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Aims: To assess whether impaired vestibular perception of self‐motion is a risk factor for unsteadiness and falls in elderly patients with type 2 diabetes (T2D). Materials and methods: 113 participants (65–75 years old) with T2D underwent tests of roll and pitch discrimination, postural stability (Berg Balance Scale, Modified Romberg Test, and quantitative posturography), clinical examination and blood chemistry analyses. Falls 1‐year after enrolment were self‐reported. We performed cluster analysis based on the values of the vestibular motion thresholds, and logistic stepwise regression to compare the clinical‐biochemical parameters between clusters. Results: We identified two clusters (VC1 n = 65 and VC2 n = 48 participants). VC2 had significantly (p < 0.001) higher (poorer) thresholds than VC1: mean pitch threshold 1.62°/s (95% CI 1.48–1.78) in VC2 and 0.91°/s (95% CI 0.84–0.98) in VC1, mean roll threshold 1.34°/s (95% CI 1.21–1.48) in VC2 and 0.69°/s (95% CI 0.64–0.74) in VC1. Diabetes duration was significantly (p = 0.024) longer in VC2 (11.96 years, 95% CI 9.23–14.68) than in VC1 (8.37 years, 95% CI 6.85–9.88). Glycaemic control was significantly (p = 0.014) poorer in VC2 (mean HbA1c 6.74%, 95% CI 6.47–7.06) than in VC1 (mean HbA1c 6.34%, 95% CI 6.16–6.53). VC2 had a significantly higher incidence of postural instability than VC1, with a higher risk of failing the Modified Romberg Test C4 (RR = 1.57, χ2 = 5.33, p = 0.021), reporting falls during follow‐up (RR = 11.48, χ2 = 9.40, p = 0.002), and greater postural sway in the medio‐lateral direction (p < 0.025). Conclusions: Assessing vestibular motion thresholds identifies individuals with T2D at risk of postural instability due to altered motion perception and guides vestibular rehabilitation. [ABSTRACT FROM AUTHOR]

Aim: To evaluate early, before the onset of cardiovascular events and of chronic renal insufficiency, the association between chronic kidney disease (CKD)-mineral bone disorder (MBD) biomarkers and vascular stiffness [Cardio Ankle Vascular Index (CAVI)] in the course of type 2 diabetes (T2DM). Method: We evaluated 174 T2DM patients [median age 56 years; male/female (M/F) 100/74] with diabetes duration < 10 years and without decreased estimated glomerular filtration rate (eGFR; ≥60 mL/min/1.73 m2) or macrovascular complications. Thirty-four age-matched healthy subjects [M/F 13/21; age 53.5 (50.0-57.7) years; eGFR 107.5 (97.0-119.7) mL/ min1.73 m2] served as local reference control for CAVI (pathological: ≥8) and the novel CKD-MBD biomarkers. Results: Albumin-to-creatinine ratio (ACR) averaged 8.5 mg/g (5.6-17.2) with 12.6% of the patients showing pathologic values, indicative of incipient diabetic nephropathy. Serum parathyroid hormone, fibroblast growth factor 23, and sclerostin were higher while 1,25-dihydroxyvitamin D and Klotho were lower than a control group. CAVI was normal (<8) in only 54% and correlated positively with age (P < 0.001), hemoglobin 1A1c (P = 0.036), and systolic (P = 0.021) and diastolic blood pressure (DBP) (P = 0.001) and negatively correlated with 25-hydroxyvitamin D (P = 0.046). In multivariate analysis, age, DBP, ACR, and serum Klotho were independent positive predictors of CAVI. Conclusion: In the absence of overt cardiovascular disease and of chronic renal insufficiency, CAVI is frequently pathologic in T2DM. DBP and ACR are modifiable risk factors of vascular stiffness in T2DM, thus warranting optimal assessment. [ABSTRACT FROM AUTHOR]

Antibodies (Abs) against intracellular epitopes of the tyrosine-phosphatase 2 (IA-2) are detected in type 1 diabetes. Abs directed against the IA-2(256-760) portion, with both intra- and extracellular epitopes, are present in people with latent autoimmune diabetes in adults (LADA) and in obese subjects with normal glucose tolerance (NGT). We aim to characterize distribution and clinical features of intra- and extra-cellular IA-2(256-760) immunoreactivities in people with LADA compared to obese people with NGT. The intracellular immunoreactivity represented by immune response against two intracellular IA-2 constructs (IA-2JM(601-630) and IA-2IC(605-979)) was analyzed and related to clinical and biochemical features in 101 people with LADA and in 20 NGT obese subjects, all testing positive for IA-2(256-760) Abs. IA-2 intracellular immunoreactivity showed a frequency of 40.6% in LADA while it was not detected among NGT obese (p<0.001). Amongst LADA, the presence of immunoreactivity against the IA-2 intracellular domains was associated with lower BMI, waist circumference, higher HDL cholesterol and lower triglycerides, lower prevalence of hypertension and higher prevalence of other autoimmune disorders. Immunoreactivity against IA-2 does not involve intracellular domains in the majority of LADA and in obese people with NGT. This study shows that there is heterogeneity in the IA-2 epitopes, associated with different clinical features. [ABSTRACT FROM AUTHOR]

