Asprosin, a novel glucogenic adipokine implicated in type 2 diabetes mellitus.

Asprosin, encoded by penultimate two exons (exon 65 and exon 66) of the gene Fibrillin 1 (FBN1), has been recently discovered to be a novel hormone secreted by white adipose tissues during fasting. The glucose metabolism disorders are often accompanied by increased asprosin level. Previous research suggests that asprosin may contribute to the development of diabetes by regulating glucose homeostasis, appetite, insulin secretion, and insulin sensitivity. In this review, we summarize the recent findings from studies on asprosin and its association with Type 2 diabetes mellitus, and discusses its mechanisms from various aspects, so as to provide clinical diagnosis and treatment ideas for T2DM.

X-box binding protein 1: A new metabolic mediator and drug target of metformin?

Accumulating evidence has demonstrated that metformin improved hypertriglyceridemia. The present study aim to investigate the molecular mechanism by which metformin improves hypertriglyceridemia via regulation of diacylglycerol O-acyltransferase 2 (DGAT2) and X-box binding protein 1 (XBP1) in the liver and whether AMP-activated protein kinase (AMPK) is involved. Mice were fed a high-fat diet (HFD) or high-fat diet with metformin for 5 weeks to evaluate the effect of metformin on triglyceride (TG) levels and expression of DGAT2 and XBP1 in the liver. In vitro HepG2 cells or XBP1 knockout AML12 hepatocytes were stimulated with metformin, palmitic acid or small interfering RNA inducing XBP1 knockdown, or dominant-negative mutant AMPK plasmid. Metformin treatment reduced hepatic TG levels in the liver of HFD-fed mice. Expression of nuclear and cytoplasmic XBP1 protein and its downstream target gene DGAT2 decreased in the liver of HFD-fed mice and HepG2 cells after metformin treatment. AMPK inactivation or overexpression of XBP1 attenuates this effect. Our preliminary results demonstrate that metformin activates AMPK to reduce TG synthesis by inhibiting the XBP1-mediated DGAT2 pathway, at least in part, suggesting that XBP1 is a new metabolic mediator for metformin treatment of hypertriglyceridemia and associated metabolic disease.

A phase 1b randomised controlled trial of a glucagon-like peptide-1 and glucagon receptor dual agonist IBI362 (LY3305677) in Chinese patients with type 2 diabetes.

The success of glucagon-like peptide-1 (GLP-1) receptor agonists to treat type 2 diabetes (T2D) and obesity has sparked considerable efforts to develop next-generation co-agonists that are more effective. We conducted a randomised, placebo-controlled phase 1b study (ClinicalTrials.gov: NCT04466904) to evaluate the safety and efficacy of IBI362 (LY3305677), a GLP-1 and glucagon receptor dual agonist, in Chinese patients with T2D. A total of 43 patients with T2D were enrolled in three cohorts in nine study centres in China and randomised in each cohort to receive once-weekly IBI362 (3.0 mg, 4.5 mg or 6.0 mg), placebo or open-label dulaglutide (1.5 mg) subcutaneously for 12 weeks. Forty-two patients received the study treatment and were included in the analysis, with eight receiving IBI362, four receiving placebo and two receiving dulaglutide in each cohort. The patients, investigators and study site personnel involved in treating and assessing patients in each cohort were masked to IBI362 and placebo allocation. Primary outcomes were safety and tolerability of IBI362. Secondary outcomes included the change in glycated haemoglobin A1c (HbA1c), fasting plasma glucose (FPG) and post-mixed-meal tolerance test (post-MTT) glucose levels. IBI362 was well tolerated. Most commonly-reported treatment-emergent adverse events were diarrhoea (29.2% for IBI362, 33.3% for dulaglutide, 0% for placebo), decreased appetite (25.0% for IBI362, 16.7% for dulaglutide, 0% for placebo) and nausea (16.7% for IBI362, 16.7% for dulaglutide and 8.3% for placebo). HbA1c, FPG and post-MTT glucose levels were reduced from baseline to week 12 in patients receiving IBI362 in all three cohorts. IBI362 showed a favourable safety profile and clinically meaningful reductions in blood glucose in Chinese patients with T2D.

