Association of Circulating Long-Chain Free Fatty Acids and Incident Diabetes Risk Among Normoglycemic Chinese Adults: A Prospective Nested Case-Control Study.

BACKGROUND: Long-chain free fatty acids (FFAs) are associated with risk of incident diabetes. However, comprehensive assessment of the associations in normoglycemic populations is lacking. OBJECTIVE: Our study aims to comprehensively investigate the prospective associations and patterns of FFA profiles with diabetes risk among normoglycemic Chinese adults. METHODS: This is a prospective nested case-control study from the China Cardiometabolic Disease and Cancer Cohort (4C) study. We quantitatively measured 53 serum FFAs using targeted metabolomics approach in 1707 incident diabetes subjects and 1707 propensity score-matched normoglycemic controls. Conditional logistic regression models were employed to estimate odds ratios (ORs) for associations. Least Absolute Shrinkage and Selection Operator (LASSO) penalty regression and quantile g-computation (qg-comp) analyses were implemented to estimate the association between multi-FFA exposures and incident diabetes. RESULTS: The majority of odd-chain FFAs exhibited an inverse association with incident diabetes, wherein the ORs per SD increment of all 7 saturated fatty acids (SFAs), monounsaturated fatty acid (MUFA) 15:1 and polyunsaturated fatty acid (PUFA) 25:2 were ranging from 0.79 to 0.88 (95%CIs ranging between 0.71 and 0.97). Even-chain FFAs comprised 99.3% of total FFAs and displayed heterogeneity with incident diabetes. SFAs with 18 to 26 carbon atoms are inversely linked to incident diabetes, with ORs ranging from 0.81 to 0.86 (95%CIs ranging between 0.73 and 0.94). MUFAs 26:1 (OR[95%CI]: 0.85[0.76-0.94]), PUFAs 20:4 (0.84[0.75-0.94]) and 24:2 (0.87[0.78-0.97]) demonstrated significant associations. In multi-FFA exposure model, 24 FFAs were significantly associated with incident diabetes, most of which were consistent with univariate results. The mixture OR was 0.78 [0.61-0.99] (P= 0.04159). Differential correlation network analysis revealed pre-existing perturbations in intraclass and interclass FFA coregulation before diabetes onset. CONCLUSIONS: These findings underscore the variations in diabetes risk associated with FFAs across chain length and unsaturation degree, highlighting the importance of recognizing FFA subtypes in the pathogenesis of diabetes.

Body size, insulin sensitivity, metabolic health and risk of cardiovascular disease in Chinese adults: Insights from the China Cardiometabolic Disease and Cancer Cohort (4C) study.

AIMS: To assess the excess risk of cardiovascular disease (CVD) associated with different criteria for metabolic health, and the interplay of body size, insulin sensitivity and metabolic health with CVD risk. MATERIALS AND METHODS: We conducted a prospective study involving 115 638 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Metabolic health was defined using three different definitions: (1) insulin sensitivity defined by homeostatic model assessment of insulin resistance index; (2) absence of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria; and (3) simultaneous absence of metabolic abnormalities (diabetes, hypertension, dyslipidaemia). The primary endpoint was a composite of incident CVD events comprising the first occurrence of myocardial infarction, stroke, heart failure, or cardiovascular death. RESULTS: During a mean 3.61-year follow-up period, obese individuals with insulin sensitivity (multivariable-adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.37-2.08), or without metabolic syndrome (HR 1.46, 95% CI 1.13-1.89) still exhibited increased CVD risks, when compared to their normal-weight counterparts. Otherwise, those with obesity but simultaneous absence of metabolic abnormalities demonstrated similar CVD risk compared to normal-weight individuals (HR 0.91, 95% CI 0.53-1.59). CVD risk increased with the number of abnormalities across body mass index categories, regardless of insulin sensitivity. CONCLUSIONS: This study emphasizes the need for refined definitions of metabolic health and advocates for meticulous screening for metabolic abnormalities to reduce cardiovascular risks, even in individuals with normal weight and insulin sensitivity.

The Association between Educational Attainment and the Risk of Nonalcoholic Fatty Liver Disease among Chinese Adults: Findings from the REACTION Study.

