scholarly journals Hepatic Insulin Clearance: Mechanism and Physiology

Physiology ◽  
2019 ◽  
Vol 34 (3) ◽  
pp. 198-215 ◽  
Author(s):  
Sonia M. Najjar ◽  
Germán Perdomo
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Insulin Receptor ◽  
Hepatic Steatosis ◽  
Insulin Clearance ◽  
Hepatic Insulin Resistance ◽  
Insulin Degrading Enzyme ◽  
Insulin Receptor Tyrosine Kinase ◽  
Impaired Insulin ◽  
Hepatic Insulin Clearance

Upon its secretion from pancreatic β-cells, insulin reaches the liver through the portal circulation to exert its action and eventually undergo clearance in the hepatocytes. In addition to insulin secretion, hepatic insulin clearance regulates the homeostatic level of insulin that is required to reach peripheral insulin target tissues to elicit proper insulin action. Receptor-mediated insulin uptake followed by its degradation constitutes the basic mechanism of insulin clearance. Upon its phosphorylation by the insulin receptor tyrosine kinase, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) takes part in the insulin-insulin receptor complex to increase the rate of its endocytosis and targeting to the degradation pathways. This review summarizes how this process is regulated and how it is associated with insulin-degrading enzyme in the liver. It also discusses the physiological implications of impaired hepatic insulin clearance: Whereas reduced insulin clearance cooperates with increased insulin secretion to compensate for insulin resistance, it can also cause hepatic insulin resistance. Because chronic hyperinsulinemia stimulates hepatic de novo lipogenesis, impaired insulin clearance also causes hepatic steatosis. Thus impaired insulin clearance can underlie the link between hepatic insulin resistance and hepatic steatosis. Delineating these regulatory pathways should lead to building more effective therapeutic strategies against metabolic syndrome.

scholarly journals Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer

2021 ◽  
Vol 22 (15) ◽  
pp. 7797
Author(s):  
Joseph A. M. J. L. Janssen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Insulin Secretion ◽  
Early Stage ◽  
Insulin Clearance ◽  
Future Research ◽  
Age Related ◽  
Hepatic Insulin Clearance

For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.

Effect of liver fat on insulin clearance

2007 ◽  
Vol 293 (6) ◽  
pp. E1709-E1715 ◽  
Author(s):  
Anna Kotronen ◽  
Satu Vehkavaara ◽  
Anneli Seppälä-Lindroos ◽  
Robert Bergholm ◽  
Hannele Yki-Järvinen
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Fat Content ◽  
Insulin Clearance ◽  
Liver Fat ◽  
Hepatic Insulin Resistance ◽  
Model Assessment ◽  
Liver Fat Content ◽  
Hepatic Insulin Sensitivity ◽  
Impaired Insulin

A fatty liver is associated with fasting hyperinsulinemia, which could reflect either impaired insulin clearance or hepatic insulin action. We determined the effect of liver fat on insulin clearance and hepatic insulin sensitivity in 80 nondiabetic subjects [age 43 ± 1 yr, body mass index (BMI) 26.3 ± 0.5 kg/m2]. Insulin clearance and hepatic insulin resistance were measured by the euglycemic hyperinsulinemic (insulin infusion rate 0.3 mU·kg−1·min−1for 240 min) clamp technique combined with the infusion of [3-3H]glucose and liver fat by proton magnetic resonance spectroscopy. During hyperinsulinemia, both serum insulin concentrations and increments above basal remained ∼40% higher ( P < 0.0001) in the high (15.0 ± 1.5%) compared with the low (1.8 ± 0.2%) liver fat group, independent of age, sex, and BMI. Insulin clearance (ml·kg fat free mass−1·min−1) was inversely related to liver fat content ( r = −0.52, P < 0.0001), independent of age, sex, and BMI ( r = −0.37, P = 0.001). The variation in insulin clearance due to that in liver fat (range 0–41%) explained on the average 27% of the variation in fasting serum (fS)-insulin concentrations. The contribution of impaired insulin clearance to fS-insulin concentrations increased as a function of liver fat. This implies that indirect indexes of insulin sensitivity, such as homeostatic model assessment, overestimate insulin resistance in subjects with high liver fat content. Liver fat content correlated significantly with fS-insulin concentrations adjusted for insulin clearance ( r = 0.43, P < 0.0001) and with directly measured hepatic insulin sensitivity ( r = −0.40, P = 0.0002). We conclude that increased liver fat is associated with both impaired insulin clearance and hepatic insulin resistance. Hepatic insulin sensitivity associates with liver fat content, independent of insulin clearance.

