Lower heart rate variability, an index of worse autonomic function, is associated with worse beta cell response to a glycemic load in vivo-The Maastricht Study.

OBJECTIVE: We investigated, using population-based data, whether worse autonomic function, estimated from lower 24-hour heart rate variability (HRV), was associated with beta cell function, assessed from beta cell response during an oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: We used cross-sectional data from The Maastricht Study, a population-based cohort study (N = 2,007; age, mean ± SD:60 ± 8 years; 52% men; and 24% with type 2 diabetes). We used linear regression analyses with adjustment for potential confounders (demographic, cardiovascular, and lifestyle factors) to study the associations of time- and frequency-domain HRV (composite scores) with overall beta cell response (estimated from a composite score calculated from: C-peptidogenic index, overall insulin secretion, beta cell glucose sensitivity, beta cell potentiation factor, and beta cell rate sensitivity). In addition, we tested for interaction by sex and glucose metabolism status. RESULTS: After full adjustment, lower time- and frequency-domain HRV was significantly associated with lower overall beta cell response composite score (standardized beta, -0.055 [-0.098; -0.011] and - 0.051 [-0.095; -0.007], respectively). These associations were not modified by sex and there was no consistent pattern of interaction by glucose metabolism status. CONCLUSION: The present etiological study found that worse autonomic function, estimated from lower HRV, was associated with worse beta cell function, estimated from a composite score in a population-based sample which covered the entire spectrum of glucose metabolism. Hence, autonomic dysfunction may contribute to beta cell dysfunction and, ultimately, to the alteration of glucose metabolism status from normal glucose metabolism to prediabetes and type 2 diabetes.

Associations between higher plasma ferritin and hepcidin levels with liver stiffness in patients with type 2 diabetes: An exploratory study.

BACKGROUND: Currently, there is no information about the association between circulating levels of ferritin and hepcidin and liver fibrosis in patients with type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). METHODS: We enrolled 153 patients with T2DM with no known liver diseases, who consecutively attended our diabetes outpatient service and who underwent liver ultrasonography and liver stiffness measurement (LSM) by vibration-controlled transient elastography (Fibroscan® for the non-invasive assessment of liver fibrosis). Plasma ferritin and hepcidin concentrations were measured with an electrochemiluminescence immunoassay and mass spectrometry-based assay, respectively. RESULTS: After stratification of patients by LSM tertiles [1st tertile median LSM: 3.6 (interquartile range: 3.3-4.0) kPa, 2nd tertile: 5.3 (4.9-5.9) kPa and 3rd tertile: 7.9 (6.7-9.4) kPa], we found that plasma ferritin and hepcidin concentrations increased across LSM tertiles [median ferritin: 68.7 (interquartile range: 25.1-147) vs. 85.8 (48.3-139) vs. 111 (59.3-203) µg/L, p = 0.021; median hepcidin: 2.5 (1.1-5.2) vs. 4.4 (2.5-7.3) vs. 4.1 (1.9-6.8) nmol/L, p = 0.032]. After adjustment for age, sex, diabetes duration, waist circumference, haemoglobin A1c, HOMA-insulin resistance score, triglycerides, haemoglobin, presence of hepatic steatosis on ultrasonography and patatin-like phospholipase domain-containing-3 (PNPLA3) rs738409 genetic variant, higher plasma ferritin levels were associated with greater LSM values (adjusted-odds ratio 2.10, 95% confidence interval 1.23-3.57, p = 0.005). Higher plasma hepcidin levels were also associated with greater LSM values (adjusted-odds ratio 1.90, 95% confidence interval 1.15-3.13, p = 0.013). CONCLUSIONS: Higher levels of plasma ferritin and hepcidin were associated with greater NAFLD-related liver fibrosis (assessed by LSM) in patients with T2DM, even after adjustment for established cardiometabolic risk factors, diabetes-related variables and other potential confounders.

