Serum Magnesium Levels Are Negatively Associated with Obesity and Abdominal Obesity in Type 2 Diabetes Mellitus: A Real-World Study.

Background: There remains controversy over the relationship between serum magnesium levels and obesity in type 2 diabetes mellitus (T2DM). Therefore, the aim of this study was to assess whether there is any association of serum magnesium levels with obesity and abdominal obesity in T2DM. Methods: This cross-sectional, real-world study was conducted in 8,010 patients with T2DM, which were stratified into quintiles according to serum magnesium levels. The clinical characteristics and the prevalence of obesity and abdominal obesity were compared across serum magnesium quintiles in T2DM. Regression analyses were used to evaluate the relationship of serum magnesium with obesity and abdominal obesity in T2DM (clinical trial registration number: ChiCTR1800015893). Results: After adjustment for age, sex, and duration of diabetes, the prevalence of obesity and abdominal obesity was significantly declined across magnesium quintiles (obesity: 51.3%, 50.8%, 48.9%, 45.3%, and 43.8%, respectively, P<0.001 for trend; abdominal obesity: 71.5%, 70.5%, 68.2%, 66.4%, and 64.5%, respectively, P=0.001 for trend). After controlling for confounders, there were clearly negative associations of serum magnesium levels and quintiles with obesity and abdominal obesity in T2DM. Moreover, C-reactive protein partly mediates the effect of serum magnesium on obesity and abdominal obesity (P=0.016 and P=0.004, respectively). Conclusion: The significantly negative relationship between serum magnesium and the risk of obesity and abdominal obesity was observed in T2DM. Furthermore, the independently negative association of serum magnesium with obesity may be explained by its anti-inflammatory functions. Serum magnesium levels may be applied to assess the risk of obesity and abdominal obesity in T2DM.

High-normal unconjugated bilirubin is associated with decreased risk of chronic kidney disease in type 2 diabetes: A real-world study.

OBJECTIVE: To investigate the association between serum unconjugated bilirubin (UCB) within normal limits and chronic kidney disease (CKD) in T2DM patients. METHOD: This cross-sectional, real-world study was performed in 8661 hospitalised T2DM patients. The subjects were stratified into quintiles based on serum UCB levels. The clinical characteristics and CKD prevalence were compared among the UCB quantile groups. The associations of serum UCB levels and quintiles with CKD were also analysed by binary logistic regression. RESULTS: After controlling for age, sex, and diabetes duration (DD), the CKD prevalence (20.4%, 12.2%, 10.6%, 8.3%, and 6.4% for the first, second, third, fourth, and fifth quintiles, respectively, p < 0.001 for trend) was significantly decreased across the serum UCB quintiles. The fully adjusted regression model showed negative associations of serum UCB levels (OR: 0.660, 95% CI: 0.585-0.744; p < 0.001 for trend) and quintiles (p < 0.001) with the presence of CKD. Compared with the subjects in the lowest UCB quintile, the risk of CKD decreased by 36.2%, 54.3%, 53.8%, and 62.1%, respectively, in those from the second to the highest UCB quintile. Additionally, C-reactive protein (CRP) levels were significantly higher in the subjects with CKD than in those without CKD (p < 0.001), and significantly decreased across the UCB quintiles (p < 0.001 for trend). CONCLUSIONS: Serum UCB levels within the normal range were significantly and negatively linked to CKD in T2DM patients. High-normal UCB may be an independent protective factor for CKD by its antioxidant and the following anti-inflammatory activities through its signalling activity, which was indicated by clearly decreased CRP levels across the UCB quintiles.

Decreased Serum Osteocalcin is an Independent Risk Factor for Metabolic Dysfunction-Associated Fatty Liver Disease in Type 2 Diabetes.

Purpose: The association between serum osteocalcin (OCN) levels and metabolic dysfunction-associated fatty liver disease (MAFLD) is still controversial. Moreover, few studies have explored their relationship in type 2 diabetes mellitus (T2DM) patients so far. The present study aimed to investigate the association of serum OCN levels with MAFLD in Chinese T2DM patients. Methods: This cross-sectional, real-world study included 1889 Chinese T2DM inpatients. MAFLD was diagnosed by abdominal ultrasonography. Participants were divided into four groups according to serum OCN quartiles, among which the clinical characteristics were compared. The association of serum OCN levels with the presence of MAFLD was also analyzed in subjects. Results: After controlling for sex, age, and diabetes duration, the prevalence of MAFLD significantly decreased across the serum OCN quartiles (55.3%, 52.0%, 48.6%, and 42.1% for the first, second, third, and fourth quartiles, respectively, P < 0.001 for trend). A fully adjusted multiple logistic regression analysis showed that serum OCN levels were independently and negatively associated with the presence of MAFLD in T2DM patients (odds ratio, 0.832; 95% confidence interval, 0.719-0.962; P = 0.013). Furthermore, there were significant decreases in HOMA-IR (P = 0.001 for trend) and C-reactive protein (P < 0.001 for trend) levels across the serum OCN quartiles after controlling for sex, age, and diabetes duration. Conclusion: Serum OCN levels were independently and negatively associated with the presence of MAFLD in Chinese T2DM patients, partially due to the improvement of insulin resistance and inflammation mediated by OCN. Serum OCN may be used as a biomarker to assess the risk of MAFLD in T2DM patients.