Background/Aims: : Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. Methods: : A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. Results: : Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. Conclusions: : In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.

Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.

OBJECTIVE: We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of mazdutide, a once-weekly glucagon-like peptide 1 and glucagon receptor dual agonist, in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes inadequately controlled with diet and exercise alone or with stable metformin (glycated hemoglobin A1c [HbA1c] 7.0-10.5% [53-91 mmol/mol]) were randomly assigned to receive 3 mg mazdutide (n = 51), 4.5 mg mazdutide (n = 49), 6 mg mazdutide (n = 49), 1.5 mg open-label dulaglutide (n = 50), or placebo (n = 51) subcutaneously for 20 weeks. The primary outcome was change in HbA1c from baseline to week 20. RESULTS: Mean changes in HbA1c from baseline to week 20 ranged from -1.41% to -1.67% with mazdutide (-1.35% with dulaglutide and 0.03% with placebo; all P < 0.0001 vs. placebo). Mean percent changes in body weight from baseline to week 20 were dose dependent and up to -7.1% with mazdutide (-2.7% with dulaglutide and -1.4% with placebo). At week 20, participants receiving mazdutide were more likely to achieve HbA1c targets of <7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol) and body weight loss from baseline of ≥5% and ≥10% compared with placebo-treated participants. The most common adverse events with mazdutide included diarrhea (36%), decreased appetite (29%), nausea (23%), vomiting (14%), and hypoglycemia (10% [8% with placebo]). CONCLUSIONS: In Chinese patients with type 2 diabetes, mazdutide dosed up to 6 mg was generally safe and demonstrated clinically meaningful HbA1c and body weight reductions.

Sex Hormone-Binding Globulin and Risk of Incident Dementia in Middle-Aged to Older Women: Results from the UK Biobank Cohort Study.

INTRODUCTION: The association of serum sex hormone-binding globulin (SHBG) concentrations with dementia risk remains uncertain in middle-aged to older women. We examined associations of serum SHBG levels with incidence of all-cause dementia and its subtypes in middle-aged to older women from the large population-based UK Biobank cohort study. METHODS: Serum total SHBG levels were measured by immunoassay. The incidence of all-cause dementia and its subtypes was recorded. Cox proportional hazards models were used to calculate hazard ratios (HR) for main outcomes. RESULTS: Among 171,482 community-dwelling women (mean [SD] age was 59.9 [5.4] years, median follow-up of 11.8 years), 2,368 developed dementia, including 1,088 from Alzheimer's disease (AD), 451 from vascular dementia (VAD), and 1,609 from other dementia. After multivariable adjustments, higher serum SHBG levels were significantly associated with higher risks of all-cause dementia, AD, and other dementia (all p < 0.05). Compared to those in the lowest quartile of SHBG levels, participants in the highest quartile of SHBG levels had a higher risk of all-cause dementia (HR: 1.34; 95% confidence interval [CI]: 1.16-1.53), AD (HR: 1.32; 95% CI: 1.07-1.62), and other dementia (HR: 1.44; 95% CI: 1.21-1.70). However, this relationship was not significant for VAD (HR: 1.16; 95% CI: 0.86-1.56). CONCLUSION: These findings indicated that higher serum SHBG concentrations were independently associated with higher risks of incident all-cause dementia, as well as AD and other dementia among middle-aged to older women. No association was found for VAD.

Transferrin receptor levels and its rare variant are associated with human obesity.

