Is there an optimal strategy for real-time continuous glucose monitoring in pediatrics? A 12-month French multi-center, prospective, controlled randomized trial (Start-In!).

AIM: To compare the efficacy of three strategies for real-time continuous glucose monitoring (RT-CGM) over 12 months in children and adolescents with type 1 diabetes. METHODS: A French multicenter trial (NCT00949221) with a randomized, controlled, prospective, open, and parallel-group design was conducted. After 3 months of RT-CGM, patients were allocated to one of three groups: return to self-monitoring of blood glucose, continuous CGM (80% of the time), or discontinuous CGM (40% of the time). The primary outcome was hemoglobin A1c (HbA1c) levels from 3 to 12 months. The secondary outcomes were acute metabolic events, hypoglycemia, satisfaction with CGM and cost. RESULTS: We included 151 subjects, aged 2 to 17 years, with a mean HbA1c level of 8.5% (SD0.7; 69 mmol/mol). The longitudinal change in HbA1c levels was similar in all three groups, at 3, 6, 9 and 12 months. The medical secondary endpoints did not differ between groups. The rate of severe hypoglycemia was significantly lower than that for the pretreatment year for the entire study population. Subjects reported consistent use and good tolerance of the device, regardless of age or insulin treatment. The use of full-time RT-CGM for 3 months costs the national medical insurance system €2629 per patient. CONCLUSION: None of the three long-term RT-CGM strategies evaluated in pediatric type 1 diabetes was superior to the others in terms of HbA1c levels. CGM-use for 3 months decreased rates of severe hypoglycemia. Our results confirm the feasibility of long-term RT-CGM-use and the need to improve educational support for patients and caregivers.

Characteristics of newly diagnosed type 1 diabetes in paediatric and adult population from Reims University Hospital, France from 1997 to 2019.

French health insurance data showed that the incidence of type 1 diabetes mellitus (T1DM) in children increased over the years to 2015. The objective of our study was to assess the evolution of the number of incident cases of paediatric and adult type 1 diabetes in our institution, and to describe their clinical presentation and its evolution. All patients with T1DM managed at diagnosis at Reims University Hospital between 1997 and 2019 were included. The clinical and biological data were extracted from the Champagne-Ardenne Diabetes Network database. Included were 847 patients with a median age of 10.3 years. Diagnosis was established in 71% of cases before 15 years, 7.4% after 35 years. The number of newly diagnosed cases was 3.6-times higher in 2019 compared to 1997. Ketoacidosis, the frequency of which decreased with age (P < 0.0001), revealed diabetes in a total of 32% of cases and in 46% of children under 5 years. It was more severe in children than in adults (P = 0.03), and its frequency increased over the study period. Hypotrophy was found in 23% of children under 15 years of age, and was more pronounced before 5 years of age, with no improvement over time. We saw an increase in the frequency of obesity or overweight among adults. Our study showed an increase in incident cases of diabetes in our hospital that continued over time for both children and adults. Clinical features at diagnosis deteriorated during this period for those under 15 years of age with an increase in ketoacidosis frequency.

Metabolic control in children with diabetes mellitus who are younger than 6 years at diagnosis: continuous subcutaneous insulin infusion as a first line treatment?

OBJECTIVE: To assess long-term metabolic outcomes in children with diabetes mellitus that was diagnosed when they were <6 years old. STUDY DESIGN: A cohort of 66 children with diabetes mellitus that had a duration of at least 5 years and was diagnosed before they were 6 years old. Thirty-four children were treated at diagnosis with multiple daily subcutaneous insulin injections (MDI), and all these children, except 3, were switched to continuous subcutaneous insulin infusion (CSII; group A). Thirty-two children received CSII as initial treatment (group B). RESULTS: Hemoglobin A1c values were significantly lower in patients receiving CSII than MDI during all the 8 years of follow-up except one (year 1: 6.9%+/-0.9% versus 7.6%+/-1%, P=.011 ; year 4: 7.4%+/-0.8% versus 8.1%+/-0.9%, P=.006; year 7: 7.6%+/-0.5% versus 8.3%+/-0.8%, P=.001). The incidence of severe hypoglycemia was greatly decreased for the CSII group (9.8 versus 22.3 episodes/100 patient-years, P=.016). In group A, hemoglobin A1c values increased during the study period, and in group B, they increased only during the first 2 years and remained constant thereafter. Only 9.1% of patients did not use or abandoned CSII. CONCLUSION: CSII in children<6 years of age enables better long-term metabolic control and lowers the risk of severe hypoglycemia better than MDI, especially when initiated at diagnosis.