Effects of lifestyle interventions on glucose regulation and diabetes risk in adults with impaired glucose tolerance or prediabetes: a meta-analysis

ABSTRACT The prevalence of diabetes mellitus is increasing and is related to sedentary lifestyles and obesity. Many studies were published on the effect of lifestyle interventions on glucose regulation and delay the onset of diabetes in adults with impaired glucose tolerance (IGT) or prediabetes. This study aimed to investigate the role of lifestyle interventions in individuals with IGT or prediabetes using a meta-analytic approach. PubMed, Embase, and the Cochrane Central Register of Controlled Trials databases were searched from their inception up to January 2020 to select eligible randomized controlled trials (RCTs). The weighted mean difference (WMD; for fasting plasma glucose (FPG) and 2-hour plasma glucose (2hPPG)) or relative risk (RR; for the risk of diabetes) with 95% confidence interval (CI) were calculated for pooled effect estimates using the random-effects model. Thirteen RCTs involving 3376 individuals with IGT or prediabetes were selected for this meta-analysis. The results showed that lifestyle interventions were associated with lower FPG (WMD: -0.14; 95% CI: -0.24 to -0.05 mmol/L; p=0.004) and 2hPPG (WMD: -0.66; 95% CI: -1.12 to -0.20 mmol/L; p=0.005) in adults with IGT or prediabetes. Moreover, the risk of diabetes was significantly reduced in individuals who received lifestyle interventions (RR: 0.75; 95% CI: 0.60-0.95; p=0.015). Lifestyle interventions could help improve glucose dysregulation and prevent the progression of diabetes in adults with IGT or prediabetes. Further large-scale RCTs should be conducted to assess the effects of long-term lifestyle interventions on diabetic complications in adults with IGT or prediabetes.

Constitutive Androstane Receptor-Mediated Inhibition of Metformin on Phase II Metabolic Enzyme SULT2A1.

BACKGROUND: Metformin, as a first-line treatment for diabetes, interacts with many protein kinases and transcription factors which affect the expression of downstream target genes governing drug metabolism. Sulfotransferase, SULT2A1, one phase II metabolic enzyme, sulfonates both xenobiotic and endobiotic compounds to accelerate drug excretion. Herein, we designed experiments to investigate the effects and mechanisms of metformin on SULT2A1 expression in vitro. METHODS: The hepatocellular carcinoma cell line, HepaRG, was cultured with different concentrations of metformin. The cell viability was measured using CCK8 kit. HepaRG was used to evaluate the protein expression of pregnane X receptor (PXR), the constitutive androstane receptor (CAR), SULT2A1, AMP-activated protein kinase (AMPK), and phosphorylation of AMPK (p-AMPK), respectively, at different concentrations of metformin with or without rifampin (human PXR activator) and CITCO (human CAR activator). The coregulators with CAR on SULT2A1 promoter response elements have also been characterized. RESULTS: We showed that metformin did not affect the basic expression of SULT2A1 but could suppress the expression of SULT2A1 induced by the activator of human CAR. Investigations revealed that metformin which could block CAR nuclear translocation further suppress SULT2A1. In addition, we found that the prevented CAR transfer into the nucleus by metformin was partially an AMPK-dependent event. CONCLUSION: The present study indicated that the activation of AMPK-CAR pathway mediated the suppression of SULT2A1 by metformin. Metformin may affect the metabolism and clearance of drugs which are SULT2A1 substrates. The results that emerged from this work provide substantial insights into an appropriate medication in the treatment of diabetes patients.

MREG suppresses thyroid cancer cell invasion and proliferation by inhibiting Akt-mTOR signaling.

Thyroid cancer has long been considered to arise in middle age and progress to more aggressive and lethal cancers after its repeated proliferation. In this research, we aimed at investigating the biological function and the underlying molecular mechanism of Melanoregulin (MREG) in thyroid cancer. It was found that the expression of MREG was significantly downregulated in thyroid cancer tissues. The downregulation of MREG expression was caused by epigenetic methylation. MREG overexpression could suppress the invasion and proliferation of thyroid cancer cells. While MREG knockdown promoted the invasion and proliferation of thyroid cancer cells. Furthermore, the phosphorylation of Akt or mTOR was decreased by MREG overexpression and increased by MREG knockdown. Moreover, Dactolisib (the inhibitor of mTOR) could abrogate silenced MREG induced thyroid cancer cell invasion and proliferation. Taken together, MREG regulates thyroid cancer cell invasion and proliferation through PI3K/Akt-mTOR signaling pathway. MREG may serve as a promising therapeutic strategy for thyroid cancer.

The effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats.

