Association Between HDL2-C and HDL3-C with Cardiovascular Disease: A Nested Case-Control Study in an Iranian Population.

Background: The contribution of high-density lipoprotein cholesterol (HDL-C) subclasses to incident cardiovascular disease (CVD) and coronary heart disease (CHD) remains a subject of debate. Objectives: The objective of this study was to investigate these associations in a population with a high prevalence of dyslipidemia and CVD. Methods: In a nested case-control study, HDL-C and its subclasses (HDL2-C and HDL3-C) in 370 age and gender-matched case and control subjects were determined. This study employed multivariable-adjusted conditional logistic regression to calculate the odds ratios (ORs) for the associations between HDL-C, HDL2-C, HDL3-C, and HDL2-C/HDL3-C (both as continuous and categorical variables) with incident CVD and CHD. The present study models were adjusted for a comprehensive set of confounders, including body mass index, current smoking, hypertension, type 2 diabetes mellitus, use of lipid-lowering drugs, family history of premature CVD, non-HDL-C, and triglycerides. Results: In multivariate analysis, when considering lipoprotein parameters as continuous variables, a 1-unit increase in HDL-C and HDL3-C was associated with a reduced risk of incident CVD and CHD. For CVD, the ORs (95% confidence intervals [CI]) were 0.95 (0.92 - 0.98) and 0.95 (0.93 - 0.98) for HDL-C and HDL3-C, respectively. The corresponding values for CHD were 0.94 (0.91 - 0.97) and 0.94 (0.91 - 0.97). In the categorical approach to lipoprotein parameters, higher quartiles of HDL-C and HDL3-C, compared to the first quartile, were significantly associated with a lower risk of incident CVD and CHD. The ORs (95% CI) for the fourth quartiles were 0.43 (0.25 - 0.74, P for trend = 0.003) and 0.46 (0.27 - 0.78, P for trend = 0.005) for HDL-C and HDL3-C regarding CVD and 0.32 (0.17 - 0.59) and 0.32 (0.18 - 0.59) (all P for trend = 0.001) regarding CHD, respectively. Paradoxically, across quartiles of HDL2-C/HDL3-C, this lipid ratio was associated with a higher risk of CHD (92% higher risk in the fourth quartile). Conclusions: The results showed that HDL3-C, but not HDL2-C, was primarily responsible for the protective effect of HDL-C against CVD, particularly CHD, in Iranian adults.

Association of ideal cardiovascular health metrics with incident low estimated glomerular filtration rate: More than a decade follow-up in the Tehran Lipid and Glucose Study (TLGS).

AIMS: To evaluate the association between ideal cardiovascular health metrics (ICVHM) and incident low estimated glomerular filtration rate (eGFR) among the Iranian population. METHODS: The study population included 6927 Iranian adults aged 20-65 years (2942 male) without prevalent low eGFR [i.e., eGFR < 60 ml/min/1.73 m2] and free of cardiovascular disease. The ICVHM was defined according to the 2010 American Heart Association. The multivariable Cox proportional hazards regression analysis was used to calculate the hazard ratios (HRs) of ICVHM both as continuous and categorical variables. RESULTS: Over the median of 12.1 years of follow-up, we found 1259 incident cases of low eGFR among the study population. In this population, ideal and intermediate categories of body mass index (BMI) and blood pressure (BP) and only the ideal category of fasting plasma glucose (FPG) significantly decreased the risk of developing low eGFR; the corresponding HRs and (95% confidence intervals) were (0.87, 0.77-0.99), (0.84, 0.76-0.99), (0.79, 0.68-0.93), (0.70, 0.60-0.83) and (0.76, 0.64-0.91). Also, one additional ICVHM was associated with a reduced risk of low eGFR for the global (0.92, 0.88-0.97) and biological cardiovascular health (0.88, 0.82-0.93) in these participants. A sensitivity analysis using the interval-censoring approach demonstrated that our method is robust, and results remained essentially unchanged. In a subgroup population with dietary data (n = 2285), we did not find the beneficial impact of having intermediate/ideal categories of nutrition status compared to its poor one on incident low eGFR. CONCLUSION: We found a strong inverse association between having higher global ICVHM with incident low eGFR among the non-elderly Iranian population; the issue is mainly attributable to normal BP, BMI, and FPG levels.

Risk of recurrence at the time of withdrawal of short- or long-term methimazole therapy in patients with Graves' hyperthyroidism: a randomized trial and a risk-scoring model.

