Comparison of the Clinical Utility of Two Insulin Resistance Indices: IRI-HOMA and IRI-Belfiore in Diagnosing Insulin Resistance and Metabolic Complications in Children Based on the Results Obtained for the Polish Population.

Background: Recognizing insulin resistance (IR) in children remains challenging due to uncertain IRI-HOMA cut-offs and unclear recommendations for evaluating IR based on OGTT. In our study, we compare the effectiveness of IRI-HOMA and IRI-Belfiore (OGTT-based) in detecting IR and its metabolic complications in children. Methods: The analysis included 553 children who were hospitalized at the Department of Endocrinology and Metabolic Diseases of the Polish Mother's Memorial Hospital Research Institute (PMMH-RI) in Lodz, Poland, between 2002 and 2018 due to various reasons-of these, 67.5% were girls. All underwent OGTT for glucose and insulin assessment. IR diagnosis relied on IRI-HOMA and IRI-Belfiore. IR based on IRI-HOMA was evaluated using three criteria: (A) >2.5; (B) >2.67 in boys and >2.22 in girls before puberty and >5.22 and >3.82 during puberty, respectively; (C) >95th percentile according to charts for IRI-HOMA in children. Results: Prepubertal children exhibited significantly lower IRI-HOMA and IRI-Belfiore than their pubertal counterparts (p < 0.00005). IRI-HOMA and IRI-Belfiore values positively correlated with age and BMI SDS value (p < 0.000001 for all calculations). As many as 26% to 46.9% of children with normal IRI-HOMA showed elevated IRI-Belfiore, with notably higher levels of triglycerides, a lower HDL cholesterol fraction, and a lower HDL/total cholesterol ratio in this subgroup. Conclusions: A notable proportion of children exhibited elevated IRI-Belfiore levels despite having normal IRI-HOMA values. This suggests the possibility of peripheral IR preceding hepatic IR in children-omitting an OGTT may therefore lead to overlooking cases of IR. Children diagnosed with IR via OGTT displayed significantly poorer lipid profiles compared to those without IR (characterized by normal values in both IRI-HOMA and IRI-Belfiore). This underscores the ability of OGTT-derived IR indices to identify individuals at risk of developing complications associated with obesity and IR before the onset of metabolic syndrome (MS) symptoms. If IR is already detected in children based on fasting glucose and insulin levels (IRI-HOMA), further evaluation may not be warranted, as OGTT results often simply confirm the diagnosis.

Serum metabolomics identified specific lipid compounds which may serve as markers of disease progression in patients with Alström and Bardet-Biedl syndromes.

Objectives: Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) are among the so-called ciliopathies and are associated with the development of multiple systemic abnormalities, including early childhood obesity and progressive neurodegeneration. Given the progressive deterioration of patients' quality of life, in the absence of defined causal treatment, it seems reasonable to identify the metabolic background of these diseases and search for their progression markers. The aim of this study was to find metabolites characteristic to ALMS and BBS, correlating with clinical course parameters, and related to the diseases progression. Methods: Untargeted metabolomics of serum samples obtained from ALMS and BBS patients (study group; n = 21) and obese/healthy participants (control group; each of 35 participants; n = 70) was performed using LC-QTOF-MS method at the study onset and after 4 years of follow-up. Results: Significant differences in such metabolites as valine, acylcarnitines, sphingomyelins, phosphatidylethanolamines, phosphatidylcholines, as well as lysophosphatidylethanolamines and lysophosphatidylcholines were observed when the study group was compared to both control groups. After a follow-up of the study group, mainly changes in the levels of lysophospholipids and phospholipids (including oxidized phospholipids) were noted. In addition, in case of ALMS/BBS patients, correlations were observed between selected phospholipids and glucose metabolism parameters. We also found correlations of several LPEs with patients' age (p < 0.05), but the level of only one of them (hexacosanoic acid) correlated negatively with age in the ALMS/BBS group, but positively in the other groups. Conclusion: Patients with ALMS/BBS have altered lipid metabolism compared to controls or obese subjects. As the disease progresses, they show elevated levels of lipid oxidation products, which may suggest increased oxidative stress. Selected lipid metabolites may be considered as potential markers of progression of ALMS and BBS syndromes.

The incidence of insulin resistance based on indices calculated using the HOMA and Belfiore methods and its impact on the occurrence of metabolic complications in prepubertal children born small for gestational age.