AIM: Iron homeostasis is critical for functional respiratory chain complex of mitochondrial, thus potentially contributing to fat biology and energy homeostasis. Transferrin receptor (Tfrc) binds to transferrin for extracellular iron uptake and is recently reported to be involved in brown fat development and functionality. However, whether TFRC levels and variants are associated with human obesity is unknown. METHODS: To investigate the association of TFRC levels and variants with human obesity, fat biopsies were obtained from surgery. Exon-sequencing and genetic assessments were conducted of a case-control study. For TFRC levels assessment in fat biopsy, 9 overweight and 12 lean subjects were involved. For genetic study, obese (n = 1271) and lean subjects (n = 1455) were involved. TFRC levels were compared in abdominal mesenteric fat of pheochromocytoma patients versus control subjects, and overweight versus lean subjects. For genetic study, whole-exome sequencing of obese and matched control subjects were conducted and analyzed. In addition, the possible disruption in protein stability of TFRC variant was assessed by structural and molecular analysis. RESULTS: TFRC levels are increased in human browning adipose tissue and decreased in fat of overweight patients. Besides, TFRC levels are negatively correlated with body mass index and positively correlated with uncoupling protein 1 levels. Furthermore, a rare heterozygous missense variant p.I337V in TFRC shows a tendency to enrich in obese subjects. Structural and functional study reveals impaired protein stability of the TFRC variant compared to wild-type. CONCLUSIONS: Reduced TFRC levels and its rare variant p.I337V with protein instability are associated with human obesity.

Association between follicle-stimulating hormone and nonalcoholic fatty liver disease in postmenopausal women with type 2 diabetes mellitus.

BACKGROUND AND AIM: Follicle-stimulating hormone (FSH) was negatively associated with nonalcoholic fatty liver disease (NAFLD) in women older than 55 years old. People with obesity and diabetes had higher prevalence of NAFLD. Thus, we aimed to explore the association between FSH and NAFLD in postmenopausal women with type 2 diabetes mellitus (T2DM). METHODS: A total of 583 postmenopausal women with T2DM with an average age of 60.22 ± 6.49 were recruited in this cross-sectional study through January 2017 to May 2021. Anthropological data, biochemical indexes, and abdominal ultrasound results were retrospectively collected. Abdominal ultrasound was used to diagnose NAFLD. FSH was measured by enzymatic immunochemiluminescence and divided into tertiles for further analysis. The logistic regression was used to assess the association of FSH with prevalent NAFLD. Likelihood ratio tests were used to assess the interactions between groups. RESULTS: A total of 332 (56.94%) postmenopausal women had NAFLD. Compared with postmenopausal women in the lowest tertile of FSH, postmenopausal women in the highest tertile of FSH had lower prevalence of NAFLD (p < .01). After adjusting for age, diabetes duration, metabolism-related indicators, and other sex-related hormones, FSH was inversely associated with NAFLD (odds ratio: 0.411, 95% confidence intervals: 0.260-0.651, p < .001). In subgroup analysis, there were no significant interactions of FSH with strata of metabolic factors on the association of NAFLD. CONCLUSION: FSH was negatively and independently associated with NAFLD in postmenopausal women with type 2 diabetes mellitus. It might be a potential index for screening and identifying individuals with high risk of NAFLD in postmenopausal women.

Data-driven subgroups of prediabetes and the associations with outcomes in Chinese adults.

Prediabetes and its pathophysiology remain important issues. We aimed to examine the cluster characteristics of prediabetes and explore their associations with developing diabetes and its complications based on 12 variables representing body fat, glycemic measures, pancreatic ß cell function, insulin resistance, blood lipids, and liver enzymes. A total of 55,777 individuals with prediabetes from the China Cardiometabolic Disease and Cancer Cohort (4C) were classified at baseline into six clusters. During a median of 3.1 years of follow-up, significant differences in the risks of diabetes and its complications between clusters were observed. The odds ratios of diabetes stepwisely increase from cluster 1 to cluster 6. Clusters 1, 4, and 6 have increased chronic kidney diseases risks, while the prediabetes in cluster 4, characterized by obesity and insulin resistance, confers higher risks of cardiovascular diseases compared with others. This subcategorization has potential value in developing more precise strategies for targeted prediabetes prevention and treatment.

Selective PPARγ modulator diosmin improves insulin sensitivity and promotes browning of white fat.

Peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation, glucolipid metabolism, and inflammation. Thiazolidinediones are PPARγ full agonists with potent insulin-sensitizing effects, whereas their oral usage is restricted because of unwanted side effects, including obesity and cardiovascular risks. Here, via virtual screening, microscale thermophoresis analysis, and molecular confirmation, we demonstrate that diosmin, a natural compound of wide and long-term clinical use, is a selective PPARγ modulator that binds to PPARγ and blocks PPARγ phosphorylation with weak transcriptional activity. Local diosmin administration in subcutaneous fat (inguinal white adipose tissue [iWAT]) improved insulin sensitivity and attenuated obesity via enhancing browning of white fat and energy expenditure. Besides, diosmin ameliorated inflammation in WAT and liver and reduced hepatic steatosis. Of note, we determined that iWAT local administration of diosmin did not exhibit obvious side effects. Taken together, the present study demonstrated that iWAT local delivery of diosmin protected mice from diet-induced insulin resistance, obesity, and fatty liver by blocking PPARγ phosphorylation, without apparent side effects, making it a potential therapeutic agent for the treatment of metabolic diseases.

The Association of Sarcopenia and Visceral Obesity with Lean Nonalcoholic Fatty Liver Disease in Chinese Patients with Type 2 Diabetes Mellitus.

Background: Few studies have specifically observed the relationship of sarcopenia, visceral obesity, or their joint effects with lean NAFLD in patients with diabetes. We aimed to investigate the associations of lean NAFLD with sarcopenia, visceral obesity, and sarcopenic visceral obesity (SV) in Chinese patients with type 2 diabetes mellitus (T2DM). Methods: Altogether, 1,112 T2DM patients with BMI <25 kg/m2 were enrolled, and 33.18% of them were diagnosed with lean NAFLD by abdominal ultrasonography. Body composition markers were measured by bioelectrical impedance (BIA). Skeletal muscle mass index (SMI) was calculated as appendicular skeletal muscle mass (ASM) divided by weight, and sarcopenia was defined as SMI < 1 standard deviation (SD) below the sex-specific average for a young reference population. Visceral obesity was defined as visceral fat area (VFA) ≥ 100 cm2. Participants were categorized into one of the four body composition groups: nonsarcopenia/nonvisceral obesity (NN), nonsarcopenia/visceral obesity (NV), sarcopenia/nonvisceral obesity (SN), and SV. Results: Compared to those in the NN group, patients in the NV and SN groups had a higher risk of lean NAFLD after full adjustments (NV: OR = 1.74; 95% CI: 1.09, 2.78; SN: OR =2.07; 95% CI: 1.23, 3.46). Of note, patients in the SV group had the highest odds of lean NAFLD (OR = 3.29; 95% CI: 2.10, 5.17). There were no significant interaction effects between sarcopenia and metabolic risk factors on prevalent lean NAFLD. Conclusions: The current study demonstrated that SV was more closely associated with higher prevalent lean NAFLD than sarcopenia or visceral obesity alone in Chinese patients with T2DM. Besides, the harmful effect of sarcopenia on lean NAFLD was not influenced by visceral obesity or other metabolic risk factors. We hypothesize that increasing skeletal muscle mass more than just reducing visceral fat might be more optimal for the prevention and management of lean NAFLD, which needs further investigation in future studies.

Inverse Association of Fruit and Vegetable Consumption with Nonalcoholic Fatty Liver Disease in Chinese Patients with Type 2 Diabetes Mellitus.

We aimed to investigate the association of fruit and vegetable consumption with nonalcoholic fatty liver disease (NAFLD) in Chinese patients with type 2 diabetes mellitus (T2DM). This cross-sectional study included 2667 Chinese patients with T2DM aged 18 to 76 years from March 2017 to October 2021. Dietary intake was assessed using a food frequency questionnaire, and prevalent NAFLD was diagnosed with abdominal ultrasonography. High fruit−vegetable consumption was determined using ≥500 g/day consumption of both fruit and vegetable, and both fruit and vegetable consumption were divided into three categories of <200 g/day (low), 200−400 g/day (median) and >400 g (high). The primary outcome measurement was multivariate-adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for the prevalence of NAFLD in relation to the highest fruit and (or) vegetable intake compared with the lowest. Secondary analyses were conducted to assess the effects of either fruit or vegetable intake on the fatty liver index (FLI) using multivariable linear regressions. There were 1694 men and 973 women in this study, and 1445 (54.06%) participants had prevalent NAFLD. Patients with high fruit−vegetable intake had a lower prevalence of NAFLD than those with low fruit−vegetable intake (52.04% vs. 56.48%), but this difference was not statistically significant (p = 0.065). Vegetable intake had a significantly inverse association with NAFLD (OR: 0.68, 95% CI: 0.52−0.90), but this association was not pronounced with fruit intake (OR: 1.23, 95% CI: 0.89−1.69) or fruit−vegetable intake (OR: 0.90, 95% CI: 0.73−1.10). Additional analyses showed that an increase in vegetable intake was linearly associated with a significant reduction in FLI (ß: −1.028, 95% CI: −1.836, −0.219). In conclusion, higher vegetable consumption was associated with lower odds of NAFLD in Chinese patients with T2DM, which suggested that increased vegetable intake might protect patients with diabetes against NAFLD.

