Liver steatosis in patients with transfusion-dependent thalassaemia.

We evaluated the prevalence and the clinical associations of liver steatosis (LS) in patients with transfusion-dependent thalassaemia (TDT). We considered 301 TDT patients (177 females, median age = 40.61 years) enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network, and 25 healthy subjects. Magnetic resonance imaging was used to quantify iron overload and hepatic fat fraction (FF) by T2* technique and cardiac function by cine images. The glucose metabolism was assessed by the oral glucose tolerance test (OGTT). Hepatic FF was significantly higher in TDT patients than in healthy subjects (median value: 1.48% vs. 0.55%; p = 0.013). In TDT, hepatic FF was not associated with age, gender, serum ferritin levels or liver function parameters, but showed a weak inverse correlation with high-density lipoprotein cholesterol. The 36.4% of TDT patients showed LS (FF >3.7%). Active hepatitis C virus (HCV) infection, increased body mass index and hepatic iron were independent determinants of LS. A hepatic FF >3.53% predicted the presence of an abnormal OGTT. Hepatic FF was not correlated with cardiac iron, biventricular volumes or ejection fractions, but was correlated with left ventricular mass index. In TDT, LS is a frequent finding, associated with iron overload, increased weight and HCV, and conveying an increased risk for the alterations of glucose metabolism.

Longitudinal evaluation of two different COVID-19 vaccination strategies in individuals with and without previous SARS-CoV-2 infection.

Background: We tested the antibody response to SARS-CoV-2 vaccination in individuals with and without previous infection that received different vaccination strategies. Methods: We recruited 203 volunteers. Individuals who have had SARS-CoV-2 infection during the six months preceding vaccination received one dose (group 1), the others received two (group 2). After 3 months, 98 subjects received a booster dose. Anti-SARS-CoV-2 Spike RBD IgG were tested in all subjects before vaccination (T0), and at 15 (T15), 90 (T90), 180 (T180) and 360 (T360) days after second or single dose; additionally, in group 2, IgG were tested 10 days after the vaccination (T10). Results: The difference of IgG concentration between the groups was statistically significant (p<0.05) at T0, T15 and T90, but not at T180 (p=0.713) and T360 (p=0.069). At T0 and T90 the antibody titre was higher in group 1, but it dropped in all volunteers 90 days after vaccination. Most of infections after vaccination occurred between T90 and T180. Conclusions: Antibody titre is significantly associated with a previous SARS-CoV-2 infection. Probability of contracting the infection increases after three months from primary vaccination, even among who had a previous infection, confirming the efficacy of vaccination as a preventive measure against SARS-CoV-2 infections and the need of booster administrations.

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.

Development of a Thalassemia International Prognostic Scoring System (TIPSS).

A prognostic scoring system that can differentiate ß-thalassemia patients based on mortality risk is lacking. We analysed data from 3145 ß-thalassemia patients followed through a retrospective cohort design for the outcome of death. An a priori list of prognostic variables was collected. ß Coefficients from a multivariate cox regression model were used from a development dataset (n = 2516) to construct a formula for a Thalassemia International Prognostic Scoring System (TIPSS) which was subsequently applied to a validation dataset (n = 629). The median duration of observation was 10.0 years. The TIPSS score formula was constructed as exp (1.4 × heart disease + 0.9 × liver disease + 0.9 × diabetes + 0.9 × sepsis + 0.6 × alanine aminotransferase ≥42 IU/L + 0.6 × hemoglobin ≤9 g/dL + 0.4 × serum ferritin ≥1850 ng/mL). TIPSS score thresholds of greatest differentiation were assigned as <2.0 (low-risk), 2.0 to <5.0 (intermediate-risk), and ≥5.0 (high-risk). The TIPSS score was a good predictor for the outcome of death in the validation dataset (AUC: 0.722, 95%CI: 0.641-0.804) and survival was significantly different between patients in the three risk categories (P < 0.001). Compared to low-risk patients, the hazard ratio for death was 2.778 (95%CI: 1.335-5.780) in patients with intermediate-risk and 6.431 (95%CI: 3.151-13.128) in patients with high-risk. This study provides a novel tool to support mortality risk categorization for patients with ß-thalassemia that could help management and research decisions.

