Branched-chain amino acids supplementation induces insulin resistance and pro-inflammatory macrophage polarization via INFGR1/JAK1/STAT1 signal pathway.

BACKGROUND: Obesity is a global epidemic, and the low-grade chronic inflammation of adipose tissue in obese individuals can lead to insulin resistance and type 2 diabetes. Adipose tissue macrophages (ATMs) are the main source of pro-inflammatory cytokines in adipose tissue, making them an important target for therapy. While branched-chain amino acids (BCAA) have been strongly linked to obesity and type 2 diabetes in humans, the relationship between BCAA catabolism and adipose tissue inflammation is unclear. This study aims to investigate whether disrupted BCAA catabolism influences the function of adipose tissue macrophages and the secretion of pro-inflammatory cytokines in adipose tissue, and to determine the underlying mechanism. This research will help us better understand the role of BCAA catabolism in adipose tissue inflammation, obesity, and type 2 diabetes. METHODS: In vivo, we examined whether the BCAA catabolism in ATMs was altered in high-fat diet-induced obesity mice, and if BCAA supplementation would influence obesity, glucose tolerance, insulin sensitivity, adipose tissue inflammation and ATMs polarization in mice. In vitro, we isolated ATMs from standard chow and high BCAA-fed group mice, using RNA-sequencing to investigate the potential molecular pathway regulated by BCAA accumulation. Finally, we performed targeted gene silence experiment and used immunoblotting assays to verify our findings. RESULTS: We found that BCAA catabolic enzymes in ATMs were influenced by high-fat diet induced obesity mice, which caused the accumulation of both BCAA and its downstream BCKA. BCAA supplementation will cause obesity and insulin resistance compared to standard chow (STC) group. And high BCAA diet will induce pro-inflammatory cytokines including Interlukin-1beta (IL-1ß), Tumor Necrosis Factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) secretion in adipose tissue as well as promoting ATMs M1 polarization (pro-inflammatory phenotype). Transcriptomic analysis revealed that a high BCAA diet would activate IFNGR1/JAK1/STAT1 pathway, and IFNGR1 specific silence can abolish the effect of BCAA supplementation-induced inflammation and ATMs M1 polarization. CONCLUSIONS: The obesity mice model reveals the catabolism of BCAA was disrupted which will cause the accumulation of BCAA, and high-level BCAA will promote ATMs M1 polarization and increase the pro-inflammatory cytokines in adipose tissue which will cause the insulin resistance in further. Therefore, reducing the circulating level of BCAA can be a therapeutic strategy in obesity and insulin resistance patients.

The Cardiovascular Benefits of Glucagon-Like Peptide-1 Receptor Agonists as Novel Diabetes Drugs Are Mediated via the Suppression of miR-203a-3p and miR-429 Expression.

Coronary artery disease (CAD) is associated with a high fatality rate and a heavy global health care burden. Glucagon-like peptide-1 (GLP-1) exerts positive cardiovascular effects, although the molecular mechanisms are unclear. Therefore, this study aimed to verify whether the cardioprotective effects of GLP-1 are mediated through the regulation of micro-RNA (miRNA) expression. Follow-up assessments were conducted for 116 patients with type 2 diabetes mellitus (T2DM) alone (controls) and 123 patients with both T2DM and CAD. After matching, each group comprised 63 patients, and age, body mass index, and serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglycerides (TG), and hemoglobin A1C (HbA1c) were compared. Subsequently, the expression profiles of four circulating miRNAs (miR-203a-3p, miR-429, miR-205-5p, and miR-203b-5p) were assessed via quantitative reverse transcription real-time polymerase chain reaction in the 63 patients with diabetes and CAD between 6 months (baseline) and 12 months after the initiation of GLP-1 receptor (GLP-1R) therapy. As expected, the metabolic factors were significantly improved after 6 months of treatment with GLP-1R compared with pre-treatment values, and the expression levels of two of the miRNAs (miR-203a-3p and miR-429) decreased from baseline levels in those with diabetes and CAD. The results suggest that the cardiovascular benefits induced by GLP-1R are mediated via suppressed expression of two miRNAs: miR-203a-3p and miR-429.

