Targeted analysis of Ubiquitin-Specific Peptidase (USP8) in a population of Iranian people with Cushing's disease and a systematic review of the literature.

OBJECTIVE: Activating mutation in Ubiquitin-specific peptidase (USP8) is identified to enhance cell proliferation and adrenocorticotropic hormone (ACTH) secretion from corticotroph pituitary adenoma. We investigated the USP8 variant status in a population of Iranian people with functional corticotroph pituitary adenoma (FCPA). Moreover, a systematic review was conducted to thoroughly explore the role of USP8 variants and the related pathways in corticotroph adenomas, genotype-phenotype correlation in USP8-mutated individuals with FCPA, and the potential role of USP8 and epidermal growth factor receptor (EGFR) as targeted therapies in PFCAs. METHODS: Genetic analysis of 20 tissue samples from 19 patients with PFCAs was performed using Sanger sequencing. Moreover, a systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, web of Sciences, and Cochrane databases were searched. The last search was performed on 20 September 2023 for all databases. RESULTS: In our series, we found two somatic mutations including a 7-bp deletion variant: c.2151_2157delCTCCTCC, p. Ser718GlnfsTer3, and a missense variant: c.2159 C > G, p. Pro720Arg (rs672601311) in exon 14. The Systematic review indicated USP8 variant in 35% of corticotroph adenomas, with the highest frequency (25%) in 720 code regions, p. Pro720Arg. Data regarding the impact of USP8 mutational status on clinical characteristics and outcomes in FCPAs are inconsistent. Moreover, Pasireotide as well as inhibitors of EGFR such as Gefitinib and Lapatinib, as well as USP8 inhibitors including -ehtyloxyimino9H-indeno (1, 2-b) pyrazine-2, 3-dicarbonitrile, DUBs-IN-2, and RA-9 indicated promising results in treatment of corticotroph adenomas. CONCLUSION: Although the USP8-EGFR system has been identified as the main trigger and target of corticotroph tumorigenesis, more precise multicenter studies are required to yield more consistent information regarding the phenotype-genotype correlation and to develop effective targeted therapies.

Improving diabetic retinopathy screening at the point of care: integrating telemedicine to overcome current challenges.

OBJECTIVE: To investigate the utility of point of care screening of diabetic retinopathy (DR) and the impact of a telemedicine program to overcome current challenges. METHODS: This was a retrospective study on people with type 2 diabetes mellitus (T2DM) who were screened for DR using the single-field non-mydriatic fundus photography at the point of care during routine follow-up visits at endocrinology clinic. Retinal images were uploaded and sent to a retina specialist for review. Reports indicating retinopathy status and the need for direct retinal examination were transmitted back to the endocrinology clinic. All patients were informed about DR status and, if needed, referred to the retina specialist for direct retinal examination. RESULTS: Of the 1159 individuals screened for DR, 417 persons (35.98%) were screen-positive and referred to the retina specialist for direct retinal examination. A total of 121 individuals (29.01%) underwent direct retinal examination by the specialist. Diabetes macular edema (DME) was detected in 12.1%. In addition, non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) were detected in 53.4% and 2.6% of the patients, respectively. CONCLUSION: Integrating DR screening program at the point of care at the secondary care services improves the rate of DR screening as well as detection of sight threatening retinopathy and provides the opportunity for timely intervention in order to prevent advanced retinopathy in people with T2DM.

Efficacy and safety of basal insulins in people with type 2 diabetes mellitus: a systematic review and network meta-analysis of randomized clinical trials.