Crosstalk between genetic variability of adiponectin and leptin, glucose-insulin system and subclinical atherosclerosis in patients with newly diagnosed type 2 diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study 14.

AIM: To evaluate the relationship of genetic variability of adiponectin (ADIPOQ), leptin (LEP) and leptin receptor (LEPR) genes with glucose-insulin system and markers of subclinical atherosclerosis (ATS) in patients with newly diagnosed type 2 diabetes. MATERIALS AND METHODS: In 794 subjects we performed: 1) euglycemic hyperinsulinemic clamp to assess insulin sensitivity; 2) mathematical modelling of a 5h-OGTT to estimate ß-cell function; 3) resting ECG; 4) carotid artery and lower limb artery eco-doppler sonography to identify ATS; 5) genotyping of tag-SNPs within ADIPOQ, LEP and LEPR gene. RESULTS: Regression analyses showed: 1) adiponectin levels were negatively associated with BMI, waist-to-hip ratio and triglycerides and positively with HDL and insulin sensitivity (p-all<0.03); 2) leptin levels were positively associated with BMI, HDL-cholesterol and plasma triglycerides and negatively with insulin sensitivity (p-all<0.001). Two SNPs (rs1501299 and rs2241767) within ADIPOQ gene were associated with circulating levels of adiponectin. The ADIPOQ-GAACA haplotype was associated with plasma adiponectin (p=0.034; ß=-0.24), ECG abnormalities (p=0.012; OR=2.76), carotid ATS (p=0.025; OR=2.00) and peripheral limb artery ATS (p=0.032; OR=1.90). The LEP-CTA haplotype showed an association with ischemic ECG abnormalities (p=0.017; OR=2.24). Finally, LEPR-GAACGG was associated with circulating leptin (p=0.005; ß=-0.31) and worst ß-cell function (p=0.023; ß=-15.10). Omnibus haplotype analysis showed that ADIPOQ haplotypes were associated with levels of adiponectin and common carotid artery ATS, LEP with peripheral limb artery ATS, whereas LEPR haplotypes influenced circulating levels of leptin. CONCLUSIONS: Results of this study reinforce knowledge on adipokines' role in regulating glucose metabolism; in particular highlighted the potential atherogenic role of leptin and the anti atherogenic role of adiponectin.

Association between PNPLA3 rs738409 variant and 5-year estimated glomerular filtration rate decline in post-menopausal women with type 2 diabetes: A panel-data analysis.

BACKGROUND AND AIMS: Little is known about the relationship between patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 variant and decline in estimated glomerular filtration rate (eGFR) over time in individuals with type 2 diabetes (T2DM). METHODS AND RESULTS: We enrolled an outpatient sample of 46 post-menopausal women with T2DM and preserved kidney function at baseline (in 2017), who were followed through 2022. eGFR and albuminuria were measured annually. Genotyping of PNPLA3 rs738409 was performed by TaqMan-based RT-PCR system. Overall, 25 (54.3%) patients had PNPLA3 rs738409 CC (homozygous wild-type) genotype and 21 had CG or GG genotypes. During the 5-year follow-up, the presence of rs738409 CG/GG genotypes was associated with faster eGFR decline (coefficient: -6.55; 95% CI -11.0 to -2.08; p = 0.004 by random-effects panel data analysis). This association remained significant even after adjustment for 5-year changes in age, hemoglobin A1c, hypertension status, albuminuria and use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists. CONCLUSIONS: This pilot study suggests that in post-menopausal T2DM women with preserved kidney function at baseline, the risk allele (G) of PNPLA3 rs738409 is associated with a faster eGFR decline during a 5-year follow-up, independent of annual changes in common renal risk factors and use of certain glucose-lowering medications.

Association between KLF6 rs3750861 polymorphism and plasma ceramide concentrations in post-menopausal women with type 2 diabetes.

