The Association Of ANGPTL8 With Glucose And Lipid Metabolism And Its Regulation And Effect Study

Context and Objective: Angiopoietin-like protein 8(ANGPTL8)was regarded as protein regulating triglyceride(TG)metabolism in mice.In ANGPTL8-/-mice,plasma levels of TG significantly decreased.However,no evidence was found that it was required for maintenance of glucose homeostasis.But,clinically,a number of observations showed that ANGPTL8 levels altered in type 2 diabetic patients with similar lipid profile compared with control subjects.Therefore,whether ANGPTL8 is involved in glucose and/or lipid metabolism in human remained unclear.To explore the role of ANGPTL8 in glucose and lipid metabolism in human,we examine circulating ANGPTL8 levels in subjects with hyperglycemia and/or dyslipidemia and their correlation with glucose and lipid metabolism.Design,Setting and Participants: Serum ANGPTL8 levels were measured using ELISA in age-,sex-,and BMI-matched healthy control subjects(n = 92),subjects with isolated hyperglycemia(n = 87,fast glucose 3 7 mmol/l),with isolated dyslipidemia(n = 86,TG ≥ 2.0 mmol/l or/and HDL ≤ 0.9 mmol/l)and hyperglycemia combined dyslipidemia(n = 99,fasting glucose 3 7 mmol/l + TG ≥ 2.0 mmol/l or/and HDL ≤ 0.9 mmol/l)from the Risk Evaluation of c Ancers in Chinese diabe Tic Individuals: a l ONgitudinal(REACTION)study.Results: Serum ANGPTL8 was significantly elevated in patients with hyperglycemia combined dyslipidemia compared to control subjects.Among glucose-related variables,ANGPTL8 levels positively correlated with fasting plasma glucose(r = 0.113,P < 0.05)and triglycerides and glucose(Ty G)index(r = 0.194,P < 0.01).After controlling for age,sex and blood lipid,ANGPTL8 levels positively correlated with fasting plasma glucose(partial r = 0.154,P < 0.01),Hb A1c(partial r = 0.110,P < 0.05)and triglycerides and glucose(Ty G)index(age,sex adjusted)(partial r = 0.224,P < 0.01).Among lipid-related variables,ANGPTL8 levels positively correlated with TG(r = 0.161,P < 0.01),total cholesterol(r = 0.149,P < 0.01),TG/HDL(r = 0.143,P < 0.01)and non-HDL/HDL(r = 0.120,P < 0.05).After controlling for age,sex and FPG,ANGPTL8 levels positively correlated with TG(partial r = 0.163,P < 0.01),TG/HDL(partial r = 0.147,P < 0.01)and non-HDL/HDL(partial r = 0.134,P < 0.05).Conclusion: Circulating ANGPTL8 levels are increased in patients with hyperglycemia combined dyslipidemia and may play an important role in linking glucose and lipid metabolism.Aim: ANGPTL8 is regarded as a liver-produced protein regulating triglyceride(TG)metabolism in mice.Our previous study found ANGPTL8 might play an important role in linking glucose and lipid metabolism.And insulin resistance(IR)is the pathway which both damaging glucose and lipid metabolism.We,therefore,want to study whether IR or insulin could regulate ANGPTL8 expression and the corresponding mechanisms.Design and methods: ANGPTL8 levels were examined in 6 in vitro IR models which were established using human hepatocytes L02 with different agents,including tumor necrosis factor-α,interleukin-1 β,dexamethasone,palmitic acid,high glucose and insulin.Furthermore,PI3K/Akt inhibitors(LY294002 and MK-2206)and agonist(IGF-1)were used to study the regulation of pathway mechanisms.Then,in vivo,we treated mice with insulin and the administration IR mice with metformin.Finally,serum ANGPTL8 levels were determined in 38 type 2 diabetic patients with or without insulin treatment.Results: In all IR models,ANGPTL8 levels were only elevated in the insulin group which was accompanied with phosphorylation of Akt,and IR reduced insulin-induced Akt phosphorylaton.The levels of ANGPTL8 increased with insulin dose and time of treatment.These results suggest that it is insulin,not IR that promotes ANGPTL8 expression.Combined the results above with the observation that LY294002 and MK-2206 could inhibit insulin-upregulated ANGPTL8 levels and IGF-1 had a stimulating effect,these results reflect that insulin stimulates ANGPTL8 secretion through PI3K/Akt pathway and IR may reduce ANGPTL8 levels by impairing insulin pathway.In mice,the treatment of insulin in mice dose-dependently upregulated ANGPTL8 levels,and the administration of metformin in IR mice also stimulated ANGPTL8 production since published study showed metformin improved PI3K/Akt pathway and IR.In humans,serum ANGPTL8 levels were increased in type 2 diabetic patients with insulin treatment compared with those without insulin treatment(508.30 ± 64.61 vs.303.02 ± 48.20 pg/ml,P < 0.05).Conclusions: Insulin stimulates ANGPTL8 secretion through PI3K/Akt pathway and IR may play an opposite role.Aim: ANGPTL8 is a liver-produced protein that increases blood triglyceride(TG)levels by inhibiting the activity of lipoprtein lipase(LPL).The increase of blood TG may cause liver insulin resistance,lipid deposition and inflammatory pathway activation,which lead to nonalcoholic fatty liver disease(NAFLD).Therefore,ANGPTL8 may be an important protein that causes NAFLD.At present,the role of ANGPTL8 in lipid metabolism remains unclear.We,therefore,want to study the effect of ANGPTL8 on NAFLD in mice liver cells.Design and methods: Lentivirus was used to set up mice hepatocytes that overexpressed ANGPTL8 stably.NAFLD cell model was established by treating hepatocytes with palmitic acid(125 μM)for 18 hours.Then,the levels of triglyceride、insulin resistance and inflammation were tested to explore the effect of ANGPTL8 on NAFLD.Results: Compared with control,the expression of ANGPTL8 in mice hepatocytes was upregulated significantly(P < 0.05).And in the cell overexpressed ANGPTL8,the content of TG was higher than control group(P < 0.05).Moreover,in NAFLD models,the content of TG in the cell overexpressed ANGPTL8 was also higher than control NAFLD group(P < 0.05).However,no difference was found in insulin resistance and inflammation factors levels between the two groups(P > 0.05).Conclusions: ANGPTL8 promoted lipid deposition in mice liver cells and the development of NAFLD.