Role of copper in central nervous system physiology and pathology

Copper is a transition metal and an essential element for the organism,as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs,including the central nervous system.Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B,Menkes disease and Wilson’s disease,respectively,and also in multifactorial neurological disorders such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and multiple sclerosis.This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology,reports about unbalances in copper levels and/or distribution under disease,describes relevant animal models for human disorders where copper metabolism genes are dysregulated,and discusses relevant therapeutic approaches modulating copper availability.Overall,alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.

Unveiling hidden outcomes in malignant gastric outlet obstruction research–insights from a"Pancreas 2000"review

Malignant gastric outlet obstruction(mGOO)is a major condition affecting patients with periampullary tumors,including pancreatic cancer.The current treatment options include surgical gastroenterostomy,endoscopic stenting and more recently EUS-guided gastroenterostomy.Most studies comparing the outcomes of the three procedures focus on technical success,clinical success and safety.Several“occult”outcomes relevant to the patient’s viewpoints and perspective may ultimately impact on cancer-related and overall survival,such as body mass composition,nutritional biomarkers,chemotherapy tolerance and patient-reported quality of life.The aim of this review is to provide an overview of potential key outcomes that should be explored in future comparative research around mGOO treatment options.

胰肾联合移植治疗1型糖尿病并尿毒症22例

对22例合并尿毒症的1型糖尿病患者实施胰肾联合移植术(SPKT),采用肠—肠内引流(ED)术式;术后给予他克莫司、环孢霉素、霉酚酸酯及皮质激素预防排斥反应,同时常规抗菌、抗真菌、抗病毒和抗凝治疗。22例手术均获成功,2例并发血管栓塞(1例药物治疗好转,1例再次手术切除移植物),3例出现排斥反应(抗排斥治疗好转),1例原发性移植胰腺无功能再次手术切除,2例消化道出血(1例药物治疗好转,1例手术止血),所有患者均存活。认为SPKT治疗糖尿病并尿毒症是可行的,但围手术期并发症发生率较高,防止并发症的发生是手术成功的技术关键。

国际糖尿病足工作组:糖尿病足溃疡减压指南——《国际糖尿病足工作组:糖尿病足防治国际指南(2019)》的一部分

1999年,国际糖尿病足工作组(IWGDF)根据循证医学证据发表了采用减压治疗促进糖尿病足溃疡愈合的预防和管理指南,这一版指南是在此基础上的更新。我们遵循GRADE方法学,采用患者-干预-比较-结果(PICO)模式设计临床问题和关键的重要结局,对医学科学文献进行系统评价分析后撰写了建议并阐述其理由。这些建议是基于系统评价、专家意见(尚无有效证据时)的基础上建立,并在患者依从性、可行性、实用性以及干预的成本等方面进行了利弊权衡。针对糖尿病患者前足或中足底的溃疡愈合,我们建议不可拆卸齐膝高减压装置作为减压治疗的首选。若出现禁忌或患者不耐受不可拆卸减压装置,则可拆卸齐膝高和齐踝高减压装置可作为二线或三线减压治疗方法。合适的鞋袜结合泡沫毡垫可被视为四线减压治疗选择。如果非外科手术减压失败,我们建议通过外科减压干预以促进跖骨头和足趾溃疡愈合。我们还增加了采用减压治疗促进合并感染、缺血的复杂足溃疡和足跟溃疡愈合的新的推荐意见。减压是促进糖尿病神经性足底溃疡愈合诸多干预措施中最重要的手段。遵循这些建议将帮助医务人员和团队,为那些具有感染、住院和截肢风险的糖尿病足溃疡患者提供更好的治疗。