BACKGROUND AND AIM: Based on the emerging role of Kruppel-like factor 6 (KLF6) in lipid metabolism, we examined whether there is a relationship between the KLF6 rs3750861 genetic variant and plasma ceramide levels in people with type 2 diabetes mellitus (T2DM). METHODS AND RESULT: We measured six previously identified plasma ceramides, which have been associated with increased cardiovascular risk [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)] amongst 101 Caucasian post-menopausal women with T2DM, who consecutively attended our diabetes outpatient service during a 3-month period. Plasma ceramides were measured by targeted liquid chromatography-tandem mass spectrometry assay. Genotyping of the KLF6 rs3750861 polymorphism was performed by TaqMan-Based RT-PCR system. Overall, 87 (86.1%) patients had KLF6 rs3750861 C/C genotype and 14 (13.9%) had C/T or T/T genotypes. After adjustment for age, diabetes-related variables, use of lipid-lowering drugs and other potential confounders, patients with C/T or T/T genotypes had higher plasma Cer(d18:1/18:0) (0.159 ± 0.05 vs. 0.120 ± 0.04 µmol/L, p = 0.012), Cer(d18:1/20:0) (0.129 ± 0.04 vs. 0.098 ± 0.03 µmol/L, p = 0.008), and Cer(d18:1/24:1) (1.236 ± 0.38 vs. 0.978 ± 0.36 µmol/L, p = 0.032) compared with those with C/C genotype. CONCLUSIONS: The C/T or T/T genotypes of rs3750861 in the KLF6 gene were closely associated with higher levels of specific plasma ceramides in post-menopausal women with T2DM.

MAFLD and CKD: An Updated Narrative Review.

Accumulating evidence now indicates that non-alcoholic fatty liver disease (NAFLD), which is the most common chronic liver disease observed in clinical practice worldwide, is independently associated with an increased risk of incident chronic kidney disease (CKD). Given that NAFLD is linked to insulin resistance, obesity and type 2 diabetes mellitus, an international panel of experts have recently proposed a name change from NAFLD to metabolic associated fatty liver disease (MAFLD). Since the diagnostic criteria for NAFLD and MAFLD are different, observational studies assessing the potential concordance (or even superiority) of MAFLD, compared with NAFLD, in detecting patients at increased risk of hepatic and extra-hepatic complications (including CKD) are required. Hence, in the last two years, some observational studies have investigated the potential relationship between MAFLD and CKD. The result is that, at present, evidence regarding the concordance or even superiority of MAFLD, compared with NAFLD, in detecting patients at higher risk of CKD is still preliminary, although some data indicate that MAFLD identifies patients with CKD as accurately as NAFLD. In this narrative review, we will discuss: (a) the epidemiological evidence assessing the association between NAFLD and risk of incident CKD, (b) the epidemiological data investigating the association between MAFLD and risk of CKD and (c) the biological mechanisms underlying the association between NAFLD/MAFLD and CKD.

Influence of genetic variants in FADS2 and ELOVL2 genes on BMI and PUFAs homeostasis in children and adolescents with obesity.

BACKGROUND: Several studies identified genetic variants in FADS and ELOVL2 genes associated with obesity-related conditions, such as alterations in blood lipid parameters and insulin homeostasis. The aim of this cross-sectional study was to determine whether FADS and ELOVL2 genetic variants were associated with obesity and adiposity, besides dyslipidaemia and insulin resistance, in a large sample of obese children and adolescents. MATERIALS AND METHODS: One thousand six hundred and forty-nine obese children underwent physical examination, anthropometry, fasting blood tests measuring plasma glucose, lipid and liver profile. Two genetic variants were genotyped: rs2236212 in ELOVL2 gene and rs1535 in FADS2, for the gene cluster FADS. In a subgroup of obese children (n = 105), erythrocyte fatty acid composition was measured. Generalized linear models were used to assess association between genotypes and variables. RESULTS: A positive association between zBMI and the minor allele of rs2236212 (p = 0.028), the major allele of rs1535 (p = 0.046) and the genetic score (p = 0.008), created by summing up both risk alleles, were found. The estimation of enzymatic activity revealed that minor alleles were associated significantly with a reduction of the enzymatic activity of elongase and desaturase (p = 0.048 and p = 0.0001, respectively). DISCUSSION AND CONCLUSIONS: Common variants in the FADS2 and ELOVL2 genes were associated with BMI in a large population of obese Italian children. These SNPs were associated with alterations in LC-PUFAs homeostasis, not accompanied by modifications of plasma lipids or HOMA-IR. These findings provide additional support to the genetics accounting for BMI interindividual variability and the molecular basis of obesity.

