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

ID: 79: INSULIN TREATMENT INCREASES MICROVESICULAR INSULIN-DEGRADING ENZYME IN DIABETES

2016 ◽  
Vol 64 (4) ◽  
pp. 926.2-927
Author(s):  
MV Purbaugh ◽  
CV Desouza ◽  
R Heineman ◽  
RG Bennett ◽  
FG Hamel
Keyword(s):  
Insulin Resistance ◽  
Western Blot ◽  
Insulin Treatment ◽  
Statistical Significance ◽  
Diabetic Group ◽  
Insulin Clearance ◽  
Diabetic Patients ◽  
Insulin Degrading Enzyme ◽  
Healthy Group ◽  
Degrading Enzyme

Insulin-degrading enzyme (IDE) in the blood may play a role in insulin clearance, thus decreased IDE activity could contribute to hyperinsulinemia and possibly type 2 diabetes mellitus (T2DM). We hypothesized that decreased IDE in plasma may be associated with obesity and/or T2DM. We recruited non-obese (BMI<30, no significant disease), obese (BMI>30) and diabetic (T2DM; ICD-9 code) patients and obtained fasting blood samples. Microvesicular (containing exosomes) and soluble fractions were isolated from plasma by ultracentrifugation Insulin degrading activity was assayed by trichloroacetic acid precipitation of 125I-iodoinsulin (TCA assay), while IDE protein was detected by Western blotting. Differences were analyzed by ANOVA with a Bonferroni posttest. There was no IDE present in the soluble fraction as confirmed by both the TCA assay and Western blot. IDE activity was present in the microvesicular fraction, and the Western blot intensity correlated significantly with activity (p=.01). However, there were no significant differences in IDE activity or protein levels among the 3 groups. We then conducted a post hoc analysis byseparating the non-obese and obese patients into two groups: a healthy group (HbA1c<6) and a pre-diabetic group (HbA1c of 6.0–6.4). We also separated the diabetic patients into two groups: a diabetic group and an insulin-treated group. Although there was no statistical difference in IDE activity among the healthy group, pre-diabetic and diabetic groups, the latter two groups showed a trend toward decreased IDE activity. Interestingly, in patients receiving insulin treatment, the effect of diabetes was reversed, with, increased microvesicular degrading activity compared to the pre-diabetic group (p<0.05) and the diabetic group (p<0.05). The increased IDE activity in the insulin-treated diabetics roughly correlated with the patient's insulin dose, but did not reach statistical significance (r2=.38; p=0.14). We saw no statistically significant correlations of degrading activity with a number of clinical parameters including: fasting glucose; triglycerides, LDL, HDL, age, eGFR, and HbA1c by linear regression. This shows that the microvesicular IDE is not affected by glucose or lipid control. We conclude: A) IDE is present in the blood, but does not significantly contribute to insulin clearance because the microvesicular fraction showed no insulin clearance unless they were first frozen and thawed. This freezing and thawing process most likely allowed the microvesicular membranes to rupture releasing the enzyme. B) enzymatically active IDE is associated with a fraction consistent with exosomes and may be decreased in pre-diabetes and diabetes; and C) insulin treatment increases microvesicular IDE. IDE in the exosomes may serve as a marker for the progression of the pre-diabetic and diabetic disease states independent of glucose control. One could speculate that inflammation and/or insulin resistance result in a decrease of vesicular IDE activity and that insulin treatment reverses this through its anti-inflammatory properties, or by overcoming insulin resistance and increasing insulin signaling.

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 Caloric Restriction Reverses Hepatic Insulin Resistance and Steatosis in Rats with Low Aerobic Capacity

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5157-5164 ◽  
Author(s):  
Thomas A. Bowman ◽  
Sadeesh K. Ramakrishnan ◽  
Meenakshi Kaw ◽  
Sang Jun Lee ◽  
Payal R. Patel ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Caloric Restriction ◽  
Visceral Obesity ◽  
Insulin Clearance ◽  
Hepatic Insulin Resistance ◽  
The Metabolic Syndrome ◽  
Cell Adhesion Molecule 1 ◽  
Muscle Triglyceride

Rats selectively bred for low aerobic running capacity exhibit the metabolic syndrome, including hyperinsulinemia, insulin resistance, visceral obesity, and dyslipidemia. They also exhibit features of nonalcoholic steatohepatitis, including chicken-wire fibrosis, inflammation, and oxidative stress. Hyperinsulinemia in these rats is associated with impaired hepatic insulin clearance. The current studies aimed to determine whether these metabolic abnormalities could be reversed by caloric restriction (CR). CR by 30% over a period of 2–3 months improved insulin clearance in parallel to inducing the protein content and activation of the carcinoembryonic antigen-related cell adhesion molecule 1, a main player in hepatic insulin extraction. It also reduced glucose and insulin intolerance and serum and tissue (liver and muscle) triglyceride levels. Additionally, CR reversed inflammation, oxidative stress, and fibrosis in liver. The data support a significant role of CR in the normalization of insulin and lipid metabolism in liver.