Elevated levels of fructosamine are independently associated with SARS-CoV-2 reinfection: A 12-mo follow-up study.

BACKGROUND: The association between blood levels of fructosamine (FMN) and recurrent coronavirus disease 2019 (COVID-19) is currently unclear. AIM: To investigate a prospective relationship between blood levels of FMN and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection. METHODS: A total of 146 Chinese hospitalized patients infected with SARS-CoV-2 were consecutively collectively recruited and followed from January 2020 to May 2021. Diagnosis of COVID-19 and SARS-CoV-2 reinfection was based on the diagnostic criteria and treatment protocol in China. The levels of FMN were determined in blood and divided into tertiles based on their distribution in the cohort of COVID-19 patients. Multivariate-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated for SARS-CoV-2 reinfection across the tertiles of FMN levels. A Cox regression model was used to generate the HR for SARS-CoV-2 reinfection in the participants in the top tertile of FMN levels compared with those at the bottom. Disease-free survival was used as the time variable, and relapse was used as the state variable, adjusted for age, gender, influencing factors such as diabetes mellitus, hypertension, and corticosteroid therapy, and clinical indexes such as acute liver failure, acute kidney failure, white blood cell (WBC) count, C-reactive protein, prognostic nutritional index (PNI), and blood lipids. Kaplan-Meier analysis with log-rank tests was used to compare the survival rate between patients with elevated FMN levels (FMN > 1.93 mmol/L, the top tertile) and those with nonelevated levels. RESULTS: Clinical data for the 146 patients with confirmed COVID-19 [age 49 (39-55) years; 49% males] were analyzed. Eleven patients had SARS-CoV-2 reinfection. The SARS-CoV-2 reinfection rate in patients with elevated FMN levels was significantly higher than that in patients with nonelevated FMN (17% vs 3%; P = 0.008) at the end of the 12-mo follow-up. After adjustments for gender, age, diabetes mellitus, hypertension, corticosteroid therapy, WBC count, PNI, indexes of liver and renal function, and blood lipids, patients with nonelevated FMN levels had a lower risk of SARS-CoV-2 reinfection than those with elevated FMN levels (HR = 6.249, 95%CI: 1.377-28.351; P = 0.018). Kaplan-Meier analysis showed that the cumulative survival rate of patients infected with SARS-CoV-2 was higher in patients with nonelevated FMN levels than in those with elevated FMN levels (97% vs 83%; log rank P = 0.002). CONCLUSION: Elevated levels of FMN are independently associated with SARS-CoV-2 reinfection, which highlights that patients with elevated FMN should be cautiously monitored after hospital discharge.

The Inverse Association of Leg Fat Mass and Osteoporosis in Individuals with Type 2 Diabetes Independent of Lean Mass.