Aim: The comparative effectiveness of basal insulins has been examined in several studies. However, current treatment algorithms provide a list of options with no clear differentiation between different basal insulins as the optimal choice for initiation. Methods: A comprehensive search of MEDLINE, Embase, Cochrane Library, ISI, and Scopus, and a reference list of retrieved studies and reviews were performed up to November 2023. We identified phase III randomized controlled trials (RCTs) comparing the efficacy and safety of basal insulin regimens. The primary outcomes evaluated were HbA1c reduction, weight change, and hypoglycemic events. The revised Cochrane ROB-2 tool was used to assess the methodological quality of the included studies. A random-effects frequentist network meta-analysis was used to estimate the pooled weighted mean difference (WMD) and odds ratio (OR) with 95% confidence intervals considering the critical assumptions in the networks. The certainty of the evidence and confidence in the rankings was assessed using the GRADE minimally contextualized approach. Results: Of 20,817 retrieved studies, 44 RCTs (23,699 participants) were eligible for inclusion in our network meta-analysis. We found no significant difference among various basal insulins (including Neutral Protamine Hagedorn (NPH), ILPS, insulin glargine, detemir, and degludec) in reducing HbA1c. Insulin glargine, 300 U/mL (IGlar-300) was significantly associated with less weight gain (mean difference ranged from 2.9 kg to 4.1 kg) compared to other basal insulins, namely thrice-weekly insulin degludec (IDeg-3TW), insulin degludec, 100 U/mL (IDeg-100), insulin degludec, 200 U/mL (IDeg-200), NPH, and insulin detemir (IDet), but with low to very low certainty regarding most comparisons. IDeg-100, IDeg-200, IDet, and IGlar-300 were associated with significantly lower odds of overall, nocturnal, and severe hypoglycemic events than NPH and insulin lispro protamine (ILPS) (moderate to high certainty evidence). NPH was associated with the highest odds of overall and nocturnal hypoglycemia compared to others. Network meta-analysis models were robust, and findings were consistent in sensitivity analyses. Conclusion: The efficacy of various basal insulin regimens is comparable. However, they have different safety profiles. IGlar-300 may be the best choice when weight gain is a concern. In contrast, IDeg-100, IDeg-200, IDet, and IGlar-300 may be preferred when hypoglycemia is the primary concern.

Barriers to the Use of Insulin Therapy and Potential Solutions: A Narrative Review of Perspectives from the Asia-Pacific Region.

The rising prevalence of type 2 diabetes (T2D) is posing major challenges for the healthcare systems of many countries, particularly in the Asia-Pacific Region, in which T2D can present at younger ages and lower body mass index when compared with Western nations. There is an important role for insulin therapy in the management of T2D in these nations, but available evidence suggests that insulin is under-utilized and often delayed, to the detriment of patient prognosis. The authors of this article gathered as an advisory panel (representative of some of the larger Asia-Pacific nations) to identify their local barriers to insulin use in T2D, and to discuss ways in which to address these barriers, with their outputs summarized herein. Many of the key barriers identified are well-documented issues of global significance, including a lack of healthcare resources or of an integrated structure, insufficient patient education, and patient misconceptions about insulin therapy. Barriers identified as more innate to Asian countries included local inabilities of patients to afford or gain access to insulin therapy, a tendency for some patients to be more influenced by social media and local traditions than by the medical profession, and a willingness to switch care providers and seek alternative therapies. Strategies to address some of these barriers are provided, with hypothetical illustrative case histories.

Insulin Resistance/Sensitivity Measures as Screening Indicators of Metabolic-Associated Fatty Liver Disease and Liver Fibrosis.

BACKGROUND: Measures of insulin resistance (IR)/sensitivity (IS) are emerging tools to identify metabolic-associated fatty liver disease (MAFLD). However, the comprehensive assessment of the performance of various indicators is limited. Moreover, the utility of measures of IR/IS in detecting liver fibrosis remains unclear. AIMS: To evaluate the predictive ability of seventeen IR/IS and two beta cell function indices to identify MAFLD and liver fibrosis. METHODS: A cross-sectional study was conducted on individuals aged 25-75 years. Transient elastography was used to estimate liver stiffness and controlled attenuation parameter. The following measures were computed: homeostatic model assessment (HOMA/HOMA2) for IR, IS, and beta cell function; QUICKI; Bennett index; glucose/insulin; FIRI; McAuley index; Reynaud index; SPISE index; TyG; TyG-BMI; TyG-WC; TyG-WHtR; TG/HDL; and METS-IR. Subgroup analyses were performed according to age, gender, diabetes status, and body weight. RESULTS: A total of 644 individuals were included in our analysis. MAFLD and significant liver fibrosis were detected in 320 (49.7%) and 80 (12.4%) of the participants, respectively. All measures of IR/IS identified MAFLD and liver fibrosis. However, TyG-WC, TyG-BMI, and TyG-WHtR were the top three indicators that identified MAFLD. Measures that include insulin level in their mathematical calculation, namely, Raynaud index, HOMA-IR, HOMA 2-IR, FIRI, and QUICKI had the best performance in identifying liver fibrosis in the entire population, as well as among the study subgroups. CONCLUSIONS: TyG-WC, TyG-BMI, and TyG-WHtR were the best predictors of MAFLD. Insulin-based measures had better performances in the detection of advanced fibrosis. This was independent of age, gender, obesity, or diabetes status.