GA/HbA1c ratio is a simple and practical indicator to evaluate the risk of metabolic dysfunction-associated fatty liver disease in type 2 diabetes: an observational study.

BACKGROUND: It is still debatable whether glycated albumin/glycated hemoglobin A1C (GA/HbA1C) ratio is associated with metabolic dysfunction-associated fatty liver disease (MAFLD), and few studies have been conducted in type 2 diabetes mellitus (T2DM). Therefore, we aimed to investigate the association between GA/HbA1C ratio and MAFLD and to evaluate whether GA/HbA1C ratio can be used an indicator of MAFLD in Chinese patients with T2DM. METHODS: This cross-sectional study consisted of 7117 T2DM patients including 3296 men and 3821 women from real-world settings. Abdominal ultrasonography was performed to diagnose MAFLD. In addition to comparing the clinical characteristics among the GA/HbA1C ratio quartile groups, we also investigated the associations of GA/HbA1C ratio and quartiles with MAFLD in T2DM subjects. RESULTS: There was a significantly decreased trend in the MAFLD prevalence across the GA/HbA1C ratio quartiles (56.3%, 47.4%, 37.8%, and 35.6% for the first, second, third, and fourth quartile, respectively, P < 0.001 for trend) after adjusting for gender, age, and diabetes duration. Fully adjusted Binary logistic regression indicated that both GA/HbA1C ratio (OR: 0.575, 95% CI: 0.471 to 0.702, P < 0.001) and quartiles (P < 0.001 for trend) were inversely associated with the presence of MAFLD among T2DM patients. Additionally, HOMA2-IR values were clearly increased in the T2DM subjects with MAFLD compared with those without MAFLD (P < 0.001), and markedly increased from the highest to the lowest GA/HbA1C ratio quartile (P < 0.001 for trend). CONCLUSIONS: GA/HbA1C ratio is closely and negatively associated with MAFLD in T2DM subjects, which may attribute to that GA/HbA1C ratio reflects the degree of insulin resistance. GA/HbA1C ratio may act as a simple and practical indicator to evaluate the risk of MAFLD in T2DM.

Waist-to-height ratio is a simple and practical alternative to waist circumference to diagnose metabolic syndrome in type 2 diabetes.

Background: As an indicator of abdominal obesity, waist circumference (WC) varied with race and gender in diagnosing metabolic syndrome (MetS). Therefore, it is clinically important to find an alternative indicator of abdominal obesity independent of these factors to diagnose MetS. Our aims were to evaluate the association between waist-to-height ratio (WHtR) and MetS and further determine whether WHtR could be used as a simple and practical alternative to WC to diagnose MetS in patients with type 2 diabetes mellitus (T2DM). Methods: This cross-sectional, real-world study recruited 8488 hospitalized T2DM patients including 3719 women (43.8%) aged from 18 to 94 years and 4769 men (56.2%) aged from 18 to 91 years. A WHtR cut-off of 0.52 was used to diagnose MetS in both men and women T2DM patients based on our previous study. The association of WHtR with MetS in T2DM patients was analyzed by binary logistic regression. The consistency of two diagnostic criteria for MetS according to WC and WHtR was determined by Kappa test. Results: The prevalence of MetS according to WHtR was 79.4% in women and 68.6% in men T2DM patients, which was very close to the prevalence of MetS according to WC in both women (82.6%) and men (68.3%). The prevalence of MetS diagnosed by WC in both men and women with WHtR ≥ 0.52 was significantly higher than in those with WHtR < 0.52 after adjustment for age and duration of diabetes (89.2 vs. 38.7% for men; 92.8 vs. 57.4% for women; respectively, all p < 0.001). Binary logistic regression analysis displayed that after adjusting for confounding factors, WHtR was significantly associated with the presence of MetS in both men and women (men: OR = 4.821, 95% CI: 3.949-5.885; women: OR = 3.096, 95% CI: 2.484-3.860; respectively, all p < 0.001). Kappa test revealed that there was an excellent consistency between the diagnosis of MetS based on WC and on WHtR in T2DM patients (men: kappa value = 0.929, 95% CI: 0.918-0.940; women: kappa value = 0.874, 95% CI: 0.854-0.894; total: kappa value = 0.911, 95% CI: 0.901-0.921; respectively, all p < 0.001). Conclusion: WHtR is independently associated with the presence of MetS and can be used as a simple and practical alternative to WC to diagnose MetS regardless of gender in T2DM patients.

