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.

Characterization, evolution and risk factors of diabetes and prediabetes in a pediatric cohort of renal and liver transplant recipients.

Background: Hyperglycemia (HG) and prediabetes are rarely sought in pediatric liver (LT) and renal (RT) transplantation, yet their presence indicates a high risk of diabetes and cardiovascular disease. The objectives of our DIABGRAFT study were to retrospectively (rDIABGRAFT) and longitudinally (pDIABGRAFT) characterize HG and (pre)diabetes in a cohort of children with LT or/and RT. Methods: We retrospectively analyzed risk factors of HG from 195 children with LT from 2012 to 2019 and twenty children with RT from 2005 to 2019 at Cliniques universitaires Saint-Luc. In addition, we prospectively followed four LT and four RT children to evaluate the evolution of their glucose metabolism. Results: Our rDIABGRAFT study showed that 25% and 35% of LT and RT children respectively presented transient HG and 20% of RT developed diabetes. The occurrence of HG was associated with the use of glucocorticoids and with acute events as graft rejection and infection. In our pDIABGRAFT cohort, biological markers of diabetes were in the normal range for HbA1C, fasting glucose and insulin levels. However, oral glucose tolerance test and glucose sensors showed insulin resistance, impaired glucose tolerance and HG in the post-prandial afternoon period. Conclusion: Our study shows that children with LT and RT were more at risk of developing HG when glucocorticoids were required and that HbA1C and fasting glucose lack sensitivity for early detection of glucose intolerance. Also, measurement of glycemia immediately after the transplantation and in postprandial period is key to detect dysglycemia since insulin resistance prevailed in our cohort. ClinicalTrialsgov ID: NCT05464043.

Characterization and risk factors of hyperglycaemia during treatment of childhood hematologic malignancies.

BACKGROUND: Secondary forms of diabetes are often understudied and underdiagnosed in children and adolescents with cancer. The objectives of our cohort study were to study the incidence and risk factors for hyperglycaemia in leukaemia and lymphoma patients. METHODS: We retrospectively collected 15 years of data from paediatric patients treated for acute lymphoblastic leukaemia (ALL), Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL) immediately at cancer diagnosis. We studied risk factors for hyperglycaemia in univariate and multivariate analyses. RESULTS: Our study cohort included 267 patients corresponding to 179 patients with ALL, 48 with NHL and 40 with HL. Eighteen per cent of ALL patients (32/179) and 17% of NHL patients (8/48) developed hyperglycaemia, with more than 61% developing hyperglycaemia within the first month of treatment. No hyperglycaemia was observed in HL patients. Multivariate analysis showed the following hyperglycaemia risk factors for ALL patients: overweight or obesity (OR 3.793) and pubertal onset (OR 4.269) at cancer diagnosis, steroid-resistant disease (OR 3.445) and hematopoietic stem cell transplant (HSCT) (OR 4.754). CONCLUSION: In our cohort, 18% of patients with ALL or NHL developed early-onset hyperglycaemia after chemotherapy/radiotherapy. Patients with ALL with increased hyperglycaemia risk can be readily identified by measuring BMI and puberty stage at cancer diagnosis. Also, glucose monitoring should be reinforced when patients show steroid-resistant disease and/or require HSCT.

Early Treatment with Empagliflozin and GABA Improves ß-Cell Mass and Glucose Tolerance in Streptozotocin-Treated Mice.

While the autoimmune character of T1D (type 1 diabetes) is being challenged, it is currently recognized that inflammation plays a key role in its development. We hypothesized that glucotoxicity could contribute to ß-cell mass destruction through participation in islet inflammation. We evaluated the potential of empagliflozin (EMPA) and GABA (gamma-aminobutyric acid) to protect ß-cell mass against glucotoxicity and to increase ß-cell mass after diagnosis of T1D. Empagliflozin is a SGLT2 (sodium-dependent glucose cotransporter) inhibitor which thereby blocks glucose recapture by the kidney and promotes glucose excretion in urine. GABA is an inhibitory neurotransmitter, which stimulates α-to-ß cell transdifferentiation. In streptozotocin-treated mice, empagliflozin and/or GABA were delivered for a period of five days or three weeks. As compared to untreated T1D mice, EMPA-treated T1D mice had decreased FFA (free fatty acid) levels and improved glucose homeostasis. EMPA-treated T1D mice had higher islet density, with preserved architecture, compared to T1D mice, and EMPA-treated T1D mice also differed from T1D mice by the total absence of immune cell infiltration within islets. Islets from EMPA-treated mice were also less subjected to ER (endoplasmic reticulum) stress and inflammation, as shown by qPCR analysis. Glucose homeostasis parameters and islet area/pancreas area ratio improved, as compared to diabetic controls, when T1D mice were treated for three weeks with GABA and EMPA. T1D EMPA+GABA mice had higher glucagon levels than T1D mice, without modifications of glucagon area/islet area ratios. In conclusion, empagliflozin and GABA, used in monotherapy in streptozotocin-induced diabetic mice, have positive effects on ß-cell mass preservation or proliferation through an indirect effect on islet cell inflammation and ER stress. Further research is mandatory to evaluate whether empagliflozin and GABA may be a potential therapeutic target for the protection of ß-cell mass after new-onset T1D.