A novel homozygous CYP17A1 mutation causes partial 17 α-hydroxylase/17,20-lyase deficiency in 46,XX: a case report and literature review.

Aim: 17 α-hydroxylase/17,20-lyase deficiency (17-OHD) is an extremely rare autosomal recessive disorder that typically causes hypertension, hypokalaemia, primary amenorrhoea, and the absence of secondary sex characteristics in 46,XX individuals. Partial 17-OHD is even rarer than complete 17-OHD and is prone to missed diagnosis due to its subtler symptoms. The aim of this study was to help early detection and diagnosis of partial 17-OHD.Methods: We present a case of a 41-year-old female (46,XX) patient with partial 17-OHD caused by a novel missense CYP17A1 mutation, c.391 A > C (p.T131P). This patient experienced hypertension, hypokalaemia and adrenal hyperplasia, but did not present with primary amenorrhoea or absence of secondary sex characteristics. Initially, she was misdiagnosed and underwent right and left adrenalectomy, but the procedures were ineffective. Afterward, she received a one-month treatment of 0.5 mg dexamethasone, which greatly relieved her symptoms. Additionally, we reviewed reports of thirteen other patients with partial 17-OHD in 46,XX individuals from the literature, totalling fourteen probands.Results: We found that primary amenorrhoea, hypertension, hypokalaemia, and ovarian cysts accounted for 15.4%, 42.9%, 38.5%, and 72.7% of these patients, respectively. In contrast, elevated serum progesterone was present in all patients.Conclusion: Based on our literature review, the absence of primary amenorrhoea, hypertension or hypokalaemia cannot rule out suspicion for 17-OHD in 46,XX individuals. However, an elevation in serum progesterone levels is a highly sensitive indicator for diagnosing 17-OHD.

What is the context?17-OHD is a rare cause of secondary hypertension, often with hypokalaemia, primary amenorrhoea and absence of secondary sex characteristics.Partial 17-OHD is an even rarer subtype of 17-OHD, with subtler symptoms.There are few reports concerning partial 17-OHD, especially in 46,XX patients.What is new?We reported a case of a 46,XX patient with partial 17-OHD caused by a novel missense CYP17A1 mutation, c.391 A > C (p.T131P).We also conducted a literature review to summarise the clinical, hormonal and genetic characteristics of fourteen 46,XX probands with partial 17-OHD.From the literature review, we found that:Most 46,XX patients with partial 17-OHD presented with partial pubic hair, breast development, oligomenorrhea or secondary amenorrhoea, normotension, and/or normokalemia.All 46,XX patients with partial 17-OHD presented with elevated serum progesterone.However, the relationship between in vitro enzyme activities of the 17-hydroxylase and/or17,20-lyase and clinical severity is still unclear.What is the impact?The current study can help early detection and diagnosis of partial 17-OHD.

Type 2 diabetes mellitus-related environmental factors and the gut microbiota: emerging evidence and challenges.

The gut microbiota is a group of over 38 trillion bacterial cells in the human microbiota that plays an important role in the regulation of human metabolism through its symbiotic relationship with the host. Changes in the gut microbial ecosystem are associated with increased susceptibility to metabolic disease in humans. However, the composition of the gut microbiota in those with type 2 diabetes mellitus and in the pathogenesis of metabolic diseases is not well understood. This article reviews the relationship between environmental factors and the gut microbiota in individuals with type 2 diabetes mellitus. Finally, we discuss the goal of treating type 2 diabetes mellitus by modifying the gut microbiota and the challenges that remain in this area.

Type 2 diabetes mellitus-related environmental factors and the gut microbiota: emerging evidence and challenges

The gut microbiota is a group of over 38 trillion bacterial cells in the human microbiota that plays an important role in the regulation of human metabolism through its symbiotic relationship with the host. Changes in the gut microbial ecosystem are associated with increased susceptibility to metabolic disease in humans. However, the composition of the gut microbiota in those with type 2 diabetes mellitus and in the pathogenesis of metabolic diseases is not well understood. This article reviews the relationship between environmental factors and the gut microbiota in individuals with type 2 diabetes mellitus. Finally, we discuss the goal of treating type 2 diabetes mellitus by modifying the gut microbiota and the challenges that remain in this area.