Acute recurrent pancreatitis:Etiopathogenesis, diagnosis and treatment

Acute recurrent pancreatitis (ARP) refers to a clinical entity characterized by episodes of acute pancreatitis which occurs on more than one occasion. Recurrence of pancreatitis generally occurs in a setting of normal morpho-functional gland, however, an established chronic disease may be found either on the occasion of the first episode of pancreatitis or during the follow-up. The aetiology of ARP can be identified in the majority of patients. Most common causes include common bile duct stones or sludge and bile crystals; sphincter of oddi dysfunction; anatomical ductal variants interfering with pancreatic juice outflow; obstruction of the main pancreatic duct or pancreatico-biliary junction; genetic mutations; alcohol consumption. However, despite diagnostic technologies, the aetiology of ARP still remains unknown in up to 30% of cases: in these cases the term “idiopathic” is used. Because occult bile stone disease and sphincter of oddi dysfunction account for the majority of cases, cholecystectomy, and eventually the endoscopic biliary and/or pancreatic sphincterotomy are curative in most of cases. Endoscopic biliary sphincterotomy appeared to be a curative procedure per se in about 80% of patients. Ursodeoxycholic acid oral treatment alone has also been reported effective for treatment of biliary sludge. In uncertain cases toxin botulin injection may help in identifying some sphincter of oddi dysfunction, but this treatment is not widely used. In the last twenty years, pancreatic endotherapy has been proven effective in cases of recurrent pancreatitis depending on pancreatic ductal obstruction, independently from the cause of obstruction, and has been widely used instead of more aggressive approaches.

Optical coherence tomography in detection of dysplasia and cancer of the gastrointestinal tract and bilio-pancreatic ductal system

Optical coherence tomography(OCT) is an optical imaging modality that performs high-resolution,cross-sectional,subsurface tomographic imaging of the microstructure of tissues.The physical principle of OCT is similar to that of B-mode ultrasound imaging,except that it uses infrared light waves rather than acoustic waves.The in vivo resolution is 10-25 times better(about 10 μm) than with high-frequency ultrasound imaging,but the depth of penetration is limited to 1-3 mm,depending upon tissue structure,depth of focus of the probe used,and pressure applied to the tissue surface.In the last decade,OCT technology has evolved from an experimental laboratory tool to a new diagnostic imaging modality with a wide spectrum of clinical applications in medical practice,including the gastrointestinal(GI) tract and pancreatic-biliary ductal system.OCT imaging from the GI tract can be done in humans by using narrow-diameter,catheter-based probes that can be inserted through the accessory channel of either a conventional front-view endoscope,for investigating the epithelial structure of the GI tract,or a side-view endoscope,inside a standard transparent ERCP catheter,for investigating the pancreatico-biliary ductal system.Esophagus and the esophago-gastric junction has been the most widely investigated organ so far;more recently,also duodenum,colon and pancreatico-biliary ductal system have been extensively investigated.OCT imaging of the gastro-intestinal wall structure is characterized by a multiple-layer architecture that permits an accurate evaluation of the mucosa,lamina propria,muscularis mucosae,andpart of the submucosa.The technique may be,therefore,used to identify pre-neoplastic conditions of the GI tract,such as Barrett's epithelium and dysplasia,and evaluate the depth of penetration of early-stage neoplastic lesions.OCT imaging of the pancreatic and biliary ductal system could improve the diagnostic accuracy for ductal epithelial changes and the differential diagnosis between neoplastic and non-neoplastic lesions.

High-definition colonoscopy with i-Scan:Better diagnosis for small polyps and flat adenomas