PURPOSE: In Graves' disease, administration of low-dose methimazole for more than 60 months induces higher remission rates compared with the conventional duration of 12-18 months. However, the risk of recurrence and its predictors beyond 48 months of drug withdrawal are not known. The aims of this study were to determine the risk of recurrence during 84 months after withdrawal of short- or long-term methimazole therapy and a risk stratification for recurrence of hyperthyroidism. METHODS: A total of 258 patients were treated with methimazole for a median of 18 months and randomized to discontinuation of the drug(conventional short-term group; n = 128) or continuation of the treatment up to 60-120 months(long-term group; n = 130). Patients were followed for 84 months after methimazole withdrawal. Cox proportional hazards modeling was performed to identify factors associated with relapse and develop a risk-scoring model at the time of discontinuing the treatment. RESULTS: Hyperthyroidism recurred in 67 of 120(56%) of conventionally-treated patients versus 20 of 118(17%) of those who received long-term methimazole treatment, p < 0.001. Age, sex, goiter grade, triiodothyronine, thyrotropin, and thyrotropin receptor antibodies were significant predictors of recurrence in both "conventional" and "long-term" groups but free thyroxine just in the "long-term" group. The risk-scoring model had a good discrimination power (optimism corrected c-index = 0.78,95%CI = 0.73-0.82) with a range of 0-14 and sensitivity of 86% and specificity of 62% at the risk-score of eight. CONCLUSION: A relapse-free state was achieved in 83% of patients with Graves' hyperthyroidism 84 months after cessation of long-term methimazole treatment which could be predicted by some significant predictors in a simple risk-scoring system.

Rapid decline of kidney function increases fracture risk in the general population: Insights from TLGS.

BACKGROUND: Although the association between Chronic Kidney Disease (CKD) and all-cause fractures was addressed in previous studies, the association between estimated glomerular filtration rate (eGFR) decline and fractures was poorly addressed. For the first time we examined the association between rapid kidney function decline (RKFD) and fracture incidence among Iranian general population. METHODS: In a Tehranian community-based cohort, RKFD was defined as a 30 % decline in eGFR over 2-3 years. Cox proportional hazards models, adjusted for age, sex, current eGFR, diabetes mellitus, hypertension, dyslipidemia, current smoking, obesity status, waist circumference, prevalent cardiovascular diseases, aspirin, steroid use, education level, and marital status, were used to examine the association of RKFD with different fracture outcomes. RESULTS: Among 5305 (3031 women) individuals aged ≥30 years, during the median follow-up of 9.62 years, 226 fracture events were observed. The multivariable hazard ratio of RKFD for any-fracture events, lower-extremity, and major osteoporotic fractures were 2.18 (95 % CI, 1.24-3.85), 2.32 (1.15-4.71), and 2.91 (1.29-6.58), respectively. These associations remained significant after accounting for the competing risk of death. The impact of RKFD on the development of incident all-cause fractures was not modified by gender [men: 2.64 (1.11-6.25) vs. women: 2.11 (1.00-4.47)] and according to current CKD status [without CKD: 2.34 (1.00-5.52) vs. with CKD: 2.59 (1.04-6.44)] (all P for interaction >0.5). CONCLUSIONS: RKFD can increase the incidence of fractures among general population, the issue that was equally important among non-CKD individuals, emphasizing the need for early identification and management in those with rapidly declining eGFR.

The association between metabolic syndrome and insulin resistance with risk of cardiovascular events in different states of cardiovascular health status.

AIMS/INTRODUCTION: The aim was to examine the joint effect of metabolic syndrome (MetS) and insulin resistance (IR) with ideal cardiovascular health (iCVH) status on incident cardiovascular diseases (CVDs). MATERIALS AND METHODS: The study included 6,240 Iranian adults ≥30 years, free of prior cardiovascular disease. Ideal cardiovascular health was determined based on American Heart Association's Life Simple 7. Metabolic syndrome was defined according to the Joint Interim Statement Criteria, and insulin resistance was defined as HOMA-IR ≥1.85 in women and ≥2.17 in men. Multivariable Cox proportional hazard ratios (HRs) were applied to examine the impact of metabolic syndrome, and insulin resistance at various levels of iCVH status. RESULTS: During the median follow-up of 14.0 years, 909 cases of cardiovascular disease occurred. Metabolic syndrome and insulin resistance were significantly associated with incident cardiovascular disease events. In the poor and intermediate status, metabolic syndrome increased cardiovascular disease events with HRs of 1.83 and 1.57, respectively; the corresponding values for insulin resistance in the mentioned categories were 1.91 and 1.25, respectively (P values < 0.05). In the intermediate and poor iCVH status, hypertriglyceridemia was linked to a 40% and 35% higher risk of cardiovascular disease, the corresponding values for low HDL-C was 20% and 60%, respectively (P values < 0.05). Although adding metabolic syndrome, its dyslipidemia and insulin resistance to iCVH status in both poor and intermediate status significantly improve the prediction of cardiovascular disease using net reclassification improvement (P values < 0.05), the value of C-index did not change. CONCLUSIONS: Metabolic syndrome and the dyslipidemia component had a negligible but significant improvement in the prediction of cardiovascular disease among individuals with non-optimal iCVH status.

