A New Tool to Identify Pediatric Patients with Atypical Diabetes Associated with Gene Polymorphisms.

Background: Recent diabetes subclassifications have improved the differentiation between patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus despite several overlapping features, yet without considering genetic forms of diabetes. We sought to facilitate the identification of monogenic diabetes by creating a new tool that we validated in a pediatric maturity-onset diabetes of the young (MODY) cohort. Methods: We first created the DIAgnose MOnogenic DIAbetes (DIAMODIA) criteria based on the pre-existing, but incomplete, MODY calculator. This new score is composed of four strong and five weak criteria, with patients having to display at least one weak and one strong criterion. Results: The effectiveness of the DIAMODIA criteria was evaluated in two patient cohorts, the first consisting of patients with confirmed MODY diabetes (n=34) and the second of patients with T1DM (n=390). These DIAMODIA criteria successfully detected 100% of MODY patients. Multiple correspondence analysis performed on the MODY and T1DM cohorts enabled us to differentiate MODY patients from T1DM. The three most relevant variables to distinguish a MODY from T1DM profile were: lower insulin-dose adjusted A1c score ≤9, glycemic target-adjusted A1c score ≤4.5, and absence of three anti-islet cell autoantibodies. Conclusion: We validated the DIAMODIA criteria, as it effectively identified all monogenic diabetes patients (MODY cohort) and succeeded to differentiate T1DM from MODY patients. The creation of this new and effective tool is likely to facilitate the characterization and therapeutic management of patients with atypical diabetes, and promptly referring them for genetic testing which would markedly improve clinical care and counseling, as well.

Post-Hypoglycemic hyperglycemia are highly relevant markers for stratification of glycemic variability and partial remission status of pediatric patients with new-onset type 1 diabetes.

AIMS: To evaluate whether parameters of post-hypoglycemic hyperglycemia (PHH) correlated with glucose homeostasis during the first year after type 1 diabetes onset and helped to distinguish pediatric patients undergoing partial remission or not. METHODS: In the GLUREDIA (GLUcagon Response to hypoglycemia in children and adolescents with new-onset type 1 DIAbetes) study, longitudinal values of clinical parameters, continuous glucose monitoring metrics and residual ß-cell secretion from children with new-onset type 1 diabetes were analyzed during the first year after disease onset. PHH parameters were calculated using an in-house algorithm. Correlations between PHH parameters (i.e., PHH frequency, PHH duration, PHH area under the curve [PHHAUC]) and glycemic homeostasis markers were studied using adjusted mixed-effects models. RESULTS: PHH parameters were strong markers to differentiate remitters from non-remitters with PHH/Hyperglycemia duration ratio being the most sensitive (ratio<0.02; sensitivity = 86% and specificity = 68%). PHHAUC moderately correlated with parameters of glucose homeostasis including TIR (R2 = 0.35, p-value < 0.05), coefficient of variation (R2 = 0.22, p-value < 0.05) and Insulin-Dose Adjusted A1c (IDAA1C) (R2 = 0.32, p-value < 0.05) and with residual ß-cell secretion (R2 = 0.17, p-value < 0.05). Classification of patients into four previously described glucotypes independently validated PHH parameters as reliable markers of glucose homeostasis and improved the segregation of patients with intermediate values of IDAA1C and estimated C-peptide (CPEPEST). Finally, a combination of PHH parameters identified groups of patients with specific patterns of hypoglycemia. CONCLUSION: PHH parameters are new minimal-invasive markers to discriminate remitters from non-remitters and evaluate glycemic homeostasis during the first year of type 1 diabetes. PHH parameters may also allow patient-targeted therapeutic management of hypoglycemic episodes.

Deep Analysis of Clinical Parameters and Temporal Evolution of Glycemic Parameters Based on CGM Data for the Characterization of Severe Hypoglycemia in a Cohort of Children and Adolescents with Type 1 Diabetes.

This study aims to evaluate the determinants and clinical markers of patients at risk for severe hypoglycemia (SH) in children and adolescents with type 1 diabetes. In the EPI-GLUREDIA study, clinical parameters and continuous glucose monitoring metrics from children and adolescents with type 1 diabetes were retrospectively analyzed between July 2017 and June 2022. Their clinical parameters were collected during traditional and quarterly medical consultations according to whether they experienced severe hypoglycemia or not. Then, continuous glucose monitoring metrics were analyzed on days surrounding SH during specific periods. According to the glycemic parameters, glycemic hemoglobin and glycemic mean were significantly lower in the three months preceding a SH compared with during three normal months (p < 0.05). Moreover, the time spent in hypoglycemia(time below the range, TBR<3.3) and its strong correlation (R = 0.9, p < 0.001) with the frequency of SH represent a sensitive and specific clinical parameter to predict SH (cut-off: 9%, sensitivity: 71%, specificity: 63%). The second finding of the GLUREDIA study is that SH is not an isolated event in the glycemic follow-up of our T1DM patients. Indeed, most of the glycemic parameters (i.e., glycemic mean, glycemic variability, frequency of hypoglycemia, and glycemic targets) vary considerably in the month preceding an SH (all p < 0.05), whereas most of these studied glycemic parameters remain stable in the absence of a severe acute complication (all p > 0.05). Furthermore, the use of ROC curves allowed us to determine for each glycemic parameter a sensitive or specific threshold capable of more accurately predicting SH. For example, a 10% increase in the frequency of hypoglycemia predicts a risk of near SH with good combination of sensitivity and specificity (sensitivity: 80%, specificity: 60%). The GLUREDIA study aimed to target clinical and glycemic parameters to predict patients at risk for SH. First, we identified TBR<3.3 < 9% as a sensitive and specific tool to reduce the frequency of SH. In addition, SH was not an isolated event but rather it was accompanied by glycemic disturbances in the 30 days before SH.

Congenital hyperinsulinemic hypoglycemia (HH) requiring treatment as the presenting feature of Kabuki syndrome.

Kabuki syndrome is a congenital condition characterized by a set of facial dysmorphic features that often help the clinician to suspect the diagnosis. However, more insidious symptoms can rarely occur, such as manifestations of hypoglycemia in newborns with congenital hyperinsulinism hypoglycemia, especially when a variant of the KDM6A gene is found. In those cases, a treatment with diazoxide can be started and can be replaced with lanreotide if a satisfying glycemic control is not achieved. We report the case of a female patient born at 37 weeks of gestational age, without any obvious facial dysmorphic features, after a non-complicated pregnancy, that presented with feeding difficulties, drowsiness, and irritability revealing a hyperinsulinemic hypoglycemia. Further testing at 6 months old found a KDM6A mutation. The patient was initially treated by diazoxide alone, but its dosage had to be lowered because of the occurrence of treatment side effects, and lanreotide had been added to maintain acceptable blood sugar levels. A congenital hyperinsulinemia hypoglycemia revealed heterozygous truncating variant in the KDM6A gene, also known as X-linked Kabuki syndrome in a newborn. In cases of neonatal hypoglycemia, the first-line therapy is diazoxide. Our report shows that analogues of somatostatin such as lanreotide should be considered if the diazoxide regimen is not tolerated.