Successful treatment of young infants presenting neonatal diabetes mellitus with continuous subcutaneous insulin infusion before genetic diagnosis

Neonatal Diabetes: Nurse Navigator Role

In recent years, meters for continuous monitoring of interstitial fluid glucose have been introduced to help people with type 1 diabetes mellitus (T1DM) to achieve better control of their disease. The objective of this project was to summarise the evidence on the clinical effectiveness and cost-effectiveness of the MiniMed(®) Paradigm™ Veo system (Medtronic Inc., Northridge, CA, USA) and the Vibe™ (Animas(®) Corporation, West Chester, PA, USA) and G4(®) PLATINUM CGM (continuous glucose monitoring) system (Dexcom Inc., San Diego, CA, USA) in comparison with multiple daily insulin injections (MDIs) or continuous subcutaneous insulin infusion (CSII), both with either self-monitoring of blood glucose (SMBG) or CGM, for the management of T1DM in adults and children. A systematic review was conducted in accordance with the principles of the Centre for Reviews and Dissemination guidance and the National Institute for Health and Care Excellence Diagnostic Assessment Programme manual. We searched 14 databases, three trial registries and two conference proceedings from study inception up to September 2014. In addition, reference lists of relevant systematic reviews were checked. In the absence of randomised controlled trials directly comparing Veo or an integrated CSII + CGM system, such as Vibe, with comparator interventions, indirect treatment comparisons were performed if possible. A commercially available cost-effectiveness model, the IMS Centre for Outcomes Research and Effectiveness diabetes model version 8.5 (IMS Health, Danbury, CT, USA), was used for this assessment. This model is an internet-based, interactive simulation model that predicts the long-term health outcomes and costs associated with the management of T1DM and type 2 diabetes. The model consists of 15 submodels designed to simulate diabetes-related complications, non-specific mortality and costs over time. As the model simulates individual patients over time, it updates risk factors and complications to account for disease progression. Fifty-four publications resulting from 19 studies were included in the review. Overall, the evidence suggests that the Veo system reduces hypoglycaemic events more than other treatments, without any differences in other outcomes, including glycated haemoglobin (HbA1c) levels. We also found significant results in favour of the integrated CSII + CGM system over MDIs with SMBG with regard to HbA1c levels and quality of life. However, the evidence base was poor. The quality of the included studies was generally low, often with only one study comparing treatments in a specific population at a specific follow-up time. In particular, there was only one study comparing Veo with an integrated CSII + CGM system and only one study comparing Veo with a CSII + SMBG system in a mixed population. Cost-effectiveness analyses indicated that MDI + SMBG is the option most likely to be cost-effective, given the current threshold of £30,000 per quality-adjusted life-year gained, whereas integrated CSII + CGM systems and Veo are dominated and extendedly dominated, respectively, by stand-alone, non-integrated CSII with CGM. Scenario analyses did not alter these conclusions. No cost-effectiveness modelling was conducted for children or pregnant women. The Veo system does appear to be better than the other systems considered at reducing hypoglycaemic events. However, in adults, it is unlikely to be cost-effective. Integrated systems are also generally unlikely to be cost-effective given that stand-alone systems are cheaper and, possibly, no less effective. However, evidence in this regard is generally lacking, in particular for children. Future trials in specific child, adolescent and adult populations should include longer term follow-up and ratings on the European Quality of Life-5 Dimensions scale at various time points with a view to informing improved cost-effectiveness modelling. PROSPERO Registration Number CRD42014013764. The National Institute for Health Research Health Technology Assessment programme.

Type 1 Diabetes in Children and Adolescents.

