes and siblings (Table 1). There were no significant differences on any measure, though mean scores trended lower in the affected group. Conclusion: Our findings show no difference in IF, EF, VMI, AA in children diagnosed with diabetes in infancy compared to their unaffected siblings. Our conclusions are limited due to a small sample size; differences may be subtle and require a larger sample size to be identified. Disclosure M. McCauley: None. A.M. Denson: None. L.R. Letourneau-Freiberg: None. M.N. Scott: None. S.W. Greeley: None. Funding American Diabetes Association (1-17-JDF-008 to S.A.W.G.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942, P30DK0205950); National Center for Advancing Translational Sciences (UL1TR002389)

Congenital diabetes mellitus.

Congenital diabetes mellitus is a rare disorder characterized by hyperglycemia that occurs shortly after birth. We define "Diabetes of Infancy" if hyperglycemia onset before 6 months of life. From the clinical point of view, we distinguish two main types of diabetes of infancy: transient (TNDM), which remits spontaneously, and permanent (PNDM), which requires lifelong treatment. TNDM may relapse later in life. About 50% of cases are transient (TNDM) and 50% permanent. Clinical manifestations include severe intrauterine growth retardation, hyperglycemia and dehydration. A wide range of different associated clinical signs including facial dysmorphism, deafness and neurological, cardiac, kidney or urinary tract anomalies are reported. Developmental delay and learning difficulties may also be observed. In this paper we review all the causes of congenital diabetes and all genes and syndromes involved in this pathology. The discovery of the pathogenesis of most forms of congenital diabetes has made it possible to adapt the therapy to the diagnosis and in the forms of alteration of the potassium channels of the pancreatic Beta cells the switch from insulin to glibenclamide per os has greatly improved the quality of life. Congenital diabetes, although it is a very rare form, has been at the must of research in recent years especially for pathogenesis and pharmacogenetics. The most striking difference compared to the more frequent autoimmune diabetes in children (type 1 diabetes) is the possibility of treatment with hypoglycemic agents and the apparent lower frequency of chronic complications.

SUN-280 Sulfonylurea-Responsive Neonatal Diabetes: A Low Hanging Fruit That Has yet to Be Picked?

INTRODUCTION We present 2 contrasting cases of Neonatal Diabetes (NDM) switched from insulin to sulfonylurea in infancy vs adolescence. Importance of having high index of suspicion, making prompt diagnosis, choosing the right therapy is highlighted. METHODOLOGY Case1 13 mo/Female born premature 34 weeks presented with hyperglycemia after birth requiring insulin. Mother herself reported "Type1 Diabetes" (T1DM) diagnosed at 3 weeks. Patient was started on Glyburide 0.1mg/kgBID at 2 weeks, titrated with insulin wean. Blood sugars improved, stable at Glyburide dose 0.2mg/kg/day. HbA1c 6.4%, no hypoglycemia. Genetic testing showed KCNJ11 mutation (c.602G>A). Mother's testing showed same mutation, switched to glyburide, doing well. Case2 13 yo/Male transferred care for "T1DM" on insulin pump, diagnosed at 6 days old. Mother herself reported "T1DM" diagnosed at 2 weeks, on insulin pump. Maternal cousin diagnosed at 1 week, reported to have ABCC8 mutation. Patient's A1c >14%, feeling burnt out. DNA sequencing showed ABCC8 gene mutation (c.4136G>A;p.arg1379His). Glyburide 0.1 mg/kgBID started, titrated weekly with insulin wean. He is currently insulin-free, blood sugars range 72-118 at glyburide dose 0.7 mg/kg/day. Mother's genetic testing pending. DISCUSSION/CONCLUSION Most diabetes in infancy are monogenic. Technology for NDM diagnosis has been available for at least a decade. Oral sulfonylureas may be used in patients with KCNJ11 or ABCC8 mutation. Prompt diagnosis can make dramatic impact on quality of life, as illustrated by Case 1 (likely to be insulin-free for life) vs Case 2 who was burnt out. More education for diabetes providers is paramount regarding NDM and its proper management.

