Plasma bile acid changes in type 2 diabetes correlated with insulin secretion in two-step hyperglycemic clamp

Bile acids (BAs) conduct crucial signals in human metabolism. Correlations between changes in plasma BA concentrations, insulin secretion defects, and progression of type 2 diabetes mellitus (T2DM) in humans have not been sufficiently investigated. This study explored the trajectories of changes in human plasma BA concentrations and their association with insulin secretion dynamics during a two-step hyperglycemic clamp.

Eleven healthy subjects with normal glucose tolerance (NGT) and 33 drug-naïve T2DM subjects were enrolled in the study. The two-step hyperglycemic clamp consisted of a classic clamp as Step 1 with fasting, followed by a Step 2 clamp after ingestion of a carbohydrate meal, illustrating basal and incretin-amplified insulin responses to glucose. Plasma BA were assayed using liquid chromatography-tandem mass spectrometry. Nine T2DM subjects were followed-up, and the two-step clamp was repeated after 3 months sulfonylurea treatment.

Ursodeoxycholic acid (UDCA) was lower and lithocholic acid (LCA) and taurocholic acid (TCA) were higher in T2DM compared with NGT subjects. The dynamics of plasma UDCA concentrations and the UDCA/LCA ratio was positively correlated with insulin secretion in T2DM subjects and were corrected after treatment. Moreover, fasting ratios of UDCA/LCA and unconjugated/conjugated BAs were correlated with the first phase of insulin secretion in T2DM subjects.

The abnormal BA composition in T2DM subjects and its correlation with insulin secretion during the clamp suggest an interaction between BA signals and insulin secretion capacity, and the potential to use fasting plasma BA composition indices to predict and evaluate the progression and prognosis of T2DM.