Neonatal diabetes mellitus (NDM) is a rare genetic disease characterized by severe hyperglycemia requiring insulin therapy with onset mostly within the first 6 months and rarely between 6-12 months of age. The disease can be classified into transient (TNDM) or permanent neonatal diabetes mellitus (PNDM), or it can be a component of a syndrome. The most frequent genetic causes are abnormalities of the 6q24 chromosomal region and mutations of the ABCC8 or KCNJ11 genes coding for the pancreatic beta cell’s potassium channel (KATP). After the acute phase, patients with ABCC8 or KCNJ11 mutations treated with insulin therapy can switch to hypoglycemic sulfonylureas (SU). These drugs close the KATP channel binding the SUR1 subunit of the potassium channel and restoring insulin secretion after a meal. The timing of this switch can be different and could affect long-term complications. We describe the different management and clinical outcome over the time of two male patients with NDM due to KCNJ11 pathogenetic variants. In both cases, continuous subcutaneous insulin infusion pumps (CSII) were used to switch therapy from insulin to SU, but at different times after the onset. The two patients kept adequate metabolic control after the introduction of glibenclamide; during the treatment, insulin secretion was evaluated with c-peptide, fructosamine, and glycated hemoglobin (HbA1c), which were within the normal range. In neonates or infants with diabetes mellitus, genetic testing is an indispensable diagnostic tool and KCNJ11 variants should be considered. A trial of oral glibenclamide must be considered, switching from insulin, the first line of NDM treatment. This therapy can improve neurological and neuropsychological outcomes, in particular in the case of earlier treatment initiation. A new modified protocol with glibenclamide administered several times daily according to continuous glucose monitoring profile indications, was used. Patients treated with glibenclamide maintain good metabolic control and prevent hypoglycemia, neurological damage, and apoptosis of beta cells during long‐term administration.

The history of the development of glucose sensors is synonym of the history of biosensor research. Glucose sensors created the past and current largest market in the industrialized biosensors. The most of the commercially available glucose sensors have been dedicated to the disposable sensor strips for self-monitoring of blood glucose (SMBG), thereby diabetic patients know which treatments and amounts of treatments to self-administer and to learn how activities affect their blood glucose levels. Currently, continuous glucose monitoring (CGM) systems have been recognized as the ideal monitoring systems for glycemic control of diabetic patients, expecting the replacement of SMBG sensors. Glucose monitoring using SMBG sensors requires taking tiny blood sample using a “lancet” to prick your finger or some other alternate sites for testing, whereas CGM systems monitor glucose level at interstitial fluid (ISF) where CGM sensor is inserted. At present, the glucose concentration in blood and ISF samples are recognized as the clinically relevant values. In 2018, the U.S. Food and Drug Administration (FDA) approved a medical device comprising CGM system, a continuous subcutaneous insulin infusion pump and a control algorithm that can supply an appropriate amount of basal insulin based on the CGM results as an artificial pancreas. Consequently, it became possible to automatically and continuously control the blood glucose level. In 2019, synthetic receptor employing long-term implantable CGM system, was approved as the prescription device, which realized up to 90 days (180 days in Europe) operation. These technological achievements boosted up CGM systems and sensors as the flagship technologies in the biosensor research.In this presentation, I will overview the current status and future perspectives of sensors for CGM systems.

Neonatal diabetes mellitus (NDM) results from impaired insulin secretion, occurring within the first 6 months of life. NDM is classified as transient NDM (TNDM) or permanent NDM. To date there are no universal guidelines regarding its management. Intravenous insulin infusion represents the first and most adequate therapeutic approach for sustained hyperglycemia, but this can provide only a short-term solution. Several factors should be taken into account in the choice of the long-term treatment. We describe our experience with two infants affected by TNDM. The first child was treated with continuous subcutaneous insulin infusion, whereas the second infant was treated with subcutaneous insulin glargine injections. Our experience shows that the two different therapeutic approaches, if properly managed, are equally effective.