Transition from insulin to sulfonylurea in a child with diabetes due to a mutation in KCNJ11 encoding Kir6.2—initial and long-term response to sulfonylurea therapy

Mutations in the KCNJ11 gene encoding the adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP)) subunit Kir6.2 are the most frequent cause of diabetes in infancy. Sulfonylurea (SU) treatment restores insulin secretion in patients with KCNJ11 mutations. We report a 9-year-old boy who presented at the age of three months with diabetic ketoacidosis. Results Sequencing of the KCNJ11 gene revealed an R201H mutation. Therefore, he was transferred from insulin to oral SU therapy. He required a high-threshold dose before insulin could be discontinued. After transition, a subsequent dose reduction was necessary to avoid hypoglycemia. Improved sustained metabolic control without complications was achieved on a low SU maintenance dose twice daily over 36 months. SU therapy is safe for patients with diabetes due to KCNJ11 mutations. The mechanism of a threshold dose and the twice-daily requirement needs further attention.

Computational Analysis of Mutations in Neonatal Diabetes (KCNJ11) Gene Reveals no Relation with Microsatellites

Gain-of-function mutations in the genes encoding the ATP-sensitive potassium (K (ATP)) channel subunit Kir6.2 (KCNJ11) is a common cause of neonatal diabetes mellitus.(de Wet H 2007 et al). Neonatal diabetes was defined as hyperglycemia that requires insulin treatment and occurs during the first month of life ,it is also known as monogenic diabetes of infancy, which includes both the permanent and the transient types (Barbetti F. Endocr Dev. 2007) and the mutations in KCNJ11 gene causes Neonatal diabetes(Mlynarski W 2007 et al). We tried to find out whether the presence of micro satellite or simple sequence repeats in the KCNJ11 gene has any significance in the generation of these mutations and checked whether these mutations are fallen in the regions of those microsatillites and if so is there any significance of these microsatillites in the functional domains of the each gene. Our analysis reveled that all the microsatellites (National diabetes information clearinghouse) of the KCNJ11 does not contain any mutations and these mutations also does not fall in the functional domains of the KCNJ11 thus indicating that here there is no role of microsatellites in the mutations of KCNJ11 gene.

Does emotional stress play a role in the initiation of autoimmune diabetes in infancy?

Does emotional stress play a role in the initiation of autoimmune diabetes in infancy?

Vitamin D in Type 1 Diabetes Prevention

Limited data from human observational studies suggest that early supplementation with 10 μg/d (400 IU/d) or less of vitamin D may not reduce the risk for type 1 diabetes but that doses of 50 μg/d (2000 IU/d) and higher may have a strong protective effect. Current U.S. recommendations (5–25 μg/d, 200-1000 IU/d) fall in the largely unstudied dose range in between. All infants and children should receive between 5 μg/d and 25 μg/d of supplemental vitamin D, particularly if they have limited sun exposure, live in northern areas, are exclusively breastfed, or are dark skinned. Caretakers of infants and children at increased risk of type 1 diabetes might wish to consider supplementation toward the upper end of that range or above. Additional studies are needed that 1) investigate the association between 25-hydroxyvitamin D and autoantibodies predictive of type 1 diabetes in infancy and beyond, 2) test the ability of vitamin D supplement doses between 5 and 50 μg/d to prevent autoantibodies and/or type 1 diabetes in infancy and beyond, and 3) examine the safety of vitamin D intakes of 25 μg/d and higher. Also, we need to consider the possible benefits of vitamin D supplementation when deciding whether or not to screen children for type 1 diabetes risk and to add type 1 diabetes to the growing list of outcomes that are considered when vitamin D recommendations are next revised.

Early Development and Spreading of Autoantibodies to Epitopes of IA-2 and Their Association with Progression to Type 1 Diabetes

Autoimmunity precedes clinical type 1 diabetes, and indicators of maturing autoimmune responses may be useful markers for disease prediction. To study this, epitope maturation of autoantibodies to the related protein tyrosine phosphatase (PTP)-like autoantigens IA-2 and IA-2beta was examined in sequential samples from birth in a cohort of 21 offspring developing multiple islet autoantibodies and a similar cohort of 48 relatives of patients with type 1 diabetes recruited at an older age. Initial reactivity in offspring was heterogeneous against the IA-2 juxtamembrane region (10/21) and PTP domains (13/21), and both specificity and extent of initial IA-2/IA-2beta autoantibodies were associated with HLA class II genotype. Intra-IA-2 epitope spreading and/or intermolecular spreading to IA-2beta epitopes were observed in seven offspring. In contrast, in older relatives, IA-2/IA-2beta Ab reactivity was stable and spreading rare. Development of diabetes in children was associated with the presence of Abs to the IA-2 juxtamembrane region (risk by age 5 yr, 52% vs 0% in those with PTP domain Abs only; p < 0.02), and 5 of 26 relatives who developed diabetes had IA-2 Abs only against the juxtamembrane region. The findings show that autoantibody reactivity to IA-2/IA-2beta is dynamic in the young, show that the juxtamembrane region of IA-2 is an early IA-2 autoantibody target, and suggest that these Abs are a risk factor for development of type 1 diabetes in infancy.

