Haoyong Yu

Circadian Rhythm of Circulating Fibroblast Growth Factor 21 Is Related to Diurnal Changes in Fatty Acids in Humans

BACKGROUND Fibroblast growth factor (FGF) 21 is an endocrine factor actively involved in glucose and lipid metabolism in rodents. However, little is known about its physiological function and regulation in humans. This study investigated the diurnal changes in circulating FGF21 concentrations and their association with other metabolic markers in both obese and lean individuals. METHODS A total of 36 volunteers were assigned to 2 groups. One group received 3 standardized meals and another group was fasted for 24 h. Blood samples were drawn every 30 min throughout a 24-h period. Circulating FGF21 concentrations were measured with an in-house chemiluminescence immunoassay. The effects of fatty acids on hepatic production of FGF21 were determined by using real-time PCR. RESULTS In both the fasting and standardized meals groups, circulating FGF21 began to rise at midnight, reaching a peak in the early morning and then declining to basal concentrations early in the afternoon. Baseline concentrations of circulating FGF21 were much higher in obese individuals than in lean individuals (P < 0.05). However, the magnitude of the nocturnal rise in circulating FGF21 was significantly blunted in obese individuals. The 24-h oscillatory pattern of circulating FGF21 resembled that of free fatty acids and cortisol, but was opposite to the patterns of insulin and glucose. Unsaturated fatty acids induced time-dependent expression of FGF21 mRNA in human hepatocytes. CONCLUSIONS These findings support the role of FGF21 as an important metabolic regulator that integrates the circadian rhythm with energy homeostasis in humans. Diurnal rhythms of circulating FGF21 could be partly caused by the oscillation of free fatty acids.

Serum betatrophin concentrations are significantly increased in overweight but not in obese or type 2 diabetic individuals.

In this study, circulating serum betatrophin levels were quantitated and their relationships with insulin resistance (IR) and other metabolic parameters in Chinese subjects with varying degrees of obesity and glucose tolerance were examined.

Visceral fat area as a new predictor of short-term diabetes remission after Roux-en-Y gastric bypass surgery in Chinese patients with a body mass index less than 35 kg/m2.

BACKGROUND Metabolic surgery has been proposed for inadequately controlled type 2 diabetes mellitus (T2DM) in association with obesity. However, prediction of successful T2DM remission after surgery has not been clearly studied in Chinese patients. The objective of this study was to predict the outcome in those with T2DM after metabolic surgery to help in patient selection. METHODS A retrospective review of prospectively collected data of 68 ethnic Chinese with mean body mass index (BMI) of 31.5 and T2DM were examined for the metabolic outcomes at 1 year after Roux-en-Y gastric bypass (RYGB). Visceral and abdominal subcutaneous fat areas were assessed using magnetic resonance imaging before and 1 year after RYGB. Remission was defined as a glycated hemoglobin (HbA1 c)<6.5% and no medications at 1 year. Binary logistic regression analysis was used to identify predictors. RESULTS At 1 year after surgery, the BMI in the study group decreased from 31.5±3.6 to 24.5±2.5 kg/m2. Remission was achieved in 50 patients (73.5%) at 1 year. Compared with patients in the nonremission group, patients in the remission group had a shorter duration of diabetes, lower preoperative HbA1 c level, higher fasting C-peptide level, and more visceral fat area (VFA). Preoperative BMI and waist circumference did not differ between the 2 groups. CONCLUSION The metabolic improvement in T2DM after RYGB in the mildly obese is greater with a shorter duration of diabetes, higher fasting C-peptide. Those who have more visceral adiposity may obtain greater benefit from RYGB.

Protective role of PGC-1α in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling.

