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Aims: In this study we evaluated the use of Continuous Glucose Monitoring system in adults with insulin-dependent diabetes in the course of Wolfram syndrome (WFS) in comparison to patients with type 1 diabetes (T1D). Methods: Individuals with WFS (N = 10) used continuous glucose monitoring for 14 days and were compared with 30 patients with T1D matched using propensity score for age and diabetes duration. Glycemic variability was calculated with Glyculator 3.0. Results: We revealed significant differences in glycemic indices between adults with Wolfram syndrome-related diabetes and matched comparison group. Patients with Wolfram syndrome presented lower mean glucose in 24-h and nighttime records [24h: 141.1 ± 30.4mg/dl (N = 10) vs 164.9 ± 31.3mg/dl (N = 30), p = 0.0427; nighttime: 136.7 ± 39.6mg/dl vs 166.2 ± 32.1mg/dl (N = 30), p = 0.0442]. Moreover, they showed lower standard deviation of sensor glucose over all periods [24h: 50.3 ± 9.2mg/dl (N = 10) vs 67.7 ± 18.7 mg/dl (N = 30), p = 0.0075; daytime: 50.8 ± 8.7mg/dl (N = 10) vs 67.4 ± 18.0mg/dl (N = 30), p = 0.0082; nighttime: 45.1 ± 14.9mg/dl (N = 10) vs 65.8 ± 23.2mg/dl (n = 30), p = 0.0119] and coefficient of variation at night [33.3 ± 5.8% (N = 10) vs 40.5 ± 8.8% (N = 30), p = 0.0210]. Additionally, WFS patients displayed lower time in high-range hyperglycemia (> 250mg/dl) across all parts of day [24h: 4.6 ± 3.8% (N = 10) vs 13.4 ± 10.5% (N = 30), p = 0.0004; daytime: 4.7 ± 3.9% (N = 10) vs 13.8 ± 11.2% (N = 30), p = 0.0005; nighttime: 4.2 ± 5.5% (N = 10) vs 12.1 ± 10.3% (N = 30), p = 0.0272]. Conclusions: Adult patients with Wolfram syndrome show lower mean blood glucose, less extreme hyperglycemia, and lower glycemic variability in comparison to patients with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Monogenic diabetes are a heterogenic group of diseases with varied phenotypes. It is assumed that they may total up to 10% of all cases of diabetes. Diagnosis of these clinical conditions by an efficient selection of patients for genetic diagnostics may be problematic even for experienced diabetologists. Helpful information about selecting and directing patients for further examinations can be gained from guidelines created by diabetologic societies such as International Society of Pediatric and Adolescent Diabetes (ISPAD). This paper focuses on key aspects of these guidelines and elucidates crucial features of the clinical picture which can be used for differential diagnosis of diabetes. Among factors suggesting monogenic background of diabetes the most notable are: low daily insulin requirement (<0.5 U/kg), moderate hyperglycemia (5.5-8.5 mmol/l), positive familial history with a dominant pattern of inheritance, lack of immunologic markers typical for type I diabetes and presence of structural or functional abnormalities within other organs and systems. ISPAD guidelines however, are burdened by some inconsistencies, reflecting different screening and investigative approaches used by various authors. These incongruities have been resolved by the authors of this paper with added suggestions of how to implement relevant solutions in clinical practice. In this article current guidelines on the treatment of monogenic diabetes in children were also presented. Current therapeutic standards were taken into consideration as well as prospects for treatment of selected forms of monogenic diabetes. It will enable in the near future effective and causal treatment of genetic forms of diabetes in children. [ABSTRACT FROM AUTHOR]