Serum iron is closely associated with metabolic dysfunction-associated fatty liver disease in type 2 diabetes: A real-world study.

Aims: There is still a debate about the relationship between serum iron and metabolic dysfunction-associated fatty liver disease (MAFLD). Furthermore, few relevant studies were conducted in type 2 diabetes mellitus (T2DM). Therefore, this study aimed to explore the association of serum iron levels with MAFLD in Chinese patients with T2DM. Methods: This cross-sectional, real-world study consisted of 1,467 Chinese T2DM patients. MAFLD was diagnosed by abdominal ultrasonography. Based on serum iron quartiles, the patients were classified into four groups. Clinical characteristics were compared among the four groups, and binary logistic analyses were used to assess the associations of serum iron levels and quartiles with the presence of MAFLD in T2DM. Results: After adjusting for gender, age, and diabetes duration, significantly higher prevalence of MAFLD was found in the second (45.7%), third (45.2%), and fourth (47.0%) serum iron quartiles than in the first quartiles (26.8%), with the highest MAFLD prevalence in the fourth quartile (p < 0.001 for trend). Moreover, increased HOMA2-IR (p = 0.003 for trend) and decreased HOMA2-S (p = 0.003 for trend) were observed across the serum iron quartiles. Fully adjusted binary logistic regression analyses indicated that both increased serum iron levels (OR: 1.725, 95% CI: 1.427 to 2.085, p < 0.001) and quartiles (p < 0.001 for trend) were still closely associated with the presence of MAFLD in T2DM patients even after controlling for multiple confounding factors. Conclusions: There is a positive correlation between the presence of MAFLD and serum iron levels in T2DM patients, which may be attributed to the close association between serum iron and insulin resistance. Serum iron levels may act as one of the indicators for evaluating the risk of MAFLD in T2DM individuals.

Albuminuria but not low eGFR is closely associated with atherosclerosis in patients with type 2 diabetes: an observational study.

BACKGROUND: There is still controversy regarding the associations of urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) with atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Therefore, it is necessary to explore the correlation between them in T2DM patients. METHODS: We conducted a survey involving 2565 T2DM patients from a single center. The study cohort was classified into three groups based on the levels of albuminuria: normal UAE (UAE < 30 mg/24 h), moderate UAE (UAE between 30 and 299 mg/24 h) and high UAE (UAE ≥ 300 mg/24 h). Additionally, the patients were divided into three separate groups according to eGFR levels, including low eGFR (eGFR < 60 ml/min/1.73 m2), intermediate eGFR (eGFR 60-89 ml/min/1.73 m2) and normal eGFR (eGFR ≥ 90 ml/min/1.73 m2) groups. Atherosclerotic lesions were compared among the three UAE and eGFR groups. Regression analyses were used to assess the associations of atherosclerotic lesions with UAE and eGFR in T2DM. RESULTS: After controlling for age, sex and diabetes duration, the prevalence of atherosclerotic plaque and stenosis were significantly increased from the normal to high UAE groups (plaque: 72.2%, 78.6% and 87.3%, respectively, p = 0.016 for trend; stenosis: 14.0%, 25.5% and 37.3%, respectively, p < 0.001 for trend). Likewise, the values of carotid intima-media thickness (CIMT) and femoral intima-media thickness (FIMT) were also obviously increased from the normal to high UAE groups (CIMT: p < 0.001 for trend; FIMT: p = 0.001 for trend). Conversely, only the FIMT value was clearly increased from the low to normal eGFR groups (p = 0.001 for trend). Fully adjusted regression analyses revealed that UAE was closely associated with the presence of atherosclerotic plaque (OR 1.20, 95% CI 1.03-1.40, p = 0.020) and stenosis (OR 1.17, 95% CI 1.01-1.35, p = 0.036), and with the values of CIMT (ß 0.05, 95% CI 0.01-0.10, p = 0.029) and FIMT (ß 0.07, 95% CI 0.03-0.11, p = 0.001) in T2DM patients. However, there was no significant association between eGFR levels and atherosclerotic lesions in T2DM after adjustment for multiple confounding factors. CONCLUSIONS: Overall, albuminuria rather than low eGFR is closely associated with atherosclerotic lesions in T2DM patients. Albuminuria is an independent risk factor for carotid and femoral atherosclerotic lesions in T2DM. Therefore, albuminuria may be a potential early marker to predict the development of atherosclerosis in patients with T2DM.

Chaetocin attenuates atherosclerosis progression and inhibits vascular smooth muscle cell phenotype switching.