Published estimates of the incidence of type 1 diabetes (T1D) in children in the last decade varies between 2% and 4% per annum. If this trend continued, the disease incidence would double in the next 20 years. The risk of developing T1D is determined by a complex interaction between multiple genes (mainly human leukocyte antigens) and environmental factors. Notwithstanding that genetic susceptibility represents a relevant element in T1D risk, genetics alone cannot explain the increase in incidence. Various environmental factors have been suggested as potential triggers for T1D, including several viruses and the hygiene hypothesis; however, none of these seems to explain the large increase in T1D incidence observed over the last decades. Several studies have demonstrated that the prevalence of childhood/adolescence overweight and obesity has risen during the past 30 years in T1D. Currently, at diagnosis, the majority of patients with T1D have normal or elevated body weight and ~50% of patients with longstanding T1D are either overweight or obese. The growing prevalence of obesity in childhood and adolescence offers a plausible explanation for the increase in T1D incidence observed in recent decades. Possible mechanisms of the enhancement of β‐cell autoimmunity by obesity include: a) insulin resistance‐induced β‐cell secretory demand triggering autoimmunity through cytokine release, neo‐epitope antigen formation and increase in β‐cell apoptosis, and b) obesity‐induced low‐grade inflammation with pro‐inflammatory cytokines secreted by locally infiltrating macrophages, which contribute to the presentation by islet cells of autoantigens generally not accessible to T cells. Further studies are needed to clarify whether the control of body weight can prevent or delay the current and continuing rise in T1D incidence. [ABSTRACT FROM AUTHOR]

In a previous study, we found that wrist circumference, in particular its bone component, was associated with insulin resistance in a population of overweight/obese children. The aim of the present study was to evaluate the intra- and inter-operator variability in wrist circumference measurement in a population of obese children and adolescents. One hundred and two (54 male and 48 female) obese children and adolescents were consecutively enrolled. In all subjects wrist circumferences were measured by two different operators two times to assess intra- and inter-operator variability. Statistical analysis was performed using SAS v.9.4 and JMP v.12. Measurements of wrist circumference showed excellent inter-operator reliability with Intra class Correlation Coefficients (ICC) of 0.96 and ICC of 0.97 for the first and the second measurement, respectively. The intra-operator reliability was, also, very strong with a Concordance Correlation Coefficient (CCC) of 0.98 for both operators. The high reproducibility demonstrated in our results suggests that wrist circumference measurement, being safe, non-invasive and repeatable can be easily used in out-patient settings to identify youths with increased risk of insulin-resistance. This can avoid testing the entire population of overweight/obese children for insulin resistance parameters. [ABSTRACT FROM AUTHOR]

