Abstract

Angiopoietin-like 8 (ANGPTL8) a hepatic protein, implicated by several studies with a role in promoting pancreatic beta-cell proliferation and improving glucose tolerance. Although a matter of controversy, a growing number of reports support ANGPTL8 potential, yet unclear role in type 2 diabetes mellitus (T2D).

Objectives

To examine changes in fasting ANGPTL8 level in people with morbid obesity, with or without diabetes following laparoscopic sleeve gastrectomy (LSG) in 1-year prospective study.

Methods

Fasting serum ANGPTL8 was measured by ELISA at baseline in participants with morbid obesity, 17 with diabetes and 23 without diabetes, and in normal weight participants, 19 with and 15 without diabetes, and during 1-year post-LSG in participants with morbid obesity.

Results

At baseline, people with T2D had higher ANGPTL8 level, (morbid obese, Mean ±SEM; 1415 ±196.4 pg/ml, and normal-weight, 2231 ±328.1 pg/ml), compared with individuals without T2D (morbid obese, 876 ±155.0 pg/ml, and normal weight controls 868.9 ±218.7 pg/ml). In participants with diabetes and morbid obesity, T2D remission occurred 15 days post-LSG, defined by a sustained reduced fasting blood glucose levels <6.9 mmol/L. In this group, the 1-year post-LSG measurement of ANGPTL8 showed unique biphasic changes, first a prominent elevation (day 60, 3336 ±916.5 pg/ml, P <0.01), followed by a gradual decrease to reach almost the baseline level (day 360, 1184 ±119.3 pg/ml).

Conclusion

Elevated baseline ANGPTL8 in participants with diabetes at baseline reflected a link to T2D. Interestingly, the unique biphasic pattern of change in fasting ANGPTL8 post-LSG, occurred only in people with diabetes, suggesting ANGPTL8 potential role in T2D remission.

Keywords

Angiopoietin-like 8; Betatrophin; Type 2 diabetes mellitus; Bariatric surgery; Laparoscopic sleeve gastrectomy; Morbid obesity

Abstract

Many inconsistent findings are reported on the correlation between circulating betatrophin and insulin resistance in the different population. The aim of this analysis was to explore the correlation between the level of betatrophin and insulin resistance in the general population. The databases of PubMed, EMBASE, and the Cochrane Library (inception to October 26, 2016) were searched without language restrictions for publications that reported studies on associations between betatrophin and insulin resistance in adults. Subgroup analyses were performed to investigate potential sources of heterogeneity. The pooled effect size was calculated using a random-effects model. Twenty-five studies were included in this meta-analysis. Meta-analysis showed that betatrophin was positively and significantly correlated with insulin resistance (r=0.16, 95% CI: 0.08–0.25). When all participants were divided into DM, GDM, and Non-DM groups, this association was also significant in T2DM, GDM, and Non-DM participants (T2DM: r=0.09, 95% CI: 0.01–0.17; I 2=45.1%; GDM: r=0.39, 95% CI: 0.24–0.55; I 2=0.0%; non-DM: r=0.15, 95% CI: 0.04–0.26; I 2=89.3%), and it was obvious that heterogeneity existed in Non-DM group (I 2=89.3%, p<0.001). Subgroup analysis revealed that gender, serum sample and ELISA kits for full-length betatrophin had significant influence on the association between betatrophin and insulin resistance. In conclusion, the level of circulating betatrophin is positively associated with insulin resistance in the general population, especially in T2DM and GDM patients. Gender, serum sample, and ELISA kits for full-length betatrophin may affect this association. More large-scale studies are needed to determine whether improving insulin resistance concomitantly declines betatrophin levels in different diseases.

Abstract

Hyperlipidemia is often associated with obesity and diabetes, and can lead to serious complications like atherosclerosis and fatty liver disease. Coagonist of GLP-1 and glucagon receptors is a therapy under clinical investigation for treatment of obesity and diabetes. In this study, we have characterized the mechanism of hypolipidemic effect of a balanced coagonist using high cholesterol-fed hamsters. Tyloxapol-induced hypertriglyceridemia, lipolysis in adipose tissue, and bile homeostasis were assessed after repeated dose treatment of the coagonist of GLP-1 and glucagon receptors (Aib2 C24 chimera 2, SC). Antagonists of GLP-1, glucagon, and FGF21 receptors were coadministered, and FGF21 sensitivity was determined in liver and adipose tissue. Repeated dose treatment of coagonist reduced cholesterol and increased FGF21 in blood and liver. Coagonist treatment reduced hepatic triglyceride secretion, increased lipolysis and reduced body weight. Antagonism of GLP-1 and glucagon receptors partially blocked the effect of the coagonist on lipid metabolism in circulation and liver, while FGF21 receptor antagonist completely abolished it. Glucagon and GLP-1 receptors antagonists blocked the action of coagonist on cholesterol excretion and bile flow in liver, but FGF21 antagonist was not effective. Treatment with the coagonist increased expression of FGF21, FGF21R and cofactor ?Klotho in liver and adipose. In conclusion, coagonist of GLP-1 and glucagon receptors improved lipid metabolism in liver of dyslipidemic hamsters. This effect is partially mediated by GLP-1 and glucagon receptors, and the improved FGF21 sensitivity could be the mechanism of hypolipidemic action of the coagonist of GLP-1/glucagon receptors.

Abstract

Damage-associated molecular patterns (DAMP) trigger innate immune response and exacerbate inflammation to combat infection and cellular damage. Identifying DAMPs and revealing their functions are thus of crucial importance. Here we report that two molecules, N-myc and STAT interactor (NMI) and interferon-induced protein 35 (IFP35) act as DAMPs and are released by activated macrophages during lipopolysaccharide-induced septic shock or acetaminophen-induced liver injury. We show that extracellular NMI and IFP35 activate macrophages to release proinflammatory cytokines by activating nuclear factor-kB through the Toll-like receptor 4 pathway. In addition, the serum levels of NMI are increased in patients who succumbed to severe inflammation. NMI deficiency reduces inflammatory responses and mortality in mouse models of sepsis and liver injury. We therefore propose that extracellular NMI and IFP35 exacerbate inflammation as DAMPs, making them potential therapeutic targets for clinical intervention.

Abstract

TDP-43 accumulates in nerve cells of nearly all cases of amyotrophic lateral sclerosis (ALS; the commonest form of motor neuron disease) and in the majority of Tau-negative frontotemporal lobar degeneration (FTLD). There is currently no biochemical test or marker of disease activity for ALS or FTLD, and the clinical diagnosis depends on the opinion of an experienced neurologist. TDP-43 has a key role in the pathogenesis of ALS/FTLD. Measuring TDP-43 in easily accessible biofluids, such as blood or cerebrospinal fluid, might reduce diagnostic delay and offer a readout for use in future drug trials. However, attempts at measuring disease-specific forms of TDP-43 in peripheral biofluids of ALS and FTLD patients have not yielded consistent results, and only some of the pathological biochemical features of TDP-43 found in human brain tissue have been detected in clinical biofluids to date. Reflecting on the molecular pathology of TDP-43, this review provides a critical overview on biofluid studies and future directions to develop a TDP-43-based clinical biomarker for ALS and FTLD.

Keywords

TDP-43 Biomarker Cerebrospinal fluid Amyotrophic lateral sclerosis Frontotemporal dementia TARDBP