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 Acute Exercise Improves Insulin Clearance and Increases the Expression of Insulin-Degrading Enzyme in the Liver and Skeletal Muscle of Swiss Mice

PLoS ONE ◽  
2016 ◽  
Vol 11 (7) ◽  
pp. e0160239 ◽  
Author(s):  
Mirian A. Kurauti ◽  
Ricardo Freitas-Dias ◽  
Sandra M. Ferreira ◽  
Jean F. Vettorazzi ◽  
Tarlliza R. Nardelli ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Acute Exercise ◽  
Insulin Clearance ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Swiss Mice

scholarly journals Reduced insulin clearance and lower insulin-degrading enzyme expression in the liver might contribute to the thrifty phenotype of protein-restricted mice

2014 ◽  
Vol 112 (6) ◽  
pp. 900-907 ◽  
Author(s):  
Luiz F. Rezende ◽  
Rafael L. Camargo ◽  
Renato C. S. Branco ◽  
Ana P. G. Cappelli ◽  
Antonio C. Boschero ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Insulin Clearance ◽  
Protein Diet ◽  
Restricted Diet ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Thrifty Phenotype

Nutrient restriction during the early stages of life usually leads to alterations in glucose homeostasis, mainly insulin secretion and sensitivity, increasing the risk of metabolic disorders in adulthood. Despite growing evidence regarding the importance of insulin clearance during glucose homeostasis in health and disease, no information exists about this process in malnourished animals. Thus, in the present study, we aimed to determine the effect of a nutrient-restricted diet on insulin clearance using a model in which 30-d-old C57BL/6 mice were exposed to a protein-restricted diet for 14 weeks. After this period, we evaluated many metabolic variables and extracted pancreatic islet, liver, gastrocnemius muscle (GCK) and white adipose tissue samples from the control (normal-protein diet) and restricted (low-protein diet, LP) mice. Insulin concentrations were determined using RIA and protein expression and phosphorylation by Western blot analysis. The LP mice exhibited lower body weight, glycaemia, and insulinaemia, increased glucose tolerance and altered insulin dynamics after the glucose challenge. The improved glucose tolerance could partially be explained by an increase in insulin sensitivity through the phosphorylation of the insulin receptor/protein kinase B and AMP-activated protein kinase/acetyl-CoA carboxylase in the liver, whereas the changes in insulin dynamics could be attributed to reduced insulin secretion coupled with reduced insulin clearance and lower insulin-degrading enzyme (IDE) expression in the liver and GCK. In summary, protein-restricted mice not only produce and secrete less insulin, but also remove and degrade less insulin. This phenomenon has the double benefit of sparing insulin while prolonging and potentiating its effects, probably due to the lower expression of IDE in the liver, possibly with long-term consequences.

scholarly journals Bile acid TUDCA improves insulin clearance by increasing the expression of insulin-degrading enzyme in the liver of obese mice

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Jean Franciesco Vettorazzi ◽  
Mirian Ayumi Kurauti ◽  
Gabriela Moreira Soares ◽  
Patricia Cristine Borck ◽  
Sandra Mara Ferreira ◽  
...  
Keyword(s):  
Bile Acid ◽  
Insulin Clearance ◽  
Obese Mice ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme

scholarly journals Targeting Insulin-Degrading Enzyme in Insulin Clearance

2021 ◽  
Vol 22 (5) ◽  
pp. 2235 ◽  
Author(s):  
Malcolm A. Leissring ◽  
Carlos M. González-Casimiro ◽  
Beatriz Merino ◽  
Caitlin N. Suire ◽  
Germán Perdomo
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Clearance ◽  
Diabetic Patients ◽  
Insulin Degradation ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Intermediate Size ◽  
Pros And Cons ◽  
Hepatic Insulin Clearance

Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50–80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin-degrading enzyme (IDE) is a highly conserved Zn2+-metalloprotease that degrades insulin and several other intermediate-size peptides. Both, insulin clearance and IDE activity are reduced in diabetic patients, albeit the cause-effect relationship in humans remains unproven. Because historically IDE has been proposed as the main enzyme involved in insulin degradation, efforts in the development of IDE inhibitors as therapeutics in diabetic patients has attracted attention during the last decades. In this review, we retrace the path from Mirsky’s seminal discovery of IDE to the present, highlighting the pros and cons of the development of IDE inhibitors as a pharmacological approach to treating diabetic patients.

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.

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