ABSTRACT
BACKGROUND & AIMS: We investigated possible involvements of bile acids (BA) and leptin in hepatogenous insulin resistance being present in up to 90% of cirrhotic patients. METHODS: Blood was analysed in 10 cirrhotic patients (8m/2f, 48 ± 10.4 yrs) and 10 controls (8m/2f, 43 ± 9.3 yrs) after oral nutrition and during 1 h of parenteral feeding. In patients, leptin was additionally analysed from mesenteric and arterial blood. RESULTS: Cirrhosis patients showed typical signs of hepatogenous insulin resistance (hyperinsulinaemia, normoglycaemia, hyperglucagonaemia). Both fasting BA (r = .714, p = 0.047) and fasting leptin (r = .867, p = 0.001) correlated to HOMA and predicted insulin response after oral feeding (R²adj = .783, p = 0.002). But during parenteral nutrition only leptin predicted insulin response (p = 0.005). The prandial glucose response was negatively correlated to the BA increase after oral nutrition (r = -.733, p = 0.028) and to the change in leptin during parenteral nutrition (r = -.738, p = 0.037) pointing towards a nutritional route-dependent positive impact on glucose tolerance of both substances. Prandial glucagon response was correlated to BA under both feeding conditions (p < 0.05). We found no relevant intestinal release of leptin during fasting or feeding conditions. CONCLUSION: Our results suggest a substantial involvement of BA and leptin by improving postprandial glucose tolerance related to liver cirrhosis.
Subject(s)
Bile Acids and Salts/blood , Glucose/metabolism , Insulin Resistance , Leptin/blood , Liver Cirrhosis/metabolism , Liver/metabolism , Adipose Tissue, White/metabolism , Adult , Female , Glucagon/blood , Glucagon/metabolism , Humans , Hyperglycemia/etiology , Intestinal Mucosa/metabolism , Leptin/metabolism , Liver Cirrhosis/blood , Liver Cirrhosis/physiopathology , Male , Middle Aged , Parenteral Nutrition , Postprandial PeriodABSTRACT
BACKGROUND/AIMS: Animal studies implicate a role of bile acids (BA) in thyroid-regulated energy expenditure (EE) via activation of the TGR-5/adenylate cyclase/deiodinase type 2 pathway. Here we investigated these possible associations in humans. METHODS: EE, BA, and thyroid hormone status were assessed in 10 healthy subjects and eight patients with liver cirrhosis at baseline and after oral nutrition. In cirrhosis, blood was additionally sampled from the mesenteric vein and the radial artery. RESULTS: At baseline, BA and EE related positively (r = 0.648, P = 0.048 in healthy subjects; r = 0.833, P = 0.010 in cirrhosis; r = 0.556, P =0.017 in all), with the highest correlation with deoxycholic acid levels. The respiratory quotient associated negatively to baseline BA (all, r = -0.639, P = 0.004). Postprandially, serum TSH decreased in both groups (P < 0.05 each). In cirrhosis, the decrease of TSH after 60 min correlated to the meal-stimulated BA increase (r = -0.762, P = 0.028). To assess the mechanism involved, we studied a single human TSHoma and TαT1 mouse thyrotrope cells. In TSHoma cells, TGR-5 was predominantly expressed cytoplasmically, and in vitro stimulation with BA did not substantially alter cAMP or deiodinase type 2. CONCLUSIONS: Our data support a role of BA in human energy metabolism and in thyroid hormone control. Even though no convincing response to BA was demonstrated in TSHoma and TαT1 cells, the TSH decrease after a nutritional challenge suggests an interaction of BA on the set point of the thyroid axis.
Subject(s)
Bile Acids and Salts/blood , Energy Metabolism/physiology , Thyroid Gland/physiology , Adult , Biopsy , Calorimetry, Indirect , Female , Humans , Liver Cirrhosis/blood , Liver Cirrhosis/pathology , Liver Cirrhosis/surgery , Longitudinal Studies , Male , Middle Aged , Nutritional Status , Portasystemic Shunt, Transjugular Intrahepatic , Thyroid Function TestsABSTRACT
OBJECTIVE: Peptide YY(3-36) (PYY(3-36)) is a gut hormone with anorectic action that also affects energy expenditure. Anorexia and malnutrition are often observed in patients with decompensated liver cirrhosis (LC), whereas patients with LC after insertion of transjugular portosystemic stent shunts (TIPS) show normal eating behavior. The underlying mechanism of anorexia in decompensated LC and its resolution in patients with TIPS is still unclear. We thus investigated fasting and postprandial PYY(3-36) serum levels in patients with decompensated LC, patients with compensated LC with in situ TIPS, and healthy controls. METHODS: We analyzed fasting PYY(3-36) levels in six patients with decompensated LC (four men and two women, 55 ± 11 y of age), nine patients with TIPS (seven men and two women, 48 ± 11 y of age), and 10 controls (eight men and two women, 43 ± 9 y of age) postprandially after a standardized meal of 300 kcal and during 1-h continuous parenteral nutrition. Energy expenditure was determined by indirect calorimetry. RESULTS: At baseline PYY(3-36) was comparable in controls and patients with TIPS (91 ± 10 and 89 ± 25 ng/L) but was increased in patients with decompensated LC (165 ± 44 ng/L, P < 0.01). Although the cumulative postprandial PYY(3-36) increase was similar in controls (mean 2089 ng/240 min per liter) and patients with decompensated LC (mean 1735 ng/240 min per liter), no postprandial PYY(3-36) increase was observed in patients with TIPS (mean -579 ng/240 min per liter). Parenteral nutrition did not significantly affect PYY(3-36) levels in any group. Fasting PYY(3-36) values were negatively related to resting energy expenditure (r = -0.443, P = 0.030). PYY(3-36) was not associated to liver parameters (e.g., bilirubin, alanine aminotransferase). CONCLUSION: Our results demonstrate an abnormal neuroendocrine regulation of PYY(3-36) in patients with decompensated LC and those with TIPS.