We aimed to explore the effect of chaetocin on atherosclerosis and its possible mechanism. In vitro, we observed that chaetocin treatment significantly inhibited the proliferation of VSMCs in concentration- and time-dependent manner. We also found that chaetocin suppressed the migration of VSMCs. Moreover, chaetocin treatment induced a contractile phenotype in VSMCs by increasing α-SMA and SM22α expression. In addition, chaetocin treatment attenuated the accumulation of H3K9me3 on VSMCs contractile gene promoters, which promoted the expression of α-SMA and SM22α. In vivo, chaetocin treatment decreased the H3K9me3 expression, diminished atherosclerotic plaque formation, and increased plaque stability by decreasing necrotic core area and lipid accumulation and increasing collagen content and contractile VSMC phenotype. We demonstrated a new function of chaetocin in inhibiting atherosclerosis progression and increasing plaque stability partly by inhibiting pathological phenotypic switching of VSMCs. These newly identified roles of chaetocin might provide a novel therapeutic target in atherosclerosis.

Serum Retinol-Binding Protein Levels Are Associated with Nonalcoholic Fatty Liver Disease in Chinese Patients with Type 2 Diabetes Mellitus: A Real-World Study.

BACKGROUND: The association of serum retinol-binding protein (RBP) levels with nonalcoholic fatty liver disease (NAFLD) remains controversial. Furthermore, few studies have investigated their relationship in type 2 diabetes mellitus (T2DM) patients. Therefore, the aim of the present study was to explore the association between serum RBP levels and NAFLD in Chinese inpatients with T2DM. METHODS: This cross-sectional, real-world study included 2,263 Chinese T2DM inpatients. NAFLD was diagnosed by abdominal ultrasonography. The subjects were divided into four groups based on RBP quartiles, and clinical characteristics were compared among the four groups. The associations of both RBP levels and quartiles with the presence of NAFLD were also analyzed. RESULTS: After adjustment for sex, age, and diabetes duration, there was a significant increase in the prevalence of NAFLD from the lowest to the highest RBP quartiles (30.4%, 40.0%, 42.4%, and 44.7% for the first, second, third, and fourth quartiles, respectively, P<0.001 for trend). Fully adjusted multiple logistic regression analysis revealed that both increased RBP levels (odds ratio, 1.155; 95% confidence interval, 1.012 to 1.318; P=0.033) and quartiles (P=0.014 for trend) were independently associated with the presence of NAFLD in T2DM patients. CONCLUSION: Increased serum RBP levels were independently associated with the presence of NAFLD in Chinese T2DM inpatients. Serum RBP levels may be used as one of the indicators to assess the risk of NAFLD in T2DM patients.

Waist-to-height ratio has a stronger association with cardiovascular risks than waist circumference, waist-hip ratio and body mass index in type 2 diabetes.

AIMS: To compare the associations between four anthropometric indices including waist-to-height ratio (WHtR), waist circumference (WC), waist-hip-ratio (WHR) and body mass index (BMI) and cardio-cerebrovascular events (CCBVEs) in Chinese T2DM patients. METHODS: The associations of four anthropometric measures with CCBVEs and metabolic syndrome (MetS) were compared by multiple regression model in 3108 T2DM patients. CCBVEs was defined as a history of myocardial infarction, angina, angioplasty, coronary artery bypass surgery, transient ischemic attack, ischemic or hemorrhagic stroke. RESULTS: After controlling for age, sex and diabetes duration, the prevalence of CCBVEs and MetS significantly increased across the WHtR, WC, WHR and BMI quartiles in T2DM patients, respectively. However, when controlling for these four anthropometric measurements together, although four anthropometric measures were closely associated with MetS prevalence, only WHtR quartile was significantly associated with CCBVEs prevalence (6.5%, 13.8%, 16.9% and 21.3%, p < 0.001 for trend). After adjusting for multiple confounders including four anthropometric parameters, a regression analysis revealed that only WHtR was independently and positively associated with the presence of CCBVEs (p = 0.029). CONCLUSIONS: Compared with WC, WHR and BMI, WHtR have a stronger association with CCBVEs in T2DM subjects. WHtR maybe a better indicator than other anthropometric measurements for evaluating cardiovascular risks in T2DM.

Deletion of Fam172a accelerates advanced atherosclerosis and induces plaque instability.

