The HNF1A transcription factor, implicated in the regulation of pancreatic beta cells, as well as in glucose and lipid metabolism, is responsible for type 3 maturity-onset diabetes of the young ...(MODY3). HNF1A is also involved in increased susceptibility to polygenic forms of diabetes, such as type 2 diabetes (T2D) and gestational diabetes (GD), while its possible role in type 1 diabetes (T1D) is not known. In this study, 277 children and adolescents with T1D and 140 healthy controls were recruited. The following SNPs in
gene were selected: rs1169286, rs1169288, rs7979478, and rs2259816. Through linear or logistic regression analysis, we analyzed their association with T1D susceptibility and related clinical traits, such as insulin dose-adjusted glycated hemoglobin A1c (IDAA1c) and glycated hemoglobin (HbA1c). We found that rs1169286 was associated with IDAA1c and HbA1c values (
-value = 0.0027 and
-value = 0.0075, respectively), while rs1169288 was associated with IDAA1c (
-value = 0.0081). No association between
SNPs and T1D development emerged. In conclusion, our findings suggest for the first time that
variants may be a risk factor for beta cell function and glycaemic control in T1D individuals.
This study aims to compare the frequency of Diabetic Ketoacidosis (DKA) at diagnosis in 2014–2016 with the one previously reported in 2004–2013; and to assess the association between family ...socioeconomic status and DKA at type 1 diabetes (T1D) diagnosis in children <15 years of age from 2014 to 2016.
Methods:
This nationwide, population-based, observational study included 2,679 children diagnosed with T1D from 54 Italian centers for pediatric diabetes during 2014–2016. The ISPAD criteria for DKA were used as a standard reference. The overall and by age frequency of DKA between the two time periods were compared. The association between family socioeconomic status and DKA was assessed using multiple logistic regression analysis.
Results:
Nine hundred and eighty nine children had DKA (36.9, 95% CI: 35.1–38.8). The frequency of DKA was significantly lower in 2014–2016 in comparison to 2004–2013 (40.3, 95% CI: 39.3–41.4,
p
= 0.002). The probability of having DKA at diagnosis was lower in mothers with a high level of education (OR = 0.69, 95% CI: 0.51–0.93) or a high level of occupation (OR = 0.76, 95% CI: 0.58 0.99), and in fathers with a high level of occupation (OR = 0.72, 95% CI: 0.55–0.94). Children living in Southern Italy had a higher probability of diagnosis with severe DKA than children living in Central Italy.
Conclusion:
There was a decrease in the frequency of DKA in children diagnosed with T1D under 15 years of age during 2014–2016. However, DKA frequency remains unacceptably high. This study demonstrated that socioeconomic inequalities, measured as low education and occupational levels, were associated with an increased probability of DKA at T1D diagnosis.
Wolfram syndrome type 1 is a rare recessive monogenic form of insulin-dependent diabetes mellitus with progressive neurodegeneration, poor prognosis, and no cure. Based on preclinical evidence we ...hypothesized that liraglutide, a glucagon-like peptide-1 receptor agonist, may be repurposed for the off-label treatment of Wolfram Syndrome type 1. We initiated an off-label treatment to investigate the safety, tolerability, and efficacy of liraglutide in pediatric patients with Wolfram Syndrome type 1.
Pediatric patients with genetically confirmed Wolfram Syndrome type 1 were offered off-label treatment approved by The Regional Network Coordination Center for Rare Diseases, Pharmacological Research IRCCS Mario Negri, and the internal ethics committee. Four patients were enrolled; none refused nor were excluded or lost during follow-up. Liraglutide was administered as a daily subcutaneous injection. Starting dose was 0.3 mg/day. The dose was progressively increased as tolerated, up to the maximum dose of 1.8 mg/day. The primary outcome was evaluating the safety, tolerability, and efficacy of liraglutide in Wolfram Syndrome type 1 patients. Secondary endpoints were stabilization or improvement of C-peptide secretion as assessed by the mixed meal tolerance test. Exploratory endpoints were stabilization of neurological and neuro-ophthalmological degeneration, assessed by optical coherence tomography, electroretinogram, visual evoked potentials, and magnetic resonance imaging.
Four patients aged between 10 and 14 years at baseline were treated with liraglutide for 8-27 months. Liraglutide was well-tolerated: all patients reached and maintained the maximum dose, and none withdrew from the study. Only minor transient gastrointestinal symptoms were reported. No alterations in pancreatic enzymes, calcitonin, or thyroid hormones were observed. At the latest follow-up, the C-peptide area under the curve ranged from 81 to 171% of baseline. Time in range improved in two patients. Neuro-ophthalmological and neurophysiological disease parameters remained stable at the latest follow-up.
