The Role of Continuous Glucose Monitoring in Detecting Early Dysglycemia and Clinical Outcomes in Patients with Cystic Fibrosis.

Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity in patients with cystic fibrosis (CF). CFRD has been correlated with important clinical outcomes, including poor nutrition, reduced pulmonary function, and earlier mortality. However, clinical decline due to abnormalities of blood glucose (dysglycemia) begins early in CF, before the diagnosis of CFRD by the gold-standard oral glucose tolerance test (OGTT). Continuous glucose monitoring (CGM) has been validated in patients with CF and has been recognized as a valuable tool in detecting early glucose abnormalities in patients with CF. Several CGM parameters have been used to predict CFRD in some but not all studies, and there is no consensus regarding CGM use for diagnostic purposes. Thus, it remains a complementary test to OGTT in CFRD diagnosis. The aim of this review is to provide an update on the pathophysiological mechanisms of CFRD, recent advances in the use of CGM for CFRD screening, and the association between CGM measures and CF-related clinical outcomes.

Presentation of Graves' orbitopathy within European Group On Graves' Orbitopathy (EUGOGO) centres from 2012 to 2019 (PREGO III).

BACKGROUND: Graves' orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves' Orbitopathy (EUGOGO) tertiary referral centres and initial management over time. METHODS: Prospective observational multicentre study. All new referrals with diagnosis of GO within September-December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012. RESULTS: Besides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; p<0.001), but no significant change in proportion of active cases (41.3% vs 36.6%; p 0.217). After first diagnosis of GO, median referral time to an EUGOGO tertiary centre was shorter (2 (0-350) vs 6 (0-552) months; p<0.001) in 2019. At the time of first visit, more patients were already on antithyroid medications (80.2% vs 45.0%; p<0.001) or selenium (22.3% vs 3.0%; p<0.001). In 2019, the initial management plans for GO were similar to 2012, except for lid surgery (2.4% vs 13.9%; p<0.001) and prescription of selenium (28.5% vs 21.0%; p 0.027). CONCLUSION: GO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment.

Ambulatory Glucose Profile Changes During Pregnancy in Women With Type 1 Diabetes Using Intermittently Scanned Continuous Glucose Monitoring Empowered by Personalized Education.

The ambulatory glucose profile is a valuable tool in managing type 1 diabetes during pregnancy. Time in range (TIR) in the third trimester is one of the most significant parameters contributing to good pregnancy outcomes. This study aimed to evaluate the effect of intermittently scanned continuous glucose monitoring (isCGM) empowered by education on glucose dynamics and to predict third trimester TIR. Data were retrospectively analyzed from 38 pregnant patients with type 1 diabetes (mean age 30.4 ± 6.4 years, BMI 23.7 ± 3.7 kg/m2, disease duration 15.4 ± 9.5 years, preconception A1C 6.9 ± 1%) who used a first-generation FreeStyle Libre isCGM system for at least 3 months before conception and had sensor data captured >70% of the time the system was used. Patients received personalized education on diabetes and on minimizing hypoglycemia and hyperglycemia using CGM trend arrows and frequent sensor scanning. This intervention improved glycemic parameters of glucose regulation (TIR, glucose management indicator, and mean glucose), hyperglycemia (time above range), glucose variability (SD and coefficient of variation [%CV]), and scanning frequency, but did not improve parameters of hypoglycemia (time below range and a number of low glucose events). Logistic regression analysis showed that the first trimester %CV and scanning frequency contributed to the third trimester TIR (P <0.01, adjusted R2 0.40). This study suggests that the use of isCGM empowered by personalized education improves glycemic control in pregnant women with type 1 diabetes. Scanning frequency and %CV in the first trimester predicts TIR in the third trimester, which could help clinicians intervene early to improve outcomes.

Genetic and Clinical Characterization of Patients with HNF1B-Related MODY in Croatia.