Association of LDL-cholesterol subfractions with cardiovascular disorders: a systematic review.

BACKGROUND: Cardiovascular disorders (CVDs) are the leading cause of death worldwide. This study aimed to evaluate the association between low-density lipoprotein (LDL) subfractions and cardiovascular disorders. METHODS: To ensure the rigor of the systematic review, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used. For this systematic review, a comprehensive search strategy was performed in important databases including PubMed, Scopus, Embase, International Statistical Institute (ISI) Web of Science, and google scholar from 2009 to February 2021. The following terms were used for systematic search: low-density lipoprotein, LDL, subfractions, subclasses, nuclear magnetic resonance, NMR, chromatography, high-pressure liquid, HPLC, cardiovascular disease, cerebrovascular, and peripheral vascular disease. Also, for evaluating the risk of bias, the Newcastle-Ottawa scale was employed. RESULTS: At the end of the search process, 33 articles were included in this study. The results of most of the evaluated studies revealed that a higher LDL particle number was consistently associated with increased risk for cardiovascular disease, independent of other lipid measurements. Also, small dense LDL was associated with an increased risk of CVDs. There was no association between LDL subfraction and CVDs in a small number of studies. CONCLUSIONS: Overall, it seems that the evaluation of LDL subclasses can be used as a very suitable biomarker for the assessment and diagnosis of cardiovascular diseases. However, further studies are required to identify the mechanisms involved.

Diagnostic dilemma in a patient with history of medullary thyroid carcinoma and abnormal serum liver enzymes; a case report with six years follow up.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor that originates from parafollicular C-cells. Calcitonin (Ctn) and carcinoembryonic antigen (CEA) are useful biomarkers for monitoring MTC cases. CASE PRESENTATION: Here, we describe a 48-year-old woman, who presented in 2014 with bilateral thyroid nodules. Report of fine needle aspiration was suspicious for MTC; initial laboratory evaluation showed serum Ctn level of 1567 pg/mL. After excluding type 2 multiple endocrine neoplasia syndrome clinically, total thyroidectomy and neck lymph node dissection were performed. The final histopathological diagnosis was right lobe MTC with neither vascular invasion nor lymph node involvement. On regular follow-up visits, Ctn and CEA levels have been undetectable, and repeated cervical ultrasonographic exams were unremarkable from 2014 to 2021. As liver enzymes became elevated in 2016, the patient was further evaluated by a gastroenterologist. Abdominopelvic ultrasonography revealed a coarse echo pattern of the liver parenchyma with normal bile ducts. A liver fibroscan showed a low fibrosis score (7kPa). The patient was recommended to use ursodeoxycholic acid. According to the progressive rise of liver enzymes with a cholestatic pattern in October 2020, a liver biopsy was performed that showed tiny nests of neuroendocrine-like cells with a background of primary biliary cholangitis (PBC). Immunohistochemical stainings were positive for chromogranin A (CgA), and synaptophysin and negative for Ctn, CEA, and thyroglobulin. Further imaging investigations did not reveal any site of a neuroendocrine tumor in the body. Considering normal physical exam, imaging findings, as well as normal serum levels of Ctn, CEA, CgA, and procalcitonin, the patient was managed as a PBC. CONCLUSION: In follow-up of a patient with MTC, we reported progressively increased liver enzymes with a cholestatic pattern. Liver biopsy revealed nests of neuroendocrine-like cells with a background of PBC, the findings that might suggest acquiring neuroendocrine phenotype by proliferating cholangiocytes.

Pharmacodynamic and pharmacokinetic properties of the combined preparation of levothyroxine plus sustained- release liothyronine; a randomized controlled clinical trial.