AIM： To investigate if high-definition （HD） colonoscope with i-Scan gave a higher detection rate of mucosal le- sions vs standard white-light instruments. METHODS： Data were collected from the computer- ized database of the endoscopy unit of our tertiary referral center. We retrospectively analyzed 1101 con- secutive colonoscopies that were performed over 1 year with standard white-light （n = 849） or HD＋ with i-Scan （n = 252） instruments by four endoscopists, in an outpatient setting. Colonoscopy records included patients＇ main details and family history for colorectal cancer, indication for colonoscopy （screening, diagnos- tic or surveillance）, type of instrument used （standard white-light or HD＋ plus i-Scan）, name of endoscopist and bowel preparation. Records for each procedure included whether the cecum was reached or not and the reason for failure, complications during or imme- diately after the procedure, and number, size, location and characteristics of the lesions. Polyps or protruding lesions were defined as sessile or pedunculated, and nonprotruding lesions were defined according to Paris classification. For each lesion, histological diagnosis was recorded. RESULTS： Eight hundred and forty-nine colonosco- pies were carried with the standard white-light video colonoscope and 252 with the HD＋ plus i-Scan video colonoscope, The four endoscopists did 264, 300, 276 and 261 procedures, respectively; 21.6%, 24.0%, 21.7% and 24.1% of them with the HD＋ plus i-Scan technique. There were no significant differences be- tween the four endoscopists in either the number of procedures done or the proportions of each imaging technique used. Both techniques detected one or more mucosal lesions in 522/1101 procedures （47.4%）. The overall number of lesions recognized was 1266; 645 in the right colon and 621 in the left. A significantly higher number of colonoscopies recognized lesions in the HD＋ plus i-Scan mode （171/252 = 67.9%） than with the standard white-light technique （408/849 = 48.1%） （P 〈 0.0001）. HD＋ with i-Scan colonoscopies identified more lesions than standard white-light imag- ing （459/252 and 807/849, P 〈 0.0001）, in the right or left colon （mean ：1： SD, 1.62±1.36 vs 1.33±0.73, P 〈 0.003 and 1.55±0.98 vs 1.17±0.93, P = 0.033）, more lesions 〈 10 mm （P 〈 0.0001） or nonprotruding （P 〈 0.022）, and flat polyps （P = 0.04）. The cumulative mean number of lesions per procedure detected by the four endoscopists was significantly higher with HD＋ with i-Scan than with standard white-light imaging （1.82 ± 2.89 vs 0.95± 1.35, P 〈 0.0001）. CONCLUSION： HD imaging with i-Scan during the withdrawal phase of colonoscopy significantly increased the detection of colonic mucosal lesions, particularly small and nonprotruding polyps.

Sedation and analgesia in gastrointestinal endoscopy: What’s new?

Various types of sedation and analgesia technique have been used during gastrointestinal endoscopy procedures.The best methods for analgesia and sedation during gastrointestinal endoscopy are still debated.Providing an adequate regimen of sedation/analgesia might be considered an art,influencing several aspects of endoscopic procedures: the quality of the examination,the patient’s cooperation and the patient’s and physician’s satisfaction with the sedation.The properties of a model sedative agent for endoscopy would include rapid onset and offset of action,analgesic and anxiolytic effects,ease of titration to desired level of sedation,rapid recovery and an excellent safety prof ile.Therefore there is an impulse for development of new approaches to endoscopic sedation.This article provides an update on the methods of sedation today available and future directions in endoscopic sedation.

Apparent diffusion coefficient by diffusion-weighted magnetic resonance imaging as a sole biomarker for staging and prognosis of gastric cancer

Objective： To investigate the role of apparent diffusion coefficient （ADC） from diffusion-weighted magnetic resonance imaging （DW-MRI） when applied to the 7th TNM classification in the staging and prognosis of gastric cancer （GC）. Methods： Between October 2009 and May 2014, a total of 89 patients with non-metastatic, biopsy proven GC underwent 1.5T DW-MRI, and then treated with radical surgery. Tumor ADC was measured retrospectively and compared with final histology following the 7th TNM staging （local invasion, nodal involvement and according to the different groups -- stage Ⅰ, Ⅱ and Ⅲ）. Kaplan-Meier curves were also generated. The follow-up period is updated to May 2016. Results： Median follow-up period was 33 months and 45/89 （51%） deaths from GC were observed. ADC was significantly different both for local invasion and nodal involvement （P〈0.001）. Considering final histology as the reference standard, a preoperative ADC cut-offof 1.80×10-3 mm^2/s could distinguish between stages I and Ⅱ and an ADC value of ≤1.36-10-3 mm^2/s was associated with stage Ⅲ（P〈0.001）. Kaplan-Meier curves demonstrated that the survival rates for the three prognostic groups were significantly different according to final histology and ADC cut-offs （P〈0.001）. Conclusions： ADC is different according to local invasion, nodal involvement and the 7th TNM stage groups for GC, representing a potential, additional prognostic biomarker. The addition of DW-MRI could aid in the staging and risk stratification of GC.