Purpose: Recent studies revealed that high levels of thigh fat were independently associated with better glucose and lipid metabolism, as well as lower risk of hypertension and cardiometabolic disease. Therefore, the purpose of this study was to evaluate the association between leg fat mass (FM) and osteoporosis (OP) in individuals with type 2 diabetes (T2DM). Patients and Methods: In this cross-sectional study, a total of 1,259 individuals aged 50 years or older with T2DM (female 536, male 723) were included. A bioelectrical impedance analyser was used to assess the segment body composition containing FM and lean mass (LM) of arms, legs, and trunk. Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry. Results: Leg FM was positively correlated with BMD of all sites in females and BMD of femoral neck and total hip in males after adjusting age, diabetes duration, glucose and lipid metabolism indexes, and lifestyle (all P<0.05). LM was positively associated with BMD at almost sites (P<0.001), while leg FM/LM ratio had no relationship with BMD at any skeleton sites (P>0.05). Compared with the bottom tertile group of leg FM, the risk of OP was significantly lower in the top tertile group both in females (T3 vs T1: OR=0.206, 95% CI=0.098-0.433, P<0.001) and males (T3 vs T1: OR=0.385, 95% CI=0.182-0.815, P<0.05), even after adjusting for LM. Conclusion: In the present study, higher leg FM was correlated with the lower risk of OP in both men and postmenopausal women with T2DM independently of total LM.

Effect of aerobic exercise as a treatment on type 2 diabetes mellitus with depression-like behavior zebrafish.

BACKGROUND: Depression is the most known complication of type 2 diabetes mellitus (T2DM). Aerobic exercise improves glycemic control in T2DM, although the underlying mechanisms of comorbid depression-like behaviors in T2DM have not yet been fully elucidated. METHODS: 120 zebrafish were randomly assigned to four groups: Control, T2DM, T2DM + metformin, and T2DM + aerobic exercise. Then, all animals except the control group were fed with high glucose fairy shrimp (~40 g/kg/day) and exposed reserpine (40 µg/ml for 20 min) for 10 days. Here, behavioral tests were used for model verification. Following the verification, all groups were treated as before. Additionally, the T2DM + metformin group received metformin (~10.6 mg/kg/day) at the same time, while the T2DM + aerobic exercise group received aerobic exercise 30 min/day. Finally, blood glucose and behavioral tests, as well as protein and molecular levels were determined at Day 11 and 12. RESULTS: Aerobic exercise alleviated depressive-like behavior and enhanced the levels of antidepressant biomarkers (NE, 5-HIAA) in zebrafish after 10 consecutive days of exercise. Additionally, 10 consecutive days of aerobic exercise decreased the levels of inflammatory biomarkers (IFN-γ, IL-1, IL-4) and depressive biomarkers (cortisol). Meanwhile, it also aided in the reduction of CD11b, IL-6, IL-6R, and caspase-3 expression to combat the neuroinflammation induced by T2DM, mediated the BDNF-TrkB pathway, and increased Bcl-2/Bax levels. CONCLUSION: Given the remarkable similarity in neurochemistry between humans and zebrafish, this study supports the effectiveness of aerobic exercise as clinical guidance in preventing and treating T2DM complicated with depression.

Antibiotic Azithromycin inhibits brown/beige fat functionality and promotes obesity in human and rodents.

Obesity, a metabolic disease caused by multiple factors, has become a global health problem. In addition to nutrient intake and sedentary lifestyle, environmental pollutants exposure has been shown to be involved in obesity epidemics. Antibiotics, a new type of environmental pollutant, have been widely used in animal husbandry, aquaculture and microorganism. However, the effects of antibiotics exposure on fat metabolism and metabolic diseases are largely unknown. Methods: We screened major types of antibiotics to examine their effects on the differentiation capacity and thermogenic functionality of brown and beige adipocytes, and found that azithromycin, one major kind of macrolide antibiotics suppressed brown and beige adipocyte functionality. We thus examined azithromycin accretion in adipose tissues of obese patients that correlates with BMI by high performance liquid chromatography-tandem mass spectrometry and systematically explore the influences of azithromycin on adiposity and metabolic performance in mice under high diet. Results: Azithromycin (macrolides) inhibits the mitochondrial and thermogenic gene programs of brown and beige adipocytes, thus disrupting their mitochondrial function and thermogenic response. Consistently, azithromycin treatment are more prone to diet-induced obesity in mice, and this was associated with impaired energy expenditure. Importantly, azithromycin is more accumulated in adipose tissue of obese patients and correlates with BMI and body weight. Mechanistically, we found that azithromycin inhibits mitochondria respiratory complex I protein levels and increases reactive oxidative species (ROS) levels, which causes damage of mitochondrial function in brown and beige adipocytes. The deleterious effects of azithromycin can be ameliorated by antioxidant N-acetyl-L-cysteine. Conclusions: Taken together, this work highlights the possible role of azithromycin in obesity epidemic and presents strategies for safe applications of antibiotics in the future.