BACKGROUND: Understanding pharmacokinetics (PK) and pharmacodynamics (PD) of the sustained-release liothyronine (SR-T3) is of paramount importance to design therapeutic regimens that are able to simulate normal thyroid hormone secretion while avoiding excursions in the T3 serum concentration. Here, we designed a parallel randomized clinical trial to characterize the PK and PD of the combined preparations of LT4 + SR-T3 in hypothyroid patients. METHODS: Radioiodine-treated hypothyroid patients over 20 years of age, who attained euthyroidism with LT4 monotherapy were recruited from the Endocrine Clinic in Tehran. The patients were allocated to two intervention groups of group A: 9 µg SR-T3 plus 68.5 µg LT4 (ratio 1:7.5) and group B: 12 µg SR-T3 plus 60 µg LT4 (ratio 1:5), and a control group with LT4 monotherapy. For PD study, thyroid hormone profile was evaluated at 8 and 12 weeks intervals after intervention. To assess PK properties of SR-T3, T3-Cmax, T3-Tmax and AUC0 - 24 were calculated at the last visit. RESULTS: Serum T4 and FT4 concentrations decreased in the intervention groups after 3 months. No significant difference was observed in serum T3 and FT3 concentrations before and after intervention. Serum T3/T4 ratio increased significantly in the intervention groups after intervention, with the highest increase in group B from 8.6 ± 2.03 at baseline to 12.2 ± 1.6. Comparison of trial groups at follow-up showed no differences in serum TSH, T4, T3 and T3/T4 concentrations among different groups. During 24 h, minimal variation in serum T3 concentration was observed in group B with mean ∆T3 of 15.4 ± 10.5 ng/dl. T3-Tmax, T3-Cmax and AUC0 - 24 in the combined sustained-release preparation were 4.38 ± 1.1 h., 101.0 ± 5.7 ng/dl and 2257 ± 110 ng.h/L, respectively which were significantly different from the control group. CONCLUSION: Combined treatment with a single dose of SR-T3 plus LT4 is associated with increased serum T3/T4 ratio and minimal excursions in serum T3 concentration during 24 h; however, it was not significantly different from the control group. To incorporate sustained-release T3 in the management of hypothyroidism, a higher ratio of SR-T3 to LT4 than that of the previously recommended by the international organizations is suggested. IRCT REGISTRATION NUMBER: IRCT20100922004794N13. https://www.irct.ir/search/result?query=IRCT20100922004794N13 . Registration date: 08/12/2021.

Prevalence and metabolic determinants of abnormal alanine aminotransferase: A cross-sectional study of Iranian adults, 2018-2022.

BACKGROUND: Alanine aminotransferase (ALT) is an enzyme whose activity became the principal biomarker for liver disease. In the current study, we aimed to determine the prevalence of abnormal ALT, as a surrogate of nonalcoholic fatty liver disease (NAFLD) and its associated determinants using different criteria among Tehranian subjects between 2018 and 2022. METHODS: This is a cross-sectional study on 5676 Tehranian individuals aged 20-70 years. The weighted prevalence of abnormal ALT was calculated using both the National Health and Nutrition Examination Survey in the United States (US-NHANCE; ALT ≥30 U/L for females and ≥40 U/L for males) and the American College of Gastroenterology (ACG) guideline (ALT >25 U/L for females, and >33 U/L for males) thresholds. Moreover, uni/multivariable logistic regression analysis was performed to find the determinants of abnormal ALT. RESULTS: The weighted prevalence of abnormal ALT was 12.8% (7.6% females and 18% males) and 22.5% (17.7% females and 27.3% males) based on US-NHANCE and ACG criteria, respectively. Our results showed every decade increase in age decreased the risk of abnormal ALT by 32%. We also found that generally male gender, being overweight/obese, central adiposity, TG ≥6.9 mmol/L, non-HDL-C ≥3.37 mmol/L, lipid-lowering medications, pre-diabetes/T2DM were associated with abnormal ALT using different cutoff points. Moreover, among men resting tachycardia (≥90 beats per min), hypertension, and females past-smoker were also found as other determinants of abnormal ALT. CONCLUSION: High prevalence of abnormal ALT among non-elderly Iranian adults, especially among men, necessitates immediate multifaceted strategies by policymakers to prevent potential complications caused by NAFLD.

Gender differences in the impact of 3-year status changes of metabolic syndrome and its components on incident type 2 diabetes mellitus: a decade of follow-up in the Tehran Lipid and Glucose Study.

Background: The aim of this study was to examine the gender differences in the association between status changes of metabolic syndrome (MetS) and its components, using Joint Interim Statement (JIS) criteria, with the risk of type 2 diabetes mellitus (T2DM) among an urban population. Methods: The study included 4,463 Iranian adult participants (2,549 women) aged ≥20 years. Based on status changes of MetS and its components during 3 years, subjects were categorized into four groups: MetS-free (reference), MetS-developed, MetS-recovery, and MetS-stable. A similar categorization was applied to MetS components. Multivariable Cox regression models were used for estimating hazard ratios (HRs) and women-to-men ratios of HRs (RHRs). Results: During a median follow-up of 9.3 years, 625 T2DM events (351 women) occurred. Compared with the reference, the HRs of the MetS-developed, -recovery, and -stable groups among men for incident T2DM were 2.90, 2.60, and 4.92; the corresponding values for women were 2.73, 2.88, and 5.21, respectively (all p-values < 0.01), without significant gender difference in these relationships. In both genders, the fasting plasma glucose (FPG) component, regardless of the change in status, was strongly and significantly associated with incident T2DM with HRs ranging from 2.49 to 9.42; a similar association was also found for high waist circumference (WC)-recovery and -stable groups, with HRs ranging from 1.58 to 2.85 (p-values ≤ 0.05). Regarding gender differences, the development and persistence of high blood pressure (BP) status exposed men to greater T2DM risk than women with women-to-men RHRs of 0.43 (0.26-0.72) and 0.58 (0.39-0.86), respectively. Moreover, stable low levels of high-density lipoprotein cholesterol (HDL-C) and high triglyceride (TG) levels conferred higher T2DM risk in women than in men, with women-to-men RHRs of 1.67 (0.98-2.86) and 1.44 (0.98-2.14), respectively (both p-values = 0.06). Conclusion: Among Tehranian adults, in both genders, all status changes of MetS, even those recovered from MetS, have a higher risk of T2DM compared to those who never had MetS. Also, all statuses of high FPG, in addition to recovered and stable high WC, were strongly associated with T2DM risk. Specifically, men with stable or developed high BP and women with stable dyslipidemic status were at differentially increased risk of incident T2DM.

