The Silent Epidemic of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Children and Adolescents in Italy During the COVID-19 Pandemic in 2020.

Aim/Hypothesis: To compare the frequency of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes in Italy during the COVID-19 pandemic in 2020 with the frequency of DKA during 2017-2019. Methods: Forty-seven pediatric diabetes centers caring for >90% of young people with diabetes in Italy recruited 4,237 newly diagnosed children with type 1 diabetes between 2017 and 2020 in a longitudinal study. Four subperiods in 2020 were defined based on government-imposed containment measures for COVID-19, and the frequencies of DKA and severe DKA compared with the same periods in 2017-2019. Results: Overall, the frequency of DKA increased from 35.7% (95%CI, 33.5-36.9) in 2017-2019 to 39.6% (95%CI, 36.7-42.4) in 2020 (p=0.008), while the frequency of severe DKA increased from 10.4% in 2017-2019 (95%CI, 9.4-11.5) to 14.2% in 2020 (95%CI, 12.3-16.4, p<0.001). DKA and severe DKA increased during the early pandemic period by 10.4% (p=0.004) and 8% (p=0.002), respectively, and the increase continued throughout 2020. Immigrant background increased and high household income decreased the probability of presenting with DKA (OR: 1.55; 95%CI, 1.24-1.94; p<0.001 and OR: 0.60; 95 CI, 0.41-0.88; p=0.010, respectively). Conclusions/Interpretation: There was an increase in the frequency of DKA and severe DKA in children newly diagnosed with type 1 diabetes during the COVID-19 pandemic in 2020, with no apparent association with the severity of COVID-19 infection severity or containment measures. There has been a silent outbreak of DKA in children during the pandemic, and preventive action is required to prevent this phenomenon in the event of further generalized lockdowns or future outbreaks.

Corrigendum: The silent epidemic of diabetic ketoacidosis at diagnosis of type 1 diabetes in children and adolescents in italy during the covid-19 pandemic in 2020.

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Monitoring of treatment adherence with easypod™ in six Italian centers: a real-world experience.

BACKGROUND: A poor adherence to r-hGH therapy is associated to a low growth rate in patients with growth deficiency. For this reason, the choice of an objective method, such as an electronic device, for monitoring treatment adherence is very important. This retrospective study evaluated the r-hGH treatment adherence of patients with growth deficiency, monitored through the easypod™ device. METHODS: Data from 90 patients (52 males and 38 females; mean age at the end of the study: 11.9 years ±3.40) enrolled in six Italian centers, was collected from the beginning of the r-hGH therapy until the end of the study through the easypod™ device. The primary endpoint, i.e. treatment adherence, was the ratio between actual days of treatment and planned days of treatment. Secondary endpoints were: relationship between heights measured at the beginning and at the end of the study, the change of the height SDS and the growth rate. RESULTS: Data from easypod™ showed that the mean adherence was 70±13%. The mean age-adjusted growth of the patients was 28.68±13.8 cm during the treatment period of 977 days, and the 6-month growth rate for the planned period was 3.78±8.1 cm. A positive correlation between the adherence rate and the change of the height SDS value was observed (P<0.0006). CONCLUSIONS: The easypod™ device seems to be a valid tool for quickly identifying non-adherence habits, allowing physicians to implement actions focused on reinforcing the importance of treatment both for patients and caregivers.

Association of a homozygous GCK missense mutation with mild diabetes.

BACKGROUND: Homozygous inactivating GCK mutations have been repeatedly reported to cause severe hyperglycemia, presenting as permanent neonatal diabetes mellitus (PNDM). Conversely, only two cases of GCK homozygous mutations causing mild hyperglycemia have been so far described. We here report a novel GCK mutation (c.1116G>C, p.E372D), in a family with one homozygous member showing mild hyperglycemia. METHODS: GCK mutational screening was carried out by Sanger sequencing. Computational analyses to investigate pathogenicity and molecular dynamics (MD) were performed for GCK-E372D and for previously described homozygous mutations associated with mild (n = 2) or severe (n = 1) hyperglycemia, used as references. RESULTS: Of four mildly hyperglycemic family-members, three were heterozygous and one, diagnosed in the adulthood, was homozygous for GCK-E372D. Two nondiabetic family members carried no mutations. Fasting glucose (p = 0.016) and HbA1c (p = 0.035) correlated with the number of mutated alleles (0-2). In-silico predicted pathogenicity was not correlated with the four mutations' severity. At MD, GCK-E372D conferred protein structure flexibility intermediate between mild and severe GCK mutations. CONCLUSIONS: We present the third case of homozygous GCK mutations associated with mild hyperglycemia, rather than PNDM. Our in-silico analyses support previous evidences suggesting that protein stability plays a role in determining clinical severity of GCK mutations.