Coronavirus disease 2019 (COVID-19) in children and/or adolescents: a meta-analysis.

BACKGROUND: To assess the overall prevalence of clinical signs, symptoms, and radiological findings in children and/or adolescents with COVID-19. METHODS: We systematically researched in PubMed, Scopus and Web of Science databases observational studies describing COVID-19 in children and/or adolescents until April 11, 2020. Data regarding clinical and radiological features were extracted from eligible studies and meta-analysis was performed using random-effects modeling. RESULTS: We examined 19 eligible studies for a total of 2855 children and/or adolescents with COVID-19. Approximately 47% of subjects had fever (95% confidence interval [CI] 22-72%; I2 = 98.6%), 37% cough (95%CI 15-63%; I2 = 98.6%), 4% diarrhea (95%CI 0-12%; I2 = 92.2%), 2% nasal congestion (95%CI 0-7%; I2 = 87.7%), 1% dyspnea (95%CI 0-7%; I2 = 91.5%) and 0% abdominal pain (95%CI 0-1%; I2 = 76.3%). Subjects presented mild symptoms in 79% (95%CI 65-91%; I2 = 93.5%) of cases, whereas only 4% (95%CI 1-9%; I2 = 76.4%) were critical. Among those with pneumonia on computed tomography, 26.4% (95%CI 13-41%; I2 = 80.8%) presented a unilateral involvement, 16% (95%CI 5-29%, I2 = 81.2%) had bilateral involvement and 9% (95%CI 0-24%; I2 = 88.7%) had interstitial pneumonia. CONCLUSIONS: Children and/or adolescents tend to have a mild COVID-19 course with a good prognosis. IMPACT: Compared to adults, children and/or adolescents tend to have a mild COVID-19 course with a good prognosis. This study provides new and consistence information on the clinical and radiological characteristics of COVID-19 in pediatrics. This study may help to fight COVID-19 in pediatric population.

The risk of metabolic derangements is higher in children and adolescents with overweight or obesity born small for gestational age.

BACKGROUND AND AIMS: Birth weight (BW) has been associated with the risk of obesity and metabolic derangements in children and adults. The aims of this study were: i. to evaluate the distribution of BW in a sample of overweight and obese children and adolescents compared with the general reference population; ii. to explore the relationship between the BW and insulin resistance and other cardiometabolic derangements in a population of children and adolescents with overweight and obesity. METHODS AND RESULTS: 710 overweight and obese children and adolescents were recruited and categorized into small (SGA), appropriate (AGA), and large (LGA) for gestational age, according to the BW percentile. Arterial blood pressure, lipid profile, glucose metabolism and hepatic steatosis were evaluated to assess cardiometabolic obesity-related derangements. The distribution of BW categories in our population was significantly different compared with the general population (SGA 6.9% vs. 8.6%, AGA 74.6% vs. 81.4%, LGA 18.5% vs. 10%; p < 0.0001). We found a higher frequency of prediabetes conditions (21.7% vs 8.9%, OR 2.97, 95% CI 1.38-6.38, p = 0.005) and borderline/high low-density lipoprotein cholesterol (31.8% vs 18.6%, OR 2.13, 95% CI 1.09-4.18, p = 0.033) in overweight and obese children born SGA compared to those born non-SGA, independently of age, sex, and BMI. CONCLUSIONS: BW is a risk factor of cardiometabolic derangements in a population of children and adolescents with overweight and obesity. Therefore, adequate obesity prevention strategies should be planned for children born SGA to minimize their risk to become obese and to reduce their short- and long-term cardiometabolic risks.

