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.

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.

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.

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.

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.

GLUCAGON-LIKE PEPTIDE-1 AFFECTS TASTE PERCEPTION DIFFERENTLY IN WOMEN: A RANDOMIZED, PLACEBO-CONTROLLED CROSSOVER STUDY.

Gastrointestinal tract is an important connector between food intake and body weight, it senses basic tastes in a similar manner as the tongue. The aim of the study was to find out how gut hormone glucagon-like peptide-1 (GLP-1) influences taste preference. Fourteen healthy participants (six male and eight female) were included in this double-blind, placebo-controlled crossover study. After overnight fast and salty fluid (oral sodium load), participants were randomized to receive placebo (500 mL of 0.9% saline) or GLP-1 infusion (1.5 pmol/kg/min) over a 3-hour period. At the end of infusion, participants chose food preferences from illustrations of food types representing 5 tastes. After 7 days, the protocol was repeated, this time those that had received placebo first got GLP-1 infusion, and those having received GLP-1 first got placebo. Change of taste preference after GLP-1 infusion but not after placebo was reported as response, and non-response was reported in case of taste persistence. A statistically significant difference in response type was found between genders, with women being more likely to change their taste preference after GLP-1 than men. The change of taste upon GLP-1 infusion observed in women might be ascribed to estrogen weight-lowering effects accomplished by receptor-mediated delivery.

Treatment of Diabetic Ketoacidosis Associated With Antipsychotic Medication: Literature Review.

BACKGROUND: The second-generation antipsychotics (SGAs) are associated with metabolic disturbances. Diabetic ketoacidosis (DKA) is a rare, but potentially fatal sign of acute glucose metabolism dysregulation, which may be associated with the use of SGAs. This study aims to review published reports of patients with schizophrenia and antipsychotic drug-associated DKA, focusing on the effective management of both conditions. METHODS: Using a predefined search strategy, we searched PubMed and EMBASE from their inception to July 2016. The search terms were related to "diabetic ketoacidosis" and "antipsychotic medication." Case reports, case series, and reviews of case series written in English language were included in the review. RESULTS: Sixty-five reports were analyzed. In most patients who developed antipsychotic-associated DKA, 1 or more suspected antipsychotic medications were discontinued. In 5 cases, a rechallenge test was trialed, and in only 1 case, it resulted in the elevation of blood glucose. The majority was subsequently treated with a different SGA in combination with insulin/oral hypoglycemic agents; although approximately a third of patients had a complete resolution of symptoms or could control diabetes with diet only at the point of discharge. CONCLUSIONS: Patients taking antipsychotic medications should be regularly screened for insulin resistance and educated about potential complications of antipsychotic medications. This will allow clinicians to individualize treatment decisions and reduce iatrogenic contribution to morbidity and mortality. To achieve best treatment outcomes, antipsychotic-induced DKA should be treated jointly by psychiatry and endocrinology teams.

Diabetic ketoacidosis associated with antipsychotic drugs: case reports and a review of literature.

BACKGROUND: Second generation antipsychotics (SGAs) are associated with metabolic disturbances. Diabetic ketoacidosis (DKA) is a rare, but potentially fatal sign of acute glucose metabolism dysregulation linked to the use of SGAs. The aims of this article are to present patients with a history of psychotic disorders and of severe metabolic diabetic ketoacidosis, possibly associated with the use of antipsychotics, and to review the current literature on the topic of antipsychotic-induced DKA. METHOD: PubMed/Medline and EBSCO databases were searched using the keywords: diabetic ketoacidosis, antipsychotics, atypical antipsychotics, second generation antipsychotics, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, paliperidone, amisulpride and haloperidol. Case reports, case series and reviews of case series were included in the review. RESULTS: The majority of patients who developed DKA following treatment with antipsychotics were treated with olanzapine and clozapine in monotherapy or in combination with other antipsychotics. DKA mostly occurred in the first six months of antipsychotic treatment. Other risk factors included insulin resistance prior to antipsychotic treatment, male gender and middle age. CONCLUSION: Clinicians should consider the risk of DKA when starting treatment with SGAs. Preventive measures for patients with psychotic disorders using antipsychotics should include regular assessment of risk factors and screening for diabetes before and after administering antipsychotics, especially in the first months of treatment. Whenever possible, polypharmacy should be avoided.

[KIDNEY DISEASE IN DIABETIC PATIENTS ­ THE ROLE OF FAMILY MEDICINE PHYSICIAN].