OBJECTIVE Since patients with type 2 diabetes and positive for type 1 diabetes-specific antibodies have wide variations in BMI, this study evaluated whether the frequency and pattern of islet autoantibody positivity is related to BMI. RESEARCH DESIGN AND METHODS Clinical and biochemical characteristics and islet autoantibodies including GAD and protein tyrosine phosphatases islet antigen-2 (IA-2)IC and IA-2(256-760) were evaluated in 1,850 patients with type 2 diabetes from the Non-Insulin Requiring Autoimmune Diabetes study cohort. BMI was evaluated in all patients, who were then subdivided in three groups according to BMI (<25, ≥25 to <30, and <30 kg/m²). RESULTS Out of 1,850, 120 (6.5%) patients were positive for at least one of the following antibodies: GAD (4.1%), IA-2(256-760) (3.3%), or IA-2IC (1.1%). GAD and IA-2IC antibodies showed decreasing frequencies with increasing BMI (P < 0.0001 and 0.0006, respectively, for trend); in contrast, the frequency of IA-2(256-760) antibodies increased with increasing BMI (P = 0.005 for trend). Patients with type 2 diabetes positive for IA-2(256-760) alone showed a phenotype resembling classical obese type 2 diabetes, with higher BMI, waist circumference, and uric acid (P < 0.005 for all), lower thyroid peroxidase antibodies, and lower progression to insulin requirement than GAD antibody--positive patients (P = 0.04 and P = 0.0005, respectively). CONCLUSIONS The IA-2(256-760) antibody appears to represent an antibody marker that mainly identifies a clinical phenotype very similar to obese type 2 diabetes, suggesting a possible different pathogenetic mechanism. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to determine whether glutamic acid decarboxylase antibody (GADA) titer and other clinical parameters could define the risk of progression to insulin therapy in latent autoimmune diabetes in adults (LADA) patients during a 7-year follow-up. Methods: This study involved 220 LADA and 430 type 2 diabetes subjects followed up for 7 years from the time of GADA screening to evaluate their progression toward insulin therapy. Kaplan-Meier curves and multivariate logistic regression analysis were performed to identify the markers capable of influencing this progression. Results: During the follow-up, the drop out was 4% in both groups. A total of 119 (56.1%) out of 212 LADA patients required insulin during the 7 years of follow-up. The Kaplan-Meier plots showed that 74/104 (71.1%) of high GADA titer required insulin compared with 45/108 (41.6%) of low GADA titer and with 86/412 (20.9%) of type 2 diabetes (P<0.0001 for both). A BMI of <25 kg/m² and IA-2|C and zinc transporter 8 (ZnT8) positivity were also shown as the markers of faster progressio (P<0.0001 for both). The proportion of LADA patients requiring insulin was significantly higher in the group of subjects treated also with sulfonylurea in the first year from diagnosis compared with those treated with diet and/or insulin sensitizers (P<0.001). The multivariate analysis confirmed that the presence of high GADA titer was a significant predictor of insulin requirement (P<0.0001, OR = 6.95). Conclusions: High GADA titer, BMI < 25, ZnT8 and IA-2IC positivity and sulfonylurea treatment, in the first year from diagnosis, significantly increase the progression toward insulin requirement in LADA patients. [ABSTRACT FROM AUTHOR]

Adrenergic receptors regulate lipid mobilization, energy expenditure and glycogen breakdown. The β2 adrenergic receptor (β2-AR) gene may constitute a potential candidate gene to explain part of the genetic predisposition to human obesity and correlated traits. With regard to the association between β2-AR gene polymorphisms and obesity-related metabolic disorders, published reports give conflicting results. We investigated the role of three polymorphisms, and related haplotypes of the β2-AR in the obesity and related traits in a cohort of overweight/obese subjects. We characterized one single nucleotide polymorphism (SNP) in the promoter region (5′LC-Cys19Arg) and two in the coding region (Gly16Arg and Gln27Glu) of the β2-AR in 642 consecutively recruited overweight/obese subjects in whom extensive clinical and biochemical analysis was performed. The effect of the polymorphisms on quantitative variables was investigated using multiple linear regression analysis. 5′LC-Cys19 homozygous showed higher triglyceride and LDL-cholesterol levels compared to 5′LC-Arg19 homozygous (P=0.03 and P=0.01, respectively). Similar increase in triglyceride and LDL-cholesterol levels was observed for Arg/Arg genotype compared to Gly/Gly genotype of Gly16Arg polymorphism (P=0.02 and P=0.01, respectively) and for Gln/Gln genotype compared to Glu/Glu genotype of the Gln27Glu polymorphism (P=0.01 and P=0.03, respectively). The 5′LC-Cys19Arg16Gln27 haplotype determined a significant increase in triglyceride and LDL-cholesterol levels compared to 5′LC-Arg19Gly16Glu27 haplotype (P=0.05 and P=0.02, respectively). Our findings provide additional weight to previous observations on the influence of these three genetic variants on lipid phenotypes; particularly on the increase of triglycerides and LDL-cholesterol levels in overweight/obese subjects carrying the 5′LC-Cys19Arg16Gln27 haplotype.European Journal of Human Genetics (2006) 14, 94–100. doi:10.1038/sj.ejhg.5201521; published online 26 October 2005 [ABSTRACT FROM AUTHOR]