Statins and thyroid eye disease (TED): a systematic review.

PURPOSE: Thyroid eye disease (TED) is the foremost extrathyroidal manifestation of Graves' disease (GD). Currently, available treatments do not entirely prevent the long-term consequences of TED and have distinct disadvantages. Therefore, this systematic review explored available evidence regarding the efficacy of statins in preventing and treating TED. METHODS: Relevant studies investigating statin usage in patients with GD or TED were identified by searching Medline (Pubmed and Ovid), Scopus, Web of Science, ProQuest, and Cochrane Library databases (from the database inception to September 2023). The review was done according to the PRISMA statement. Web searching was done independently by two investigators. Two researchers independently extracted the data, and any disagreement was adjudicated by consensus. Based on the study design, the studies' quality appraisal was done using the Newcastle-Ottawa Scale (NOS) and Version 2 of the Cochrane risk-of-bias tool (RoB2). RESULTS: The literature search identified 145 publications, of which four met the inclusion criteria (Three retrospective cohort studies and one randomized clinical trial) and were reviewed in full text. The two retrospective cohort studies demonstrated the beneficial effects of statins on TED in newly diagnosed GD Stein et al. showed that statins, regardless of the type, prevent or delay TED (HR: 0.74 (0.65-0.84)), especially in men or treatment duration of more than one year. Nilsson et al. fascinatingly revealed that at least 60 days of statin usage in the preceding year could decrease the risk of TED development by around 40%. One RCT showed a higher treatment response for active moderate-to-severe TED in patients with hypercholesterolemia who took atorvastatin 20 mg in addition to ivGC for 24 weeks without any increase in serious side effects. The retrospective study revealed that the need for reconstructive surgery was reduced in patients with severe TED who received statin therapy. CONCLUSION: Statin therapy could be a potential adjunctive modality for preventing and treating TED. TRIAL REGISTRATION: PROSPERO registration number: CRD42022315522.

Glucagon-Like Peptide 1 (GLP-1) Receptor Variants and Glycemic Response to Liraglutide: A Pharmacogenetics Study in Iranian People with Type 2 Diabetes Mellitus.

INTRODUCTION: Pharmacogenetics studies suggest that genetic variants have a possible influence on the inter-individual differences in therapeutic response to glucagon-like peptide 1 receptor agonists (GLP-1 RAs). We aimed to examine the potential role of genetic variability of glucagon-like peptide 1 receptor (GLP-1R) on glycemic response to GLP-1 RAs in a population of Iranian people with type 2 diabetes mellitus (T2DM). METHODS: In this study, we analyzed the data from participants in a non-inferiority randomized clinical trial between 2019 and 2020. Patients received liraglutide 1.8 mg/day subcutaneously for 24 weeks. They were stratified by the baseline hemoglobin A1c (HbA1c) into four categories: 7-7.99, 8-8.99, 9-9.99, and ≥ 10%. In each category, subjects with HbA1c reduction greater than the median ΔHbA1c value for that group were defined as optimal responders. The pooled number of optimal/suboptimal responders in the four groups was used for the comparison. We evaluated two genetic variants of GLP-1R, rs6923761 and rs10305420, using Sanger sequencing. Logistic regression analyses were performed to examine the associations of the GLP-1R variants with the glycemic response in different genetic models. RESULTS: Out of 233 participants, 120 individuals were optimal responders. Median HbA1c reduction was - 2.5% in the optimal responder group compared with - 1.0% in the suboptimal responder group (P < 0.001). In genetic models, rs10305420 T allele homozygosity was associated with optimal glycemic response to liraglutide compared with heterozygous and wild-type homozygous states (recessive model: OR 3.28, 95% CI 1.41-7.65, P = 0.006; codominant model: OR 2.52, 95% CI 1.03-6.13, P = 0.04). No significant association was found between rs6923761 variant and HbA1c reduction. CONCLUSION: GLP-1R rs10305420 polymorphism can explain some of the inter-individual differences in glycemic response to liraglutide in a population of Iranian people with T2DM.

