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

Abstract

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/m2, Homeostatic Model Assessment of Insulin Resistance [HOMA-IR] < 2.0, n = 19), overweight/obese nondiabetic who were either insulin sensitive (Obsensitive, BMI > 25 kg/m2, HOMA-IR < 1.5, n = 11) or insulin resistant (Obresistant, BMI > 25 kg/m2, 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 Obresistant 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 Obsensitive individuals, despite similar total adiposity in Obresistant and Obsensitive. Total BA concentrations were higher in Obresistant (2.62 ± 0.333 mmol/L, P = .03) and T2D (3.36 ± 0.582 mmol/L, P < .001) vs Obsensitive (1.16 ± 0.143 mmol/L), but were similar between Obsensitive 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.

Changes in bile acid subtypes and long‐term successful weight‐loss in response to weight‐loss diets: The POUNDS lost trial

“…GCDCA and GUDCA were related to unfavourable adiponectin levels at baseline in our study participants with overweight and obesity. These findings are consistent with a recent cross‐sectional study showing significant associations of the primary or secondary bile acid subtypes with visceral adiposity and adiponectin levels 27 . An experimental study also suggests that several bile acids may be related to regulating the secretion of adiponectin 18 …”

“…These findings are consistent with a recent cross-sectional study showing significant associations of the primary or secondary bile acid subtypes with visceral adiposity and adiponectin levels. 27 An experimental study also suggests that several bile acids may be related to regulating the secretion of adiponectin. 18 We found that unconjugated and conjugated primary bile acids were significantly decreased in response to the low-calorie weightloss diet interventions.…”

Substantial Fat Loss in Physique Competitors Is Characterized by Increased Levels of Bile Acids, Very-Long Chain Fatty Acids, and Oxylipins

“…Compared to lean, healthy controls, obese insulin-resistant individuals have higher levels of fasting BAs, whereas obese normoglycemic individuals have been characterized with the lowest levels of fasting BAs of these subgroups [ 20 , 28 , 33 ]. A possible explanation for the above findings and lack of clear association between fasting BAs and BMI or weight loss is that a stronger link seems to exist through glycemic control, as increased levels of fasting BAs have repeatedly been associated with (i) higher levels of visceral fat mass, (ii) insulin resistance, and (iii) diabetes, regardless of overall adiposity [ 34 ]. Moreover, phenotypes characterized by insulin resistance have been repeatedly associated with an increased ratio of 12α-hydroxy/non-12α-hydroxy bile acid profile [ 33 ].…”

Myocardial Infarction and Coronary Artery Disease in Menopausal Women With Type 2 Diabetes Mellitus Negatively Correlate With Total Serum Bile Acids

“…In addition, it has been suggested that baseline TBA levels are positively associated with T2DM risk and longitudinal changes in glucose metabolism; meanwhile, IR may partially mediate the correlation between TBA and T2DM (27). Considering the influence of obesity, which is also a risk factor for CAD, Bishay et al have suggested that IR is closely related to incommensurate alterations to the composition of BA pool, and they have emphasized that increased BAs in IR, rather than obesity possibly contribute to the defects in insulin signaling (28). In addition, although the spline analysis failed to describe a clear relationship between TBA variation and T2DM status in menopausal women, the smooth spline analysis based on GAM indicated the potential value of TBA level to predict the probability for T2DM in the CAD and MI populations.…”