Background: WFS1-spectrum disorders are caused by a mutation in the WFS1 gene. The term includes a wide range of rare disorders, from the most severe Wolfram syndrome with autosomal recessive inheritance to milder clinical manifestations with a single causative variant in the WFS1 gene, such as Wolfram-like syndrome, low-frequency sensorineural hearing loss (LFSNHL), isolated diabetes mellitus (DM), nonsyndromic optic atrophy (OA), and isolated congenital cataracts. Methods: The aim of this study was to evaluate genotype–phenotype correlations in Polish patients with WFS1-spectrum disorders. The study group constituted 22 patients (10 F; 12 M), including 10 patients (3 F; 7 M) referred to the Outpatient Clinic for Rare Diseases in Children and Adolescents and Diabetogenetics between 2019 and 2024 with clinical symptoms suggestive of WFS1-spectrum disorders, and 12 of their first-degree relatives (7 F; 5 M) from 10 families in Poland. Molecular testing was performed using tNGS (Targeted Next Generation Sequencing; Illumina) and analyzed for variants in the WFS1 gene. Results: Thirteen different variants in the WFS1 gene were found in 22 individuals (10 patients and family members), including the identification of two new variants (c.1535T>C and c.2485C>G). All patients had hyperglycemia or DM, hearing impairment, OA, or a combination of these symptoms. Four patients in the study group were diagnosed with Wolfram syndrome and all were compound heterozygotes for variants in the WFS1 gene. Conclusions: The evaluation of molecular characteristics in combination with clinical symptoms broadens the understanding of WFS1-spectrum disorders and allows more accurate management and prognosis for patients with this diagnosis. [ABSTRACT FROM AUTHOR]

Background: Wolfram syndrome (WFS, OMIM: #222300) is an ultrarare autosomal recessive disorder characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy and deafness. It has been reported that the average retinal thickness in WFS patients decreases with the progression of the disease. Aim: To investigate retinal thickness and wolframin expression disorders in Wolfram syndrome 1 gene knockout (Wfs1KO) mice compared to their wild-type (WT) littermates. Materials and methods: Both bulbs with optic nerves of three mice Wfs1WT and three Wfs1KO were taken for the histopathological examination. A strain of knockout mice with mutation in exon 8 was used. Results: No expression of wolframin protein in the retina and neurodegeneration of the optic nerve of Wfs1KO mice as compared among Wfs1WT mice was observed. The mean central retinal thickness was thinner and the retinal thickness/longitudinal diameter ratio was significantly lower in hte Wfs1KO as compared to the Wfs1WT mice. In four (67%) eyeballs of Wfs1KO mice, intra-retinal neovessels were observed. Conclusions: Wfs1KO mice retina with mutation in exon 8 present similar clinical features as patients with WFS in the form of reduced retinal thickness and neurodegeneration of the optic nerve. The presence of proliferative retinopathy observed in Wfs1KO mice requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Intense exercise leads to neutrophil extracellular traps (NETs) formation, which triggers cell disintegration. NET, as well as other processes of apoptosis, necrosis, and spontaneous secretion, result in increased levels of cell-free DNA (cf-DNA) in the circulation. An increment of cf-DNA is also observed in autoimmune diseases, such as type 1 diabetes mellitus (T1DM). Repeated exhaustive exercises are an impulse for physiological adaptation; therefore, in this case–control study, we compared the exercise-induced increase in cf-DNA in men with T1DM and healthy controls to determine the development of the tolerance to exercise. Methods: Volunteers performed a treadmill run to exhaustion at a speed matching 70% of their personal VO2 max at three consecutive visits, separated by a 72 h resting period. Blood was collected before and after exercise for the determination of plasma cell-free nuclear and mitochondrial DNA (cf n-DNA, cf mt-DNA) by real-time PCR, blood cell count and metabolic markers. Results: Each bout of exhaustive exercise induced a great elevation of cf n-DNA levels. An increase in cf mt-DNA was observed after each run. However, the significance of the increase was noted only after the second bout in T1DM participants (p < 0.02). Changes in cf-DNA concentration were transient and returned to baseline values during 72 h of resting. The exercise-induced increment in circulating cf n-DNA and cf mt-DNA was not significantly different between the studied groups (p > 0.05). Conclusions: Cf-DNA appears to be a sensitive marker of inflammation, with a lower post-exercise increase in individuals with T1DM than in healthy men. [ABSTRACT FROM AUTHOR]