The alarming rates of diabetes mellitus incidence and progression continue despite deployment of all current treatments. Kidney disease can be a particularly devastating complication, as it is associated with significant reductions in both length and quality of life. A variety of forms of kidney disease can be seen in people with diabetes, including diabetic nephropathy, ischemic damage related to vascular disease and hypertension, as well as other renal diseases that are unrelated to diabetes. Following an extensive PubMed search, this review provides a brief view on the screening for chronic kidney disease (CKD) in people with diabetes, how to treat them to slow down the progression of CKD and when to refer them to specialist care. This review also emphasizes the basic challenge in treating diabetic patients, which is to shift the main criterion from the disease-oriented to person-centered approach in the context of treating the patient as a whole.

Information retrieval and terminology extraction in online resources for patients with diabetes.

Terminology use, as a mean for information retrieval or document indexing, plays an important role in health literacy. Specific types of users, i.e. patients with diabetes need access to various online resources (on foreign and/or native language) searching for information on self-education of basic diabetic knowledge, on self-care activities regarding importance of dietetic food, medications, physical exercises and on self-management of insulin pumps. Automatic extraction of corpus-based terminology from online texts, manuals or professional papers, can help in building terminology lists or list of "browsing phrases" useful in information retrieval or in document indexing. Specific terminology lists represent an intermediate step between free text search and controlled vocabulary, between user's demands and existing online resources in native and foreign language. The research aiming to detect the role of terminology in online resources, is conducted on English and Croatian manuals and Croatian online texts, and divided into three interrelated parts: i) comparison of professional and popular terminology use ii) evaluation of automatic statistically-based terminology extraction on English and Croatian texts iii) comparison and evaluation of extracted terminology performed on English manual using statistical and hybrid approaches. Extracted terminology candidates are evaluated by comparison with three types of reference lists: list created by professional medical person, list of highly professional vocabulary contained in MeSH and list created by non-medical persons, made as intersection of 15 lists. Results report on use of popular and professional terminology in online diabetes resources, on evaluation of automatically extracted terminology candidates in English and Croatian texts and on comparison of statistical and hybrid extraction methods in English text. Evaluation of automatic and semi-automatic terminology extraction methods is performed by recall, precision and f-measure.

Camurati-Engelmann disease in a family from Croatian Island: an old bone scan confirmed pattern of inheritance.

34-year old patient had history of muscular wasting, easy fatigability, pain in extremities and waddling gait since age of four. During the time, neuromuscular disease was suspected, but not confirmed. Elevated bone alkaline phosphatase as well as other bone turnover markers (osteocalcin, procollagen, telopeptide) indicated further skeletal evaluation. Symmetrical enhanced uptake on technetium methylene diphosphonate [99mTc]MPD bone scintigraphy at diaphyses of longitudinal bones and scull matched cortical thickening of long bones and sclerosis of the scull seen at radiograms. Those findings pointed to Camurati-Engelmann disease misdiagnosed for the long time. This rare genetic autosomal dominant disorder was retrospectively diagnosed in asymptomatic father too on the basis of bone scans done long time ago. Old family member scans confirmed heredity pattern of the disease.

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.

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.

Targets for medical therapy in obesity.

Obesity has more than doubled since 1980 all over the world, and in the European perspective it does not seem to be better. Obesity-related diseases like diabetes, hypertension, coronary heart disease, stroke and hyperlipidemia are the main cause of mortality and morbidity in developed countries. These are the reasons for continuous search for efficient treatment of obesity. One of the options is medical therapy. Over history, many anti-obesity drugs were introduced and subsequently removed from the market due to various side effects. Unfortunately, there is still no ideal drug for the treatment of obesity, and the current ones are very strictly evaluated. The anti-obesity drug should target patients that have previously failed to lose weight with lifestyle interventions, with body mass index (BMI) ≥30, or those with BMI ≥27 plus concomitant obesity-related risk factors or diseases. The only drug currently approved in Europe is orlistat, a pancreatic lipase inhibitor. Sibutramine, an appetite suppressant (serotonin-norepinephrine reuptake inhibitor), has been off the market since 2010 due to cardiovascular side effects. There is a large group of drugs used for other indications with weight loss effects, e.g. incretin mimetics or analogues used in the treatment of diabetes type 2, topiramate used as an anticonvulsant, and fluoxetine and sertraline used in the treatment of depression.