Oropharyngeal acid reflux and motility abnormalities of the proximal esophagus

AIM To investigate the relationship between pathological oropharyngeal(OP) acid exposure and esophageal motility in patients with extra-esophageal syndromes.METHODS In this prospective study we enrolled consecutive outpatients with extra-esophageal symptoms suspected to be related to gastroesophageal reflux disease(GERD). We enrolled only patients with a reflux symptom index(RSI) score-higher than 13 and with previous lung, allergy and ear, nose and throat evaluations excluding other specific diagnoses. All patients underwent 24-h OP pH-metry with the Dx probe and esophageal highresolution manometry(HRM). Patients were divided into two groups on the basis of a normal or pathological p H-metric finding(Ryan Score) and all manometric characteristics of the two groups were compared.RESULTS We examined 135 patients with chronic extra-esophageal syndromes. Fifty-one were considered eligible for the study. Of these, 42 decided to participate in the protocol. Patients were divided into two groups on the basis of normal or pathological OP acid exposure. All the HRM parameters were compared for the two groups. Significant differences were found in the median upper esophageal sphincter resting pressure(median 71 mmH g vs 126 mmH g, P = 0.004) and the median proximal contractile integral(median 215.5 cm·mmH g·s vs 313.5 cm·mmH g·s, P = 0.039), both being lower in the group with pathological OP acid exposure, and the number of contractions with small or large breaks, which were more frequent in the same group. This group also had a larger number of peristaltic contractions with breaks in the 20 mm Hg isobaric contour(38.7% vs 15.38%, P < 0.0001).CONCLUSION In patients with suspected GERD-related extraesophageal syndromes pathological OP acid exposure was associated with weaker proximal esophageal motility.

Early changes of graft function,cytokines and superoxide dismutase serum levels after donor liver denervation and Kupffer cell depletion in a rat-to-rat liver transplantation model

BACKGROUND: Hepatic reperfusion injury may cause acute inflammatory damage, producing significant organ dysfunction, and is an important problem in liver transplantation. This experiment aimed to study early changes of hepatic function after donor liver denervation and Kupffer cell depletion in rat-to-rat liver transplantation and to evaluate the effect of pre-treatment on liver reperfusion injury. METHODS: Donor rats were divided into four groups: control group; group G was pre-treated with gadolinium chloride (G), an inhibitor of Kupffer cells; group H with hexamethonium (H), a sympathetic ganglionic blocking agent; and group HG, with combined H and G pre-treatment. Under the same conditions, serum alanine aminotransferase (ALT), arterial ketone body ratio (AKBR), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and superoxide dismutase (SOD) of recipient rats were assessed at 4, 8, 16 and 24 hours after liver transplantation. Histological studies of the grafts were compared. RESULTS: HG pre-treatment significantly decreased ALT, TNF-alpha, and IL-6 levels, increased AKBR and SOD levels, and demonstrated less pathological damage at 8, 16 and 24 hours compared with the control group. Similar trends were also found in the other groups (G and H). However, the differences among them were not significant at 4 postoperative hours. CONCLUSIONS: Donor denervation and Kupffer cell depletion had preventive effect on liver reperfusion injury. HG pre-treatment is a feasible and reproducible method to protect grafts from reperfusion injury.

Transoral incisionless fundoplication for gastro-esophageal reflux disease: Techniques and outcomes

Gastro-esophageal reflux disease(GERD)is a verycommon disorder that results primarily from the loss of an effective antireflux barrier,which forms a mechanical obstacle to the retrograde movement of gastric content.GERD can be currently treated by medical therapy,surgical or endoscopic transoral intervention.Medical therapy is the most common approach,though concerns have been increasingly raised in recent years about the potential side effects of continuous longterm medication,drug intolerance or unresponsiveness,and the need for high dosages for long periods to treat symptoms or prevent recurrences.Surgery too may in some cases have consequences such as longlasting dysphagia,flatulence,inability to belch or vomit,diarrhea,or functional dyspepsia related to delayed gastric emptying.In the last few years,transoral incisionless fundoplication(TIF)has proved an effective and promising therapeutic option as an alternative to medical and surgical therapy.This review describes the steps of the TIF technique,using the Esophy X&#174;device and the MUSETM system.Complications and their management are described in detail,and the recent literature regarding the outcomes is reviewed.TIF reconfigures the tissue to obtain a full-thickness gastroesophageal valve from inside the stomach,by serosato-serosa plications which include the muscle layers.To date the procedure has achieved lasting improvement of GERD symptoms(up to six years),cessation or reduction of proton pump inhibitor medication in about 75%of patients,and improvement of functional findings,measured by either p H or impedance monitoring.