Variations in several nuclear genes predisposing humans to the development of MODY diabetes have been very well characterized by modern genetic diagnostics. However, recent reports indicate that variants in the mtDNA genome may also be associated with the diabetic phenotype. As relatively little research has addressed the entire mitochondrial genome in this regard, the aim of the present study is to evaluate the genetic variations present in mtDNA among individuals susceptible to MODY diabetes. In total, 193 patients with a MODY phenotype were tested with a custom panel with mtDNA enrichment. Heteroplasmic variants were selected for further analysis via further sequencing based on long-range PCR to evaluate the potential contribution of frequent NUMTs (acronym for nuclear mitochondrial DNA) insertions. Twelve extremely rare variants with a potential damaging character were selected, three of which were likely to be the result of NUMTs from the nuclear genome. The variant m.3243A>G in MT-TL1 was responsible for 3.5% of MODY cases in our study group. In addition, a novel, rare, and possibly pathogenic leucine variant m.12278T>C was found in MT-TL2. Our findings also found the MT-CO1 gene to be over-represented in the study group, with a clear phenotype–genotype correlation observed in one family. Our data suggest that heteroplasmic variants in MT-COI and MT-TL2 genes may play a role in the pathophysiology of glucose metabolism in humans. [ABSTRACT FROM AUTHOR]

Annual vaccination is the most effective protection against influenza and its serious complications. It is especially important for people at high risk of severe course of the disease and serious complications: individuals with specific chronic medical conditions, pregnant women, children aged 6-59 months, older people, and healthcare workers. Despite a progressive increase in seasonal vaccine coverage, influenza-related morbidity, mortality, and hospitalization rates remain high and have continued to increase in people aged 65 years and over. Standard vaccines against influenza are less efficient in this group due to immunosenescence. Consequently, more effective vaccines are needed to prevent influenza and its complications in older adults. [ABSTRACT FROM AUTHOR]

Bardet–Biedl syndrome (BBS) and Alström syndrome (ALMS) are rare multisystem diseases with an autosomal recessive mode of inheritance and genetic heterogeneity, characterized by visual impairment, hearing impairment, cardiomyopathy, childhood obesity, and insulin resistance. The purpose of our study was to evaluate the indicators of nervous system changes occurring in patients with ALMS and BBS using optical coherence tomography (OCT) and magnetic resonance spectroscopy (MRS) methods compared to a group of healthy subjects. The OCT results showed significantly lower macular thickness in the patient group compared to the control group (p = 0.002). The MRS study observed differences in metabolite levels between the study and control groups in brain areas such as the cerebellum, thalamus, and white matter. After summing the concentrations from all areas, statistically significant results were obtained for N-acetylaspartate, total N-acetylaspartate, and total creatine. Concentrations of these metabolites were reduced in ALMS/BBS patients by 38% (p = 0.0004), 35% (p = 0.0008), and 28% (p = 0.0005), respectively. Our results may help to understand the pathophysiology of these rare diseases and identify strategies for new therapies. [ABSTRACT FROM AUTHOR]

Alström syndrome (ALMS) and Bardet–Biedl syndrome (BBS) are rare genetic diseases with a number of common clinical features ranging from early-childhood obesity and retinal degeneration. ALMS and BBS belong to the ciliopathies, which are known to have the expression products of genes, encoding them as cilia-localized proteins in multiple target organs. The aim of this study was to perform transcriptomic and proteomic analysis on cellular models of ALMS and BBS syndromes to identify common and distinct pathological mechanisms present in both syndromes. For this purpose, epithelial cells were isolated from the urine of patients and healthy subjects, which were then cultured and reprogrammed into induced pluripotent stem (iPS) cells. The pathways of genes associated with the metabolism of lipids and glycosaminoglycan and the transport of small molecules were found to be concomitantly downregulated in both diseases, while transcripts related to signal transduction, the immune system, cell cycle control and DNA replication and repair were upregulated. Furthermore, protein pathways associated with autophagy, apoptosis, cilium assembly and Gli1 protein were upregulated in both ciliopathies. These results provide new insights into the common and divergent pathogenic pathways between two similar genetic syndromes, particularly in relation to primary cilium function and abnormalities in cell differentiation. [ABSTRACT FROM AUTHOR]