We report preliminary data on the safety, tolerability, and efficacy of liraglutide in four pediatric patients with Wolfram Syndrome type 1. The apparent benefits both in terms of residual C-peptide secretion and neuro-ophthalmological disease progression warrant further studies on the repurposing of glucagon-like peptide-1 receptor agonists as disease-modifying agents for Wolfram Syndrome type 1.
Obesity epidemic in childhood/adolescence may influence the mode of presentation of diabetes in conditions usually diagnosed in lean people like T1DM and MODY. The aim of our study was to identify ...clinical parameters useful for distinguishing betweeen obese patients with T1DM (T1DMob) and patients with T2DM with onset in adolescence (T2DMad). For this study, overweight/obesity was defined as BMI ≥ 95th centile for age and sex according to BMI calculator for child and teen of CDC. We compared 60 T1DMob patients (at least one T1DM autoab with high titer) with 36 patients with T2DMad (negative to T1DM autoabs). Patients with T2DMad and a parent with diabetes were considered as possibly being MODY, and excluded. We evaluated sex, ethnicity, birth weight, and age, plasma glucose, HbA1c, C-peptide, Cholesterol, HDL/Cholest., triglycerides (TG), and blood pressure (BP) at diabetes onset. Mean age at diagnosis was lower in T1DMob (9.7±3.0) than T2DMad (13.9±2.4) (p<0.001), while fasting plasma glucose (20±10.5 vs. 16.2±8.6 mmol/L respectively) and HbA1c were not statistically different. C-peptide (1.0±0.9 vs. 4.0±3.5 ng/ml, p<0.001), TG (104.9±77.9 vs. 284.5±297.6, p<0.001), total Cholesterol (159.9±35.9 vs. 194.5±30.2, mg/dl, p=0.006), systolic BP (111.3±11.2 vs. 126.6±14.3 mm/Hg, p<0.001) were lower, and HDL/Cholest. (48.7±23 vs. 32.3±10.1, p<0.001) was higher in T1DMob. In 17 pubertal T1DMob patients (age at onset 13.2±2.2) C-peptide (1.5±1, p=0.001), TG (115.7±81.7, p=0.005), systolic BP (116.9±6.6, p=0.04) were still lower, and HDL/Cholest. (57.0±35.3, p=0.001) still higher than T2DMad. TG/HDL ratio, another index of insulin resistance (IR) was higher (11.2±15.2 vs. 2.6±2.2, p=0.001) in T2DMad. We conclude that parameters indicative of IR, a pathophyiologic component of T2DM, are profoundly altered in patients with T2DMad when compared to T1DMob, and that this does not appear to be linked to differences in age at diabetes presentation.
Disclosure
F. Barbetti: Consultant; Self; Amring. R. Bonfanti: Advisory Panel; Self; Abbott, Medtronic, Roche Diabetes Care. D. Iafusco: None.
To evaluate whether the diagnosis of pediatric type 1 diabetes or its acute complications changed during the early phase of the coronavirus disease 2019 (COVID-19) pandemic in Italy.
This was a ...cross-sectional, web-based survey of all Italian pediatric diabetes centers to collect diabetes, diabetic ketoacidosis (DKA), and COVID-19 data in patients presenting with new-onset or established type 1 diabetes between 20 February and 14 April in 2019 and 2020.
Fifty-three of 68 centers (77.9%) responded. There was a 23% reduction in new diabetes cases in 2020 compared with 2019. Among those newly diagnosed patients who presented in a state of DKA, the proportion with severe DKA was 44.3% in 2020 vs. 36.1% in 2019 (
= 0.03). There were no differences in acute complications. Eight patients with asymptomatic or mild COVID-19 had laboratory-confirmed severe acute respiratory syndrome coronavirus 2.
The COVID-19 pandemic might have altered diabetes presentation and DKA severity. Preparing for any "second wave" requires strategies to educate and reassure parents about timely emergency department attendance for non-COVID-19 symptoms.