The overproduction of mitochondrial reactive oxygen species (ROS) plays a key role in the pathogenesis of diabetic nephropathy (DN). However, the underlying molecular mechanism remains unclear. Our aim was to investigate the role of PGC-1α in the pathogenesis of DN. Rat glomerular mesangial cells (RMCs) were incubated in normal or high glucose medium with or without the PGC-1α-overexpressing plasmid (pcDNA3-PGC-1α) for 48 h. In the diabetic rats, decreased PGC-1α expression was associated with increased mitochondrial ROS generation in the renal cortex, increased proteinuria, glomerular hypertrophy, and higher glomerular 8-OHdG (a biomarker for oxidative stress). In vitro, hyperglycemia induced the downregulation of PGC-1α, which led to increased DRP1 expression, increased mitochondrial fragmentation and damaged network structure. This was associated with an increase in ROS generation and mesangial cell hypertrophy. These pathological changes were reversed in vitro by the transfection of pcDNA3-PGC-1α. These data suggest that PGC-1α may protect DN via the inhibition of DRP1-mediated mitochondrial dynamic remodeling and ROS production. These findings may assist the development of novel therapeutic strategies for patients with DN.

Vitamin D deficiency increases the risk of retinopathy in Chinese patients with Type 2 diabetes

To investigate the relationship between vitamin D deficiency and diabetic retinopathy.

Circulating Unsaturated Fatty Acids Delineate the Metabolic Status of Obese Individuals

Background Obesity is not a homogeneous condition across individuals since about 25–40% of obese individuals can maintain healthy status with no apparent signs of metabolic complications. The simple anthropometric measure of body mass index does not always reflect the biological effects of excessive body fat on health, thus additional molecular characterizations of obese phenotypes are needed to assess the risk of developing subsequent metabolic conditions at an individual level. Methods To better understand the associations of free fatty acids (FFAs) with metabolic phenotypes of obesity, we applied a targeted metabolomics approach to measure 40 serum FFAs from 452 individuals who participated in four independent studies, using an ultra-performance liquid chromatograph coupled to a Xevo G2 quadruple time-of-flight mass spectrometer. Findings FFA levels were significantly elevated in overweight/obese subjects with diabetes compared to their healthy counterparts. We identified a group of unsaturated fatty acids (UFAs) that are closely correlated with metabolic status in two groups of obese individuals who underwent weight loss intervention and can predict the recurrence of diabetes at two years after metabolic surgery. Two UFAs, dihomo-gamma-linolenic acid and palmitoleic acid, were also able to predict the future development of metabolic syndrome (MS) in a group of obese subjects. Interpretation These findings underscore the potential role of UFAs in the MS pathogenesis and also as important markers in predicting the risk of developing diabetes in obese individuals or diabetes remission after a metabolic surgery.

Oral Supplementation with Cholecalciferol 800 IU Ameliorates Albuminuria in Chinese Type 2 Diabetic Patients with Nephropathy

Background Low vitamin D levels can be associated with albuminuria, and vitamin D analogs are effective anti-proteinuric agents. The aim of this study was to investigate differences in vitamin D levels between those with micro- and those with macroalbuminuria, and to determine whether low dose cholecalciferol increases vitamin D levels and ameliorates albuminuria. Methods Two studies were performed in which 25-OH vitamin D3 (25(OH)D3) concentrations were determined by electrochemiluminescence immunoassay: 1) a cross-sectional study of patients with type 2 diabetes mellitus (T2DM) (n = 481) and healthy controls (n = 78); and 2) a longitudinal study of T2DM patients with albuminuria treated with conventional doses, 800 IU, of cholecalciferol for 6 months (n = 22), and a control group (n = 24). Results 1) Cross-sectional study: Compared to controls and T2DM patients with normoalbuminuria, serum 25(OH)D3 concentrations were significantly lower in patients with macro-albuminuria, but not in those with micro-albuminuria. Serum 25(OH)D3 levels were independently correlated with microalbuminuria. 2) Longitudinal study: Cholecalciferol significantly decreased microalbuminuria in the early stages of treatment, in conjunction with an increase in serum 25(OH)D3 levels. Conclusions Low vitamin D levels are common in type 2 diabetic patients with albuminuria, particularly in patients with macroalbuminuria, but not in those with microalbuminuria. Conventional doses of cholecalciferol may have antiproteinuric effects on Chinese type 2 diabetic patients with nephropathy.

The combination of carotid and lower extremity ultrasonography increases the detection of atherosclerosis in type 2 diabetes patients.