BACKGROUND AND AIMS: Vascular smooth muscle cells (VSMCs) play a critical role in atherosclerosis. The family with sequence similarity 172, member A (FAM172A) is a novel protein and its role in atherosclerosis has not been explored so far. Therefore, our aim is to investigate whether FAM172A affects atheroprogression through VSMCs and its possible mechanism. METHODS: Fam172a-/- mice were generated using CRISPR/Cas9 technology. Fam172a-/- and Apoe-/- double knockout (Fam172a-/-/Apoe-/-) mice and their littermates (Fam172a+/+/Apoe-/-) were fed with a Western diet for 18 weeks to induce advanced atherosclerotic lesions. The role and mechanism of Fam172a in phenotypic switching, proliferation and migration of VSMCs were investigated through in vivo and in vitro experiments. RESULTS: Compared with Fam172a+/+/Apoe-/- mice, Fam172a-/-/Apoe-/- mice showed increased atherosclerotic lesion size and plaque instability such as increased necrotic core area and decreased fiber deposition. Additionally, knockout of Fam172a promoted expression of CD68 and KLF4 and decreased expression of α-SMA and SM22α in atherosclerotic lesions. Furthermore, overexpression of Fam172a promoted Movas cells proliferation and migration, increased expression of α-SMA and SM22α and decreased expression of KLF4. Meanwhile, knockdown of Fam172a in Movas cells and deletion of Fam172a in VSMCs from Fam172a-/-/Apoe-/- mice showed opposite phenotypes. Similar phenotypes were also observed in human aortic smooth muscle cells. CONCLUSIONS: Our results provide the first direct evidence that Fam172a has a protective role in advanced atherosclerosis by increasing atherosclerotic plaque stability and inhibiting transition of VSMCs from contractile to synthetic phenotype, which may be through KLF4-dependent pathway.

Insulin Therapy Is Associated With an Increased Risk of Carotid Plaque in Type 2 Diabetes: A Real-World Study.

Background: Controversies concerning the association between insulin therapy and atherosclerotic lesions in type 2 diabetes mellitus (T2DM) remain to exist. The purpose of this study was to investigate whether insulin therapy in T2DM patients is linked with the increased risk of carotid atherosclerosis in real-world settings. Methods: We retrospectively enrolled 2,356 hospitalized patients with T2DM, including 1,716 subjects receiving insulin therapy and 640 subjects without receiving insulin therapy. Carotid atherosclerotic lesions including carotid intima-media thickness (CIMT), carotid plaque and carotid stenosis were assessed by Doppler ultrasonography and were compared between T2DM patients treated with and without insulin. Results: After adjusting for age and duration of diabetes, there was a significant increase in the prevalence of carotid plaque in both men (52.0 vs. 41.7%, p = 0.007) and women (49.6 vs. 39.7%, p = 0.003) receiving insulin therapy than in those without receiving insulin therapy. After further controlling for other confounding factors, compared with the patients without receiving insulin therapy, the risk of carotid plaque was still significantly increased not only in women treated with insulin (OR: 1.810; 95% CI: 1.155-2.837, p = 0.010), but also in men treated with insulin (OR: 1.867; 95% CI: 1.307-2.666; p = 0.001). Additionally, HOMA2-B% was higher in both women and men without receiving insulin therapy compared with those receiving insulin therapy (p < 0.001 in both men and women), but HOMA-IR was significantly higher in patients treated with insulin than in those without receiving insulin therapy (p < 0.001 in both men and women). Conclusions: Insulin therapy is associated with markedly increased risk of carotid atherosclerotic lesions in type 2 diabetes, which partly attribute to the more serious insulin resistance in T2DM patients receiving insulin therapy.

Prevalence and clinical characteristics of hypertension and metabolic syndrome in newly diagnosed patients with ketosis-onset diabetes: a cross-sectional study.

BACKGROUND: To investigate the prevalence and clinical characteristics of hypertension (HTN) and metabolic syndrome (MetS) in newly diagnosed diabetes with ketosis-onset. METHODS: A cross-sectional study was adopted in 734 newly diagnosed diabetics including 83 type 1 diabetics with positive islet-associated autoantibodies, 279 ketosis-onset diabetics without islet-associated autoantibodies and 372 non-ketotic type 2 diabetics. The clinical characteristics of HTN and MetS were compared across the three groups, and the risk factors of them were appraised in each group. RESULTS: The prevalence of HTN and MetS were substantially higher in the ketosis-onset diabetics (34.4% for HTN and 58.8% for MetS) than in the type 1 diabetics (15.7% for HTN, P = 0.004; 25.3% for MetS, P < 0.001), but showed no remarkable difference compared with the type 2 diabetics (42.7% for HTN, P = 0.496; 72.3% for MetS, P = 0.079). Furthermore, the risk factors for both HTN and MetS in the ketosis-onset diabetics resembled those in the type 2 diabetics, but significantly different from those in the type 1 diabetics. CONCLUSIONS: The prevalence of HTN and MetS in the ketosis-onset diabetics were magnificently higher than in the type 1 diabetics but showed no difference in comparison to the type 2 diabetics. Likewise, the clinical features and risk factors of HTN and MetS in the ketosis-onset diabetes resembled those in the type 2 diabetes but differed from those in the type 1 diabetes. Our findings indicate that ketosis-onset diabetes should be classified into type 2 diabetes rather than idiopathic type 1 diabetes.