Background/Objectives: Patients referred for HNF1B testing present very heterogeneous phenotypes. Despite suggestive characteristics, many do not harbor mutations in HNF1B. Our objective was to evaluate the clinical characteristics of probands referred for HNF1B genetic testing through a nationwide monogenic diabetes screening program. Methods: Probands tested for HNF1B mutations in the 2005‐2018 period (N = 50) were identified in the Polish Monogenic Diabetes Registry, which prospectively recruits primarily pediatric patients and their families on a nationwide scale. Variants that had been reported pathogenic were reassessed using criteria of the American College of Medical Genetics and Genomics (ACMG). A structured medical interview was performed with all available individuals, their parents, and/or their physicians. For each patient, HNF1B score was calculated based on available clinical information. Results: The study group numbered 36 unrelated probands (28% lost to follow‐up): 14 with pathogenic or likely‐pathogenic variants in HNF1B, one with a variant of uncertain significance, and 21 negative for HNF1B mutations. Presence of cystic kidneys (OR = 9.17, 95% CI:1.87‐44.92), pancreatic abnormalities (OR = 15, 95% CI:1.55‐145.23), elevated liver enzymes (OR = 15, 95% CI:1.55‐145.23) best discriminated HNF1B‐positive cases from the negative ones. Presence of impaired glucose tolerance coupled with kidney disease in the proband and one parent was also highly predictive for HNF1B mutations (OR = 11.11, 95% CI:1.13‐109.36). HNF1B‐score with recommended cutoff distinguished patients with and without HNF1B findings with 100% sensitivity and 47.6% specificity. Addition of four clinical variables to select patients based on HNF1B score improved specificity to 71.4% (95% CI:47.8%‐88.7%) while retaining 100% sensitivity. Conclusions: Detailed medical interview may enable more accurate patient selection for targeted genetic testing. [ABSTRACT FROM AUTHOR]

Introduction. It remains unclear how HbA1c recommendations influence metabolic control of paediatric patients with type 1 diabetes mellitus. To evaluate this we compared reported HbA1c with guideline thresholds. Materials and Methods. We searched systematically MEDLINE and EMBASE for studies reporting on HbA1c in children with T1DM and grouped them according to targeted HbA1c obtained from regional guidelines. We assessed the discrepancies in the metabolic control between these groups by comparing mean HbA1c extracted from each study and the differences between actual and targeted HbA1c. Results. We included 105 from 1365 searched studies. The median (IQR) HbA1c for the study population was 8.30% (8.00%–8.70%) and was lower in “6.5%” than in “7.5%” as targeted HbA1c level (8.20% (7.85%–8.57%) versus 8.40% (8.20%–8.80%); p=0.028). Median difference between actual and targeted HbA1c was 1.20% (0.80%–1.70%) and was higher in “6.5%” than in “7.5%” (1.70% (1.30%–2.07%) versus 0.90% (0.70%–1.30%), resp.; p<0.001). Conclusions. Our study indicates that the 7.5% threshold results in HbA1c levels being closer to the therapeutic goal, but the actual values are still higher than those observed in the “6.5%” group. A meta-analysis of raw data from national registries or a prospective study comparing both approaches is warranted as the next step to examine this subject further. [ABSTRACT FROM AUTHOR]