External validation of the UK prospective diabetes study (UKPDS) risk engine in patients with type 2 diabetes identified in the national diabetes program in Iran.

Background: Cardiovascular diseases are the first leading cause of mortality in the world. Practical guidelines recommend an accurate estimation of the risk of these events for effective treatment and care. The UK Prospective Diabetes Study (UKPDS) has a risk engine for predicting CHD risk in patients with type 2 diabetes, but in some countries, it has been shown that the risk of CHD is poorly estimated. Hence, we assessed the external validity of the UKPDS risk engine in patients with type 2 diabetes identified in the national diabetes program in Iran. Methods: The cohort included 853 patients with type 2diabetes identified between March 21, 2007, and March 20, 2018 in Lorestan province of Iran. Patients were followed for the incidence of CHD. The performance of the models was assessed in terms of discrimination and calibration. Discrimination was examined using the c-statistic and calibration was assessed with the Hosmer-Lemeshow χ2 statistic (HLχ2) test and a calibration plot was depicted to show the predicted risks versus observed ones. Results: During 7464.5 person-years of follow-up 170 first Coronary heart disease occurred. The median follow-up was 8.6 years. The UKPDS risk engine showed moderate discrimination for CHD (c-statistic was 0.72 for 10-year risk) and the calibration of the UKPDS risk engine was poor (HLχ2 = 69.9, p < 0.001) and the UKPDS risk engine78% overestimated the risk of heart disease in patients with type 2 diabetes identified in the national diabetes program in Iran. Conclusion: This study shows that the ability of the UKPDS Risk Engine to discriminate patients who developed CHD events from those who did not; was moderate and the ability of the risk prediction model to accurately predict the absolute risk of CHD (calibration) was poor and it overestimated the CHD risk. To improve the prediction of CHD in patients with type 2 diabetes, this model should be updated in the Iranian diabetic population.

MiR-20b Tissue Expression Level Displays the Diagnostic Value in Papillary Thyroid Carcinoma.

Background: Detection of cancer in patients with thyroid nodules requires sensitive and specific diagnostic modalities that are accurate and inexpensive. This study aimed to identify a potential microRNA(miRNA) panel to detect papillary thyroid carcinoma (PTC). Methods: Following a comprehensive literature review as well as miRNA target predictor databases, Real-time PCR was used to quantify the expression of candidate miRNAs in 59 tissue specimens from 30 patients with PTC and 29 patients with benign nodules. A receiver operating characteristic (ROC) curve analysis was used to assess the accuracy of miRNA expression levels compared to the pathology report as the gold standard. Based on prediction results, four miRNAs, including miR-9, miR-20b, miR-221, and miR-222, were selected to evaluate their expression level in Iranian thyroid samples. Results: A significant difference between the tissue expression level of miR-20b, miR-9, miR-222, and miR-221 was detected in the PTC group compared with non-PTC (P < 0.05). The area under the curves for the included miRs were 1, 0.98, 0.99, 0.98, and 1, respectively. Conclusion: Our results confirmed deregulations of miR-20b as well as miR-222, miR-221, and miR-9 in PTC and, therefore, could be used as a helpful miRNA panel to differentiate PTC from benign nodules, which results in the more efficient clinical management of PTC patients.

The Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Body Composition in Type 2 Diabetes Mellitus: A Narrative Review.

Body composition is related to cardiometabolic disorders and is a major driver of the growing incidence of type 2 diabetes mellitus (T2DM). Altered fat distribution and decreased muscle mass are related to dysglycemia and impose adverse health-related outcomes in people with T2DM. Hence, improving body composition and maintaining muscle mass is crucial in T2DM. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are novel glucose-lowering medications gaining popularity because of their cardiorenal-protective effects and weight-lowering characteristics. However, reports on myopathy secondary to SGLT2 inhibitor treatment raised a safety concern. The importance of maintaining muscle mass in people with T2DM necessitates further investigation to explore the impact of novel medications on body composition. In this review, we discussed current evidence on the impact of SGLT2 inhibitors on body composition in people with T2DM.