Novel Insight into the Effect of Probiotics in the Regulation of the Most Important Pathways Involved in the Pathogenesis of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is considered one of the most common disorders worldwide. Although several treatment modalities have been developed, the existing interventions have not yielded the desired results. Therefore, researchers have focused on finding treatment choices with low toxicity and few adverse effects that could control T2DM efficiently. Various types of research on the role of gut microbiota in developing T2DM and its related complications have led to the growing interest in probiotic supplementation. Several properties make these organisms unique in terms of human health, including their low cost, high reliability, and good safety profile. Emerging evidence has demonstrated that three of the most important signaling pathways, including nuclear factor kappa B (NF-κB), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and nuclear factor erythroid 2-related factor 2 (Nrf2), which involved in the pathogenesis of T2DM, play key functions in the effects of probiotics on this disease. Hence, we will focus on the clinical applications of probiotics in the management of T2DM. Then, we will also discuss the roles of the involvement of various probiotics in the regulation of the most important signaling pathways (NF-κB, PI3K/Akt, and Nrf2) involved in the pathogenesis of T2DM.

Cohort profile update: Tehran cardiometabolic genetic study.

The Tehran cardiometabolic genetic study (TCGS) is a large population-based cohort study that conducts periodic follow-ups. TCGS has created a comprehensive database comprising 20,367 participants born between 1911 and 2015 selected from four main ongoing studies in a family-based longitudinal framework. The study's primary goal is to identify the potential targets for prevention and intervention for non-communicable diseases that may develop in mid-life and late life. TCGS cohort focuses on cardiovascular, endocrine, metabolic abnormalities, cancers, and some inherited diseases. Since 2017, the TCGS cohort has augmented by encoding all health-related complications, including hospitalization outcomes and self-reports according to ICD11 coding, and verifying consanguineous marriage using genetic markers. This research provides an update on the rationale and design of the study, summarizes its findings, and outlines the objectives for precision medicine.

Are HOMA-IR and HOMA-B good predictors for diabetes and pre-diabetes subtypes?

BACKGROUND: To investigate the association between the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Homeostasis Model Assessment of Beta-cell function (HOMA-B) with the incidence of diabetes and pre-diabetes subtypes. METHODS: A total of 3101 normoglycemic people aged 20-70 years were included in the 6-year follow-up study. Multinomial logistic regression was used to calculate the incidence possibility of isolated Impaired Fasting Glucose (iIFG), isolated Impaired Glucose Tolerance (iIGT), Combined impaired fasting glucose & impaired glucose tolerance (CGI), and Diabetes Mellitus (DM) per standard deviation (SD) increment in HOMA-IR and HOMA-B in the crude and multivariable model. RESULTS: In the multivariate model, an increase in one SD change in HOMA-IR was associated with a 43, 42, 75, and 92% increased risk of iIFG, iIGT, CGI, and DM, respectively. There was a positive correlation between the increase in HOMA-B and the incidence of iIGT; however, after adjusting the results for metabolic syndrome components, it was inversely correlated with the incidence of iIFG [Odds Ratio = 0.86(0.75-0.99)]. CONCLUSIONS: HOMA-IR is positively correlated with diabetes and pre-diabetes subtypes' incidence, and HOMA-B is inversely correlated with the incidence of iIFG but positively correlated with iIGT incidence. However, none of these alone is a good criterion for predicting diabetes and pre-diabetes.

Association of triglycerides to high-density lipoprotein cholesterol ratio to identify future prediabetes and type 2 diabetes mellitus: over one-decade follow-up in the Iranian population.