PNPLA3 I148M gene variant and chronic kidney disease in type 2 diabetic patients with NAFLD: Clinical and experimental findings.

BACKGROUND AND AIMS: Emerging evidence suggests an association between patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 (I148M protein variant) and risk of chronic kidney disease (CKD), but the mechanisms underpinning this association are poorly understood. METHODS: We studied 157 patients with type 2 diabetes (T2DM) who underwent ultrasonography and vibration-controlled transient elastography for diagnosing nonalcoholic fatty liver disease (NAFLD). CKD was defined as estimated glomerular filtration rate (e-GFR) <60 mL/min/1.73 m2 and/or abnormal albuminuria. We surveyed PNPLA3 mRNA expression in human tissues, using the liver as a positive control, and also measured PNPLA3 mRNA and protein expression levels in human cell lines represented in the kidney and the liver. RESULTS: In all, 112 patients had NAFLD and 43 had CKD. Patients homozygous for the I148M variant (n = 11) had lower e-GFR levels (60.6 ± 11.7 vs 77.8 ± 15.9 vs 83.5 ± 16.5 mL/min/1.73 m2 , P = .0001) and higher prevalence of CKD (63.6% vs 24.2% vs 25.0%, P = .028), compared to those with I/M (n = 66) and I/I (n = 80) PNPLA3 genotype. The association of I148M homozygosity with lower e-GFR levels (P < .0001) and higher risk of CKD (adjusted-odds ratio 6.65; 95% CI 1.65-26.8, P = .008) was independent of liver disease severity (as detected by liver stiffness ≥7kPa) and other risk factors. PNPLA3 mRNA expression was greatest in liver and renal cortex, and podocytes showed high PNPLA3 mRNA and protein levels, comparable to that of hepatocytes and hepatic stellate cells respectively. CONCLUSIONS: The PNPLA3 I148M variant was associated with CKD, independently of common renal risk factors and severity of NAFLD PNPLA3 expression levels were particularly high in renal podocytes.

"IGT-like" status in normoglucose tolerant obese children and adolescents: the additive role of glucose profile morphology and 2-hours glucose concentration during the oral glucose tolerance test.

OBJECTIVE: To assess whether combining glucose shape and 2-h glucose concentration during an oral glucose tolerance test (OGTT) may help identifying normal glucose tolerant obese children/adolescents with an impaired glucose tolerant (IGT)-like metabolic profile in term of insulin sensitivity (Matsuda index) and ß-cell function (disposition index: DI). SUBJECTS, METHODS, AND MAIN OUTCOME MEASURE: In total, 654 non-diabetic obese children/adolescents underwent a 2 h OGTT. The whole population was classified according to 2-hour plasma glucose ( < 100, 100-119, 120-139, 140-200 mg/dL) and glucose shape (monophasic or biphasic). Monophasic morphology was characterized by an increase in OGTT glucose concentration followed by a decline of at least 4.5 mg/dL, a biphasic response was defined as a decrease in glucose after an initial increase, followed by a second increase of ≥ 4.5 mg/dL. A subset of 69 participants had also a prolonged OGTT to estimate ß-cell function in "biphasic" versus "monophasic" patients. RESULTS: Matsuda index and DI decreased across 2-h glucose categories (both p < 0.001) and were lower in monophasic compared with biphasic children, independently of 2-h glucose category (both p < 0.001, both p for glucose category×shape interaction > 0.05). Normal glucose tolerant children with 2-h glucose of 120-139 mg/dl and monophasic glucose shape did not differ from IGT children, as regards Matsuda index and DI (both p > 0.05). Among children undergoing a prolonged OGTT, those with a monophasic glucose shape had worse ß-cell function, modeled as proportional control, than those with a biphasic shape (p = 0.031). CONCLUSIONS: A monophasic OGTT glucose shape is associated with unfavorable glucose metabolism independently of 2-h glucose concentration. Children combining monophasic shape and normal-high 2-h glucose have an IGT-like glucose metabolism.