Assessment of patient-led or physician-driven continuous glucose monitoring in patients with poorly controlled type 1 diabetes using basal-bolus insulin regimens: a 1-year multicenter study.

OBJECTIVE: The benefits of real-time continuous glucose monitoring (CGM) have been demonstrated in patients with type 1 diabetes. Our aim was to compare the effect of two modes of use of CGM, patient led or physician driven, for 1 year in subjects with poorly controlled type 1 diabetes. RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes aged 8-60 years with HbA(1c) ≥ 8% were randomly assigned to three groups (1:1:1). Outcomes for glucose control were assessed at 1 year for two modes of CGM (group 1: patient led; group 2: physician driven) versus conventional self-monitoring of blood glucose (group 3: control). RESULTS: A total of 257 subjects with type 1 diabetes underwent screening. Of these, 197 were randomized, with 178 patients completing the study (age: 36 ± 14 years; HbA(1c): 8.9 ± 0.9%). HbA(1c) improved similarly in both CGM groups and was reduced compared with the control group (group 1 vs. group 3: -0.52%, P = 0.0006; group 2 vs. group 3: -0.47%, P = 0.0008; groups 1 + 2 vs. group 3: -0.50%, P < 0.0001). The incidence of hypoglycemia was similar in the three groups. Patient SF-36 questionnaire physical health score improved in both experimental CGM groups (P = 0.004). Sensor consumption was 34% lower in group 2 than in group 1 (median [Q1-Q3] consumption: group 1: 3.42/month [2.20-3.91] vs. group 2: 2.25/month [1.27-2.99], P = 0.001). CONCLUSIONS: Both patient-led and physician-driven CGM provide similar long-term improvement in glucose control in patients with poorly controlled type 1 diabetes, but the physician-driven CGM mode used fewer sensors.

Incremental value of continuous glucose monitoring when starting pump therapy in patients with poorly controlled type 1 diabetes: the RealTrend study.

OBJECTIVE: To compare the improvements in glycemic control associated with transitioning to insulin pump therapy in patients using continuous glucose monitoring versus standard blood glucose self-monitoring. RESEARCH DESIGN AND METHODS: The RealTrend study was a 6-month, randomized, parallel-group, two-arm, open-label study of 132 adults and children with uncontrolled type 1 diabetes (A1C >or=8%) being treated with multiple daily injections. One group was fitted with the Medtronic MiniMed Paradigm REAL-Time system (PRT group), an insulin pump with integrated continuous subcutaneous glucose monitoring (CGM) capability, with instructions to wear CGM sensors at least 70% of the time. Conventional insulin pump therapy was initiated in the other group (continuous subcutaneous insulin infusion [CSII] group). Outcome measures included A1C and glycemic variability. RESULTS: A total of 115 patients completed the study. Between baseline and trial end, A1C improved significantly in both groups (PRT group -0.81 +/- 1.09%, P < 0.001; CSII group -0.57 +/- 0.94%, P < 0.001), with no significant difference between groups. When the 91 patients who were fully protocol-compliant (including CGM sensor wear >or=70% of the time) were considered, A1C improvement was significantly greater in the PRT group (P = 0.004) (PRT group -0.96 +/- 0.93%, P < 0.001; CSII group -0.55 +/- 0.93%, P < 0.001). Hyperglycemia parameters decreased in line with improvements in A1C with no impact on hypoglycemia. CONCLUSIONS: CGM-enabled insulin pump therapy improves glycemia more than conventional pump therapy during the first 6 months of pump use in patients who wear CGM sensors at least 70% of the time.

Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy: a report from the French ND (Neonatal Diabetes) Study Group.