The coexistence of carotid and lower extremity atherosclerosis further increases cardio-cerebrovascular risk in type 2 diabetes.

BACKGROUND: Both carotid and lower limb atherosclerosis are associated with increased cardiovascular and cerebrovascular risks. However, it is still unclear whether the concomitant presence of carotid and lower extremity atherosclerosis further increases the cardiovascular and cerebrovascular risks. Therefore, our aim is to investigate whether the coexistence of carotid and lower extremity atherosclerosis was associated with higher cardiovascular and cerebrovascular risks in patients with type 2 diabetes. METHODS: This cross-sectional study was performed in 2830 hospitalized patients with type 2 diabetes. Based on carotid and lower limb Doppler ultrasound results, the patients were divided into three groups including 711 subjects without atherosclerosis, 999 subjects with either carotid or lower limb atherosclerosis, and 1120 subjects with both carotid and lower limb atherosclerosis. And we compared the clinical characteristics and prevalence of both cardio-cerebrovascular events (CCBVEs) and self-reported cardio- cerebrovascular diseases (CCBVDs) among the three groups. RESULTS: After adjusting for age, sex, and duration of diabetes, there were significant increases in the prevalence of both CCBVEs (3.8 vs. 11.8 vs. 26.4 %, p < 0.001 for trend) and self-reported CCBVDs (6.9 vs. 19.9 vs. 36.5 %, p < 0.001 for trend) across the three groups (diabetics without atherosclerosis, diabetics with either carotid or lower limb atherosclerosis, and diabetics with both carotid and lower extremity atherosclerosis). A fully adjusted logistic regression analysis also revealed that compared with those without atherosclerosis, those with either carotid or lower limb atherosclerosis had higher risk of CCBVEs (OR 1.724, 95 % CI 1.001-2.966) and self-reported CCBVDs (OR 1.705, 95 % CI 1.115-2.605), and those with concomitant presence of carotid and lower extremity atherosclerosis had the highest risk of CCBVEs (OR 2.869, 95 % CI 1.660-4.960) and self-reported CCBVDs (2.147, 95 % CI 1.388-3.320)(p < 0.001 for trend in CCBVEs and p = 0.002 for trend in CCBVDs, respectively). CONCLUSIONS: Either carotid or lower limb atherosclerosis was obviously related to increased cardio-cerebrovascular risk in type 2 diabetes. The concomitant presence of carotid and lower extremity atherosclerosis further increased cardio-cerebrovascular risk in patients with type 2 diabetes. The combined application of carotid and lower extremity ultrasonography may help identify type 2 diabetics with higher cardio-cerebrovascular risk.

High Glucose Increases the Expression of Inflammatory Cytokine Genes in Macrophages Through H3K9 Methyltransferase Mechanism.

Recent studies suggest that histone modification is one of the mechanisms regulating inflammatory cytokine gene expression in hyperglycemic conditions. However, it remains unknown how histone methylation is initiated and involved in changes of inflammatory cytokine gene expression under high glucose (HG) conditions. Our aim was to investigate whether H3K9 methylation was involved in HG-induced expression of inflammatory cytokines in macrophages. Expression profile of cytokine genes under hyperglycemia in THP-1-derived macrophages was determined by human cytokine antibody array. Based on the results from the human cytokine antibody array analyses, the H3K9me3 levels of 4 inflammatory cytokine genes, including interleukin-6 (IL-6), IL-12p40, macrophage inflammatory protein-1α (MIP-1α), and MIP-1ß under HG were determined by ChIP assays. Furthermore, the expression of these 4 inflammatory cytokine genes under either HG or chaetocin (an inhibitor of SUV39H1 methyltransferase) exposure or overexpression of SUV39H1 (a H3K9me3-specific methyltransferase) was analyzed by quantitative polymerase chain reaction. Macrophages cultured in HG conditions showed increased gene expression and decreased H3K9me3 levels of inflammatory cytokine genes compared with macrophages incubated in normal glucose (NG) culture. Inhibition of SUV39H1 with chaetocin in NG-treated macrophages also increased the expression of IL-6, IL-12p40, MIP-1α, and MIP-1ß. Furthermore, inhibition of SUV39H1 with chaetocin in HG-treated macrophages further increased the expression of these inflammatory cytokines. Contrarily, NG-treated macrophages transfected with SUV39H1 plasmids show decreased expression of inflammatory cytokines. Furthermore, overexpression of SUV39H1 in HG-treated macrophages alleviated the expression of inflammatory cytokines under HG conditions. Finally, HG also increases the expression of inflammation cytokines in mouse bone marrow-derived macrophages. Our data demonstrated that HG increases the expression of inflammatory cytokines in macrophages through decreased H3K9me3 levels, which was partly mediated by SUV39H1. Dysregulation of epigenetic histone modification may be one of the underlying mechanisms for HG-induced inflammatory cytokine expression in macrophages.