Minor diplotypes of FMO3 might protect children and adolescents from obesity and insulin resistance.

In order to assess whether flavin-containing monooxygenase-3 (FMO3) might be involved in early cardiovascular risk, we assessed adiposity and traditional metabolic variables in children/adolescents grouped according to their genotypes in two FMO3 exonic polymorphisms, rs2266782 (E158K) and rs2266780 (E308G), which are in linkage disequilibrium and have been associated with decreased FMO3 activity. Among 776 children/adolescents (10.8 ± 2.2 years) recruited from the general population (452) and from our obesity outpatient clinic (324), the 68 carrying either the 158K-308G/158K-308E or the 158K-308G/158K-308G diplotype had lower mean z-BMI and prevalence of obesity compared to their 708 peers carrying any of the other diplotypes (0.39 vs 0.80, p = 0.01; OR = 0.39[0.17-0.87], p = 0.018, respectively), and to the sub-sample of 303 children carrying the major diplotype (158E-308E/158E-308E) (0.39 vs 0.87, p = 0.008; OR = 0.35[0.16-0.81], p = 0.014, respectively). They also had lower z-BMI-adjusted lnHOMA-IR compared to all the other children (0.75 vs 0.97, p = 0.001) and those carrying the major diplotype, (0.75 vs 0.98, p = 0.03), as well as lower z-BMI-adjusted iln-triglycerides compared to all the other children (3.98 vs 4.17, p = 0.037). These associations provide the first evidence that FMO3 may be involved in early body weight, insulin sensitivity, and lipid regulation in humans.

Analysis of RBFOX1 gene expression in lymphoblastoid cell lines of Italian discordant autism spectrum disorders sib-pairs.

Several lines of evidence suggest that RBFOX1 is a key regulator of transcriptional and splicing programs in neural cells during development, and that it is expressed in a neuronal module enriched for known autism susceptibility genes. We have investigated its expression by semiquantitative RT-PCR in accessible nonbrain resources in eighteen autism spectrum disorder sib-pairs belonging to the Italian Autism Network cohort. RBFOX1 gene expression was detected in lymphoblastoid cell lines but not in lymphocytes. No significant differences between autism spectrum disorders and non-affected brothers were found. We were not able to replicate in lymphoblastoid cell lines the previously reported RBFOX1 gene downregulation in autism, even if a trend was observed. This might be due to less pronounced transcription level differences in RBFOX1 gene expression in lymphoblastoid cell lines than in brain samples.

A longitudinal study of glucose tolerance in cystic fibrosis: the central role of beta cell functional mass.

CONTEXT: The pathophysiological mechanisms underlying the natural history of glucose intolerance and its fluctuations in subjects with cystic fibrosis (CF) are still unclear. OBJECTIVE: To investigate the relationship between longitudinal changes in glucose tolerance and concomitant changes in the main parameters of insulin secretion/metabolism/action determining glucose regulation in CF subjects. METHODS: Insulin sensitivity and glucose-stimulated insulin secretion (GSIS, a biomarker of beta cell functional mass), as estimated by the Oral Glucose Sensitivity Index (OGIS) and by a sophisticated mathematical model, respectively, and insulin clearance were assessed in 127 CF subjects, aged 10-25 years, who underwent two OGTT tests over at least 1-year follow-up period. Subjects were classified a posteriori as regressors (improved glucose tolerance), stable, or progressors (worsened glucose tolerance). The interplay between beta cell compensatory action and insulin sensitivity over time was analyzed by vector plots of insulin clearance adjusted GSIS (PCadj) versus OGIS. RESULTS: OGIS decreased in progressors and stable. Insulin clearance decreased in both regressors and progressors. GSIS (beta cell functional mass) improved in regressors and worsened in progressors, whereas it did not change in stable. Vector plot analysis confirmed that glucose regulation changed differently in each group. Multinomial logistic regression analysis showed that baseline glucose tolerance and GSIS changes were the only significant predictors of the changes in glucose tolerance (p<0.02, R2Nagelkerke=0.55), whereas age, gender, z-BMI, CF genotypes, and baseline PCadj were not. CONCLUSIONS: In CF subjects, changes in beta cell functional mass are associated with favorable or detrimental changes of glucose tolerance over time.