BACKGROUND: To determine the association between triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) for identifying subjects at risk of incident prediabetes and type 2 diabetes mellitus (T2DM). METHODS: In 5064 subjects (men = 2247) aged ≥ 20 years, using Cox proportional hazards regression analyses, the associations of TG/HDL-C with incident prediabetes and T2DM were examined among normoglycemic men and women. Furthermore, the association of this lipid ratio with incident T2DM was also assessed among prediabetic subjects (n = 1414). The multivariable analyses were adjusted for age, body mass index, waist-to-height ratio, wrist circumference, systolic blood pressure, family history of T2DM, education level, history of cardiovascular diseases, and fasting plasma glucose (FPG). RESULTS: During a median follow-up of 11.2 years, 2140 new cases of prediabetes (men = 1070) and 360 incident T2DM (men = 152) were identified among normoglycemic individuals. In the prediabetic population, 574 new cases of T2DM (men = 252) were developed. Among the whole population, compared to the first quartile (reference), higher quartiles of TG/HDL-C were significantly associated with higher risks of incident prediabetes and T2DM among normoglycemic individuals and incident T2DM in the prediabetic population (all P for trend < 0.001). The corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) for the fourth quartiles were 1.37(1.20-1.58), 1.92(1.34-2.75), and 1.57(1.22-2.01), respectively. The sex-stratified analyses demonstrated similar significant associations in both sexes; however, TG/HDL-C lost its association with incident T2DM among prediabetic men. Among the normoglycemic population, 1 unit increase in TG/HDL-C was significantly associated with incident prediabetes and T2DM [1.02(1.00-1.03) and 1.06(1.03-1.08), respectively]. The corresponding value for incident T2DM in prediabetic individuals was 1.01(1.00-1.03). In a subgroup population having insulin data (n = 2897), the associations between TG/HDL-C and incident prediabetes and T2DM among normoglycemic individuals generally persisted even after replacing FPG with an index of insulin resistance (IR), i.e., homeostasis model assessment of IR (HOMA-IR) in the adjusted model. CONCLUSIONS: In conclusion, in the normoglycemic population, the increasing value of TG/HDL-C was unfavorably associated with incident prediabetes and T2DM, especially among women. Similarly, TG/HDL-C was associated with incident T2DM in prediabetic individuals. Generally, we found that the correlation between TG/HDL-C and different states of dysglycemia is independent of HOMA-IR.

Synthesis of Biocompatible Nanoporous ZIF-8-Gum Arabic as a New Carrier for the Targeted Delivery of Curcumin.

The synthesis of biocompatible nanoporous zeolitic imidazolate framework-8 (ZIF-8) was performed in the presence of gum arabic (GA), curcumin (CCM), and folic acid (FA) as a template for the biomineralization process, a natural anticancer component, and a targeting agent, respectively. The synthesis of ZIF-8-GA-CCM-FA was completed in a single step at room temperature in aqueous media with a minimum amount of ethanol at a linker/metal molar ratio of 10. FA was dissolved by the alkaline medium produced by a 2-methyl imidazolium (HmIm) linker without using any toxic organic solvent or additional conjugation agents. The FA-modified carrier can target the folate receptors on Hela cells. To the best of our knowledge, this is the first report about the one-pot encapsulation of CCM and FA in a biocompatible ZIF-8-GA framework in a green solvent. This method enables high CCM loading in the ZIF-8-GA framework structure (ca. 90%) at a short time of 15 min. The effect of CCM concentration was investigated on the size, morphology, and crystallinity of the synthesized structures. The products were characterized with field emission scanning electron microscopy, Brunauer-Emmett-Teller surface area analysis, X-ray diffraction, Fourier transform infrared, and UV-vis spectroscopy techniques. The release rate of CCM from ZIF-8-GA-CCM-FA was studied at different pH values. In vitro drug release of CCM was higher in the acidic medium (pH 5.5, 6.5) compared to physiological pH (7.4). The cytotoxicity of ZIF-8-GA, ZIF-8-GA-CCM, and ZIF-8-GA-CCM-FA structures was evaluated by the standard 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on the three cell lines (fibroblast (normal cell), Hela (FR-positive), and A549 (FR-negative). These results suggested that the ZIF-8-GA-CCM-FA framework can have a promising effect on the targeted treatment of cancer cells.

Sex-specific Trajectories of Insulin Resistance Markers and Reduced Renal Function During 18 Years of Follow-up: TLGS.