scholarly journals Targeted Disruption of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Promotes Diet-Induced Hepatic Steatosis and Insulin Resistance

Endocrinology ◽  
2009 ◽  
Vol 150 (8) ◽  
pp. 3503-3512 ◽  
Author(s):  
Elaine Xu ◽  
Marie-Julie Dubois ◽  
Nelly Leung ◽  
Alexandre Charbonneau ◽  
Claire Turbide ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Adhesion ◽  
Hepatic Steatosis ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Insulin Clearance ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
Related Cell ◽  
Cell Adhesion Molecule 1

Carcinoembryonic antigen-related cell adhesion molecule 1 (CC1) is a cell adhesion molecule within the Ig superfamily. The Tyr-phosphorylated isoform of CC1 (CC1-L) plays an important metabolic role in the regulation of hepatic insulin clearance. In this report, we show that CC1-deficient (Cc1−/−) mice are prone to hepatic steatosis, as revealed by significantly elevated hepatic triglyceride and both total and esterified cholesterol levels compared with age-matched wild-type controls. Cc1−/− mice were also predisposed to lipid-induced hepatic steatosis and dysfunction as indicated by their greater susceptibility to store lipids and express elevated levels of enzymatic markers of liver damage after chronic feeding of a high-fat diet. Hepatic steatosis in the Cc1−/− mice was linked to a significant increase in the expression of key lipogenic (fatty acid synthase, acetyl CoA carboxylase) and cholesterol synthetic (3-hydroxy-3-methylglutaryl-coenzyme A reductase) enzymes under the control of sterol regulatory element binding proteins-1c and -2 transcription factors. Cc1−/− mice also exhibited impaired insulin clearance, glucose intolerance, liver insulin resistance, and elevated hepatic expression of the key gluconeogenic transcriptional activators peroxisome proliferator-activated receptor-γ coactivator-1 and Forkhead box O1. Lack of CC1 also exacerbated both glucose intolerance and hepatic insulin resistance induced by high-fat feeding, but insulin clearance was not further deteriorated in the high-fat-fed Cc1−/− mice. In conclusion, our data indicate that CC1 is a key regulator of hepatic lipogenesis and that Cc1−/− mice are predisposed to liver steatosis, leading to hepatic insulin resistance and liver damage, particularly when chronically exposed to dietary fat.

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

2021 ◽  
Author(s):  
Zhenzhen Fu ◽  
Qinyi Wu ◽  
Wen Guo ◽  
Jingyu Gu ◽  
Xuqin Zheng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Insulin Clearance ◽  
Serum Bile Acid ◽  
Intravenous Glucose ◽  
Impaired Insulin ◽  
Obese Subjects

<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>

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

2021 ◽  
Author(s):  
Zhenzhen Fu ◽  
Qinyi Wu ◽  
Wen Guo ◽  
Jingyu Gu ◽  
Xuqin Zheng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Insulin Clearance ◽  
Serum Bile Acid ◽  
Intravenous Glucose ◽  
Impaired Insulin ◽  
Obese Subjects

<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>

scholarly journals Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice

Metabolism ◽  
2018 ◽  
Vol 88 ◽  
pp. 1-11 ◽  
Author(s):  
Pablo Villa-Pérez ◽  
Beatriz Merino ◽  
Cristina M. Fernández-Díaz ◽  
Pilar Cidad ◽  
Carmen D. Lobatón ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Intolerance ◽  
Insulin Clearance ◽  
Hepatic Insulin Resistance ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme

1516-P: A Comparison of the Contributions of Impaired Insulin Secretion and Insulin Resistance to the Development of Type 2 Diabetes in a Japanese Community: The Hisayama Study

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1516-P
Author(s):  
MASAHITO YOSHINARI ◽  
YOICHIRO HIRAKAWA ◽  
JUN HATA ◽  
MAYU HIGASHIOKA ◽  
TAKANORI HONDA ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin
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