First-degree family history of diabetes is associated with nonalcoholic fatty liver disease independent of glucose metabolic status.

BACKGROUND: The first-degree relatives of patients with diabetes (FDRs) share a common genetic background with patients with diabetes. Insulin resistance is recognized as a common contributor to diabetes and nonalcoholic fatty liver disease (NAFLD). The present study aimed to investigate the association between a first-degree family history of diabetes (FHD) and NAFLD and the influence of glucose metabolic status. METHODS: The present work analyzed a part of the baseline data of the REACTION study conducted in a community population. A total of 11,162 participants with an average age of 55.57 ± 9.66 years were enrolled, including 9870 non-FDRs and 1292 FDRs. First-degree FHD was defined as at least one patient with diabetes among parents, siblings or children. The fatty liver index (FLI) was calculated to identify NAFLD. RESULTS: The proportions of subjects without NAFLD, with intermediate FLI, and with NAFLD differed significantly between non-FDRs and FDRs (P < 0.001). FLI was one of the metabolic factors independently associated with first-degree FHD (P = 0.006). Multivariate variance analysis revealed positive associations of first-degree FHD and glucose metabolic status (both P < 0.001) with FLI, which were independent of each other (P for interaction = 0.182). Multiple stepwise linear regression analysis identified that first-degree FHD was independently and positively associated with FLI in men, premenopausal women, and postmenopausal women (all P < 0.05). CONCLUSION: A first-degree FHD was an independent risk factor for NAFLD. Regardless of the status of glucose metabolism, FDRs were more susceptible to NAFLD.

Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study.

Non-fasting lipidemia (nFL), mainly contributed by postprandial lipidemia (PL), has recently been recognized as an important cardiovascular disease (CVD) risk as fasting lipidemia (FL). PL serves as a common feature of dyslipidemia in Type 2 Diabetes (T2D), albeit effective therapies targeting on PL were limited. In this study, we aimed to evaluate whether the therapy combining probiotics (Prob) and berberine (BBR), a proven antidiabetic and hypolipidemic regimen via altering gut microbiome, could effectively reduce PL in T2D and to explore the underlying mechanism. Blood PL (120 min after taking 100 g standard carbohydrate meal) was examined in 365 participants with T2D from the Probiotics and BBR on the Efficacy and Change of Gut Microbiota in Patients with Newly Diagnosed Type 2 Diabetes (PREMOTE study), a random, placebo-controlled, and multicenter clinical trial. Prob+BBR was superior to BBR or Prob alone in improving postprandial total cholesterol (pTC) and low-density lipoprotein cholesterol (pLDLc) levels with decrement of multiple species of postprandial lipidomic metabolites after 3 months follow-up. This effect was linked to the changes of fecal Bifidobacterium breve level responding to BBR alone or Prob+BBR treatment. Four fadD genes encoding long-chain acyl-CoA synthetase were identified in the genome of this B. breve strain, and transcriptionally activated by BBR. In vitro BBR treatment further decreased the concentration of FFA in the culture medium of B. breve compared to vehicle. Thus, the activation of fadD by BBR could enhance FFA import and mobilization in B. breve and diliminish the intraluminal lipids for absorption to mediate the effect of Prob+BBR on PL. Our study confirmed that BBR and Prob (B. breve) could exert a synergistic hypolipidemic effect on PL, acting as a gut lipid sink to achieve better lipidemia and CVD risk control in T2D.

Neck-to-height ratio is positively associated with diabetic kidney disease in Chinese patients with type 2 diabetes mellitus.