Endoscopic pancreatic duct stent placement for inflammatory pancreatic diseases

The role of endoscopic therapy in the management of pancreatic diseases is continuously evolving; at present most pathological conditions of the pancreas are successfully treated by endoscopic retrograde cholangio- pancreatography （ERCP） or endoscopic ultrasound （EUS）, or both. Endoscopic placement of stents has played and still plays a major role in the treatment of chronic pancreatitis, pseudocysts, pancreas divisum, main pancreatic duct injuries, pancreatic fistulae, complications of acute pancreatitis, recurrent idiopathic pancreatitis, and in the prevention of post-ERCP pancreatitis. These stents are currently routinely placed to reduce intraductal hypertension, bypass obstructing stones, restore lumen patency in cases with dominant, symptomatic strictures, seal main pancreatic duct disruption, drain pseudocysts or fluid collections, treat symptomatic major or minor papilla sphincter stenosis, and prevent procedure-induced acute pancreatitis. The present review aims at updating and discussing techniques, indications, and results of endoscopic pancreatic duct stent placement in acute and chronic inflammatory diseases of the pancreas.

Role of gadoxetic acid-enhanced liver magnetic resonance imaging in the evaluation of hepatocellular carcinoma after locoregional treatment

Locoregional treatments,as alternatives to surgery,play a key role in the management of hepatocellular carcinoma(HCC).Liver magnetic resonance imaging(MRI)enables a multiparametric assessment,going beyond the traditional dynamic computed tomography approach.Moreover,the use of hepatobiliary agents can improve diagnostic accuracy and are becoming important in the diagnosis and follow-up of HCC.However,the main challenge is to quickly identify classical responses to loco-regional treatments in order to determine the most suitable management strategy for each patient.The aim of this review is to provide a summary of the most common and uncommon liver MRI findings in patients who underwent loco-regional treatments for HCC,with a special focus on ablative therapies(radiofrequency,microwaves and cryoablation),transarterial chemoembolization,trans-arterial radio-embolization and stereotactic ablative radiotherapy techniques,considering the usefulness of gadoxetate disodium(Gd-EOB-DTPA)contrast agent.

Colorectal cancer screening from 45 years of age: Thesis, antithesis and synthesis

Colorectal cancer incidence and mortality in patients younger than 50 years are increasing, but screening before the age of 50 is not offered in Europe. Advancedstage diagnosis and mortality from colorectal cancer before 50 years of age are increasing. This is not a detection-bias effect;it is a real issue affecting the entire population. Three independent computational models indicate that screening from 45 years of age would yield a better balance of benefits and risks than the current start at 50 years of age. Experimental data support these predictions in a sex- and race-independent manner. Earlier screening is seemingly affordable, with minimal impediments to providing younger adults with colonoscopy. Indeed, the American Cancer Society has already started to recommend screening from 45 years of age in the United States. Implementing early screening is a societal and public health problem. The three independent computational models that suggested earlier screening were criticized for assuming perfect compliance. Guidelines and recommendations should be derived from well-collected and reproducible data, and not from mathematical predictions. In the era of personalized medicine, screening decisions might not be based solely on age, and sophisticated prediction software may better guide screening. Moreover, early screening might divert resources away from older individuals with greater biological risks. Finally, it is still unknown whether early colorectal cancer is part of a continuum of disease or a biologically distinct disease and, as such, it might not benefit from screening at all. The increase in early-onset colorectal cancer incidence and mortality demonstrates an obligation to take actions. Earlier screening would save lives, and starting at the age of 45 years may be a robust screening option.