OBJECTIVE To evaluate the prevalence of atherosclerosis detected by both carotid and lower extremity ultrasonography in hospitalized Chinese type 2 diabetic patients and to examine whether plaque formation in the carotid arteries could be an indicator of generalized atherosclerosis in type 2 diabetes mellitus. METHODS Totally, 709 hospitalized Chinese type 2 diabetic patients (men 357, women 352) aged from 18 to 88 years were included. Both carotid and lower extremity atherosclerosis were assessed by Doppler ultrasound. Atherosclerosis was defined as the presence of either the carotid or lower extremity plaque in any of the above-mentioned arteries segments. The prevalence of atherosclerosis was calculated, and the risk factors associated with atherosclerosis were evaluated using binary logistic regression. RESULTS The prevalence of atherosclerosis was 81.23% in male and 77.56% in female type 2 diabetic patients, respectively. There was no significant difference in the prevalence of atherosclerosis in patients between the sexes. The prevalence of atherosclerosis was significantly higher in the lower extremity arteries than in the carotid arteries (73.91% and 44.43%, respectively, P<.001). Atherosclerosis was significantly associated with smoking, age, duration of diabetes, systolic blood pressure, total number of white blood cells, and mean carotid and femoral intima-media thickness (IMT). CONCLUSIONS The prevalence of atherosclerosis was very high in Chinese inpatients with type 2 diabetes. Carotid atherosclerosis could not be an indicator of generalized atherosclerosis in type 2 diabetes. The combination of carotid and lower extremity ultrasound examination can significantly improve the detection of atherosclerosis in type 2 diabetes.

A Microalbuminuria Threshold to Predict the Risk for the Development of Diabetic Retinopathy in Type 2 Diabetes Mellitus Patients

Objective To test the hypothesis that a microalbuminuria (MA) threshold can help predict the risk for the development of diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM)_ patients. Design We conducted a cross-sectional study of 4739 subjects with T2DM and a prospective study of 297 subjects with T2DM in China respectively. Methods Clinical and laboratory data were collected and biologic risk factors associated with any DR were analysed. Results In the cross-sectional study, we found that MA was an independent risk factor for DR development; further, when the patients were divided into MA deciles, odds ratio (ORs) of DR for the patients in the sixth MA decile (10.7 mg/24 h) was 1.579-fold (1.161–2.147) compared to that for patients in the first MA decile. Furthermore, the OR of DR increased with a gradual increase in MA levels. Similarly, in the prospective study, during a mean follow-up of 4.5 years, we found that 51 patients (29.0%) of the 176 subjects with high MA level (10.7–30 mg/24 h) developed DR, while 17 patients (14.1%) of the 121 subjects with lower MA (<10.7 mg/24 h) developed DR, and the relative risk ratio of the development of DR is 2.13(95% CI, 1.58–3.62, P<0.001). Conclusion These data suggest that an MA threshold can predict the risk for the development of DR in type 2 diabetes mellitus, although it is still within the traditionally established normal range.

Metabolomics Study of Roux-en-Y Gastric Bypass Surgery (RYGB) to Treat Type 2 Diabetes Patients Based on Ultraperformance Liquid Chromatography–Mass Spectrometry

Roux-en-Y gastric bypass (RYGB) is one of the most effective treatments for long-term weight loss and diabetes remission; however, the mechanisms underlying these changes are not clearly understood. In this study, the serum metabolic profiles of 23 remission and 12 nonremission patients with type 2 diabetes mellitus (T2DM) were measured at baseline, 6- and 12-months after RYGB. A metabolomics analysis was performed based on ultra-performance liquid chromatography-mass spectrometry. Clinical improvements in insulin sensitivity, energy metabolism, and inflammation were related to metabolic alterations of free fatty acids (FFAs), acylcarnitines, amino acids, bile acids, and lipids species. Differential metabolic profiles were observed between the two T2DM subgroups, and patients with severity fat accumulation and oxidation stress may be more suitable for RYGB. Baseline levels of tryptophan, bilirubin, and indoxyl sulfate measured prior to surgery as well as levels of FFA 16:0, FFA 18:3, FFA 17:2, and hippuric acid measured at 6 months after surgery best predicted the suitability and efficacy of RYGB for patients with T2DM. These metabolites represent potential biomarkers that may be clinically helpful in individualized treatment for T2DM patients by RYGB.