Cardiovascular Risk Factors in Children and Adolescents with Type 1 Diabetes Mellitus: The Role of Insulin Resistance and Associated Genetic Variants.

INTRODUCTION: Type 1 diabetes (T1D) is associated with an increased risk of cardiovascular disease. Insulin resistance is an important cardiovascular risk factor (CVRF), also in subjects with T1D, but the influence of the genetic predisposition of insulin resistance on cardiovascular risk is still unknown in T1D. We aimed to determine whether a genetic score composed of six variants, previously associated with insulin resistance and type 2 diabetes (T2D) risk, associates with insulin sensitivity and known CVRFs in children and adolescents with T1D. MATERIALS AND METHODS: 330 children and adolescents (174 males; mean age 15.7 ± 3.5 years) with T1D were genotyped for the following genetic variants: rs1801278 (IRS1), rs1044498 (ENPP1), rs2295490 (TRIB3), rs1801282 (PPARG), rs780094 (GCKR), and rs35767 (IGF1). An additive genetic risk score (GRS) and cardiovascular risk score (CVRS) were calculated. Anthropometric, glycemic control, insulin sensitivity, blood pressure, and biochemical parameters were assessed. Multivariate regression between evaluated phenotypes and GRS was performed. RESULTS: We found a significant association between the GRS and estimated insulin sensitivity (ß = -0.027 [-0.040 to -0.013], R2 = 0.86, p≤ 0.001), diastolic blood pressure (ß = 0.68 [0.08-1.27], R2 = 0.20, p = 0.026), triglycerides (ß = 4.26 [1.74-6.77], R2 = 0.13, p = 0.001), waist to height ratio (ß = 0.003 [0.001-0.006], R2 = 0.75, p = 0.010), non-HDL-cholesterol (ß = 3.63 [1.39-5.87], R2 = 0.12, p = 0.002), and CVRS (ß = 0.063 [0.008-0.118], R2 = 0.19, p = 0.025), independent of age, sex, BMI, pubertal stage, diabetes duration, glycated hemoglobin, type of treatment, and total insulin requirement. The addition of the GRS to established clinical risk factors significantly improved the discriminatory capability of the regression model for predicting subjects with more CVRFs (C-statistic 0.89 [95% CI: 0.84-0.95] versus 0.83 (0.73-0.93); p = 0.037). CONCLUSIONS: Insulin resistance and T2D risk-associated genetic variants influence insulin sensitivity and known CVRFs in children and adolescents with T1D.

IGF1 and PPARG polymorphisms are associated with reduced estimated glomerular filtration rate in a cohort of children and adolescents with type 1 diabetes.