A retrospective analysis of the hemolysis occurrence during extracorporeal membrane oxygenation in a single center.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO)-associated hemolysis still represents a serious complication. The present study aimed to investigate those predictive factors, such as flow rates, the use of anticoagulants, and circuit connected dialysis, that might play a pivotal role in hemolysis in adult patients. METHODS: This is a retrospective single-center case series of 35 consecutive adult patients undergoing veno-venous ECMO support at our center between April 2014 and February 2020. Daily plasma-free hemoglobin (pfHb) and haptoglobin (Hpt) levels were chosen as hemolysis markers and they were analyzed along with patients' characteristics, daily laboratory findings, and corresponding ECMO system variables, as well as continuous renal replacement therapy (CRRT) when administered, looking for factors influencing their trends over time. RESULTS: Among the many settings related to the ECMO support, the presence of CRRT connected to the ECMO circuit has been found associated with both higher daily pfHb levels and lower Hpt levels. After correction for potential confounders, hemolysis was ascribable to circuit-related variables, in particular the membrane oxygenation dead space was associated with an Hpt reduction (B = -215.307, p = 0.004). Moreover, a reduction of ECMO blood flow by 1 L/min has been associated with a daily Hpt consumption of 93.371 mg/dL (p = 0.001). CONCLUSIONS: Technical-induced hemolysis during ECMO should be monitored not only when suspected but also during quotidian management and check-ups. While considering the clinical complexity of patients on ECMO support, clinicians should not only be aware of and anticipate possible circuitry malfunctions or inadequate flow settings, but they should also take into account the effects of an ECMO circuit-connected CRRT, as an equally important key factor triggering hemolysis.

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.

Early marker of ocular neurodegeneration in children and adolescents with type 1 diabetes: the contributing role of polymorphisms in mir146a and mir128a genes.

BACKGROUND: Early ocular neurodegenerative signs of diabetic neuropathy (DN) can be found in children and adolescents with type 1 diabetes (T1D). No data are available on the potential role of polymorphisms in miRNAs genes in predisposing T1D subjects to these signs. AIMS: To determine whether MIR146A rs2910164 and MIR128A rs11888095 polymorphisms are associated with early retinal and corneal neurodegenerative changes in pediatric patients with T1D. METHODS: A total of 140 T1D children/adolescents underwent spectral domain-optical coherence tomography (SD-OCT) and in vivo confocal microscopy (IVCM) with measurement of retinal and corneal nerve fiber parameters. Risk factors for diabetes complications (diabetes duration, blood pressure, HbA1c) were recorded. Genotyping of rs2910164 and rs1188095 SNPs and genotype-phenotype association analysis were performed. RESULTS: The C allele of rs2910164 in MIR146A was associated with higher values of IVCM parameters and minimum rim width (MRW) of the peripapillary region of optic nerve head measured in the retina, whereas the T allele of rs1188095 in MIR128A was associated with a significant impairment of them. Multiple regression analysis showed that MIR146A and MIR128A polymorphisms were significantly associated with corneal nerve fiber length (beta = 0.225 and - 0.204, respectively) and other IVCM parameters, independently from age, diabetes duration, HbA1c and systolic blood pressure percentile. Similar results were found for MRW (beta = 0.213 and - 0.286, respectively). CONCLUSIONS: These results provide new insight into the genetic predisposition to DN showing that two polymorphisms in MIR146A and MIR128A genes could significantly contribute to the development of early ocular preclinical signs of DN.

Setting for "Normal" Serum Ferritin Levels in Patients with Transfusion-Dependent Thalassemia: Our Current Strategy.

This cross-sectional study aimed to establish the association between serum ferritin levels and organ iron overload (IO) and overall morbidity in transfusion-dependent thalassemia (TDT) patients. One hundred and three TDT patients (40.03 ± 9.15 years; 57.3% females) with serum ferritin < 2500 ng/mL were included. IO was assessed by T2* magnetic resonance imaging. Three groups were identified based on mean serum ferritin levels: <500 ng/mL (group 0; N = 32), 500-1000 ng/mL (group 1; N = 43), and 1000-2500 ng/mL (group 2; N = 28). All demographic and biochemical parameters were comparable among the three groups, with the exception of the triglycerides being significantly lower in group 0 than in group 2. No difference was found in the frequency of hepatic, endocrine, and cardiac complications. Hepatic IO was significantly less frequent in group 0 versus both groups 1 and 2. No patient with a serum ferritin level < 500 ng/mL had significant myocardial IO and alterations in the main hematological parameters. No difference in the distribution of the different chelation regimens was found. Serum ferritin < 500 ng/mL appears to be achievable and safe for several TDT patients. This target is associated with the absence of significant cardiac iron and significantly lower hepatic IO and triglycerides that are well-demonstrated markers for cardiac and liver complications.

Oxidative stress in youth with type 1 diabetes: Not only a matter of gender, age, and glycemic control.