INTRODUCTION: Children born small for gestational age (SGA) are predisposed to obesity, insulin resistance (IR), and lipid disorders. The HOMA-IR index is commonly used to assess IR (IRIHOMA), calculated from fasting glucose and insulin. However, sometimes, during the oral glucose tolerance test (OGTT), elevated and prolonged postprandial insulin secretion is observed despite normal fasting insulin levels. IRIBelfiore is an IR index that analyses glucose and insulin levels during OGTT according to the method proposed by Belfiore. THE AIM OF THE STUDY: was to assess the frequency of IR based on IRIHOMA and IRIBelfiore results in SGA children aged 6-8 years, after catch-up phenomenon, to determine the usefulness of IRIBelfiore in diagnosis of IR and in predicting future metabolic complications. MATERIAL AND METHODS: In 129 SGA normal-height children, aged 6-8 years, height, weight, waist circumference, blood pressure, as well as lipids, IGF-1, cortisol, C-peptide, leptin, adiponectin, and resistin concentrations were measured. The glucose and insulin concentrations were evaluated at 0, 60, and 120 minutes of OGTT. RESULTS: IRIHOMA was normal in all children, while elevated IRIBelfiore was found in 22.5% of them. Children with IR diagnosed by IRIBelfiore were taller, had higher blood pressure, higher leptin, and lower HDL-cholesterol concentrations. CONCLUSIONS: It seems worth recommending IRIBelfiore derived from OGTT as a valuable diagnostic tool for identifying IR in SGA prepubertal children. Abnormal IRIBelfiore is related to higher blood pressure and lower HDL-cholesterol concentration in this group.

Searching for Effective Methods of Diagnosing Nervous System Lesions in Patients with Alström and Bardet-Biedl Syndromes.

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.

Association of circulating miRNAS in patients with Alstrom and Bardet-Biedl syndromes with clinical course parameters.

Background: Patients with the rare syndromic forms of monogenic diabetes: Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) have multiple metabolic abnormalities, including early-onset obesity, insulin resistance, lipid disorders and type 2 diabetes mellitus. The aim of this study was to determine if the expression of circulating miRNAs in patients with ALMS and BBS differs from that in healthy and obese individuals and determine if miRNA levels correlate with metabolic tests, BMI-SDS and patient age. Methods: We quantified miRNA expression (Qiagen, Germany) in four groups of patients: with ALMS (n=13), with BBS (n=7), patients with obesity (n=19) and controls (n=23). Clinical parameters including lipids profile, serum creatinine, cystatin C, fasting glucose, insulin and C-peptide levels, HbA1c values and insulin resistance (HOMA-IR) were assessed in patients with ALMS and BBS. Results: We observed multiple up- or downregulated miRNAs in both ALMS and BBS patients compared to obese patients and controls, but only 1 miRNA (miR-301a-3p) differed significantly and in the same direction in ALMS and BBS relative to the other groups. Similarly, 1 miRNA (miR-92b-3p) was dysregulated in the opposite directions in ALMS and BBS patients, but diverged from 2 other groups. We found eight miRNAs (miR-30a-5p, miR-92b-3p, miR-99a-5p, miR-122-5p, miR-192-5p, miR-193a-5p, miR-199a-3p and miR-205-5p) that significantly correlated with at least of the analyzed clinical variables representing an association with the course of the diseases. Conclusions: Our results show for the first time that serum miRNAs can be used as available indicators of disease course in patients with ALMS and BBS syndromes.

Identification of bone metabolism disorders in patients with Alström and Bardet-Biedl syndromes based on markers of bone turnover and mandibular atrophy.

Objectives: Causative variants in genes responsible for Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) cause damage to primary cilia associated with correct functioning of cell signaling pathways in many tissues. Despite differences in genetic background, both syndromes affect multiple organs and numerous clinical manifestations are common including obesity, retinal degeneration, insulin resistance, type 2 diabetes and many others. The aim of the study was to evaluate bone metabolism abnormalities and their relation to metabolic disorders based on bone turnover markers and presence of mandibular atrophy in patients with ALMS and BBS syndromes. Material and methods: In 18 patients (11 with ALMS and 7 with BBS aged 5-29) and in 42 age-matched (p < 0.05) healthy subjects, the following markers of bone turnover were assessed: serum osteocalcin (OC), osteoprotegerin (OPG), s-RANKL and urinary deoxypyridinoline - DPD. In addition, a severity of alveolar atrophy using dental panoramic radiograms was evaluated. Results: Lower serum OC (p = 0.0004) and urinary DPD levels (p = 0.0056) were observed in the study group compared to controls. In ALMS and BBS patients, serum OC and urinary DPD values negatively correlated with the HOMA-IR index, while a positive correlation between the OC and 25-OHD levels and a negative correlation between s-RANKL and fasting glucose concentrations were found. A significant difference in the incidence of low-grade mandibular atrophy between patients with ALMS and BBS and controls (p < 0.0001) was observed. Conclusions: The identification of bone metabolism disorders in patients with ALMS and BBS syndromes indicates the necessity to provide them with appropriate diagnosis and treatment of these abnormalities.

Next-Generation Sequencing in the Diagnosis of Patients with Bardet-Biedl Syndrome-New Variants and Relationship with Hyperglycemia and Insulin Resistance.

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.

Can we effectively predict the occurrence of cerebral edema in children with ketoacidosis in the course of type 1 diabetes? - case report and literature review.

Background Cerebral edema (CE) is one of the most serious complications of diabetic ketoacidosis (DKA) and can result in central nervous system (CNS) disorders and even lead to death of the patient. Case presentation We present the case of a 11-year-old boy with severe DKA in the course of newly diagnosed type 1 diabetes (T1D). The delay in the diagnosis of DKA and some therapeutic problems contributed to the development of CE and direct life-threatening conditions. Early diagnosis of CE development in the course of DKA using non-invasive methods such as pachymetry or transorbital ultrasound seems to be a very important prognostic factor. Conclusions This case highlights the importance of appropriate treatment according to the newest recommendations and presents the usefulness of new diagnostic methods to assess the risk of CE in children with newly diagnosed T1D.