To understand metformin's effects on fibroblast growth factors (FGFs) and fibroblast growth factor receptor 1 (FGFR1), we investigated circulating fibroblast growth factor-19 (FGF19), FGF21 levels, and FGFR1 in type 2 diabetes mellitus (T2DM). In addition, protein kinase B (Akt) signaling pathway was detected to explain the possible mechanisms. T2DM was induced by feeding rats with high-fat diet for 11 weeks, followed by a low dose of streptozotocin (STZ, 30-35 mg/kg, intraperitoneally). Control rats (Con) were fed on a normal chow; diabetic rats (DM) were fed on high-fat diet supplemented with or without metformin (METF) for 12 weeks (500 mg·kg-1·d-1). Biochemical parameters were detected at the end of 24th weeks. FGFR1 expression and protein kinase B (Akt) phosphorylation in the pancreas and visceral adipose tissues were detected using either Western blot (WB) or immunohistochemistry (IHC). Serum FGF19 and FGF21 were measured using enzyme-linked immune sorbent assay (ELISA). Metformin treated DM rats showed improved glucose, lipid and bile acid metabolism. Besides, significantly decreased FGF19 and increased FGF21 were observed in DM+METF rats. DM rats showed significantly increased FGFR1 both in the pancreas and visceral adipose tissues. While in DM+METF rats, FGFR1 was almost remained at a normal level in the pancreas and increased in the visceral adipose tissue compared to that in DM rats. Besides, metformin treatment restores Akt phosphorylation in both tissues. The altered glucose and lipid profiles by metformin treatment may be associated with the increased circulating FGF21 and tissue-specific expressions of FGFR1.

Expression of BMP-4 in papillary thyroid carcinoma and its correlation with tumor invasion and progression.

Bone morphogenetic protein 4 (BMP-4) is a member of the BMP protein family. BMP-4 was reported to induce epithelial-mesenchymal transition (EMT) and promote tumor cell immigration and invasion. This study aimed to investigate the expression of BMP-4 in papillary thyroid carcinoma (PTC) and its correlation with the patients' clinicophathological features and with tumor invasion and metastasis. Surgically resected PTC specimens from 82 patients admitted to the Department of Thyroid Surgery of Yantai Yuhuangding Hospital between Feb 1st and May 31st, 2016 were collected. The expression level of BMP-4 in PTC tissues was examined by immunohistochemical staining. The full clinical records of all patients were collected to analyze the relevance between BMP-4 expression and the clinical pathological features of PTC. Our result showed that BMP-4-positive cell rate and staining intensity were positively correlated with the patient's age (P=0.031, 0.037), tumor size (P=0.033, 0.019), capsular invasion (P=0.001, 0.002) and TNM stage (P=0.001, 0.004), while not correlated with gender, multicentricity of tumor or lymphatic metastasis. In conclusion, this study identified BMP-4 as a potential molecular marker for predicting the invasion and progression of PTC.

Treatment with acarbose in severe hypoglycaemia due to late dumping syndrome / Tratamiento con acarbosa en la hipoglicemia severa debido al síndrome de dumping tardío

BACKGROUND: We present a case of recurrent loss of consciousness, which was finally accurately diagnosed as late dumping syndrome twelve years after subtotal gastrectomy and successfully treated with acarbose. A 66-year old lean male was found unconscious repeatedly within one year. Oral glucose tolerance tests performed before and after acarbose treatment verified the diagnosis of late dumping syndrome. Acarbose can be used as a successful treatment modality for reactive hypoglycaemia due to late dumping syndrome by influencing the release of hormone.

ANTECEDENTES: Presentamos un caso de pérdida recurrente de conciencia, que fue finalmente diagnosticado con precisión como síndrome de dumping tardío, doce años después de la gastrectomía subtotal, y tratado con éxito con acarbosa. Un hombre magro de 66 años de edad fue encontrado inconsciente repetidas veces en un año. Las pruebas orales de tolerancia a la glucosa realizadas antes y después del tratamiento con acarbosa verificaron el diagnóstico de síndrome de dumping tardío. La acarbosa puede utilizarse como una modalidad de tratamiento acertado para la hipoglicemia reactiva debido al síndrome de dumping tardío por la influencia en la liberación de hormonas.

Treatment with acarbose in severe hypoglycaemia due to late dumping syndrome.

Dumping syndrome is a serious complication that may occur after gastric surgery in approximately 10% of patients in the 1990s. With the increasing number of patients undergoing bariatric surgery, the incidence of dumping syndrome is likely to increase in recent years. It is necessary for clinicians to recognize the syndrome and master its management. We present a case of recurrent loss of consciousness, which was finally accurately diagnosed as late dumping syndrome twelve years after subtotal gastrectomy and successfully treated with acarbose. A 66-year old lean male was found unconscious repeatedly within one year, oral glucose tolerance tests performed before and after acarbose treatment verified the diagnosis of late dumping syndrome. Hypoglycaemia can damage the body in acute and chronic form. Acarbose can be used as a successful treatment modality for reactive hypoglycaemia due to late dumping syndrome by influencing the release of hormone.