AIMS: We assessed whether oxidative stress (OS) is increased in children/adolescents with type 1 diabetes (T1D) compared to healthy peers. Moreover, we searched for OS predictors in the T1D population. METHODS: We compared the concentration of serum derivatives of reactive oxygen metabolites (d-ROMs) in 412 children/adolescents with T1D (3.6-23.5 years old) to that of 138 healthy children/adolescents (1.2-19.2 years old) by ANOVA adjusted for age, gender, and BMI z-score (z-BMI). Applying a general linear model, in a subgroup of 331 patients using continuous glucose monitoring, we searched for predictors of d-ROMs among 3-day, 2-week, and 4-week metrics of glucose control and variability, such as mean blood glucose, percent time in range (70-180 mg/dl,TIR70-180), coefficient of variation, and others, as well as among conventional cardiovascular risk factors like current and average HbA1c, z-BMI, blood pressure percentiles, and lipid concentrations recorded retrospectively over the entire follow-up period. RESULTS: D-ROMs levels were significantly higher in children/adolescents with T1D compared to controls [371.9 (64.2) versus 324.9 (46.3), p < 10-16]. Sex (B = 49.1, ƞ2 = 0.14, p = 1.3 * 10-9), age < 12 years in boys (B = 79.4, ƞ2 = 0.074, p = 10-7),3-day TIR70-180 (B = -0.87, ƞ2 = 0.048, p = 6.5 * 10-5), and z-BMI (B = 7.4, ƞ2 = 0.016, p = 0.022) predicted d-ROMs with an overall R2 of 0.278. CONCLUSIONS: OS is increased in youth with T1D and only partially predicted by gender, age, glucose control, and anthropometry. Other potential determinants of OS in this population should be targeted in future studies.

Retinal and Choriocapillaris Vascular Changes in Patients Affected by Different Clinical Phenotypes of ß-Thalassemia: An Optical Coherence Tomography Angiography Study.

In this cross-sectional study we assessed the vascular alterations in retinal and choriocapillaris perfusion in patients affected by ß-thalassemia, by means of optical coherence tomography angiography (OCTA). A total of 124 eyes of 62 patients (mean age 44.74 ± 5.79 years old) affected by ß-thalassemia (transfusion dependent thalassemia (TDT), non-transfusion dependent thalassemia (NTDT) and minor) were compared to 40 eyes of twenty healthy subjects. We evaluated the vessel density (VD) in superficial capillary plexus, deep capillary plexus, radial peripapillary capillary, choriocapillaris and the foveal avascular zone area. The TDT group showed a statistically significant reduction in retinal and choriocapillaris VD respect to controls and the other groups (p < 0.05). No statistically significant difference was found in OCTA parameters between ß-thalassemia minor and controls. The NTDT group showed a significant reduction in VD in deep capillary plexus respect to controls and ß-thalassemia minor. Significant negative correlations were shown in TDT group between foveal avascular zone and hemoglobin (r = -0.437, p = 0.044) and between ferritin levels and VD of choriocapillaris (r = -0.431, p = 0.038). The OCTA parameters provided a deeper understanding on retinal and choriocapillaris vascular impairment affected by tissue hypoxia levels and the oxidative stress in different clinical phenotypes of the ß-thalassemia.

Long chain fatty acids metabolism and cardiovascular risk factors in youth with type 1 diabetes.

BACKGROUND AND AIMS: Fatty acids (FAs) and their metabolizing enzymes have been associated with several cardiometabolic outcomes. Whether they correlate with cardiovascular risk in type 1 diabetes (T1D), it is unknown. We investigated whether erythrocyte FAs correlated with cardiovascular risk factors and dietary fats in youth with T1D. METHODS AND RESULTS: We recruited 154 adolescents with T1D (aged 17.3 ± 2 years, 82 boys) and assessed blood pressure, plasma lipids, HbA1c, estimated insulin sensitivity (eIS) and dietary fats based on a 3-days weighed dietary record. Erythrocyte FAs were measured by gas chromatography and desaturase and elongase activities were estimated as product/precursor ratios. Delta-6-desaturase (D6D) activity correlated inversely with eIS (r = -0.32,p = 6.6∗10-5) and directly with triglycerides (r = 0.24, p = 0.003), adjusted for z-BMI, age and gender. No single erythrocyte FA correlated with eIS. Erythrocyte membrane stearic acid (SA) correlated with HbA1c adjusted for confounders and eIS (r = -0.26, p = 0.002). We found some weak (r ≤ 0.20) correlations between erythrocyte membrane FAs and dietary fats, which were not retained by correction for multiple testing. CONCLUSION: In youth with T1D, D6D activity might exert unfavorable effects per se, beyond its role on FAs composition. This is in accordance with previous data associating D6D activity/D6D-enhancing polymorphisms with metabolic syndrome and incident type 2 diabetes, as well as D6D activity with the regulation of cellular red-ox balance. SA was a favorable marker of glycemic control. Future research is needed to clarify the biological pathways linking D6D and SA with the cardiometabolic health of youth with T1D.