CONTEXT: The evidence suggest that insulin resistance (IR) complicates chronic kidney disease (CKD); however, the longitudinal association of IR with development of CKD is unknown. OBJECTIVE: This work aimed to investigate the association between the dynamic course of insulin resistance and CKD. METHODS: In the longitudinal, population-based Tehran Lipid and Glucose Study, 3071 eligible participants aged 20 years or older were followed for 18 years at 3-year intervals. Homeostatic model assessment of insulin resistance (HOMA-IR) and clinical surrogate markers of IR, including triglyceride-glucose index (TyG), visceral adiposity index (VAI), and lipid accumulation product (LAP), were calculated. Using latent variable mixture modeling, sex-specific trajectories were plotted for each IR marker. Trajectory group association of the IR markers with CKD was determined using the multivariable Cox proportional-hazards regression model. RESULTS: For HOMA-IR, 2 distinct trajectory patterns (stable and increasing), and for TyG, VAI, and LAP, 3 trajectories (low, moderate, and high) were identified. The participants with an increasing HOMA-IR trajectory had a significantly increased risk of CKD in men (hazard ratio [HR]: 1.72; 95% CI, 1.06-2.79) and women (HR: 1.37; 95% CI, 1.00-1.89) after adjusting for confounding variables. The high TyG and VAI trajectory classes were associated with a higher risk of CKD than the low TyG and VAI trajectory classes both in men (TyG: HR: 1.97; 95% CI, 1.12-3.46; VAI: HR:1.66; 95% CI, 1.06-2.62) and women (TyG: HR: 1.50; 95% CI, 1.06-2.12; VAI: HR:1.66; 95% CI, 1.20-2.31). In contrast, the high LAP (HR: 3.38; 95% CI, 2.08-5.48) trajectory was associated with incident CKD only in women. CONCLUSION: An increasing trend of HOMA-IR is associated with a higher risk of CKD in men and women. Among clinical IR surrogate markers, abnormal trajectory patterns of LAP in women and TyG and VAI in both sexes are associated with a higher risk of CKD.

Mean versus variability of lipid measurements over 6 years and incident cardiovascular events: More than a decade follow-up.

Background: Lipid variability (LV) has emerged as a contributor to the incidence of cardiovascular diseases (CVD), even after considering the effect of mean lipid levels. However, these associations have not been examined among people in the Middle East and North Africa (MENA) region. We aimed to investigate the association of 6-year mean lipid levels versus lipid variability with the risk of CVD among an Iranian population. Methods: A total of 3,700 Iranian adults aged ≥ 30 years, with 3 lipid profile measurements, were followed up for incident CVD until March 2018. Lipid variability was measured as standard deviation (SD), coefficient of variation (CV), average real variability (ARV), and variability independent of mean (VIM). The effects of mean lipid levels and LV on CVD risk were assessed using multivariate Cox proportional hazard models. Results: During a median 14.5-year follow-up, 349 cases of CVD were recorded. Each 1-SD increase in the mean levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), TC/high-density lipoprotein cholesterol (HDL-C), and non-HDL-C increased the risk of CVD by about 26-29%; for HDL-C, the risk was significantly lower by 12% (all p-values < 0.05); these associations resisted after adjustment for their different LV indices. Considering LV, each 1-SD increment in SD and ARV variability indices for TC and TC/HDL-C increased the risk of CVD by about 10%; however, these associations reached null after further adjustment for their mean values. The effect of TC/HDL-C variability (measured as SD) and mean lipid levels, except for LDL-C, on CVD risk was generally more pronounced in the non-elderly population. Conclusion: Six-year mean lipid levels were associated with an increased future risk of incident CVD, whereas LV were not. Our findings highlight the importance of achieving normal lipid levels over time, but not necessarily consistent, for averting adverse clinical outcomes.

Risk of type 2 diabetes and KCNJ11 gene polymorphisms: a nested case-control study and meta-analysis.

Due to the central role in insulin secretion, the potassium inwardly-rectifying channel subfamily J member 11 (KCNJ11) gene is one of the essential genes for type 2 diabetes (T2D) predisposition. However, the relevance of this gene to T2D development is not consistent among diverse populations. In the current study, we aim to capture the possible association of common KCNJ11 variants across Iranian adults, followed by a meta-analysis. We found that the tested variants of KCNJ11 have not contributed to T2D incidence in Iranian adults, consistent with similar insulin secretion levels among individuals with different genotypes. The integration of our results with 72 eligible published case-control studies (41,372 cases and 47,570 controls) as a meta-analysis demonstrated rs5219 and rs5215 are significantly associated with the increased T2D susceptibility under different genetic models. Nevertheless, the stratified analysis according to ethnicity showed rs5219 is involved in the T2D risk among disparate populations, including American, East Asian, European, and Greater Middle Eastern, but not South Asian. Additionally, the meta-regression analysis demonstrated that the sample size of both case and control groups was significantly associated with the magnitude of pooled genetic effect size. The present study can expand our knowledge about the KCNJ11 common variant's contributions to T2D incidence, which is valuable for designing SNP-based panels for potential clinical applications in precision medicine. It also highlights the importance of similar sample sizes for avoiding high heterogeneity and conducting a more precise meta-analysis.

