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Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.

Leucine deprivation improves insulin sensitivity; however, whether and how this effect can be extended are unknown. We hypothesized that intermittent leucine deprivation (ILD) might produce a long-term effect on improved insulin sensitivity via the formation of metabolic memory. Consistently, seven ILD cycles of treatment (1-day leucine-deficient diet, 3-day control diet) in mice produced a long-lasting (after a control diet was resumed for 49 days) effect on improved whole-body and hepatic insulin sensitivity in mice, indicating the potential formation of metabolic memory. Furthermore, the effects of ILD depended on hepatic general control nondepressible 2 (GCN2) expression, as verified by gain- and loss-of-function experiments. Moreover, ILD increased Gcn2 expression by reducing its DNA methylation at two CpG promoter sites controlled by demethylase growth arrest and DNA damage inducible b. Finally, ILD also improved insulin sensitivity in insulin-resistant mice. Thus, ILD induces long-lasting improvements in insulin sensitivity by increasing hepatic Gcn2 expression via a reduction in its DNA methylation. These results provide novel insights into understanding of the link between leucine deprivation and insulin sensitivity, as well as potential nutritional intervention strategies for treating insulin resistance and related diseases. We also provide evidence for liver-specific metabolic memory after ILD and novel epigenetic mechanisms for Gcn2 regulation. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the pathogenesis of steatosis and insulin resistance in nonalcoholic fatty liver disease remain elusive. Increased phosphorylation of hepatic p38 has long been noticed in fatty liver; however, whether the activation of hepatic p38 is a cause or consequence of liver steatosis is unclear. Here, we demonstrate that hepatic p38 activation by MKK6 overexpression in the liver of mice induces severe liver steatosis, reduces fat mass, and elevates circulating fatty acid levels in a hepatic p38α- and FGF21-dependent manner. Mechanistically, through increasing FGF21 production from liver, hepatic p38 activation increases the influx of fatty acids from adipose tissue to liver, leading to hepatic ectopic lipid accumulation and insulin resistance. Although hepatic p38 activation exhibits favorable effects in peripheral tissues, it impairs the hepatic FGF21 action by facilitating the ubiquitination and degradation of FGF21 receptor cofactor β-Klotho. Consistently, we show that when p38 phosphorylation and FGF21 expression are increased, β-Klotho protein levels are decreased in the fatty liver of both mice and patients. In conclusion, our study reveals previously undescribed effects of hepatic p38 activation on systemic metabolism and provides new insights into the roles of hepatic p38α, FGF21, and β-Klotho in the pathogenesis of nonalcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]

Neuregulin 4 (Nrg4), an adipose tissue-enriched endocrine factor, participates in adipocyte-to-hepatocyte communication, eliciting beneficial metabolic effects in nonalcoholic fatty liver disease (NAFLD). We evaluate the physiological roles of NRG4 in humans and unravel the role of NRG4 variants in the pathogenesis of NAFLD and related metabolic disorders. We identified two rare missense mutations-p.R44H and p.E47Q-in the NRG4 EGF-like domain by whole-exome sequencing in 224 severely obese subjects and exome genotyping in 2,388 subjects from the Shanghai Obesity Study. The overexpression animal models showed that wild-type (WT) Nrg4 could attenuate high-fat diet-induced hepatic lipogenesis and improve energy metabolism. Nrg4 E47Q enhanced the protective effect, whereas Nrg4 R44H lost this function. Unlike Nrg4 R44H, Nrg4 E47Q activated the phosphorylation of ErbB4 and negatively regulated de novo lipogenesis through the ErbB4-STAT5-SREBP-1C pathway. The surface plasmon resonance experiments revealed a higher affinity of E47Q Nrg4 than WT to bind ErbB4, while R44H showed no binding. In conclusion, the study suggests that genetic variations in NRG4 could produce mutant proteins with aberrant functions and that impaired or enhanced Nrg4 function could be either a risk factor or a protective factor for NAFLD and associated metabolic disorders. [ABSTRACT FROM AUTHOR]

The incidence of type 2 diabetes (T2D) has rapidly increased over recent decades, and T2D has become a leading public health challenge in China. Compared with European descents, Chinese patients with T2D are diagnosed at a relatively young age and low BMI. A better understanding of the factors contributing to the diabetes epidemic is crucial for determining future prevention and intervention programs. In addition to environmental factors, genetic factors contribute substantially to the development of T2D. To date, more than 100 susceptibility loci for T2D have been identified. Individually, most T2D genetic variants have a small effect size (10-20% increased risk for T2D per risk allele); however, a genetic risk score that combines multiple T2D loci could be used to predict the risk of T2D and to identify individuals who are at a high risk. Furthermore, individualized antidiabetes treatment should be a top priority to prevent complications and mortality. In this article, we review the epidemiological trends and recent progress in the understanding of T2D genetic etiology and further discuss personalized medicine involved in the treatment of T2D. [ABSTRACT FROM AUTHOR]

The article offers the author's comments on the article "Impact of common diabetes risk variant in MTNR1B on sleep, circadian, and melatonin physiology" by J. M. Lane and colleagues. Topics include the diurnal pattern of melatonin secretion, the effect of the rs10830963 melatonin risk allele on type 2 diabetes (T2D) risk, and the association of sleep or circadian rhythms in the study.