FAM172A protein promotes the proliferation of human papillary thyroid carcinoma cells via the p38 mitogen-activated protein kinase pathway.

Family with sequence similarity 172, member A (FAM172A), was cloned from human aortic tissues and confirmed in our previous study in 2009, however, its functions remain to be fully elucidated. In our previous studies, the protein expression of FAM172A in human aortic smooth muscle cells was found to be upregulated by high glucose in a concentration­ and time­dependent manner. Several reports have shown that insulin resistance is associated with papillary thyroid carcinoma (PTC). Thus, in the present study, the protein expression levels of FAM172A in human papillary thyroid carcinoma were investigated, and the effect of the FAM172A protein on the proliferation of IHH­4 human papillary thyroid carcinoma cells, and its potential molecular underlying mechanisms were examined. Immunohistochemistry and western blotting demonstrated that the protein expression of FAM172A in papillary thyroid carcinoma tissues was not only significantly higher than that in noncancerous tissues adjacent to the carcinoma tissues, but it was also markedly higher than that in normal thyroid and thyroid adenoma tissues. Overexpression of the FAM172A protein activated the p38 MAPK pathway, but not the PI3K and AMPK pathways, in the IHH­4 cells. In addition, overexpression of the FAM172A protein accelerated IHH­4 cell proliferation, compared with the control group, and the pro­proliferative effect of FAM172A protein on IHH4 cells was markedly attenuated by SB202190, an inhibitor of p38 MAPK. Taken together, these results suggest that the FAM172A protein is expressed at high levels in human PTC, which may promote cell proliferation via activation of the p38 MAPK signaling pathway, and be involved in the pathogenesis of PTC.

Decreased urine uric acid excretion is associated with diabetic retinopathy but not with lower limb atherosclerosis in hospitalized patients with type 2 diabetes.

OBJECTIVE: To explore the associations between urine uric acid excretion (UUAE) and diabetic retinopathy (DR)/lower limb atherosclerotic lesions in hospitalized Chinese patients with type 2 diabetes. METHODS: This cross-sectional study was conducted in 2529 hospitalized Chinese patients with type 2 diabetes. UUAE was determined enzymatically using a single 24-h urine collection. The subjects were stratified into quartile based on UUAE levels. DR was determined by digital fundus photography. Lower limb atherosclerotic lesions were assessed by Doppler ultrasound. Both DR and lower limb atherosclerosis were compared among the UUAE quartile groups, respectively. RESULTS: There was a significant decrease in the prevalence of DR in patients across the UUAE quartiles after adjustment for sex, age and diabetic duration (35.0%, 30.7%, 26.1%, and 21.5%, respectively, p = 0.000001 for trend). A fully adjusted multiple logistic regression analyses revealed that UUAE quartiles were markedly inversely associated with the presence of DR (p = 0.030). The prevalence of lower limb plaque (73.9% vs. 62.6%, p = 0.000044) and stenosis (16.3% vs. 9.7%, p = 0.000015) was markedly higher in the diabetics with DR than in those without DR. However, there was no statistical association between the UUAE and lower limb atherosclerotic lesions in type 2 diabetes. CONCLUSIONS: Decreased UUAE was an independent risk factor for DR but not for lower limb atherosclerosis in hospitalized Chinese patients with type 2 diabetes. In selected populations, such as those with type 2 diabetes, the role of uric acid in atherosclerosis may be result from other concomitantly atherosclerotic risk factors, such as DR.

High-normal urinary albumin-to-creatinine ratio is independently associated with metabolic syndrome in Chinese patients with type 2 diabetes mellitus: A cross-sectional community-based study.

AIMS/INTRODUCTION: Microalbuminuria is positively related to metabolic syndrome (MetS). Our aim was to investigate whether urinary albumin-to-creatinine ratio (UACR) within the normal range is independently associated with MetS in Chinese community-based patients with type 2 diabetes. MATERIALS AND METHODS: A total of 514 participants (206 males and 308 females; mean age 66 years) with UACR less than 3.5 mg/mmol were enrolled from two downtown areas of Shanghai. The participants were stratified into quartiles according to UACR levels. The prevalence of MetS was assessed and compared among the four groups by binary logistic regression. RESULTS: Compared with participants with UACRs in the first quartile, the other quartiles had a higher prevalence of MetS (65.9%, 74.4% and 81.3%, respectively, P = 0.001) after adjustment for sex and age. After adjusting for potential confounders, participants in the second to the fourth quartile group had a 1.36-, 1.84- and 2.73-fold risk of MetS, respectively, relative to those in the lowest quartile. Furthermore, UACR, whether as quartile groups or as a continuous variable, is an independent predictor of MetS after fully adjusting for other variables. CONCLUSIONS: These results suggest that UACR even within the normal range is independently associated with MetS in Chinese community-based patients with type 2 diabetes mellitus.

