Fasting Serum Total Bile Acid Levels In Relation To Insulin Sensitivity,islet Function In Patients With Type 2 Diabetes

Objective Type 2 diabetes is characterized by declined insulin ensitivity,impaired islet β-cell function,elevated fasting plasma glucagon levels and impaired suppression of glucagon secretion in α-cells following oral source of hyperglycaemia.Bile acids metabolism plays a dominant role in the signaling pathways maintaining glycemic homeostasis,so we hypothesized that bile acids may have impact on action of insulin and glucagon.Therefore,the aims of this study is to explore the the association of fasting serum total bile acids(S-TBAs)with insulin sensitivity,islet β-cell function and α-cell function in patients with type 2 diabetes(T2DM):analysis from both baseline and follow-up.Methods1.Total 2952 patients with T2DM and with fasting S-TBAs in normal range were recruited for this study from 2015 to 2018.At the same time,these patients were further received a follow-up.2.All patients enrolled at baseline and patients at follow-up were received an oral glucose tolerance test for the synchronous measurement of fasting and postchallenge glucose,C-peptide and glucagon.3.Fasting and systemic insulin sensitivity were assessed by homeostasis model assessment(HOMA)and Matsuda index using C-peptide,ISHOMA-cp and ISIM-cp,respectively.Islet β-cell function was assessed by Insulin Secretion-Sensitivity Index-2 using C-peptide(ISSI-2cp).4.Fasting glucagon levels(Fgla)were determined,and postchallenge glucagon levels were assessed by the area unde the glucagon curve(AUCgla)during oral glucose tolerance tests.5.Other clinical data such as age,gender,body mass index,blood press,diabetic duration,diabetic treatments,lipid profiles,liver function,kidney function and HbAlc were aslo collected.Results1.The recruited patients had diabetic duration for 5.2713.90 years and normal fasting S-TBAs for 3.29±1.38μmol/L(range 1.3-10.0μmol/L).2.Metabolic parameters,ISHOMA-cp,ISIM-cp and ISSI-2cp decreased,while AUCgla notably increased across ascending quartiles of S-TBAs(all p for trend<0.001),but not fasting glucagon.Moreover,S-TBAs were inversely correlated with ISHOMA-cp,ISIM-cp and ISSI-2cp(r=-0.21,-0.15 and-0.25,respectively,p<0.001),and positively correlated with AUCgla(r=0.32,p<0.001),but not with fasting glucagon(r=0.033,p=0.07).3.Furthermore,after adjusting for other clinical covariates by multiple liner regression analyses,the S-TBAs were independently associated with SHOMA-cp(β=-0.04,t=-2.82,p=0.005),ISIM-cp(β=-0.11,t=-7.05,p<0.001),ISSI-2cp(β=-0.15,t=-10.26,p<0.001)and AUCgla(β=0.29,t=19.08,p<0.001).4.Finally,total 483 patients with T2DM were completed a follow-up for an average of 4 years.After 4 years of follow-up,the levels of S-TBAs were increased,the levels of ISHOMA-cp,ISIM-cp and ISSI-2cp were decreased,and the levels of Fgla and AUCgla were increased.The changes(Δ)before and after follow-up were statistically significant(p<0.001).Linear correlation analysis showed that the ΔS-TBAs were negatively correlated with ΔISHOMA-cp,ΔISIM-cp and ΔISSI-2cp(r=0.225,-0.170 and-0.269,p<0.001),and positively correlated with ΔFgia and ΔAUCgla(r=0.117 and 0.306,p<0.05).Moreover,after adjusting for other clinical covariates by multiple linear regression analysis,ΔS-TBAs was independently associated with ΔISHOMA-cp(β=-0.24,t=-5.836,p<0.001),ΔISIM-cp(β=-0.13,t=-3.080,p<0.002),ΔISSI-2cp(β=-0.02,t=-7.255,p<0.001)and ΔAUCgla(β=0.28,t=8.898,p<0.001),but not with Fgla(β=0.02,t=0.522,p=0.602).Conclusions1.Fasting S-TBAs within the normal reference range were inversely associated with fasting and systemic insulin sensitivity indices,and integrated islet β-cell function in patients with T2DM.2.Fasting S-TBA levels were postively associated with glucagon levels in response to glucose challenge in patients with T2DM,but not with fasting glucagon levels.3.Follow-up analysis further confirmed that the an increase of fasting S-TBAs contributed to a decrease of fasting insulin sensitivity index,systemic insulin sensitivity index and islet β-cell function,and to an increase of glucagon levels in response to glucose challenge in patients with T2DM.