Association between dietary glycemic index and non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus.

Objective: Managing dietary glycemic index (GI) deserves further attention in the interplay between non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). This study aimed to evaluate the relationship between dietary GI and the odds of NAFLD in patients with T2DM. Methods: A cross-sectional study was carried out between April 2021 and February 2022, including 200 participants with T2DM aged 18-70 years, of which 133 had NAFLD and 67 were in the non-NAFLD group. Cardiometabolic parameters were analyzed using standard biochemical kits and dietary intake was assessed using a validated food frequency questionnaire. Binary logistic regression was applied to explore odds ratios (ORs) and 95% confidence intervals (CIs) for NAFLD according to tertiles of dietary GI. Results: Highest vs. lowest tertile (< 57 vs. > 60.89) of energy-adjusted GI was not associated with the odds of having NAFLD (OR 1.25, 95% CI = 0.6-2.57; P-trend = 0.54) in the crude model. However, there was an OR of 3.24 (95% CI = 1.03-10.15) accompanied by a significant trend (P-trend = 0.04) after full control for potential confounders (age, gender, smoking status, duration of diabetes, physical activity, waist circumference, HbA1c, triglycerides, total cholesterol, dietary intake of total carbohydrates, simple carbohydrates, fat, and protein). Conclusion: High dietary GI is associated with increased odds of NAFLD in subjects with T2DM. However, interventional and longitudinal cohort studies are required to confirm these findings.

Efficacy and Safety of a Biosimilar Liraglutide (Melitide®) Versus the Reference Liraglutide (Victoza®) in People with Type 2 Diabetes Mellitus: A Randomized, Double-Blind, Noninferiority Clinical Trial.

INTRODUCTION: Liraglutide effectively controls blood glucose level and reduces body weight. The aim of this study was to compare the efficacy and safety of a biosimilar liraglutide (Melitide®; CinnaGen, Tehran, Iran) to the reference liraglutide (Victoza®; Novo Nordisk, Bagsvaerd, Denmark) in people with type 2 diabetes mellitus (T2DM). METHODS: In this phase 3 clinical noninferiority trial, adult patients with inadequately controlled T2DM and with hemoglobin A1C (HbA1C) levels of 7-10.5% on at least two oral glucose-lowering drugs with stable doses for at least 3 months were randomized to receive Melitide® (n = 150) or Victoza® (n = 150) 1.8 mg/day for 26 weeks. The primary outcome was assessment of the noninferiority of Melitide® to Victoza® in terms of change in HbA1C level with a prespecified margin of 0.4%. The secondary outcomes were the assessment of additional efficacy parameters (including the proportion of patients achieving HbA1C levels of < 7%), the incidence of adverse events, and immunogenicity. RESULTS: Of the 300 participants enrolled in this study, 235 were included in the per-protocol analysis (112 in the Melitide® group and 123 in the Victoza® group). The mean (standard deviation) changes in HbA1C were - 1.76% (1.22) in the Melitide® group and - 1.59% (1.31) in the Victoza® group. The upper limit of the 95% one-sided confidence interval (CI) of the mean difference between Melitide® and Victoza® in lowering HbA1C was lower than the predefined margin (mean difference - 0.18, 95% CI - 0.5 to 0.15). Similar findings were obtained with the intention-to-treat analysis. No statistically significant differences were observed between the two study arms regarding the proportion of patients achieving HbA1C < 7% (p = 0.210), other efficacy parameters (p > 0.05), and reported adverse events (p = 0.916). Furthermore, none of the patients developed anti-liraglutide antibodies. CONCLUSION: The biosimilar liraglutide (Melitide®) was noninferior in efficacy and comparable in safety when compared with the reference liraglutide. TRIAL REGISTRATION: NCT03421119.