BACKGROUND: Mutation of the gene encoding Hepatocyte Nuclear transcription Factor-1 Beta (HNF1B) causes a rare monogenetic subtype of Maturity-Onset Diabetes of the Young (MODY). HNF1B-related MODY results in the dysfunction of multiple organ systems. However, genetic analysis enables personalized medicine for patients and families. AIMS: To understand the clinical characteristics and explore the gene mutations in Croatian patients. METHODS: This was a retrospective observational study of individuals (and their relatives) who were, due to the clinical suspicion of MODY, referred to the Department of Laboratory Diagnostics at the University Hospital Centre Zagreb for genetic testing. RESULTS: A total of 118 participants, 56% females, were screened. Seven patients (three females) from five families were identified to have HNF1B-related MODY. The median age at diagnosis was 31 (11-45) years, the median c-peptide was 0.8 (0.55-1.39) nmol/L, the median HbA1c was 9.1 (5.7-18.4)%, and the median BMI was 22.9 kg/m2 (17-24.6). Patients had a variety of clinical manifestations; kidney disease was not as frequent as liver lesions, neuropsychiatric symptoms, hyperlipidemia, hyperuricemia, and hypomagnesemia. We identified two new pathogenic mutations (c.1006C > G protein p.His336Asp on exon 4 and c.1373T > G p protein Val458Gly on exon 7). CONCLUSIONS: In a study involving Croatian patients, new genetic (two previously unknown mutations) and clinical (diverse range of clinical presentations) aspects of HNF1B-related MODY were found.

Relative Frequency of Islet Autoimmunity in Children and Adolescents with Autoimmune Thyroid Disease

Objective: The aim of the present study was to investigate islet autoimmunity and susceptibility to type 1 diabetes (T1D) in children/adolescents with autoimmune thyroid disease (AITD, and in family members of AITD patients with islet autoimmunity. Methods: Islet-cell cytoplasmic, glutamic-acid decarboxylase, and tyrosine-phosphatase autoantibodies (AAbs) were measured in 161 AITD patients [127 with autoimmune thyroiditis (AT); 34 with Graves' disease (GD)], 20 family members of AITD patients with islet autoimmunity, and 155 age-matched controls. Results: Islet autoimmunity was found in 10.6% of AITD patients, significantly more frequent than in controls (1.9%; p=0.002). A higher prevalence of islet AAbs was found in females with AITD (p=0.011) but not in males (p=0.16) and in AT (p=0.013) but not in GD patients (p=0.19), compared to corresponding controls. Two or three islet AAbs were found concurrently in six AITD patients with islet autoimmunity. They all developed T1D and had significantly higher islet AAbs titers (p=0.01) than AITD patients with single islet AAbs but normal glucose metabolism. T1D was found in 3.7% of AITD patients compared to 0.2% of the age-matched, general Croatian population. Islet AAbs were found in 5/20 family members of AITD patients with islet autoimmunity, among whom two developed T1D. None of the controls was positive for more than one islet AAb or developed T1D. Conclusion: Children/adolescents with AITD, particularly females and patients with AT, appear to represent a risk group for islet autoimmunity and T1D, as do family members of AITD patients with positive islet AAbs. However, these findings should be validated in larger studies.

Nonsurgical treatment for upper eyelid retraction in patients with inactive Graves' orbitopathy.

PURPOSE: To evaluate the effectiveness of incobotulinumtoxinA (Xeomin®) in treating upper eyelid retraction in patients with Graves orbitopathy (GO) initially scheduled for surgery via two different application sites. METHODS: This is a comparative, prospective study, conducted at the Department of Ophthalmology, Medical School, University Hospital Centre Zagreb, EUGOGO site (EUropean Group On Graves' Orbitopathy) in Croatia from January 2020 till January of 2021 in accordance with national health headquarter recommendations. All patients were classified as inactive with marked eyelid retraction and randomly divided into groups according to application sites. Group A underwent transconjunctival application (18 eyes) and group B transcutaneous application (20 eyes) of incobotulinumtoxinA. The primary end point of this study was lowering the eyelid, to alleviate anterior eye segment symptoms and achieve acceptable aesthetic appearance until surgery becomes available. RESULTS: There were no nonresponders and we found no statistically significant difference in the degree of lowering the eyelid between the two application sites. Following rules for avoiding spread of SARS-CoV-19, none of the patients included in this study were infected. Moreover, participants reported diminishing of anterior eye segment irritation and improved aesthetics. CONCLUSION: Treatment of inactive GO patients with incobotulinumtoxinA for upper eyelid retraction is efficient and safe and can be used as an adjuvant treatment while patients wait for surgery, by alleviating symptoms and improving the level of aesthetic satisfaction without causing a threat to anterior eye segment and visual function. The study showed that effect of treatment was the same, whether we applied the toxin transconjunctivaly or transcutaneously.

Glycemic Variability in Type 1 Diabetes Mellitus Pregnancies-Novel Parameters in Predicting Large-for-Gestational-Age Neonates: A Prospective Cohort Study.