Diabète néonatal : une maladie aux multiples mécanismes

Background: Permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of hyperglycemia within the first six months of life. Their diabetes is associated with partial or complete insulin deficiency with variable degree of intrauterine growth retardation. Insulin therapy corrects the hyperglycemia and results in improvement of growth. However, no studies have reported the longitudinal growth of these infants (head circumference, length and weight gain) after starting insulin therapy. Patients and methods: We assessed the growth parameters weight (Wt), Length (L) and head circumference (HC) in 9 infants with PNDM, during the first 2 years of their postnatal life. Five infants were on insulin pump therapy (CSII) and 4 were on multiple doses of insulin injection (MDI) therapy. Results: On insulin therapy for 20±4 months catch-up growth occurred in the majority of infants. L-SDS increased from -1.45 to -0.65 , HC-SDS from -2.3 to - 0.51 and Wt-SDS increased from -1.94 to - 0.7 at the end of the 20±4 months of age, after starting insulin therapy. Two out of 9 infants had a L-SDS <-2 , in 4 Wt-SDS was <-2 and in 1 the HC-SDS was <-2 at at 20±4 months of postnatal growth. The level of HbA1c was lower in infants on CSII compared to those on MDI (9.6±1%) compared to those on MDI (10.2±2%). However, growth parameters improved significantly in both groups (CSII and MDI) with no significant difference among them. Conclusions: Infants with PNDM with positive anti-GAD and antiTPO were diagnosed later and their intra-uterine and postnatal growth differed compared to those with negative antibodies. The majority of infants with PNDM exhibited significant catch up growth within the first two years of life irrespective of the etiology of diabetes. HbA1c appeared to be better in infants with PNDM on CSII therapy when compared to those on MDI therapy. (www.actabiomedica.it)

To compare the long-term outcomes of continuous subcutaneous insulin infusion (CSII) pump therapy with the clinical and metabolic parameters recorded during multiple daily insulin (MDI) therapy. CSII pump was used by volunteer adolescents, who had a duration of diabetes mellitus (DM) longer than one year, regularly attended periodic examinations for the last year, measured and recorded blood glucose levels on average 3 to 4 times a day, and did not achieve the preferred metabolic control even though the use of MDI therapy. Carbohydrate counting and flexible MDI therapy was taught to these patients before CSII pump implantation. The metabolic and clinical parameters of the patients for the post-CSII pump period were compared with the data of flexible and non-flexible MDI periods. The mean CSII pump implantation age of the 17 adolescents enrolled in the study was 15.53 +/- 1.8 years, duration of DM 6.77 +/- 4.05 years, flexible MDI injection duration 0.70 +/- 0.20 years, and duration of CSII pump use 2.07 +/- 1.12 years. A decrease was detected in HbA(1c) levels of the patients with transition to CSII pump compared to flexible and non-flexible MDI injection periods; however, this decrease was not statistically significant (7.71%, 8.21%, and 8.71%, respectively, p = 0.105). No statistically significant difference was detected in frequency of hypoglycemia, lipid profiles, total daily insulin requirement, and BMI SDS values of the patients when data of the post-CSII pump state were compared with that of flexible and non-flexible MDI therapy groups. In adolescents, it was found that CSII pump therapy is efficient and safe without any increased risk for weight gain and hypoglycemia compared to flexible and non-flexible MDI injection periods. The present study also demonstrated that flexible MDI injection therapy might be efficiently and safely used in patients who cannot receive CSII pump therapy due to social and/or financial factors.