Comparison of carotid and lower limb atherosclerotic lesions in both previously known and newly diagnosed type 2 diabetes mellitus.

AIMS/INTRODUCTION: To compare carotid and lower limb atherosclerotic lesions, and examine if carotid atherosclerotic lesions are in line with lower limb atherosclerotic lesions, and can reflect generalized atherosclerosis in inpatients with type 2 diabetes. MATERIALS AND METHODS: This was an observational study carried out in 867 Chinese inpatients with type 2 diabetes, including 573 previously known and 294 newly diagnosed patients. Ultrasonographic assessments of intima-media thickness (IMT), plaques, and stenosis in the carotid and lower limb arteries were evaluated. Atherosclerotic lesions between the carotid and lower limb arteries were compared in both previously known and newly diagnosed diabetes, respectively. RESULTS: In both the known (77.3% vs 49.4%, P < 0.001) and the newly diagnosed diabetes (55.4% vs 29.9%, P < 0.001), the prevalence of atherosclerotic plaques was significantly higher in the lower limb arteries than in the carotid arteries. Likewise, the prevalence of stenosis was also significantly higher (P < 0.001) in the lower limb arteries (16.9%) than in the carotid arteries (4.2%) in the established diabetes patients. However, there was no significant difference in the mean IMT between common carotid and common femoral arteries in both the previously known (0.90 ± 0.24 mm vs 0.89 ± 0.20 mm, P = 0.675) and the newly diagnosed diabetes patients (0.86 ± 0.22 mm vs 0.85 ± 0.16 mm, P = 0.436). CONCLUSIONS: Carotid plaques might underestimate generalized plaques in inpatients with type 2 diabetes, as shown by its significantly lower prevalence compared with that of the lower extremity arteries. A combined carotid and lower limb ultrasound examination can improve the detection of atherosclerotic lesions in inpatients with type 2 diabetes.

Prevalence and clinical characteristics of lower limb atherosclerotic lesions in newly diagnosed patients with ketosis-onset diabetes: a cross-sectional study.

BACKGROUND: The clinical features of atherosclerotic lesions in ketosis-onset diabetes are largely absent. We aimed to compare the characteristics of lower limb atherosclerotic lesions among type 1, ketosis-onset and non-ketotic type 2 diabetes. METHODS: A cross-sectional study was performed in newly diagnosed Chinese patients with diabetes, including 53 type 1 diabetics with positive islet-associated autoantibodies, 208 ketosis-onset diabetics without islet-associated autoantibodies, and 215 non-ketotic type 2 diabetics. Sixty-two subjects without diabetes were used as control. Femoral intima-media thickness (FIMT), lower limb atherosclerotic plaque and stenosis were evaluated and compared among the four groups based on ultrasonography. The risk factors associated with lower limb atherosclerotic plaque were evaluated via binary logistic regression in patients with diabetes. RESULTS: After adjusting for age and sex, the prevalence of lower limb plaque in the patients with ketosis-onset diabetes (47.6%) was significantly higher than in the control subjects (25.8%, p = 0.013), and showed a higher trend compared with the patients with type 1 diabetes (39.6%, p = 0.072), but no difference was observed in comparison to the patients with non-ketotic type 2 diabetes (62.3%, p = 0.859). The mean FIMT in the ketosis-onset diabetics (0.73 ± 0.17 mm) was markedly greater than that in the control subjects (0.69 ± 0.13 mm, p = 0.045) after controlling for age and sex, but no significant differences were found between the ketosis-onset diabetics and the type 1 diabetics (0.71 ± 0.16 mm, p = 0.373), and the non-ketotic type 2 diabetics (0.80 ± 0.22 mm, p = 0.280), respectively. Age and FIMT were independent risk factors for the presence of lower limb plaque in both the ketosis-onset and non-ketotic type 2 diabetic patients, while sex and age in the type 1 diabetic patients. CONCLUSIONS: The prevalence and risk of lower limb atherosclerotic plaque in the ketosis-onset diabetes were remarkably higher than in the control subjects without diabetes. The features and risk factors of lower limb atherosclerotic lesions in the ketosis-onset diabetes resembled those in the non-ketotic type 2 diabetes, but different from those in the type 1 diabetes. Our findings provide further evidences to support the classification of ketosis-onset diabetes as a subtype of type 2 diabetes rather than idiopathic type 1 diabetes.