Primary biliary cholangitis with normal alkaline phosphatase: A neglected clinical entity challenging current guidelines.

BACKGROUND & AIM: The diagnosis of primary biliary cholangitis (PBC), an uncommon immune-mediated cholestatic liver disease, is based on positive circulating anti-mitochondrial (AMA) and/or PBC-specific anti-nuclear autoantibodies (ANA), coupled with elevated serum alkaline phopsphatase (ALP) levels. Timely initiation of treatment with ursodeoxycholic acid prevents progression to cirrhosis and liver failure. We aimed at investigating liver histology in patients with normal ALP level and positive AMA and/or PBC-specific ANA. METHODS: We searched the Swiss PBC Cohort Study database, which includes subjects with positive PBC autoimmune serology and normal ALP levels, for patients who underwent a liver biopsy. Histological slides were centrally reviewed by an expert liver pathologist, and sera were centrally re-tested for AMA and ANA. RESULTS: 30 patients were included; 90% females, median age 53 (range 27-72) years. Twenty-four (80%) had liver histology typical for (n = 2), consistent with (n = 16) or suggestive of (n = 6) PBC, including three of four AMA-negative ANA-positive patients. Among 22 ursodeoxycholic acid treated patients, 14 had elevated GGT levels before treatment; a significant decrease of the median GGT level between pre- (1.46 x ULN) and post- (0.43 x ULN) treatment (p = 0.0018) was observed. CONCLUSIONS: In our series, a high proportion of AMA positive patients with normal ALP levels have PBC. For the first time we show histological diagnosis of PBC in AMA-negative/PBC-specific ANA-positive subjects and the potential role of GGT as a biomarker in PBC patients with normal baseline ALP levels. Current guidelines for the diagnosis of PBC do not cover the whole extent of PBC presentation, with important clinical implications in terms of timely treatment initiation.

Urinary Metabolic Profile of Patients with Transfusion-Dependent ß-Thalassemia Major Undergoing Deferasirox Therapy.

INTRODUCTION: Renal dysfunction is a frequent complication in patients suffering from ß-thalassemia major (ß-TM). The aim of this study was to analyze the renal function and urine metabolomic profile of ß-TM patients undergoing transfusions and deferasirox (DFX) therapy, in order to better characterize and shed light on the pathogenesis of renal disease in this setting. METHODS AND SUBJECTS: 40 patients affected by ß-TM treated with DFX and 35 age- and gender-matched healthy controls were enrolled in the study. Renal function was assessed. Glomerular filtration rate (GFR) was estimated with CKD-EPI and Schwartz formula for adults and children, respectively. Renal tubular function and maximal urine concentration ability were tested. Urine specimens were analyzed by nuclear magnetic resonance spectroscopy to identify the urinary metabolite profiles. RESULTS: The study of renal function in ß-TM patients revealed normal estimated (e)GFR mean values and the albumin-to-creatinine ratio was <30 mg/g. The analysis of tubular function showed normal basal plasma electrolyte levels; 60% of patients presented hypercalciuria and many subjects showed defective urine concentration. Several amino acids, N-methyl compounds, and organic acids were overexcreted in the urine of thalassemic patients compared with controls. DISCUSSION: The major finding of this work is that ß-TM patients and controls exhibit different concentrations of some metabolites in the urine. Early recognition of urinary abnormalities may be useful to detect and prevent kidney damage.

Red blood cell consumption in a large cohort of patients with thalassaemia: a retrospective analysis of main predictors.

The phenotype/genotype relationship of patients with transfusion-dependent thalassaemia (TDT) is particularly complex and variable, thus generating different levels of severity and of annual transfusion volume (ATV). In this study, we explored the role and the contribution of several factors potentially involved in determining mean ATV in a cohort of TDT patients which have been followed since long time. We collected data on one-hundred and twenty-seven patients with transfusion-dependent ß-thalassaemia followed at Rare Blood Cell Disease Unit, AORN Cardarelli Hospital. Age at first transfusion, genotype, spleen status (splenectomy or not), and mean soluble transferrin receptor (sTfR) were the parameters included in the analysis. At stepwise regression analysis which included all the parameters, only splenectomy and mean sTfR significantly predicted the mean ATV (F = 70.94, P < 0.0001, R2 = 0.540). Overall, our data may suggest that in patients with TDT, the measurement of sTfR level together with the spleen status could contribute, more accurately than genotype, to provide a basal evaluation of residual erythropoietic activity and mean ATV.