Pregnancies with type 1 diabetes mellitus (T1DM) have a high incidence of large-for-gestational-age neonates (LGA) despite optimal glycemic control. In recent years, glycemic variability (GV) has emerged as a possible risk factor for LGA, but the results of the conducted studies are unclear. This study analyzed the association between GV and LGA development in pregnancies with T1DM. This was a prospective cohort study of patients with T1DM who used continuous glucose monitoring (CGM) during pregnancy. Patients were followed from the first trimester to birth. GV parameters were calculated for every trimester using the EasyGV calculator. The main outcomes were LGA or no-LGA. Logistic regression analysis was used to assess the association between GV parameters and LGA. In total, 66 patients were included. The incidence of LGA was 36%. The analysis extracted several GV parameters that were significantly associated with the risk of LGA. The J-index was the only significant parameter in every trimester of pregnancy (odds ratios with confidence intervals were 1.33 (1.02, 1.73), 3.18 (1.12, 9.07), and 1.37 (1.03, 1.82), respectively. Increased GV is a risk factor for development of LGA. The J-index is a possible novel GV parameter that may be assessed in all three trimesters of pregnancy together with glycated hemoglobin and time-in-range.

Prevalence and predictors of diabetes-related distress in adults with type 1 diabetes.

Type 1 diabetes (T1DM) is a chronic disease requiring lifelong insulin therapy and rigorous self-management. As it negatively impacts the affected individuals' quality of life, it may eventually lead to diabetes-related distress. This study evaluated the prevalence and identified the predictors of diabetes-related distress in a representative sample of adults with T1DM treated at secondary and tertiary levels in Croatia. A multicenter, cross-sectional study was conducted in adults with T1DM in Croatia (N = 100). Data were collected between January 2018 and December 2018 from medical records and interviews during a single clinical visit, when participants completed a 20-item Problem Area in Diabetes (PAID) Questionnaire. The proportion of participants with a total PAID score ≥ 40 indicating high diabetes-related distress was calculated, and binary logistic regression was run to determine predictors. High diabetes-related distress was found in 36% of participants, with a mean PAID total score of 31.9 (21.1). The predictors of diabetes-related distress were higher HbA1c level (OR = 1.491, p = 0.037, CI = 1.025-2.169) and the presence of microvascular complications (OR = 4.611, p = 0.005; 95%CI 1.546-13.754). Worrying about the future and chronic complications and feeling guilty when off-track with diabetes management were identified as items that contribute the most to distress. Diabetes-related distress is a frequent condition in adults with T1DM in Croatia. Special attention should be given to patients with suboptimal glycemic control and microvascular complications. Given the high prevalence and impact of psychosocial problems in diabetes, psychological care should be integrated into routine care for adults with type 1 diabetes.

Count Ivan VIII Draskovic: a case of Graves' orbitopathy?

There is a possibility that Count Ivan VIII Draskovic (1740-1787), a member of one of the oldest and most famous Croatian noble families, had Graves' disease and suffered from a thyroid disorder. Our suspicions were aroused by certain data, including his personal history, his lifestyle, including use of tobacco and iodine, as well as stress, and, finally, two portraits. If he was affected by Graves' disease and orbitopathy, his poor health might have been a consequence of thyroid disease, which was further worsened by injury and tobacco use. Later spontaneous remission could have been induced by higher iodine intake and bed rest.

Lower Urinary Tract Symptoms in Croatian Obese Patients.

BACKGROUND: Patients with obesity may experience lower urinary tract symptoms (LUTS). Little is known about these symptoms in obese patients in Croatia. The aim of this study was to asses LUTS in this group of patients. SUBJECTS AND METHODS: This cross-sectional study was carried out in a tertiary healthcare centre. 111 participants were included (81 women and 30 men, age 23-78 years), with BMI>30 kg/m2. LUTS were evaluated using International consultation on incontinence questionnaires (ICIQ) investigating symptoms of overactive bladder (OAB) and urinary incontinence (UI): ICIQ-OAB and ICIQ-UI Short Form (SF). We evaluated also some of the questions on the EQ-5D-5L questionnaire. RESULTS: On ICIQ-OAB patients most often reported:UI (46.85% (N=52)), nocturia (42.34% (N=47)) and increased frequency of urination (34.23% (N=38)), and on ICIQ-UI SF: UI when coughing and sneezing (44.44% (N=32)), urgency UI (43.06% (N=31)) and UI during exercise/physical activity (22.22% (N=16)). Women were found to be more significantly affected by OAB symptoms (p<0.05). Significant correlations were found between the overall results on ICIQ-OAB and hypertension (r=0.32). CONCLUSIONS: The results of this study confirm that obese patients in Croatia experience LUTS as well. A higher incidence of LUTS was found among women and gender-independent among hypertensive obese patients.