Effect of Empagliflozin and Pioglitazone on left ventricular function in patients with type two diabetes and nonalcoholic fatty liver disease without established cardiovascular disease: a randomized single-blind clinical trial.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a complex metabolic disorder that increases the risk for cardiovascular disease in patients with type 2 diabetes mellitus (T2DM). Global longitudinal strain (GLS) is an indicator of left ventricular (LV) mechanics and can detect subclinical myocardial dysfunction. We compared the effects of pioglitazone and empagliflozin on GLS in patients with T2DM and NAFLD without established atherosclerotic cardiovascular disease. METHODS: This study was a 24-week randomized, single-blind, and parallel-group (1: 1 ratio) clinical trial. Seventy-three participants with T2DM (being treated with metformin) and NAFLD but without established atherosclerotic cardiovascular disease (ASCVD) were randomized to empagliflozin or pioglitazone. Liver steatosis and fibrosis were measured using transient elastography, and GLS was measured by echocardiography. The primary endpoint was the change in GLS from baseline to week 24. Secondary end points include changes in controlled attenuation parameter (CAP) and Liver stiffness measure (LSM). RESULTS: In this study, GLS improved by 1.56 ± 2.34% (P < 0.01) in the pioglitazone group and 1.06 ± 1.83% (P < 0.01) in the empagliflozin group without a significant difference between the two groups (P = 0.31). At baseline, GLS was inversely associated with the severity of liver fibrosis: r = - 0.311, P = 0.007. LSM in the pioglitazone and empagliflozin group [(-0.73 ± 1.59) and (-1.11 ± 1.33)] kpa (P < 0.01) decreased significantly. It was without substantial difference between the two groups (P = 0.26). Empagliflozin and pioglitazone both improved controlled attenuation parameter. The improvement was more critical in the empagliflozin group: -48.22 + 35.02 dB/m vs. -25.67 + 41.50 dB/m, P = 0.01. CONCLUSION: Subclinical cardiac dysfunction is highly important in patients with T2DM and with NAFLD. Empagliflozin and Pioglitazone improve LV mechanics and fibrosis in patients without established ASCVD. This has a prognostic importance on cardiovascular outcomes in high-risk patients with T2DM. Moreover, empagliflozin ameliorates liver steatosis more effectively them pioglitazone. This study can serve as a start point hypothesis for the future. Further studies are needed to explore the concept in larger populations. TRIAL REGISTRATION: This trial was registered in the Iranian Registry of Clinical Trials (IRCT): "A Comparison between the Effect of Empagliflozin and Pioglitazone on Echocardiographic Indices in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease" IRCT20190122042450N5, 29 November 2020. https://www.irct.ir/search/result?query=IRCT20190122042450N5 .

Non-alcoholic fatty liver disease and compromised endothelial function in people with type 2 diabetes.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) frequently coexists with type 2 diabetes mellitus (T2DM) and synergistically contributes to the development of atherosclerosis. Flow-mediated dilation (FMD) is a commonly used noninvasive test for assessing endothelial function. The main objective of this study was to explore FMD in patients with T2DM with and without NAFLD. METHODS: In this cross-sectional study, conducted on people with T2DM, NAFLD was defined as controlled attenuation parameter (CAP) score > 302 dB/m. Endothelial dysfunction was detected when arterial FMD of brachial artery was equal or less than 0.7%. Regression analyses were applied to assess factors associated with impaired FMD. RESULT: A total of 147 patients (72 with NAFLD and 75 without NAFLD) were included in the final analysis. Patients with NAFLD were more likely to develop FMD ≤ 7% (77.8% vs. 58.7%, P = 0.01). In multivariate analysis, NAFLD (OR = 2.581, 95% CI (1.18-5.62), P = 0.017) and hypertension (HTN) (OR = 3.114, 95% CI (1.31-7.35), P = 0.010) were associated with an increased risk of impaired FMD. However, female sex was associated with a decreased risk of impaired FMD (OR = 0.371, 95% CI (0.15-0.87), P = 0.024). CONCLUSION: NAFLD is associated with endothelial dysfunction in people with T2DM. This risk is comparable with the risk imposed by HTN, highlighting the importance of screening and management of NAFLD in these patients.