INTRODUCTION: Several genetic loci have been associated with diabetic nephropathy; however, the underlying genetic mechanisms are still poorly understood, with no robust candidate genes identified yet. AIM: We aimed to determine whether two polymorphisms, previously associated with renal decline, influence kidney impairment evaluating their association with markers of renal function in a pediatric population with type 1 diabetes (T1D). MATERIAL AND METHODS: Renal function was evaluated by glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) in a cohort of pediatric subjects with T1D (n = 278). Risk factors for diabetes complications (diabetes duration, blood pressure, HbA1c) were assessed. The IGF1 rs35767 and PPARG rs1801282 SNPs were genotyped by TaqMan RT-PCR system. An additive genetic interaction was calculated. Association analysis between markers of renal function and both SNPs or their additive interaction were performed. RESULTS: Both SNPs showed a significant association with eGFR: the A allele of rs35767 or the C allele of rs1801282 were associated to reduced eGFR compared to G alleles. Multivariate regression analysis adjusted for age, sex, z-BMI, T1D duration, blood pressure and Hba1c values showed that the additive genetic interaction was independently associated with lower eGFR (ß = -3.59 [-6.52 to -0.66], p = 0.017). No associations were detected between SNPs, their additive interaction and ACR. CONCLUSIONS: These results provide new insight into the genetic predisposition to renal dysfunction, showing that two polymorphisms in IGF1 and PPARG genes can lead to a reduction in renal filtration rate leading these patients to be exposed to a higher risk of early renal complications.

Oral Microbiota in Children and Adolescents with Type 1 Diabetes Mellitus: Novel Insights into the Pathogenesis of Dental and Periodontal Disease.

The oral microbiota can be influenced by multiple factors, but only a few studies have focused on the role of glycemic control in determining early alterations of oral microbiota and their association with pathogenesis of both periodontitis and caries. The aim of this study is to evaluate the interplay between bacteria composition, oral hygiene, and glycemic control in a cohort of children with T1D. A total of 89 T1D children were enrolled (62% males, mean age: 12.6 ± 2.2 years). Physical and clinical characteristics, glucometabolic parameters, insulin treatment, and oral hygiene habits data were collected. Microbiological analysis was performed from saliva samples. A high prevalence of cariogenic and periodontopathogens bacteria in our cohort was detected. In particular, in all subjects Actinomyces spp., Aggregatibacter actinomycetemcomitans, Prevotella intermedia, and Lactobacillus spp. were isolated. S. mutans was found in about half of the analyzed sample (49.4%), in particular in patients with imbalance values of glycemic control. Moreover, a higher presence of both S. mutans and Veillonella spp. was detected in subjects with poorer glycemic control, in terms of HbA1c, %TIR and %TAR, even adjusting for age, sex, and hygiene habits as covariates. Virtuous oral hygiene habits, such as frequency of toothbrush changes and professional oral hygiene, negatively correlated with the simultaneous presence of Tannerella forsythia, Treponema denticola, and Porphyromonas gingivalis, red complex bacteria. Our study shows it is crucial to pay attention to glycemic control and regular oral hygiene to prevent the establishment of an oral microbiota predisposing to dental and periodontal pathology in subjects with T1D since childhood.

Genetic Variation in Antioxidant Response Modulates the Level of Oxidative Stress in Youth with Type 1 Diabetes and Poor Glycemic Control.

BACKGROUND: The minor allele of the single nucleotide polymorphism (SNP) rs2364723 of NFE2L2, a gene encoding a master antioxidant transcription factor, has been associated with poor cardiovascular outcomes and with complications of type 2 diabetes. We assessed the association between rs2364723 of NFE2L2 and oxidative stress in children/adolescents with type 1 diabetes (T1D). METHODS: In 384 children/adolescents with T1D (age 15.7 ± 3.2 years, 207 males), we assessed the oxidative stress by measuring the concentration of derivatives of reactive oxygen metabolites (d-ROMs) and we genotyped the rs2364723 SNP by real time polymerase chain reaction. RESULTS: The concentration of d-ROMs was 372.8 ± 64.6 Carratelli units. The minor genotype (CC) of rs2364723 at NFE2L2 was associated with higher concentration of derivatives of d-ROMs in the subgroup with HbA1c ≥ 8% (B = 47.85, p for genotype ∗ HbA1c interaction = 0.019). CONCLUSIONS: The carriers of the minor genotype of rs2364723 may have increased oxidative stress compared to their counterparts with other genotypes, especially in case of poor glycemic control. This observation needs to be replicated and confirmed in larger independent cohorts of youth with T1D.