FGF 19 and Bile Acids Increase Following Roux-en-Y Gastric Bypass but Not After Medical Management in Patients with Type 2 Diabetes

Abstract

Purpose To quantify changes in fibroblast growth factor 19 (FGF19) and bile acids (BAs) in patients with uncontrolled type 2 diabetes randomized to Roux-en-Y gastric bypass (RYGB) vs intensive medical management (IMM) and matched for similar reduction in HbA1c after 1 year of treatment. Materials and Methods Blood samples were drawn from patients who underwent a test meal challenge before and 1 year after IMM (n=15) or RYGB (n=15). Results Mean HbA1c decreased from 9.7 to 6.4% after RYGB and from 9.1 to 6.1% in the IMM group. At 12 mo the number of diabetes medications used per subject in the RYGB group (2.5 ± 0.5) was less than in the IMM group (4.6 ± 0.3). After RYGB FGF19 increased in the fasted (93±15 to 152±19 pg/ml; P=0.008) and postprandial states (AUC, 10.8 ± 1.9 to 23.4 ± 4.1 pg × hr/ml × 103; P=0.006) but remained unchanged following IMM. BAs increased after RYGB (AUC × 103, 6.63 ± 1.3 to 15.16 ± 2.56 M × h; P=0.003) and decreased after IMM (AUC × 103 8.22 ±1.24 to 5.70 ± 0.70; P=0.01). No changes were observed in the ratio of 12α-hydroxylated/non-12α-hyroxylated BAs. Following RYGB, FGF19 AUC correlated with BAs (r=0.54, P=0.04) and trended negatively with HbA1c (r=−0.44; P=0.09); these associations were not observed after IMM. Conclusion BA and FGF19 levels increased after RYGB but not after IMM in subjects who achieved similar improvement in glycemic control. Further studies are necessary to determine whether these hormonal changes facilitate improved glucose homeostasis.

Mechanisms of Diabetes Improvement Following Bariatric/Metabolic Surgery

“…Similarly, circulating FGF-19 levels increase after RYGB and VSG, although the time course of these changes and the BA composition details are actively debated. In contrast, neither caloric restriction nor LAGB alters circulating BA or FGF-19 levels (55). The anatomical rearrangements after RYGB lead to delayed mixing of BAs with ingested food and exposure of the ileum to digestate-free chyme, offering a plausible explanation for increased circulating BAs and FGF-19 levels.…”

Targeting the gastrointestinal tract to treat type 2 diabetes

“…Indeed, FXR is essential for normal glucose homeostasis , and bile acid activation of FXR induces FGF19 (in humans and its mouse orthologue FGF15) release from the ileal intestinal epithelium (Zhang et al 2013). Improvements in glucose homeostasis following RYGB are associated with changes in FGF 19/15 (Pournaras et al 2012, Sachdev et al 2015, possibly via inhibitory effects on hepatic glucose production and lipogenesis through reductions in bile acid secretion (Gerhard et al 2013). More recently, it has been shown that central FGF 19 improves glucose tolerance, suggesting a central role for the glucoregulatory action of FGF 19 (Morton et al 2013, Marcelin et al 2014.…”

Mechanisms for the metabolic success of bariatric surgery

“…FGF19/15 improves glucose homeostasis specifically by inhibiting hepatic gluconeogenesis, enhancing hepatic mitochondrial activity and glycogenolysis, and increasing insulin‐independent glucose uptake, and does so by activating multiple fibroblast growth factor receptors in multiple target organs, including the liver, pancreas, adipose and brain . Demonstrating translational relevance of these findings, patients with T2DM have reduced FGF19 levels and RYGB increases FGF19, an effect that has been linked to the surgery‐induced T2DM remission …”

“…Interestingly, RYGB patients who have profound improvements in glucose homeostasis also have been found to have a more than three‐fold increase in plasma BA compared to weight‐matched non‐surgical controls . Specifically, RYGB in humans increases cholic acid (CA), chenodeoxycholic acid (CDCA) (primary BA) and deoxycholic acid (a secondary BA) . The difference in BA between bariatric surgery and impaired glucose metabolism may reside in differences in the ratio of the various BA species.…”