Potential metabolic biomarkers of critical limb ischemia in people with type 2 diabetes mellitus.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a significant risk factor for the development of critical limb ischemia (CLI), the most advanced stage of peripheral arterial disease. The concurrent existence of T2DM and CLI often leads to adverse outcomes, namely limb amputation. OBJECTIVE: To identify biomarkers for improving the screening of CLI in high-risk people with T2DM. METHODS: We investigated metabolome profiles in serum samples of 113 T2DM people with CLI (n = 23, G2) and without CLI (n = 45, G0: no lower limb stenosis (LLS) and n = 45, G1: LLS < 50%), using hydrogen nuclear magnetic resonance (1H NMR) approach. Principle component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were used to analyze 1H NMR data. RESULTS: Twenty potential metabolites that could discriminate people with T2DM and CLI (G2) from non-CLI patients without LLS (G0) were determined in serum samples. The correct percent of classification for the PLS-DA model for the test set samples was 85% (n = 20) and 100% (n = 5) for G0 and G2 groups, respectively. Non-CLI patients with LLS < 50% (G1) were projected on the PCA abstract space built using 20 discriminatory metabolites. Eleven people with T2DM and LLS < 50% were prospectively followed, and their ankle-brachial index (ABI) was measured after 4 years. A promising agreement existed between the PCA model's predictions and those obtained by ABI values. CONCLUSION: The findings suggest that confirmation of blood potential metabolic biomarkers as a complement to ABI for screening of CLI in a large group of high-risk people with T2DM is needed.

The association of dietary inflammatory index (DII) and central obesity with non-alcoholic fatty liver disease (NAFLD) in people with diabetes (T2DM).

Background & Objective: High prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus results in deleterious complications and morbidities related to both diseases. Thus, we aimed to investigate dietary and anthropometric risk factors for progression of Non-alcoholic Fatty Liver Disease (NAFLD) in diabetic people. Methods: Anthropometric, and dietary intakes, and hepatic steatosis and fibrosis were assessed in two hundred participants with type two diabetes (T2DM). Subjects with CAP score of more than 270 dB/m were considered to have NAFLD. Multivariable-adjusted ORs and 95% CIs were used to investigate the association between NAFLD and dietary inflammatory index (DII) score and anthropometric indices. Results: Participants in the highest tertile of DII had 2.41 (95% CI:1.16-4.97), 2,53 (95% CI: 1.04-6.16), 2.78 (95% CI: 1.09-7.13) times higher odds of developing NAFLD in comparison to the lowest tertile in crude, adjusted model 1 and 2, respectively. Among those with the highest relative to the lowest tertile of trunk-to-leg fat ratio (TLR), ORs and 95% CI were OR = 1.88, 95% CI = 0.9-3.91, and OR = 7.99, 95% CI = 2.43-26.26 in crude and full-adjusted models. Odds of NAFLD in the third tertile of metabolic score for visceral fat (METS-VF) was higher than the first tertile in crude (OR = 9.5, 95% CI = 4.01-22.46) and full-adjusted models (OR = 4.55, 95% CI = 1.46-14.2). Conclusions: In conclusion, this study highlighted an association between greater DII (pro-inflammatory diet) and higher NAFLD risk. Moreover, TLR and METS-VF are known as novel estimators of central obesity as a risk factor for NAFLD in diabetes.

Role of vitamin D in pathogenesis and severity of COVID-19 infection.

Coronavirus disease (COVID-19) is an infectious disease caused by a new virus that causes respiratory illness. Older adults and individuals who have pre-existing chronic medical conditions are at higher risk for more serious complications from COVID-19. Hypovitaminosis D is attributed to the increased risk of lung injury and acute respiratory distress syndrome (ARDS) as well as diabetes, cardiovascular events and associated comorbidities, which are the main causes of severe clinical complications in COVID-19 patients. Considering the defensive role of vitamin D, mediated through modulation of the innate and adaptive immune system as well as inhibition of the Renin Angiotensin System (RAS), vitamin D supplementation might boost the immune system of COVID-19 patients and reduce severity of the disease in vitamin D deficient individuals.

Attitude and Belief of Healthcare Professionals Towards Effective Obesity Care and Perception of Barriers; An Updated Systematic Review and Meta-analysis.