Introduction: The aim of this study was to investigate the associations of neck circumference (NC) and neck-to-height (NHR) with diabetic kidney disease (DKD) in Chinese patients with type 2 diabetes mellitus (T2DM). Materials and methods: A total of 2,615 patients with prevalent T2DM were enrolled. NHR was calculated through NC (cm) divided by height (cm), and prevalent DKD was defined as the urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g or the estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m2 in the absence of other primary kidney diseases. Results: The levels of NC and NHR were higher in DKD patients compared with non-DKD patients (38.22 vs. 37.71, P = 0.003; 0.232 vs. 0.227, P < 0.001, respectively). After full adjustments, individuals at the highest tertile of NHR had higher odds of DKD than those at the lowest tertile (multivariate-adjusted OR = 1.63, 95% CI: 1.22, 2.18), but this association was not pronounced with NC (multivariate-adjusted OR = 1.24, 95% CI: 0.87, 1.76). Individuals at the highest tertile of NHR had lower eGFR (ß = -4.64, 95% CI: -6.55, -2.74) and higher UACR levels (ß = 0.27, 95% CI: 0.10, 0.45) than those at the lowest tertile. The adverse association between NHR and prevalent DKD remained statistically significant among most of the subgroups analyzed and no interaction effects were observed. Conclusion: The increase in NHR was adversely and independently associated with DKD in this Chinese T2DM population.

Combination Usage of AdipoCount and Image-Pro Plus/ImageJ Software for Quantification of Adipocyte Sizes.

In recent decades, the prevalence of obesity has been rising. One of the major characteristics of obesity is fat accumulation, including hyperplasia (increase in number) and hypertrophy (increase in size). After histological staining, it is critical to accurately measure the number and size of adipocytes for assessing the severity of obesity in a timely fashion. Manual measurement is accurate but time-consuming. Although commercially available adipocyte counting tools, including AdipoCount, Image-Pro Plus, and ImageJ were helpful, limitations still exist in accuracy and time consuming. In the present study, we introduced the protocol of combined usage of these tools and illustrated the process with histological staining slides from adipose tissues of lean and obese mice. We found that the adipocyte sizes quantified by the tool combination were comparable as manual measurement, whereas the combined methods were more efficient. Besides, the recognition effect of monochrome segmentation image is better than that of color segmentation image. Overall, we developed a combination method to measure adipocyte sizes accurately and efficiently, which may be helpful for experimental process in laboratory and also for clinic diagnosis.

A Clinical Epidemiological Analysis of Prognostic Nutritional Index Associated with Diabetic Retinopathy.

PURPOSE: Prognostic nutritional index (PNI) is an effective tool to evaluate the nutritional conditions and predict prognosis, but clinical data are limited for the use of PNI in diabetic retinopathy (DR). This study aimed to investigate the relationship of PNI with the prevalence and severity of DR in patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: This cross-sectional analysis enrolled 1023 individuals with T2DM hospitalized between 2017-2020. PNI was calculated as 10 × serum albumin (g/l) + 0.005 × total lymphocyte count (cells/mL). DR severity was categorized as no, nonproliferative, and vision-threatened DR (VTDR) according to the modified Airlie House classification. Multivariate-adjusted odds ratio (OR) with 95% confidence interval (CI) for the prevalent DR in the top (Q4) compared with the bottom quartile (Q1) of PNI levels were estimated by using logistic regression analyses. RESULTS: PNI levels were significantly lower in individuals with VTDR than those with no and nonproliferative DR (both P < 0.001), and the proportions of individuals with DR were significantly decreased in the top quartile compared with the bottom quartile of PNI levels (P < 0.001). After adjustments for age, gender, DM duration, obesity-related risk factors and clinical biochemical parameters, the higher levels of PNI were significantly associated with a lower prevalence of DR (Q4 vs Q1: OR = 0.402, 95% CI: 0.250-0.649, P < 0.001), with a 5.9% reduction in the prevalence of DR for a per-unit increment in the levels of PNI (OR = 0.941, 95% CI: 0.911-0.972, P < 0.001). The association of PNI and obesity-related indexes (body mass index and waist circumference) with the severity of DR was independent of each other (P<0.001). CONCLUSION: PNI was inversely and independently associated with the severity and prevalence of DR, which suggested that PNI could likely be used to predict DR prognosis in clinical practice.