Tumors and new endoscopic ultrasound-guided therapies

With the advent of linear echoendoscopes, endoscopic ultrasound (EUS) has become more operative and a new field of oncological application has been opened up. From tumor staging to tissue acquisition under EUS-guided fine-needle aspiration, new operative procedures have been developed on the principle of the EUS-guided puncture. A hybrid probe combining radiofrequency with cryotechnology is now available, to be passed through the operative channel of the echoendoscope into the tumor to create an area of ablation. EUS-guided fine-needle injection is emerging as a method to deliver anti-tumoral agents inside the tumor. Ethanol lavage, with or without paclitaxel, has been proposed for the treatment of cystic tumors in non-resectable cases and complete resolution has been recorded in up to 70%-80%. Many other chemical or biological agents have been investigated for the treatment of pancreatic adenocarcinoma: activated allogenic lymphocyte culture (Cytoimplant), a replication-deficient adenovirus vector carrying the tumor necrosis factor-α gene, or an oncolytic attenuated adenovirus (ONYX-015). The potential advantage of treatment under EUS control is the real-time imaging guidance into a deep target likethe pancreas which is extremely difficult to reach by a percutaneous approach. To date there are no randomized controlled trials to confirm the real clinical benefits of these treatments compared to standard therapy so it seems wise to reserve them only for experimental protocols approved by ethics committees.

Endoscopic ultrasonography for evaluating patients with recurrent pancreatitis

Acute recurrent pancreatitis (ARP) is still a complex diagnostic and therapeutic challenge in clinical practice. In up to 30% of cases of ARP, it is not possible to establish the etiology of the disease. In the other 70%, many factors play an etiological role in ARP: microlithiasis, sphincter of Oddi dysfunction (SOD), pancreas divisum, hereditary pancreatitis, cystic fibrosis, a choledochocele, annular pancreas, an anomalous pancreatobiliary junction, pancreatic tumors or chronic pancreatitis are diagnosed. EUS should be useful in ARP as it is sensitive for diagnosing bile duct stones, gallbladder sludge, pancreatic lesions, ductal abnormalities and chronic pancreatitis. Endoscopic ultrasound (EUS) appears to be diagnostic in the majority of patients with previously unexplained pancreatitis, and offers an alternative to endoscopic retrograde cholangiopancreatography (ERCP) as the initial diagnostic test in patients with ARP.

Paradoxical association between dyspepsia and autoimmune chronic atrophic gastritis:Insights into mechanisms,pathophysiology,and treatment options

BACKGROUND Autoimmune gastritis(AIG)is a progressive,chronic,immune-mediated inflammatory disease characterized by the destruction of gastric parietal cells leading to hypo/anacidity and loss of intrinsic factor.Gastrointestinal symptoms such as dyspepsia and early satiety are very common,being second in terms of frequency only to anemia,which is the most typical feature of AIG.AIM To address both well-established and more innovative information and knowledge about this challenging disorder.METHODS An extensive bibliographical search was performed in PubMed to identify guidelines and primary literature(retrospective and prospective studies,systematic reviews,case series)published in the last 10 years.RESULTS A total of 125 records were reviewed and 80 were defined as fulfilling the criteria.CONCLUSION AIG can cause a range of clinical manifestations,including dyspepsia.The pathophysiology of dyspepsia in AIG is complex and involves changes in acid secretion,gastric motility,hormone signaling,and gut microbiota,among other factors.Managing dyspeptic symptoms of AIG is challenging and there are no specific therapies targeting dyspepsia in AIG.While proton pump inhibitors are commonly used to treat dyspepsia and gastroesophageal reflux disease,they may not be appropriate for AIG.Prokinetic agents,antidepressant drugs,and non-pharmacological treatments may be of help,even if not adequately evidence-based supported.A multidisciplinary approach for the management of dyspepsia in AIG is recommended,and further research is needed to develop and validate more effective therapies for dyspepsia.

Current scenario of the genetic testing for rare neurological disorders exploiting next generation sequencing

Next generation sequencing is currently a cornerstone of genetic testing in routine diagnostics,allowing for the detection of sequence variants with so far unprecedented large scale,mainly in genetically heterogenous diseases,such as neurological disorders.It is a fast-moving field,where new wet enrichment protocols and bioinformatics tools are constantly being developed to overcome initial limitations.Despite the as yet undiscussed advantages,however,there are still some challenges in data analysis and the interpretation of variants.In this review,we address the current state of next generation sequencing diagnostic testing for inherited human disorders,particularly giving an overview of the available high-throughput sequencing approaches;including targeted,whole-exome and whole-genome sequencing;and discussing the main critical aspects of the bioinformatic process,from raw data analysis to molecular diagnosis.

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.