Introduction: Recently the prevalence of overweight and obesity in pediatric population - also in type 1 diabetic adolescents - has increased. Aim of the study: Aim of the study was to evaluate prevalence of obesity and central obesity in type 1 diabetic youth. Material and methods: 192 patients (81 girls, 111 boys), aged 10-18 years, with diabetes duration 0.5-15 years were included into the study. The anthropometric parameters were examined. Obesity was recognized according to WHO definition: overweight - BMI 85-95 pc, obesity - BMI >95 pc and according to International Obesity Task Force (IOTF): overweight - BMI >IOTF 25 kg/m2, obesity - BMI >IOTF 30 kg/m2. Central obesity was defined as waist circumference above 90 percentile for sex and age and as waist/height rate (WHtR) >0.5. Local BMI and waist circumference percentiles charts were used. Results: According to WHO criteria overweight was found in 19 girls and 13 boys, obesity properly in 4 and 10, together in 28% and 20.9%. According to IOTF overweight was recognized in 21 girls and boys, obesity properly in 1 and 8, together in 29.3% and 26.4%. According to percentiles charts, central obesity was recognized in 21 girls (25.6%) and in 18 boys (16.4%), together in 20.3% patients. Using WHtR abdominal obesity was found in 7 girls (8.5%) and in 13 boys (11.8%), together in 10.3%. Conclusions: Irrespectively of adopted criteria, overweight/obesity was found in every fourth adolescent with type 1 diabetes. The prevalence of central obesity depends on the adopted criteria. According to local percentiles waist circumference charts, abdominal obesity was recognized twice more frequently than using WHtR. [ABSTRACT FROM AUTHOR]

The aims of the study were: 1. to evaluate the levels of insulin antibodies (IA) during the first 2 years of type 1 diabetes in children and adolescents, 2. to analyze relations between IA and several clinical and metabolic markers. Material and methods: Fifty seven patients (37 males and 20 females) aged 7.6-17.9 years (mean 13.2±2.4) participated in the study. Patients were treated with human insulins and/or with rapid acting human insulin analogs. During the 1st week after diabetes diagnosis, 6 months after diagnosis (N=57) and 24 months after diagnosis (N=42) the following parameters were studied: residual insulin secretion, daily insulin dose, HbA1c, BMI and insulin sensitivity. IA were measured by radioimmunoprecipitation (normal values <7%), C-peptide was measured by radioimmunoassay (the increase in C-peptide concentration 6 minutes after an intravenous injection of glucagon was measured, ΔC-pep). M index measured by euglycemic hyperinsulinemic clamp method by DeFronzo was the measure of insulin sensitivity (higher M index indicates higher insulin sensitivity). Results: Median values (and quartiles) of IA were: 6.7% (5.6-7.4), 16.6% (10.2-37.1) and 17.0% (9.4-38.9) respectively in the 1st week of diabetes and after 6 and 24 months of follow up. IA levels rose significantly during the first 6 months of diabetes (p<0.0001) and remained stable thereafter. After 6 months of diabetes duration the following statistically significant correlations were found: negative between IA and ΔC-pep (r=-0.36, p=0.007), positive between IA and M index (r=0.27, p=0.04) and negative between IA and BMI (ρ?=-0.4, p=0.02); a slight, statistically nonsignificant, correlation between IA and daily insulin dose was noted, too (r=0.19, p=0.16). After 24 months correlation coefficients were as follows: for IA and M index ρ?=0.16, p=0.32, for IA and ΔC-pep ?=-0.08, p=ns, for IA and BMI ρ?=-0.34, p=0.03. Conclusions: 1. Modern insulin preparations induce production of IA in young type 1 diabetic patients. 2. Patients with lower residual insulin secretion require higher daily insulin doses during the first months of diabetes, which may preclude higher IA production. 3. Negative correlation between IA and insulin resistance may be a) secondary to the well known correlation: lower BMI - higher insulin sensitivity or may be due to b) IA acting as a temporary "reservoir" of administered insulin or to c) hypoglycemic activity of IA-insulin complexes. [ABSTRACT FROM AUTHOR]