Background: Sclerostin (SC) is a monomeric glycoprotein expressed by osteocytes that affects bone formation. Recent studies have suggested a potential role for this protein in the pathophysiology of vascular diseases. The aim of the present study was to investigate SC expression in atherosclerotic plaques of patients affected by severe atherosclerotic disease who underwent carotid endarterectomy. We also evaluated possible differences in SC expression between patients with and without type 2 diabetes (T2D).Methods: This was a cross-sectional study involving 46 patients aged 55 to 80 years (mean, 71.1 ± 6.7 years, 36 men, 15 patients with T2D) who underwent carotid endarterectomy. Immunohistochemical levels of SC were evaluated in the atherosclerotic plaques by double-staining immunochemistry, and serum SC levels were evaluated by enzyme-linked immunosorbent assay.Results: Sclerostin was present in the atherosclerotic plaques of all subjects investigated and increased significantly in the media compared with the intima (P < 0.0001) as well as in vascular smooth muscle cells (VSMCs) compared with the infiltrating macrophages (P < 0.0001). However, no significant difference in SC expression was observed between patients with and without T2D. No correlation was found between serum and immunohistochemical levels of SC; significantly increased SC serum levels were detected in males compared with females (P = 0.049).Conclusions: We have demonstrated, for the first time, the expression of SC in VSMCs of atherosclerotic plaques, suggesting a potential role for this protein in the development of atherosclerosis. Further studies are needed to understand if the role played by SC is detrimental or protective in the atherosclerotic disease process. [ABSTRACT FROM AUTHOR]

Background: Recently, significant attention has been paid to the possible activation of an autoimmune response in the presence of obesity. The aim of this study was to evaluate and compare the frequencies of autoantibodies typical of autoimmune diabetes in obese patients with normal glucose tolerance (NGT), obese patients with type 2 diabetes (T2D) and controls. We also evaluated the presence of immunoreactivity to Hashimoto's thyroiditis and autoimmune gastritis.Materials and Methods: Consecutive sera from obese patients, 444 with NGT, 322 with T2D, and 212 controls were analysed by radioimmunoassay or enzyme-linked immunosorbent assay for glutamic acid decarboxylase, protein tyrosine phosphatase islet antigen-2 (IA-2)IC and IA-2(256-760) , islet beta-cell zinc cation transporter (ZnT8), thyroid peroxidase, and anti-parietal cell autoantibodies.Results: Altogether the presence of organ-specific autoantibodies was significantly more frequent in obese patients with NGT (128/444, 28.5%) and obese with T2D (79/322, 24.5%) than in controls (36/212, 17%; P = 0.002). Thyroid peroxidase immunoreactivity was prevalent in all groups of subjects investigated. The frequencies of diabetes-specific autoantibodies were slightly higher in obese patients with NGT (20/444, 4.5%) than in obese with T2D (12/322, 3.7%) and controls (4/212, 1.9%). The anti IA-2(256-760) was the most frequent islet autoantibody in obese subjects with NGT (14/20, 70%).Conclusions: We observed significant evidence of immunoreactivity specific to diabetes, thyroid, and gastric-parietal cells in obese patients with NGT. The relatively higher frequency of the diabetes-related IA-2(256-760) autoantibodies in obese patients with NGT may suggest that this autoantibody could be associated with obesity the presence of obesity itself. [ABSTRACT FROM AUTHOR]

Background: Glucagon-like peptide 1 receptor agonists (RA) are novel agents used in the management of type 2 diabetes (T2D) and obesity. Although highly effective, the response to treatment may vary significantly among patients., Objective: This perspective review aims to summarise the current knowledge about markers of poor or good response to GLP-1 RA, highlighting the possibility of tailoring treatment strategies and reducing costs associated with T2D and obesity treatment., Methods: A comprehensive literature search was conducted using PubMed, NCBI, and Scopus databases, focussing on studies published between 2016 and 2024 that evaluated factors influencing treatment outcomes with GLP-1 RA., Results: Several markers, including baseline HbA1c levels, ghrelin and glucose-dependent insulinotropic polypeptide (GIP) levels, specific gut microbiome composition, b-cell function, and genetic markers, were identified as factors associated with treatment response., Conclusion: Understanding predictive markers of response to therapy can enhance precision-based medicine for the selection of patients eligible for GLP-1 RA, improving clinical outcomes and optimising diabetes management., (© 2024 John Wiley & Sons Ltd.)

