Impaired Insulin Clearance as the Initial Regulator of Obesity-Associated Hyperinsulinemia: Novel Insight Into the Underlying Mechanism Based on Serum Bile Acid Profiles

<b>OBJECTIVE</b> <div><p>To investigate the roles of insulin clearance and insulin secretion in the development of hyperinsulinemia in obese subjects and to reveal the association between insulin clearance and bile acids (BAs).</p> <p><b> </b></p> <p><b>RESEARCH DESIGN AND METHODS</b></p> <p>In cohort 1, insulin secretion, sensitivity and endogenous insulin clearance were evaluated with an oral glucose tolerance test (OGTT) in 460 recruited participants. In cohort 2, 81 participants underwent an <a>intravenous glucose tolerance test</a> (IVGTT) and a hyperinsulinemic-euglycemic clamp to assess insulin secretion, endogenous and exogenous insulin clearance, and insulin sensitivity. Based on insulin resistance levels ranging from mild to severe, nondiabetic obese participants were further divided into 10 quantiles in cohort 1 and into tertiles in cohort 2. Forty serum BAs were measured in cohort 2 to examine the association between BAs and insulin clearance.</p> <p><b> </b></p> <p><b>RESULTS</b></p> <p>All obese participants had impaired insulin clearance, and it worsened with additional insulin resistance in nondiabetic obese subjects. However, insulin secretion was unchanged from quantile 1 to 3 in cohort 1, and no difference was found in cohort 2. After adjustments for all confounding factors, serum conjugated BAs, especially glycodeoxycholic acid (GDCA, β=-0.335, P=0.004) and taurodeoxycholic acid (TDCA, β=-0.333, P=0.003), were negatively correlated with insulin clearance<a>. The ratio of </a><a></a><a>unconjugated to conjugated BAs (UnconBA/ConBA</a>, β=0.335, P=0.002) was positively correlated with insulin clearance.</p> <p><b> </b></p> <p><b>CONCLUSIONS</b></p> <p>Hyperinsulinemia in obese subjects might be primarily induced by decreased insulin clearance rather than increased insulin secretion. Changes in circulating conjugated BAs, especially GDCA and TDCA, might play an important role in regulating insulin clearance.</p></div>

Impaired Insulin Clearance as the Initial Regulator of Obesity-Associated Hyperinsulinemia: Novel Insight Into the Underlying Mechanism Based on Serum Bile Acid Profiles

<b>OBJECTIVE</b> <div><p>To investigate the roles of insulin clearance and insulin secretion in the development of hyperinsulinemia in obese subjects and to reveal the association between insulin clearance and bile acids (BAs).</p> <p><b> </b></p> <p><b>RESEARCH DESIGN AND METHODS</b></p> <p>In cohort 1, insulin secretion, sensitivity and endogenous insulin clearance were evaluated with an oral glucose tolerance test (OGTT) in 460 recruited participants. In cohort 2, 81 participants underwent an <a>intravenous glucose tolerance test</a> (IVGTT) and a hyperinsulinemic-euglycemic clamp to assess insulin secretion, endogenous and exogenous insulin clearance, and insulin sensitivity. Based on insulin resistance levels ranging from mild to severe, nondiabetic obese participants were further divided into 10 quantiles in cohort 1 and into tertiles in cohort 2. Forty serum BAs were measured in cohort 2 to examine the association between BAs and insulin clearance.</p> <p><b> </b></p> <p><b>RESULTS</b></p> <p>All obese participants had impaired insulin clearance, and it worsened with additional insulin resistance in nondiabetic obese subjects. However, insulin secretion was unchanged from quantile 1 to 3 in cohort 1, and no difference was found in cohort 2. After adjustments for all confounding factors, serum conjugated BAs, especially glycodeoxycholic acid (GDCA, β=-0.335, P=0.004) and taurodeoxycholic acid (TDCA, β=-0.333, P=0.003), were negatively correlated with insulin clearance<a>. The ratio of </a><a></a><a>unconjugated to conjugated BAs (UnconBA/ConBA</a>, β=0.335, P=0.002) was positively correlated with insulin clearance.</p> <p><b> </b></p> <p><b>CONCLUSIONS</b></p> <p>Hyperinsulinemia in obese subjects might be primarily induced by decreased insulin clearance rather than increased insulin secretion. Changes in circulating conjugated BAs, especially GDCA and TDCA, might play an important role in regulating insulin clearance.</p></div>

Changes in Serum Lipid Profiles among Canine Patients Suffering from Chronic Hepatitis

Hyperlipidemia is a risk factor for nonalcoholic fatty liver disease (NAFLD) in humans. However, the association between serum lipids and canine chronic hepatitis remains unknown. In this study, serum lipids, hepatic profiles, and hepatic ultrasound scores of healthy dogs and dogs with chronic hepatitis were evaluated. Serum triglyceride and cholesterol concentrations were significantly higher (p < 0.01) in dogs with chronic hepatitis. There were 62.2% of dogs with chronic hepatitis accompanied by hypertriglyceridemia, hypercholesterolemia, or both. Positive correlations were observed between serum ALT and cholesterol (r = 0.8287, p < 0.01), serum ALP and cholesterol (r = 0.8436, p < 0.01), serum GGT and cholesterol (r = 0.5640, p < 0.01), serum bile acid and cholesterol (r = 0.3310, p < 0.01) and serum ALP and triglycerides (r = 0.2582, p < 0.05). No significant differences were found between ultrasound scores of diseased dogs with and without hypertriglyceridemia and diseased dogs with and without hypercholesterolemia. Canine chronic hepatitis is associated with hyperlipidemia. A significant positive association was identified between hyperlipidemia, especially hypercholesterolemia, liver enzymes, and bile acid concentration in dogs suffering from chronic hepatitis. The underlying mechanisms connecting hyperlipidemia and canine chronic hepatitis remain elusive.

