Fasting Serum Total Bile Acid Levels Are Associated With Insulin Sensitivity, Islet Beta-Cell Function And Glucagon Levels In Response To Glucose Challenge In Patients With Type 2 Diabetes

Type 2 diabetes (T2D) is characterized by islet beta-cell dysfunction and impaired suppression of glucagon secretion of alpha-cells in response to oral hyperglycaemia. Bile acid (BA) metabolism plays a dominant role in maintaining glucose homeostasis. So we evaluated the association of fasting serum total bile acids (S-TBAs) with insulin sensitivity, islet beta-cell function and glucagon levels in T2D. Total 2,952 T2D patients with fasting S-TBAs in the normal range were recruited and received oral glucose tolerance tests for determination of fasting and postchallenge glucose, C-peptide and glucagon. Fasting and systemic insulin sensitivity were assessed by homeostasis model assessment (HOMA) and Matsuda index using C-peptide, i.e., ISHOMA-cp and ISIM-cp, respectively. Islet beta-cell function was assessed by the insulin-secretion-sensitivity-index-2 using C-peptide (ISSI2(cp)). The area under the glucagon curve (AUC(gla)) was used to assess postchallenge glucagon. The results showed ISHOMA-cp, ISIM-cp and ISSI2(cp) decreased, while AUC(gla) notably increased, across ascending quartiles of S-TBAs but not fasting glucagon. Moreover, S-TBAs were inversely correlated with ISHOMA-cp, ISIM-cp and ISSI2(cp) (r = -0.21, -0.15 and -0.25, respectively, p < 0.001) and positively correlated with AUC(gla) (r = 0.32, p < 0.001) but not with fasting glucagon (r = 0.033, p = 0.070). Furthermore, after adjusting for other clinical covariates by multiple linear regression analyses, the S-TBAs were independently associated with ISHOMA-cp (beta = -0.04, t = -2.82, p = 0.005), ISIM-cp (beta = -0.11, t = -7.05, p < 0.001), ISSI2(cp) (beta = -0.15, t = -10.26, p < 0.001) and AUC(gla) (beta = 0.29, t = 19.08, p < 0.001). Increased fasting S-TBAs are associated with blunted fasting and systemic insulin sensitivity, impaired islet beta-cell function and increased glucagon levels in response to glucose challenge in T2D.