Plasma Bile Acids More Closely Align With Insulin Resistance, Visceral and Hepatic Adiposity Than Total Adiposity

Context: The etiological mechanism of bile acid (BA) effects on insulin resistance and obesity is unknown. Objective: This work aimed to determine whether plasma BAs are elevated in human obesity and/or insulin resistance. Methods: This observational study was conducted at an academic research center. Seventy-one adult volunteers formed 4 groups: lean insulin-sensitive (body mass index [BMI]<= 25 kg/m(2), Homeostatic Model Assessment of Insulin Resistance [HOMA-IR]<2.0, n=19), overweight/obese nondiabetic who were either insulin sensitive (Ob(sensitive), BMI>25 kg/m(2), HOMA-IR<1.5, n=11) or insulin resistant (Ob(resistant), BMI>25 kg/m(2), HOMA-IR>3.0, n=20), and type 2 diabetes (T2D, n=21). Main outcome measures included insulin sensitivity by hyperinsulinemic-euglycemic clamp, body composition by dual energy x-ray absorptiometry, abdominal fat distribution, and liver density by computed tomography and plasma BA. Results: In the Ob(resistant) group, glucose infusion rate/fat-free mass (GIR/FFM, an inverse measure of insulin resistance) was significantly lower, and visceral and liver fat higher, compared to lean and Ob(sensitive) individuals, despite similar total adiposity in Ob(resistant) and Ob(sensitive). Total BA concentrations were higher in Ob(resistant) (2.620.333 mmol/L, P=.03) and T2D (3.36 +/- 0.582 mmol/L, P< .001) vs Ob(sensitive) (1.16 +/- 0.143 mmol/L), but were similar between Ob(sensitive) and lean (2.31 +/- 0.329 mmol/L) individuals. Total BAs were positively associated with waist circumference (R=0.245, P=.041), visceral fat (R=0.360, P=.002), and fibroblast growth factor 21 (R=0.341, P=.004) and negatively associated with insulin sensitivity (R=-0.395, P=.001), abdominal subcutaneous fat (R=-0.352, P=.003), adiponectin (R=-0.375, P=.001), and liver fat (Hounsfield units, an inverse marker of liver fat, R=-0.245, P=.04). Conjugated BAs were additionally elevated in T2D individuals (P<.001). Conclusions: BA concentrations correlated with abdominal, visceral, and liver fat in humans, though an etiological role in insulin resistance remains to be verified.

Automated summary

In obese individuals with insulin resistance, there was a significant decrease in glucose infusion rate/fat-free mass (GIR/FFM), and higher levels of visceral and liver fat, despite similar overall adiposity compared to insulin-sensitive individuals. Total bile acid (BA) concentrations were higher in the obese insulin-resistant group and individuals with type 2 diabetes compared to the insulin-sensitive obese group. Total BAs were positively associated with waist circumference, visceral fat, and fibroblast growth factor 21, and negatively associated with insulin sensitivity, abdominal subcutaneous fat, adiponectin, and liver fat. Conjugated BAs were also elevated in individuals with type 2 diabetes.