Pregnancy in Patients with Type One Diabetes Mellitus Treated with Continuous Subcutaneous Insulin Infusion-Preconception Basal Insulin Dose as a Potential Risk Factor for Fetal Overgrowth?

Despite widespread use of technology, type one diabetes mellitus (T1DM) is still a great clinical challenge during pregnancy. This study aims to assess how prenatal variables of T1DM patients using continuous subcutaneous insulin infusion (CSII) influence pregnancy outcomes. We performed a retrospective study of 35 patients with T1DM treated with CSII during pregnancy. Alterable preconception variables (A1C, body mass index, basal and bolus insulin dose) were analysed as possible contributors to birth weight and large-for-gestational-age (LGA) prevalence. Inclusion criteria were presence of T1DM for more than two years, A1C < 7.4% and treatment with CSII for at least three months prior to conception. The preconception basal insulin dose and A1C had a significant correlation to the neonatal birth weight (p = 0.01, r = 0.4 and p = 0.04, r = 0.3, respectively) and were significant in regression analysis together contributing 22% of the variance in birth weight percentiles (sig = 0.17, R square = 0.22). Prevalence of LGA was 46%. Women who had LGA neonates also had a higher preconception basal insulin dose compared to women with non-LGA neonates (26 ± 9 vs. 18 ± 7 IU (international units), p = 0.01). The LGA group had a higher preconception A1C, but it did not reach statistical significance (6.5 ± 0.5% vs. 6.2 ± 0.9%, respectively, p = 0.2). Women with T1DM treated with CSII who had unregulated glycaemia and more basal insulin were at greater risk for development of LGA neonates.

Case report of chloroquine therapy and hypoglycaemia in type 1 diabetes: What should we have in mind during the COVID-19 pandemic?

A type 1 diabetes patient experienced remission associated with chloroquine therapy while travelling to a malaria-endemic area. Chloroquine has immunomodulatory and hypoglycaemic effects and may become more frequently used due to the COVID-19 pandemic. Patients with type 1 diabetes treated with chloroquine should be monitored for hypoglycaemia, even after recovery.

Hypoglycemia in patients with type 2 diabetes treated with oral antihyperglycemic agents detected by continuous glucose monitoring: a multi-center prospective observational study in Croatia.

BACKGROUND: Hypoglycemia in type 2 diabetes mellitus (T2DM) is still unsolved issue. The aim of this study was to investigate hypoglycemia in T2DM in participants treated with oral antihyperglycemic agents using different glucose cut-off values and to explore influence of different therapies. METHODS: This multi-center prospective observational study included participant with T2DM from primary care offices across Croatia treated with antihyperglycemic agents who were monitored using professional continuous glucose monitoring (CGM) device (iPro™2). Hypoglycemia was defined as at least 1% of the monitored period spent in the hypoglycemic range and/or area under the curve of glycemia registered ever under the defined cut-off value. The higher upper limit of blood glucose cut-off value was 3.9 mmol/L (70 mg/dL) and the lower one 3.0 mmol/L (54 mg/dL). RESULTS: Study included 94 participants. Median hemoglobin A1C levels, age, T2DM duration, body mass index, and CGM use duration were 7 (5.8-11.5) %, 65 (40-86) years, 7 (1-36) years, 30.4 (21.3-41.5) kg/m2 and 6 (1-7) days, respectively. Fifty participants were treated with sulfonylurea, primarily gliclazide (84%). The percentage of participant with hypoglycemia based on the higher cut-off value was 42.6% vs. 16% based on the higher cut-off value. The percentage of participant with nocturnal hypoglycemia (23 PM to 06 AM) was significantly lower among participant with hypoglycemia based on the higher cut-off value compared to lower one (7.8% vs. 22.9%). Sulfonylurea treatment did not influence the occurrence of hypoglycemia. Analysis of the data from participants having hypoglycemia based on the lower cut-off value pointed to other possible risk factors for hypoglycemia like prolonged overnight fasting, physical activity, alcohol consumption, and concomitant therapy with angiotensin-converting enzyme inhibitors. CONCLUSIONS: In participant with T2DM treated with oral antihyperglycemic agents hypoglycemia based on the blood glucose cut-off value of 3.9 mmol/L was more prevalent, but with less nocturnal hypoglycemia. Sulfonylurea therapy was not risk factor for hypoglycemia regardless of cut-off value. In participants having hypoglycemia based on the blood glucose cut-off value of 3.0 mmol/L some other possible factors were identified related to concomitant therapy, nutrition and daily habits. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03253237.