Growth hormone treatment in prepubertal children with celiac disease and growth hormone deficiency.

OBJECTIVE: To evaluate the growth response to growth hormone (GH) replacement therapy during a gluten-free diet in patients with celiac disease (CD) associated with GH deficiency (GHD). PATIENTS AND METHODS: A total of 14 prepubertal children affected by CD and GHD with no catch-up growth after >/=12 months of gluten-free diet and a reversion to seronegativity for antiendomysium antibodies and 10 age-matched prepubertal children with idiopathic GHD (IGHD) entered the study. All of the patients were treated with the same GH dosage (0.25 mg/kg subcutaneously each week). Height, growth rate, and body mass index were measured at the time of diagnosis of CD, at the time of endocrinological evaluation, and after the first, second, and third year of GH replacement therapy. RESULTS: Growth rate strikingly increased (P < 0.005) during the first year of therapy in a similar way in subjects with CD/GHD and IGHD (from a median standard deviation score [SDS] of -2.34 to an SDS of 3.25 and from an SDS of -1.29 to an SDS of 2.79, respectively). During the second and third years of GH treatment, the growth rate tended to decrease but the values at the third year were always positive (CD/GHD, median SDS, 1.10; IGHD, median SDS, 0.11), indicating continued catch-up growth. CONCLUSIONS: In patients with CD with GH deficiency confirmed after >/=12 months of gluten-free diet, GH replacement therapy should be started to allow complete catch-up growth in children. In addition, the effect of GH treatment in patients who comply with a gluten-free diet seems to be comparable to that observed in children with IGHD.

Effects of acarbose in patients with beta-thalassaemia major and abnormal glucose homeostasis.

Seventeen TM patients with impaired glucose tolerance (IGT) or non-insulin dependent diabetes mellitus (NIDDM) and hyperinsulinism were treated for 12 months with acarbose (100 mg. orally with breakfast, lunch and evening meals). An improvement in glucose tolerance was observed in 2 out of 11 TM patients with IGT and in all TM patients with NIDDM. Acarbose does not appear to directly improve insulin resistance but may have an indirect effect delaying the absorption of glucose of complex carbohydrates and disaccharides. It may be concluded that acarbose may represent a useful first-line therapy for improving glycemic control in TM patients with abnormalities of glucose homeostasis and hyperinsulinism.

Effects of acarbose in beta-thalassaemia major patients with normal glucose tolerance and hyperinsulinism.

The pathogenesis of diabetes in thalassaemia is complex and multifactorial. Understanding the sequence of abnormalities in the progression from normal glucose tolerance to impaired glucose tolerance may help in the formulation of ways to intervene in this process. In our study, we assessed the effects of acarbose, an alpha-glucosidase inhibitor, in five young adult thalassaemic patients with hyperinsulinism and normal oral glucose tolerance test (OGTT). A decrease of fasting insulin levels, insulin peak and area under the curve (AUC) after OGTT, were observed in thalassaemic patients receiving acarbose therapy. These values remained unchanged in an untreated group of eight thalassaemic patients. We believe that acarbose may have a potential role in the treatment of abnormalities of glucose homeostasis and insulin release.

The prevalence of growth hormone deficiency and celiac disease in short children.

OBJECTIVES: To assess the occurrence of growth hormone deficiency (GHD) in patients with celiac disease (CD) referred for short stature. DESIGN: A retrospective, multi-center study. A total of 7066 children with short stature were referred to a number of centers for second-line evaluation over a 5-year period. All patients were screened for CD by antiendomysial antibodies (EMA) and antitissue transglutaminase IgA. Those with positive sera underwent intestinal biopsy. The EMA-negative patients and the EMA-positive ones who did not grow after 1 year of gluten-free diet underwent endocrinological investigation. RESULTS: Among the 7066 short children (age 2-14 years) evaluated, 650 (9.2%) had GHD and 44 (0.63%) had CD. An association of both CD and GHD was found in 16 short children (0.23%); these children did not grow after 1 year of gluten-free diet and therefore GH treatment was started. CONCLUSIONS: GH secretion should be evaluated in celiac patients showing no catch-up growth after an appropriate period on a gluten-free diet in spite of reversion to seronegativity for EMA.