OBJECTIVE--Hepatocyte nuclear factor 1β (HNF1β) is a transcription factor that is critical for pancreatic cell formation and glucose homeostasis. Previous studies have reported that common variants of HNF1β were associated with type 2 diabetes in Caucasians and West Africans. However, analysis in the subjects from the Botnia study and Malmö Preventive Project produced conflicting results, and the role for HNF1β in type 2 diabetes susceptibility remains unclear. We therefore investigated common variants across the HNF1β gene in a Chinese population. RESEARCH DESIGN AND METHODS--Fifteen tagging single nucleotide polymorphisms (SNPs) were analyzed for association with type 2 diabetes in subjects with type 2 diabetes (n = 1,859) and normal glucose regulation (n = 1,785). RESULTS--Consistent with the initial study, we observed evidence that the risk G allele of rs4430796 in intron 2 was significantly associated with type 2 diabetes (odds ratio 1.16 [95% CI 1.05-1.29], P = 0.0035, empirical P = 0.0475). Furthermore, the at-risk G allele was associated with earlier age at diagnosis in the type 2 diabetic subjects (P = 0.0228). CONCLUSIONS--The result of this study provides evidence that variants in the HNF1β region contribute to susceptibility to type 2 diabetes in the Chinese population. Diabetes 58:1023-1027, 2009 [ABSTRACT FROM AUTHOR]

Objectives: Bariatric surgery is emerging as the most effective treatment option for patients with obesity. Hypothalamic arcuate nucleus plays an important role in metabolic homeostasis. However, the influence of mutations related to the feeding center on weight loss after bariatric surgery is still unclear. We aimed to diagnose monogenic obesity by whole-exome sequencing (WES) and explore whether monogenic mutations influence the effectiveness of bariatric surgery. Methods: We collected obese patients aged 15 to 55 with a BMI >28 kg/m2 and who underwent laparoscopic sleeve gastrectomy from March 2011 to June 2017 in Shanghai. Data related to weight loss and metabolic characteristics preoperatively and postoperatively were collected, including fasting blood glucose (FBG), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides. WES was performed in obese patients using genomic DNA from whole blood samples. Results: We investigated the proportion of 131 obese adults with one mutation as high as to 8.4% and then evaluated the association between these mutations and weight loss. Mutation carriers had less weight loss over both short-term and long-term periods. Survival analyses indicated it was harder to attain the goal of 20% weight loss for mutation carriers (Plog-rank=0.001; Pbreslow<0.001), and the difference remained significant with a Cox regression model. Improvement in FBG, HDL cholesterol and triglycerides postoperatively were observed in both groups, while there were significant differences between the two groups. Conclusions: Our data indicated that 8.4% of obesity cases were caused by change in genetics, and mutations had negative effects on the efficacy of bariatric surgery. Disclosure: C. Hu: None. [ABSTRACT FROM AUTHOR]

In the previous study, we had identified four variants in the melanocortin-4 receptor (MC4R) gene in Chinese subjects. Three polymorphisms (nt-216C/T, nt-178A/C and V103I) were detected in both obese and non-obese subjects and one missense mutation (F261S) was found in an early-onset obesity pedigree. The aim of this study is to investigate the association between the polymorphisms of MC4R gene and obesity, and to analyze the functional defect of F261S mutation in MC4R. The genotypes of the three polymorphisms were determined through DNA sequencing in 563 Chinese from Shanghai, including 258 individuals with body mass index (BMI) over 30kg/m² and 305 individuals with BMI less than 23kg/m². |D'| and r² value were calculated. Signaling and cell surface expression of F261S MC4R were compared with that of wild-type MC4R in mammalian cells. Our data showed: 1. The frequencies of nt216C/T, nt-178A/C and Val103Ile were 1.6%, 2.5% and 3.2% respectively. Three polymorphisms were in low linkage disequilibrium. Logistic regression showed that the Val103Ile variant was an independent risk factor for obesity (OR=0.414, P=0.040). The frequency of Ile was less in the obese individuals compared with the controls. 2. α-MSH activation of MC4R was impaired by the F261S mutation. The α-MSH-stimulated reporter gene activity was significantly reduced in cells expressing F261S MC4R, with a maximal response equal to 57% of wild-type MC4R and the F261S mutation also led to a great change in the EC[sub 50] value compared with the wild-type receptor (P<0.01). By immunofluorescent assay, a marked reduction in the plasma membrane localization of the MC4R was detected in cells expressing the F261S mutant receptor. In conclusion: Val103Ile variant of MC4R gene was associated with obesity in Chinese. The decreased response to α-MSH resulted from the intracellular retention maybe the major cause of early-onset obesity of the F261S pedigree. [ABSTRACT FROM AUTHOR]

The incidence of type 2 diabetes (T2D) has rapidly increased over recent decades, and T2D has become a leading public health challenge in China. Compared with European descents, Chinese patients with T2D are diagnosed at a relatively young age and low BMI. A better understanding of the factors contributing to the diabetes epidemic is crucial for determining future prevention and intervention programs. In addition to environmental factors, genetic factors contribute substantially to the development of T2D. To date, more than 100 susceptibility loci for T2D have been identified. Individually, most T2D genetic variants have a small effect size (10-20% increased risk for T2D per risk allele); however, a genetic risk score that combines multiple T2D loci could be used to predict the risk of T2D and to identify individuals who are at a high risk. Furthermore, individualized antidiabetes treatment should be a top priority to prevent complications and mortality. In this article, we review the epidemiological trends and recent progress in the understanding of T2D genetic etiology and further discuss personalized medicine involved in the treatment of T2D., (© 2017 by the American Diabetes Association.)