ObjectiveAfter a previous survey on the incidence of diabetic ketoacidosis (DKA) at onset of type 1 diabetes in children in 2013–2014 in Italy, we aimed to verify a possible decline in the incidence ...of DKA at onset during a national prevention campaign.DesignProspective observational study.SettingMulticentre study throughout Italy.InterventionNational awareness campaign started in November 2015 and held until December 2017.PatientsDuring 2016 and 2017 we collected data on all patients aged 0–18 years with new-onset diabetes.Main outcome measuresDKA (pH <7.30), severe DKA (pH <7.1), DKA in children below 6 years and DKA treatment according to the Italian Society for Pediatric Endocrinology and Diabetology (ISPED) protocol were evaluated.ResultsRecords (n=2361) of children with newly diagnosed type 1 diabetes were collected from 58 out of 68 (85.3%) centres of the original survey participants and 100% of the previously surveyed tertiary centres. Overall, DKA was observed in 1124 patients, with an increased rate when compared with the previous survey (47.6% vs 38.5%, p=0.002), and severe DKA in 15.3%. In children below 6 years, DKA was observed in 323 out of 617 (52.5%) and severe DKA in 16.7%; in this age group, occurrence of DKA reduced by 21.3% (p=0.009). DKA treatment according to the ISPED guidelines was adopted in 95% of the centres, with a 27% improvement (p=0.025).ConclusionsDuring a 2-year awareness campaign, DKA at onset of diabetes in children and adolescents 0–18 years is still common and increased when compared with the 2013–2014 survey.
Increasing evidences suggest a correlation between gut and type 1 diabetes (T1D).
The objective of this study is to evaluate the gut inflammatory profile and microbiota in patients with T1D compared ...with healthy control (CTRL) subjects and patients with celiac disease (CD) as gut inflammatory disease controls.
The inflammatory status and microbiome composition were evaluated in biopsies of the duodenal mucosa of patients with T1D (n = 19), in patients with CD (n = 19), and CTRL subjects (n = 16) recruited at San Raffaele Scientific Institute, in Milan, Italy, between 2009 and 2015.
Inflammation was evaluated by gene expression study and immunohistochemistry. Microbiome composition was analyzed by 16S ribosomal RNA gene sequencing.
An increased expression of CCL13, CCL19, CCL22, CCR2, COX2, IL4R, CD68, PTX3, TNFα, and VEGFA was observed in patients with T1D compared with CTRL subjects and patients with CD. Immunohistochemical analysis confirmed T1D-specific inflammatory status compared with healthy and CD control tissues, mainly characterized by the increase of the monocyte/macrophage lineage infiltration. The T1D duodenal mucosal microbiome results were different from the other groups, with an increase in Firmicutes and Firmicutes/Bacteroidetes ratio and a reduction in Proteobacteria and Bacteroidetes. The expression of genes specific for T1D inflammation was associated with the abundance of specific bacteria in the duodenum.
This study shows that duodenal mucosa in T1D presents disease-specific abnormalities in the inflammatory profile and microbiota. Understanding the mechanisms underlying these features is critical to disentangle the complex pathogenesis of T1D and to gain new perspectives for future therapies targeting the intestine.
Introduction: After a long lead-in period, artificial pancreas (AP) technology is well on its way to revolutionizing the treatment of diabetes, but no AP is currently approved. Recently data about ...the use of a hybrid closed-loop (CL) insulin delivery has been presented.
Aim: We compared two devices, Minimed 640G system, (Medtronic, CA, U.S.) in the market in Italy since mid-2015 vs. Minimed 670G system (Medtronic, CA, U.S.), just entered the market on October 24th, 2018, used by the same patients.
Methods: We prospectively analyzed data of 19 patients using 640G three months before switching to 670G. Main outcome is the time in range (TIR) compared to TIR while using 640G. Secondary outcomes are predicted A1c, time in hypo, time in hyper (>160 mg/dl), insulin total daily dose (TDD), %bolus and %basal rate, coefficient of variation (CV).
Results: The 19 patients (mean age 13±4 years, range 7-20 years, diabetes duration 7±4 years) who switched to 670G, after 2 months observation had a TIR significantly lower when compared while using 640G (62.9±6.6% vs. 76.6±16.3%, p=0.03), with similar predicted A1c (6,8±0.3% vs. 6.8±0.7%, p=0.89). Time in hypo significantly increased (3.4±2.3% vs. 0.5±0.6%, p=0.001), while no difference has been observed about time in hyper (34.7±5.9% vs. 22.9±16.1%, p=0.38) and CV (40.4±8.5% vs. 43.2±6.5%, p=0.25). Interestingly, TDD is slightly, but not significantly, lower when using 670G, with a higher percentage of insulin given as bolus than as basal rate.
Conclusions: 670G system seems less effective than 640G system to achieve a higher TIR, at the expenses of a higher time in hypo. A systematic educational pathway, as the one used by 640G users, could help reach these results, as well as some constrains 670G system has (fixed glycemic target at 120 mg/dl, only simple bolus, etc.). It is solacing to know that we already have useful tools for the best possible care of our patients with type 1 diabetes while we wait for the commercial availability of an AP or a more performant hybrid CL system.
Disclosure
A.E. Scaramuzza: None. I. Rabbone: None. R. Bonfanti: Advisory Panel; Self; Abbott, Lilly Diabetes, Medtronic, Novo Nordisk A/S, Roche Diabetes Care, Sanofi.
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