The relationship between glucose intolerance status and risk of hospitalization during two decades of follow-up: Tehran lipid and glucose study.

OBJECTIVE: To assess the relationship between glucose intolerance statuses at baseline defined as normal glucose tolerance (NGT), pre-diabetes, newly diagnosed (NDM) and known diabetes mellitus (KDM) and all-cause hospitalization among Iranian men and women during 20 years of follow-up. RESEARCH DESIGN AND METHODS: This study included 8,014 individuals (3,836 men) ≥30 years from the cohort of Tehran Lipid and Glucose Study. Incidence rate ratios (IRRs) and (95% confidence interval (95% CI) for three groups of pre-diabetes, NDM and KDM was estimated using the Negative Binomial regression model, considering NGT group as reference group. Regression models were adjusted for age, body mass index, hypertension, chronic kidney disease, and cardiovascular disease (CVD). RESULTS: Among men, compared with NGT group, those with pre-diabetes, NDM and KDM had higher incidence rate for hospitalization, with IRRs (95% CI) of 1.08 (0.96-1.20), 1.38 (1.20-1.57) and 1.96 (1.66-2.26), respectively, after adjusting for confounders. The corresponding values were 1.07 (0.96-1.17), 1.40 (1.21-1.59) and 2.07 (1.72-2.42) for women. Men with diabetes, generally had a higher rate of hospitalization for CVD rather than their female counterparts (IRRs: 1.46; 1.17-1.74). In patients with diabetes, the most common causes of hospitalization were macrovascular complications (i.e. coronary heart disease and stroke). Moreover, among the individuals with diabetes, those with poor glycaemic control (fasting plasma glucose (FPG) >10 mmol/l) had 39% higher rate of hospitalization than those with fair glycaemic control (FPG <10 mmol/l) (1.39; 1.12-1.65), adjusted for confounders. CONCLUSION: Pre-diabetes, NDM, and KDM were associated with increased hospitalization rates during long-term follow-up. Interventions such as lifestyle modification or pharmacological therapies aiming to slow down the pre-diabetes and fair control of diabetes might potentially decrease the rate of hospitalization.Key messagesNDM and KDM status both increased rate of all-cause hospitalization.CVD and T2DM complication were the most common cause of hospitalization among patients with diabetes.Hospitalization due to recurrent CHD was significantly higher in men with diabetes than their female counterparts.

The association between low-density and non-high-density lipoprotein cholesterol with incident cardiovascular disease among low-risk Iranians during 2 decades follow-up.

INTRODUCTION: To examine the associations between low-density and non-high-density lipoprotein cholesterol (LDL-C and non-HDL-C, respectively) with incident cardiovascular disease (CVD) in low-risk subjects. MATERIALS AND METHODS: From a total of 2467 non-diabetic aged 40-70 years, free of CVD with LDL-C range 1.81 ≤ LDL-C < 4.91 mmol/L with 10-year atherosclerotic cardiovascular disease (ASCVD) risk < 7.5 %, the associations of LDL-C and non-HDL-C with incident CVD were assessed using multivariable Cox proportional hazard regression analyses adjusted for age, sex, body mass index, waist circumference, HDL-C, triglycerides, chronic kidney disease, current smoking, hypertension, and family history of CVD. RESULTS: During a median follow-up of 18 years, 559 CVD events occurred. Compared to the LDL-C < 2.59 mmol/L as reference, the categories of 2.59 ≤ LDL-C < 3.36, 3.36 ≤ LDL-C < 4.14, and ≥ 4.14 mmol/L were associated with hazard ratios (95 % confidence intervals) of 1.39(0.89-2.18), 1.72(1.11-2.68), and 2.19(1.36-3.51) for incident CVD (P for trend <0.0001), respectively. Compared to the non-HDL-C < 3.36 as reference, the categories of 3.36 ≤ non-HDL-C < 4.14, 4.14 ≤ non-HDL-C < 4.91, and ≥ 4.91 mmol/L were associated with 1.48(0.96-2.30), 1.37(0.89-2.16), and 2.15(1.36-3.39) higher risk for incident CVD (P for trend = 0.001), respectively. Among those with ASCVD score <5 % (n = 2070), even the 2.59 ≤ LDL-C < 3.36 mmol/L increased the risk for CVD [1.73(1.01-2.97)]. Results for non-HDL-C categories remained unchanged compared to those with ASCVD risk < 7.5%. CONCLUSIONS: Among Iranian individuals with ASCVD risk as little as < 5 %, LDL-C ≥ 2.59 mmol/L and non-HDL-C ≥ 3.36 mmol/L, independent of traditional risk factors, were associated with a significantly higher risk of incident CVD, individuals that might potentially benefit from pharmacological therapy.