A Study of Obstetric Intrahepatic Cholestasis and Its Maternal and Perinatal Outcome at a Tertiary Care Hospital in Nagpur

BACKGROUND Intrahepatic cholestasis of pregnancy (ICP) is a multifactorial pregnancy specific liver disorder which is also known as obstetric cholestasis. The purpose of this study was to establish the value of maternal serum bile acid in diagnosis of ICP, evaluate the treatment of ICP with UDCA (ursodeoxycholic acid) and its influence on maternal and neonatal outcome. METHODS It was a cross-sectional study. 90 women diagnosed with ICP were studied for a period of 2 years and 3 months at tertiary care government hospital. Statistical analysis was performed using chi square test. ‘P’ value of < 0.05 was considered as statistically significant in this observational study. RESULTS The present study evaluates that ICP is more common in multigravida and in age group of 26 years – 30 years. It recurs in subsequent pregnancies significantly. Itching, most common symptom is commenced at 34 weeks ± 2.85 weeks. Transaminases were normal with elevated serum bile acid levels in 32.33 % cases. The mean gestational age at delivery ranged between 35 to 39 weeks. Most common mode of delivery is lower segment caesarean section (LSCS) with commonest indication as meconium-stained amniotic fluid (MSAF) and 31 babies required neonatal intensive care unit (NICU). CONCLUSIONS Precise diagnosis, follow up, target medication and active management is required. Although maternal outcome for patients is good and without any long-term sequelae, fetal outcome can be devastating. Active management with close antenatal surveillance of the fetus is usually recommended for better perinatal outcome. KEYWORDS Intrahepatic Cholestasis of Pregnancy (ICP), Ursodeoxycholic Acid (UDCA), Neonatal Intensive Care Unit (NICU), Lower Segment Caesarean Section (LSCS)

Benign Recurrent Intrahepatic Cholestasis in Pregnancy: Fetal Death at 36 Weeks of Gestation

Introduction. Benign recurrent intrahepatic cholestasis is a rare hepatologic disorder characterized by recurrent, self-limited episodes of severe pruritus, jaundice, and elevated bile acids. While there are guidelines for the management of intrahepatic cholestasis of pregnancy, the literature regarding benign recurrent intrahepatic cholestasis and pregnancy is limited. Case. A 29-year-old G1P0 woman, with history of liver toxicity, had elevated total serum bile acid levels and liver enzymes documented at 8 weeks of gestation and throughout her pregnancy. She had a reactive nonstress test just 3 days prior to her induction. Fetal demise was noted when she presented at 36 weeks for her induction. Conclusion. We recommend that women with elevated total serum bile acid early in pregnancy due to a separate entity relative to intrahepatic cholestasis of pregnancy be managed in a more individualized approach.

Role of bile acids in the prediction of hepatocellular carcinoma in HCV-induced liver cirrhosis

Background Bile acids are essential organic molecules synthesized from cholesterol in the liver and regarded as indicators of hepatobiliary impairment; however, their role in the pathogenesis of hepatocellular carcinoma (HCC) is still unclear. The study aimed to examine the feasibility of bile acids in distinguishing HCC from post hepatitis C virus liver cirrhosis. A UPLC/MS was used to measure 14 bile acids in patients with noncirrhotic HCV disease (n = 50), cirrhotic HCV disease (n = 50), hepatocellular carcinoma (n = 50), and control group (n = 50). Results The progression of liver cirrhosis to HCC was associated with a significant increase in serum bile acids compared to the normal or the noncirrhotic HCV disease (p < 0.05). The fold changes in bile acids concentrations showed a trend that HCC > cirrhotic HCV disease > noncirrhotic HCV disease. Four conjugated acids GCA, GCDCA, GUDCA, and TCDCA steadily increased across the different groups. ROC curves analysis revealed that these bile acids discriminated noncirrhotic liver patients from HCC (AUC 0.850–0.963), with a weaker potential to distinguish chronic liver cirrhosis from HCC (AUC 0.414–0.638). Conclusion The level of serum bile acid was associated primarily with liver cirrhosis, with little value in predicting the progress of chronic liver cirrhotic disease into hepatocellular carcinoma.

A Retrospective Clinical Analysis of the Serum Bile Acid Alteration Caused by Traumatic Brain Injury

Traumatic brain injury (TBI) can cause damage to peripheral organ systems, such as digestive organ system, and alterations of gut microbiota in addition to brain injury. Our previous study found that TBI induced gastrointestinal dysfunction accompanied by alterations of bile acid metabolism. Bile acid and its receptors have been reported to play important roles in various neurological diseases. To further examine the changes of bile acid metabolism in TBI patients, we performed a retrospective clinical analysis. In this study, 177 patients were included, and the results showed that TBI patients had more frequent antibiotic use compared with a control group. Regression analysis identified TBI as an independent factor for reduction of serum bile acid level (B = −1.762, p = 0.006), even with antibiotic use taken into a regression model. Sub-group regression analysis of TBI patients showed that antibiotic use was negatively associated with bile acid level, while creatinine and triglyceride were positively associated with bile acid level. In conclusion, these data indicated that TBI could greatly reduce serum bile acid. This study provided preliminary but novel clinical evidence of TBI interfering with bile acid metabolism, and further studies with large sample sizes are needed to validate these findings in the future.