BACKGROUND: Obesity is a serious chronic disease that adversely affects health and quality of life. However, a significant percentage of people do not participate in or adhere to weight loss programs. Therefore, a multidisciplinary approach is needed to identify critical barriers to effective obesity management and to examine health practitioners' attitudes and behaviors towards effective obesity treatment. METHODS: This systematic review was conducted in accordance with PRISMA 2020. Eligible studies were identified through a systematic review of the literature using Medline, Scopus, Cochrane, Google Scholar, Web of Science, and Embase databases from January 1, 2011 to March 2, 2021. RESULTS: A total of 57 articles were included. Data on 12663 physicians were extracted from a total of 35 quantitative articles. Some of the most commonly perceived attitude issues included "obesity has a huge impact on overall health", "obesity is a disease" and "HCPs are to blame". Health professionals were more inclined to believe in "using BMI to assess obesity," "advice to increase physical activity," and "diet/calorie reduction advice." The major obstacles to optimal treatment of obesity were "lack of motivation", "lack of time" and "lack of success". CONCLUSION: Although the majority of health care professionals consider obesity as a serious disease which has a large impact on overall health, counseling for lifestyle modification, pharmacologic or surgical intervention occur in almost half of the visits. Increasing the length of physician visits as well as tailoring appropriate training programs could improve health care for obesity.

Appropriateness of Intensive Statin Treatment in People with Type Two Diabetes and Mild Hypercholesterolemia: A Randomized Clinical Trial.

BACKGROUND: The aim of this study was to compare moderate- versus high-intensity statin therapy in patients with type 2 diabetes and low-density lipoprotein (LDL) cholesterol less than 130 mg/dL. METHODS: This was a randomized, open-label, parallel design trial comprised of 79 patients randomly allocated into two groups receiving high-intensity [atorvastatin 40 mg (A40) or rosuvastatin 20 mg (R20) daily] or moderate-intensity [atorvastatin 20 mg (A20) or rosuvastatin 10 (R10) mg daily] statins for eight weeks. The variables investigated were lipid profile, high sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6). RESULTS: The percentage of decrease in LDL levels (±SD) for the high-intensity group (-35.5±25.5) was significantly greater than the moderate-intensity group (-24.6±23.5) (P=0.04). While 38.1% (n:8) of patients receiving A20 and 55% (n:11) of those being on R10 achieved the targets of≥30% reduction in the LDL level, these figures were 63.2% (n=12) and 73.8% (n=14) for A40 and R20 subgroups, respectively. Subsequently, the likelihood of achieving LDL reduction≥30%, was significantly greater with high-intensity statin therapy (OR: 3.1, 95% CI: 1.09, 8.90, P=0.03). Logistic regression analysis also showed that for every 1 mg/ dL increase in the baseline LDL level, the odds of achieving the LDL reduction≥30% increased by 1.04 times [95% CI: (1.01, 1.07), P=0.003]. CONCLUSION: Despite the general conception, moderate-intensity statins are not adequate for the majority of patients with T2DM and mild hyperlipidemia and greater numbers of patients could reach the LDL cholesterol target with high-intensity statin therapy.

Dietary total antioxidant capacity is inversely associated with the odds of non-alcoholic fatty liver disease in people with type-2 diabetes.

Background: This study was conducted to evaluate possible associations between Dietary Total Antioxidant Capacity (DTAC) and odds of non-alcoholic fatty liver disease (NAFLD) in people with type-2 diabetes mellitus (T2DM). Materials and methods: We recruited two hundred people with T2DM, and evaluated their liver steatosis using Fibroscan. Dietary intakes of participants were assessed using a validated food frequency questionnaire. DTAC was computed via ferric reducing antioxidant power (FRAP). Results: In the crude model, no statistically significant association was found between DTAC and the odds of NAFLD in people with diabetes. However, after adjustment for potential confounders including age, gender, diabetes duration, smoking status, physical activity, BMI, waist circumference, and energy, the most reduced adjusted OR was indicated for the third tertile vs. the first one (OR: 0.28, 95% CI: 0.09-0.81, P = 0.02), meaning that diabetic patients in the third tertile of DTAC had 72% decreased risk of NAFLD in comparison to those in the first one. The relationship was remained significant after additional adjustment for HOMA-IR, HbA1c, serum Triglyceride (TG), and low-density lipoprotein-cholesterol (LDL) levels (OR: 0.29, 95% CI: 0.09-0.93, P = 0.03). Importantly, a dose-response pattern was demonstrated for DTAC and risk of NAFLD (P = 0.04). Conclusion: Higher DTAC was related with a decreased risk of NAFLD in individuals with diabetes.