Neonatal diabetes mellitus (NDM) is a rare genetic condition with an incidence of 1 in 100,000 (1) that presents before 1 year of age (2). There are two main clinical forms of NDM: permanent NDM (PNDM), which requires lifelong treatment with insulin, and transient NDM (TNDM), which may spontaneously remit and sometimes recurs in the second to third decade of life. In most cases, TNDM and PNDM cannot be distinguished clinically at the time of diagnosis, and genetic analysis needs to be performed. The genetic origin for >90% of TNDM cases has been established. In TNDM, 68% of the cases have abnormalities in an imprinted region on chromosome 6q24; 10% have KCNJ11 gene mutations; and 13% have an ABCC8 gene mutation (3). Multiple genes involved in pancreatic development, β-cell apoptosis, or dysfunction cause PNDM (4). The most common mutations are in the KATP channel genes KCNJ11 (30%) and ABCC8 (11%) or the insulin (INS) gene (13%) (3). Insulin is acutely required in most infants to establish metabolic control in NDM (5). Early initiation of sulfonylurea treatment is also recommended (6) as a treatment option in selected cases of NDM caused by ABCC8 and KCNJ11 mutations, and, in responsive cases, sulfonylurea therapy provides better long-term metabolic control (7,8) and could even improve neurodevelopmental outcomes (9). The MiniMed 530G (Medtronic, Inc., Northridge, CA) is a first-generation artificial pancreas system approved by the U.S. Food and Drug Administration (FDA) on 26 September 2013 for the management of diabetes in people ≥16 years of age. The system includes an external glucose sensor and insulin pump, transmitter, glucose meter, and therapy management software. Sensor signals are transmitted to the MiniMed 530G insulin pump and converted into glucose values every 5 minutes. Fingerstick blood glucose testing is still required for both …

Understanding neonatal diabetes mellitus

Preview Technology offers many solutions to improve diabetes care in delivering more precise dosing of insulin and measuring glucose. Nurses are challenged to keep up with the latest technological advances available to individuals with diabetes. This chapter addresses what nurses need to know for safe and effective care of patients with diabetes wearing currently available continuous subcutaneous insulin infusion (CSII) pumps and continuous glucose monitoring (CGM) systems. Few health-care providers (HCP) will have practical knowledge of the operation of all the devices available in the rapidly changing field of diabetes technologies. HCPs will need to rely on the individual with diabetes, their caregivers, and diabetes technology experts and the manufactures for up-to-date operational information for each device. Insulin pumps have been in use for &amp;gt;35 years for insulin replacement therapy. Estimated use in patients with type 1 diabetes (T1D) is near 20–30% and &amp;lt;1% in insulin-treated type 2 diabetes (T2D). According to Tucker, “When used correctly, insulin pumps can provide more convenient insulin delivery for patients and may improve blood glucose control.” CGM systems have been in use just over 10 years. CGM devices are designed to augment self–blood glucose monitoring for individuals with diabetes. CGM devices measure interstitial glucose. Nurses need to understand basic information about these devices to safely and effectively care for patients in all health-care settings.

The current status of continuous subcutaneous insulin infusion and continuous glucose monitoring systems in the Community of Madrid

Objective To explore the clinical and genetic characteristics of neonatal diabetes mellitus (NDM) induced by insulin gene mutation. Methods A Chinese pedigree of permanent neonatal diabetes mellitus (PNDM) diagnosed in Peking Union Medical College Hospital in December 2017 was analyzed for the clinical characteristics and laboratory examinations. Sanger sequencing was performed to identify mutations in KCNJ11, ABCC8 and insulin gene in proband and her parents. Data of NDM induced by mutations in insulin gene were collected and analyzed. Results A heterozygous mutation in insulin gene (NM_000207.2) located in exon 2 (c.265C>T; p.R89C) was identified in the proband. The mutation changes the structure of insulin molecule. Literature review found that there were altogether 12 pathogenic mutations in insulin gene which had been reported to result in NDM. All NDM caused by mutations in insulin gene were classified as PNDM. The onset age of PNDM with mutations in the insulin gene ranges widely, from several weeks to several years, usually with diabetic ketoacidosis or marked hyperglycemia, with very low or undetectable C-peptide values. The patients usually need to be treated with insulin once diagnosed. Conclusion There are PNDM pedigrees caused by insulin gene (R89C) heterozygous mutation in Chinese population. Genetic testing including channel genes (KCNJ11 and ABCC8) and insulin gene should be conducted in patients with suspected PNDM for early diagnosis and appropriate treatment. Key words: Diabetes mellitus; Infant, newborn; Insulin gene; Gene mutation; Insulin therapy

Diabetes technology and devices transform the lives of people with diabetes.