Antibacterial Effectiveness of Fecal Water and in Vitro Activity of a Multi-Strain Probiotic Formulation against Multi-Drug Resistant Microorganisms.

Introduction: Intestinal colonization with multi-drug resistant (MDR) microorganisms is a consequence of antimicrobial-induced gut dysbiosis. Given the effect of probiotics in modulating gut microbiota, the aim of the study was to investigate whether the ingestion of high concentration multi-strain probiotic formulation would change the antibacterial activity of the feces against clinical strains of MDR microorganisms. The corresponding in vitro antibacterial activity was also investigated. Materials/methods: The feces of healthy donors (n = 6) were analyzed before and after a 7-day dietary supplementation with a multi-strain probiotic formulation and tested against MDR microorganisms of clinical concern (carbapenem-resistant (CR), Klebsiella pneumoniae (CR-Kp), CR-Acinetobacter baumannii (CR-Ab), CR-Pseudomonas aeruginosa (CR-Pa), and methicillin-resistant Staphylococcus aureus (MRSA)). The tested MDR pathogens were cultured with decreasing concentrations of fecal water obtained before and after the treatment period. Furthermore, to corroborate the results obtained from the feces of healthy donors, the in vitro antibacterial activity of probiotic formulation (both whole probiotic (WP) and probiotic surnatant (PS)) against the same collection of MDR microorganisms was evaluated at different incubation times throughout the minimum bactericidal dilution and the corresponding serial silution number. Results: While before probiotic administration, the fecal water samples did not inhibit MDR microorganism growth, after supplementation, a reduced bacterial growth was shown. Accordingly, a noticeable in vitro activity of WP and PS was observed. Conclusions: Although preliminary, these experiments demonstrated that a specific multi-strain probiotic formulation exhibits in vitro antibacterial activity against MDR microorganisms of clinical concern. If confirmed, these results may justify the administration of probiotics as a decolonization strategy against MDR microorganisms.

Chemical composition and antimicrobial activity of essential oil of Helichrysum italicum (Roth) G. Don fil. (Asteraceae) from Montenegro.

An experimental investigation on essential oil of a Montenegrin Helichrysum italicum (Roth) G. Don fil. (Asteraceae) is reported. The essential oil was analysed in both liquid and vapour phases. Gas chromatography-mass spectrometry analysis of the liquid oil showed the predominance of sesquiterpenes with ß-eudesmene (21.65%) and ß-bisabolene (19.90%) as the major ones. Monoterpene fraction was mainly represented by α-pinene (16.90%) and neryl acetate (10.66%). Head-space technique revealed the vapour phase enriched of monoterpenes with α-pinene (78.76%) predominance. The essential oil was tested against methicillin-sensitive Staphylococcus aureus (ATCC 29213), Escherichia coli (ATCC 25922), Candida albicans (ATCC 14053) and the clinical strains of methicillin-resistant S. aureus, carbapenem-resistant Klebsiella pneumoniae, carbapenem-resistant Acinetobacter baumannii and carbapenem-resistant Pseudomonas aeruginosa. Interesting fungicidal/bactericidal potency against C. albicans and carbapenem-resistant A. baumannii was revealed at concentration of 5% v/v.

Bone health in diabetes and prediabetes.

Bone fragility has been recognized as a complication of diabetes, both type 1 diabetes (T1D) and type 2 diabetes (T2D), whereas the relationship between prediabetes and fracture risk is less clear. Fractures can deeply impact a diabetic patient's quality of life. However, the mechanisms underlying bone fragility in diabetes are complex and have not been fully elucidated. Patients with T1D generally exhibit low bone mineral density (BMD), although the relatively small reduction in BMD does not entirely explain the increase in fracture risk. On the contrary, patients with T2D or prediabetes have normal or even higher BMD as compared with healthy subjects. These observations suggest that factors other than bone mass may influence fracture risk. Some of these factors have been identified, including disease duration, poor glycemic control, presence of diabetes complications, and certain antidiabetic drugs. Nevertheless, currently available tools for the prediction of risk inadequately capture diabetic patients at increased risk of fracture. Aim of this review is to provide a comprehensive overview of bone health and the mechanisms responsible for increased susceptibility to fracture across the spectrum of glycemic status, spanning from insulin resistance to overt forms of diabetes. The management of bone fragility in diabetic patient is also discussed.