Purpose: Bone formation is impaired in both type 1 diabetes and type 2 diabetes (T2D), whereas sclerostin, an antagonist of bone formation, is increased in T2D only. No data are available on latent autoimmune diabetes in adults (LADA), an autoimmune type of diabetes that may clinically resemble T2D at diagnosis. We evaluated serum sclerostin and bone turnover markers in LADA compared with those in T2D and whether metabolic syndrome (MetS) affects sclerostin in T2D or LADA., Methods: This cross-sectional study included 98 patients with T2D and 89 with LADA from the Action LADA and Non Insulin Requiring Autoimmune Diabetes cohorts. Patients were further divided according to MetS status. Nondiabetic participants (n = 53) were used as controls. Serum sclerostin, bone formation (pro-collagen type 1 N-terminal propeptide [P1NP]), and bone resorption (C-terminal telopeptide of type I collagen [CTX]) were analyzed., Results: Patients with T2D had higher sclerostin than did those with LADA [P = 0.0008, adjusted for sex and body mass index (BMI)], even when analysis was restricted to patients with MetS (adjusted P = 0.03). Analysis of T2D and LADA groups separately showed that sclerostin was similar between those with and those without MetS. However, a positive trend between sclerostin and number of MetS features was seen with T2D (P for trend = 0.001) but not with LADA. Patients with T2D or LADA had lower CTX than did controls (P = 0.0003) and did not have significantly reduced P1NP. Sclerostin was unrelated to age or hemoglobin A1c but was correlated with BMI (ρ = 0.29; P = 0.0001), high-density lipoprotein (ρ = -0.23; P = 0.003), triglycerides (ρ = 0.19; P = 0.002), and time since diagnosis (ρ = 0.32; P < 0.0001)., Conclusions: Patients with LADA presented lower bone resorption than did controls, similar to patients with T2D. Sclerostin is increased in T2D but not in LADA, suggesting possible roles on bone metabolism in T2D only.

Background: Excess fat is one of the main determinants of insulin resistance, representing the metabolic basis for developing future cardiovascular disease. The aim of the current study was to find an easy-to-detect clinical marker of insulin resistance which can be used to identify young subjects at increased risk of cardiovascular disease., Methods and Results: Four-hundred and seventy-seven overweight/obese children and adolescents (mean age 10.31±2.80 years) were consecutively enrolled. Standard deviation score body mass index, fasting biochemical parameters, and homeostasis model assessment of insulin resistance were evaluated. Statistical differences were investigated using multiple linear regression analysis. Manual measure of wrist circumference was evaluated in all children and adolescents. Fifty-one subjects, randomly selected, underwent nuclear magnetic resonance imaging of the wrist to evaluate transversal wrist area at the Lister tubercle level. A statistically significant association was found between manual measure of wrist circumference and insulin levels or homeostasis model assessment of insulin resistance (β=0.34 and 0.35, respectively; P<10(-5) for both comparisons). These associations were more significant than those between SD score body mass index and insulin levels or homeostasis model assessment of insulin resistance (β=0.12 and 0.10, respectively; P≤0.02 for both comparisons). Nuclear magnetic resonance imaging acquisition clarified that the association between wrist circumference and insulin levels or homeostasis model assessment of insulin resistance reflected the association with bone tissue-related areas (P≤0.01 for both) but not with the adipose tissue ones (P>0.05), explaining 20% and 17% of the variances of the 2 parameters., Conclusions: Our findings suggest a close relationship among wrist circumference, its bone component, and insulin resistance in overweight/obese children and adolescents, opening new perspectives in the prediction of cardiovascular disease.

Adrenergic receptors regulate lipid mobilization, energy expenditure and glycogen breakdown. The beta(2) adrenergic receptor (beta(2)-AR) gene may constitute a potential candidate gene to explain part of the genetic predisposition to human obesity and correlated traits. With regard to the association between beta(2)-AR gene polymorphisms and obesity-related metabolic disorders, published reports give conflicting results. We investigated the role of three polymorphisms, and related haplotypes of the beta(2)-AR in the obesity and related traits in a cohort of overweight/obese subjects. We characterized one single nucleotide polymorphism (SNP) in the promoter region (5'LC-Cys19Arg) and two in the coding region (Gly16Arg and Gln27Glu) of the beta(2)-AR in 642 consecutively recruited overweight/obese subjects in whom extensive clinical and biochemical analysis was performed. The effect of the polymorphisms on quantitative variables was investigated using multiple linear regression analysis. 5'LC-Cys19 homozygous showed higher triglyceride and LDL-cholesterol levels compared to 5'LC-Arg19 homozygous (P=0.03 and P=0.01, respectively). Similar increase in triglyceride and LDL-cholesterol levels was observed for Arg/Arg genotype compared to Gly/Gly genotype of Gly16Arg polymorphism (P=0.02 and P=0.01, respectively) and for Gln/Gln genotype compared to Glu/Glu genotype of the Gln27Glu polymorphism (P=0.01 and P=0.03, respectively). The 5'LC-Cys(19)Arg(16)Gln(27) haplotype determined a significant increase in triglyceride and LDL-cholesterol levels compared to 5'LC-Arg(19)Gly(16)Glu(27) haplotype (P=0.05 and P=0.02, respectively). Our findings provide additional weight to previous observations on the influence of these three genetic variants on lipid phenotypes; particularly on the increase of triglycerides and LDL-cholesterol levels in overweight/obese subjects carrying the 5'LC-Cys(19)Arg(16)Gln(27) haplotype.