Central Corneal Thickness can be Related to Diabetic Peripheral Neuropathy in Children with Type 1 Diabetes.

AIMS: Diabetic eye disease with its various manifestations as well as diabetic neuropathy may occur in patients with type 1 diabetes (T1D) after several years of diabetes duration. Pachymetry is a promising method evaluating central corneal thickness (CCT) in diabetic patients. The aim of the study was to evaluate the CCT values in children with T1D and its relationship to neurophysiological markers of diabetic neuropathy. METHODS: The study groups included 119 T1D children with average 5.3 years of diabetes duration and 38 age-matched controls. CCT index was measured with pachymeter in all subjects and in 19/119 of T1D patients the CCT values were referred to the ENG-EMG-SSR study results. RESULTS: In T1D patients the higher CCT values were observed as compared to healthy controls (p=0.037). Correlations between CCT values and both distal latency of the motor fibers of the median nerve (R=0.51; p=0.044) and conduction velocity of this nerve (R=-0.55; p=0.027) were noted. A conduction velocity of the sensory fibers of sural nerve correlated negatively with CCT index (R=-0.50; p=0.045) in the T1D patients. CONCLUSIONS: CCT measurement may be helpful in the referral of the asymptomatic pediatric T1D patients to assess an early stage of diabetic neuropathy.

Measurement of corneal thickness, optic nerve sheath diameter and retinal nerve fiber layer as potential new non-invasive methods in assessing a risk of cerebral edema in type 1 diabetes in children.

AIMS: Some patients with diabetic ketoacidosis develop cerebral edema (CE) in the course of type 1 diabetes mellitus (T1D), which may result in central nervous system disorders and high mortality. The imperfection of existing neuroimaging techniques for early recognition of CE forces us to search for the new and non-invasive methods. The aim of the study was to assess the usefulness of new methods (pachymetry, transorbital ultrasonography-USG, optical coherence tomography-OCT study) in the assessment of the risk of CE occurrence in children with newly diagnosed T1D. METHODS: The study group included 50 children with newly diagnosed T1D, 54 patients with long-term T1D as a reference group and 40 children without glucose tolerance disorders as controls. In all subjects, a corneal thickness (CCT) index with pachymeter, optic nerve sheath diameter (ONSD) using transorbital USG and retinal nerve fiber layer (RNFL) during OCT study were measured and compared with selected clinical parameters of T1D. RESULTS: In patients from a study group at onset of T1D, the higher CCT (p < 0.001) and ONSD (p < 0.001) values were observed as compared to the results obtained after 48 h of metabolic compensation. The ONSD correlated negatively with pH value (r = - 0.64; p < 0.001), BE (r = - 0.54, p < 0.001) and HCO3- (r = - 0.50; p < 0.001). A positive correlation between RNFL and Na+ levels (r = 0.47; p < 0.005) was also observed. CONCLUSIONS: Transorbital USG and pachymetry may serve as the potential promising methods for the non-invasive assessment of the increased risk of development of CE in patients with T1D.

Gender and Age - Dependent effect of type 1 diabetes on obesity and altered body composition in young adults.

INTRODUCTION AND OBJECTIVE: The aim of the study was to evaluate the influence of age and gender on the prevalence of overweight and obesity, body composition and fatty tissue distribution in young adults with type 1 diabetes. MATERIAL AND METHODS: 197 patients with type 1 diabetes aged 20-40 years participated in the study. The control group consisted of 138 healthy adults. Body weight, height, waist and hip circumferences were measured. Analysis of body mass composition was performed using the bioimpedance. Study groups were stratified into cohorts aged <30 and 30+ years. RESULTS: Overweight and obesity were diagnosed in 35.5% and 13.2% of diabetic patients and in 26.1% and 7.3% of the control group, respectively (p=0.016). In the whole study group, advanced age (OR=1.10; p<0.001) and diabetes mellitus (OR=2.25; p=0.001) predisposed patients to excess body weight. Women had a lower prevalence of overweight and obesity, but a trend toward excessive body mass was observed in diabetic females (OR=1.18; p=0.181). Diabetic females more often had abdominal obesity than control females (mean difference - 19.2%; p=0.020). Higher total body fat mass was found in the diabetic group (p=0.037). Diabetic females had a higher amount of absolute (p<0.001) and relative body fat mass (p=0.002), fat free mass (p=0.007), relative arm (p=0.007), leg (0<0.001) and trunk (p-=0.006) fat mass than control females. Diabetic males showed only higher relative fat mass of the lower limbs compared to control males (p=0.018). CONCLUSIONS: Patients with type 1 diabetes develop overweight and obesity in early adulthood more frequently than the general population and are characterized by higher body fat mass. Gender-related differences in body weight and composition in young type 1 diabetic adults were found.