OBJECTIVE: Permanent neonatal diabetes (PND) is defined by chronic hyperglycemia due to severe nonautoimmune insulin deficiency diagnosed in the first months of life. Several genes, including KCNJ11 and ABCC8, which encode the two subunits of the ATP-sensitive K(+) channel (K(ATP) channel) can cause PND. Mutations in the insulin (INS) gene have been recently described in families with neonatal diabetes. Our study aimed to investigate the genetic anomalies and clinical heterogeneity in PND patients who are negative for a K(ATP) channel mutation. RESEARCH DESIGN AND METHODS: We screened the INS gene by direct sequencing in 38 PND patients and in one child with nonautoimmune early-infancy diabetes, where no mutation in GCK, KCNJ11, and ABCC8 was identified. A detailed clinical phenotyping of the patients was carried out to specify the diabetes features in those found with an INS mutation. RESULTS: We identified three missense mutations in the INS gene in four probands. Two of four mutations were inherited in a dominant manner, and the familial description evidenced a marked variability in age of diagnosis and disease progression. In our cohort, the INS mutations may represent approximately 10% of all permanent neonatal diabetes cases, having a later presentation of diabetes and no associated symptoms compared with cases with K(ATP) channel mutations. CONCLUSIONS; Heterozygous INS gene mutations can cause isolated permanent early-infancy diabetes and should be assessed in neonatal as well as in childhood diabetes appearing like type 1, when autoimmune markers are absent. New pharmacogenomic strategies may be applicable, since residual beta-cell function is still present in some patients.

Deletion 2q36.2q36.3 with multiple renal cysts and severe mental retardation.

Interstitial 2q36 deletion is a rare event. We report on a patient with a de novo del(2)(q36.2q36.3) interstitial deletion of the long arm of chromosome 2 diagnosed by classical banding. The phenotype comprised facial dysmorphism, enlarged kidneys with multiple renal cysts, abnormal minora labia, asymmetric lower limbs with dysplastic patella, and severe mental retardation. By physical mapping, using array-comparative genomic hybridisation (CGH) confirmed by Fluorescent In Situ Hybridisation (FISH), the breakpoints of the deletion were mapped and the size of the deletions was measured: 5.61+/-0.19Mb. A skin biopsy was analysed using electronic microscopy showing an alteration of the structure and organisation of the dermal and peri-neuronal basement membrane. The relation between the phenotype and the deletion of both COL4A4 and COL4A3 genes, located in 2q36.3 loci, as well as the disruption of TRIP12 were discussed.

Apparent mineralocorticoid excess: report of six new cases and extensive personal experience.

In mineralocorticoid target tissues such as the cortical collecting duct in the kidney, the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) is responsible for the peripheral inactivation of cortisol to cortisone, thereby protecting the mineralocorticoid receptor from inappropriate activation by cortisol. Mutations in the HSD11B2 gene cause the syndrome of apparent mineralocorticoid excess, an autosomal recessive form of inherited hypertension in which cortisol acts as a potent mineralocorticoid. Herein are described six new families with mutations in the HSD11B2 gene causing hypokalemic hypertension, with low plasma aldosterone and low renin levels in affected individuals, indicating mineralocorticoid hypertension. Profiling of urinary steroid metabolites showed decreased cortisol inactivation, with urinary tetrahydrocortisol and tetrahydrocortisone ratio (THF + 5alphaTHF)/THE ranging 2.4 to 40 and nearly absent urinary free cortisone in all but one case. Genetic analysis of the HSD11B2 gene from these patients with apparent mineralocorticoid excess revealed distinct homozygous point mutations in four families, a compound heterozygous mutation in one family, and a large 23-bp exonic insert with frameshift and disruption of the amino acid sequence in another family. Expression studies of mutants that were expressed in HEK-293 cells showed marked reduction or abolition of 11betaHSD2 enzymatic activity. These cases are reviewed along with previous ones from the authors' extensive personal experience to highlight the importance of 11betaHSD2 in the understanding of a new biologic principle in hormone action, demonstrating that local metabolism of the glucocorticoid hormones into inactive derivatives by the enzyme 11betaHSD2 is one of the mechanisms that intervene to allow specific aldosterone regulatory effects.