Bardet-Biedl syndrome (BBS) is a rare autosomal recessively inherited disease with major clinical symptoms such as: obesity, retinal degeneration, polydactyly and renal abnormalities. The aim of the study was to assess the spectrum of gene variants among patients with BBS, identified on the basis of nationwide genetic studies of monogenic diabetes in Polish population. Out of 575 patients enrolled for genetic testing from February 2017 to July 2019, 25 patients with a clinical suspicion of BBS were selected. The identification of pathogenic variants was performed by using targeted next-generation sequencing (NGS) on Illumina NextSeq 550 platform involving the SureSelect assay (Agilent, Santa Clara, CA, USA). BBS was genetically confirmed in 10 of 25 suspected patients. In patients, 14 different variants were found in six genes, mainly in BBS9 and BBS10 gene, including two novel variants. A strong association between hyperglycemia and insulin resistance in patients and the presence of variants in BBS9 gene was observed. Identification of 14 variants, including two new mutations using the NGS method, is the first molecular characteristic of Polish patients with Bardet–Biedl syndrome. It gives hope for earlier proper diagnosis of BBS in future patients selected from children with early childhood obesity and their medical multidisciplinary care. [ABSTRACT FROM AUTHOR]

The aim of the study was to analyze the thickness of individual retinal layers in patients with type 1 diabetes (T1D) in comparison to the control group and in relation to markers of diabetes metabolic control. The study group consisted of 111 patients with an average of 6-years of T1D duration. The control group included 36 gender- and age-matched individuals. In all patients optical coherence tomography (OCT) study was performed using HD-OCT Cirrus 5000 with evaluation of optic nerve head (ONH) parameters, thickness of retinal nerve fiber layer (RNFL) with its quadrants, macular full-thickness parameters, ganglion cells with inner plexus layer (GCIPL) and choroidal thickness (CT). Lower disc area value was observed in the study group as compared to controls (p = 0.0215). Negative correlations were found both between age at examination and rim area (R = −0.28, p = 0.0007) and between superior RNFL thickness and duration of diabetes (R = −0.20, p = 0.0336). Positive correlation between center thickness and SD for average glycemia (R = 0.30, p = 0.0071) was noted. Temporal CT correlated positively with age at examination (R = 0.21, p = 0.0127). The selected parameters the HD-OCT study may in the future serve as potential markers of preclinical phase of DR in patients with T1D. [ABSTRACT FROM AUTHOR]

Background: Estimated monogenic diabetes (MD) prevalence increases as screening programs proceeds. Objective: To estimate prevalence of MD among Polish children. Subjects: Patients and their family members suspected of suffering from MD (defined as causative mutation in one of the Maturity Onset Diabetes of the Young or permanent neonatal diabetes mellitus genes) were recruited between January 2005 and December 2015. Methods: Nationwide prevalence was estimated based on data from 6 administrative provinces (out of 16 in Poland) with high referral rates of patients (>10 per 100 000 children). Results: During the analysis, probands from 322 of 788 screened families tested positive yielding a total of 409 children and 299 family members with MD. An average of 70 probands/year were referred. Screening success rate reached 40% over the study period. We estimated the prevalence of MD in 2015 to 7.52/100 000 children (1 in 13 000). The most frequent MODY in this group was GCK‐ MODY (6.88/100 000). The prevalence estimates increased nearly 2‐fold since our report in 2011 (4.4/100 000). However, the figure reached a plateau because of screening saturation in 2014 what was also proven by lowering of the median age of diagnosis lowered in time (R = −0.73, P = .0172) along with shortening of the delay between clinical and genetic diagnosis (R = −0.65, P = .0417). Conclusions: The screening for childhood MD in Poland reached a plateau phase after 10 years showing a stable prevalence estimate. The true frequency of MD in the overall population may be higher given later onset of reportedly more frequent types of MD than GCK ‐MODY. [ABSTRACT FROM AUTHOR]