Fibrocalculous pancreatic diabetes in infancy — two case reports

Fibrocalculous pancreatic diabetes (FCPD) is a form of diabetes secondary to tropical calcific pancreatitis (TCP). The usual age of onset of FCPD is between 15 and 50 years. This paper reports on two unusual cases of FCPD with age of onset below 5 years. This is the first report of FCPD in infancy and raises intriguing questions about the rapidity with which calcification occurs in this entity.

Diabetes mellitus in a sixty-seven-day-old infant.

It has been estimated that from 5 to 8% of all cases of diabetes mellitus occur in children. This incidence decreases with decreasing age. Because of the rarity of diabetes in infancy, this case in a 67-day-old child is being reported. Review of Literature Joslin and co-workers 1 reported seven cases occurring during the first year of life in 1,430 diabetic children. In 1948, Schwartzman, Crusius, and Beirne 2 collected from the world literature reports of 56 instances of diabetes developing in infants under one year of age, and they also described a case of their own. Of the 57 patients, 18 were 3 months of age or younger. Thirteen of these 18 patients died within 15 months after the diagnosis was made, 4 recovered completely, and the remaining patient was still living at the time their report was published. The four who recovered completely apparently did not have true

DIABETES MELLITUS WITH EXTENSIVE GANGRENE IN EARLY INFANCY

Although reports of diabetes with the onset in early infancy are being added to the literature with increasing frequency, the condition in this age group is still sufficiently rare to be of unusual interest. We propose first to report a case that we have observed in which there appears to have been more extensive gangrene than in any similar case heretofore reported; secondly, to review the previously reported cases of gangrene associated with diabetes in infancy, and finally, to tabulate and discuss our collection from the literature of case reports of diabetes with onset in children under 1 year of age. <h3>REPORT OF A CASE</h3> Our patient was a Negro boy aged 3 weeks, who was admitted to the Louisville City Hospital on March 14, 1934. The chief complaint was blackness and dryness of the left leg. The infant was the first-born child of a 16 year old mother. The

DIABETES IN INFANCY AND CHILDHOOD

Diabetes in children is infrequent as compared with its occurrence in adult life. Van Noorden (1) found of 3000 patients 2.8 per cent were in children under 12 years of age. In scanning the literature one is impressed by the fact that no extensive clinical studies have been made on the diabetes of infancy and ehildhood, and consequently no valuable contributions have emanated from this source. Many interesting clinical reports have been made, though they tend more to confirm the general knowledge of diabetes than to shed any new light on the subject. The literature of diabetes is replete with experimental studies on animals. In candor, however, it should be stated that the experimental results fail to explain fully the clinical manifestations in man. In many instances the conditions produced in experimental studies are not duplicated in clinical diabetes. Lorand (2) says that extirpation of the thyroid suppresses glycosuria in depancreatized animals. Normally the pancreas exercises an inhibitory influence...

DIABETES IN INFANCY AND CHILDHOOD

Diabetes in children is infrequent as compared with its occurrence in adult life. Van Noorden (1) found of 3000 patients 2.8 per cent were in children under 12 years of age. In scanning the literature one is impressed by the fact that no extensive clinical studies have been made on the diabetes of infancy and ehildhood, and consequently no valuable contributions have emanated from this source. Many interesting clinical reports have been made, though they tend more to confirm the general knowledge of diabetes than to shed any new light on the subject. The literature of diabetes is replete with experimental studies on animals. In candor, however, it should be stated that the experimental results fail to explain fully the clinical manifestations in man. In many instances the conditions produced in experimental studies are not duplicated in clinical diabetes. Lorand (2) says that extirpation of the thyroid suppresses glycosuria in depancreatized animals. Normally the pancreas exercises an inhibitory influence on the thyroid gland. In a depancreatized animal this influence is lost. In consequence the thyroid secretion is increased in these animals. This increase of thyroid secretion augments the quantity of adrenalin. If the thyroid is removed the secretion of adrenalin diminishes, and at the same time the hyperglycemia and glycosuria disappear. Standing out in apparent contradiction are these facts: Glycosuria has been observed in thyroidectomized animals, and in cases of myxedema diabetes has been described. How can these statements be reconciled?

Diabetes in Infancy and Childhood

Diabetes in Infancy and Childhood