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

The aim of this study was to investigate the insulin clearance in diet-induced obese (DIO) mice submitted to acute endurance exercise (3h of treadmill exercise at 60–70% VO2max). Glucose-stimulated insulin secretion in isolated islets; ipGTT; ipITT; ipPTT; in vivo insulin clearance; protein expression in liver, skeletal muscle, and adipose tissue (insulin degrading enzyme (IDE), insulin receptor subunitβ(IRβ), phospho-Akt (p-Akt) and phospho-AMPK (p-AMPK)), and the activity of IDE in the liver and skeletal muscle were accessed. In DIO mice, acute exercise reduced fasting glycemia and insulinemia, improved glucose and insulin tolerance, reduced hepatic glucose production, and increased p-Akt protein levels in liver and skeletal muscle and p-AMPK protein levels in skeletal muscle. In addition, insulin secretion was reduced, whereas insulin clearance and the expression of IDE and IRβ were increased in liver and skeletal muscle. Finally, IDE activity was increased only in skeletal muscle. In conclusion, we propose that the increased insulin clearance and IDE expression and activity, primarily, in skeletal muscle, constitute an additional mechanism, whereby physical exercise reduces insulinemia in DIO mice.

Download Full-text

Human red blood cell insulin-degrading enzyme and rat skeletal muscle insulin protease share antigenic sites and generate identical products from insulin.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)39898-9 ◽

1990 ◽

Vol 265 (5) ◽

pp. 2984-2987 ◽

Cited By ~ 1

Author(s):

W C Duckworth ◽

F G Hamel ◽

R Bennett ◽

M P Ryan ◽

R A Roth

Keyword(s):

Skeletal Muscle ◽

Blood Cell ◽

Red Blood Cell ◽

Rat Skeletal Muscle ◽

Insulin Degrading Enzyme ◽

Degrading Enzyme ◽

Antigenic Sites

Download Full-text

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

Journal of Investigative Medicine ◽

10.1136/jim-2016-000120.33 ◽

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.

Download Full-text

Cafeteria diet inhibits insulin clearance by reduced insulin-degrading enzyme expression and mRNA splicing

Journal of Endocrinology ◽

10.1530/joe-13-0177 ◽

2013 ◽

Vol 219 (2) ◽

pp. 173-182 ◽

Cited By ~ 28

Author(s):

P Brandimarti ◽

J M Costa-Júnior ◽

S M Ferreira ◽

A O Protzek ◽

G J Santos ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Secretion ◽

Alternative Splicing ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Insulin Clearance ◽

Cafeteria Diet ◽

Mrna Levels ◽

Insulin Degrading Enzyme ◽

Diet Induced Obesity

Insulin clearance plays a major role in glucose homeostasis and insulin sensitivity in physiological and/or pathological conditions, such as obesity-induced type 2 diabetes as well as diet-induced obesity. The aim of the present work was to evaluate cafeteria diet-induced obesity-induced changes in insulin clearance and to explain the mechanisms underlying these possible changes. Female Swiss mice were fed either a standard chow diet (CTL) or a cafeteria diet (CAF) for 8 weeks, after which we performed glucose tolerance tests, insulin tolerance tests, insulin dynamics, and insulin clearance tests. We then isolated pancreatic islets for ex vivo glucose-stimulated insulin secretion as well as liver, gastrocnemius, visceral adipose tissue, and hypothalamus for subsequent protein analysis by western blot and determination of mRNA levels by real-time RT-PCR. The cafeteria diet induced insulin resistance, glucose intolerance, and increased insulin secretion and total insulin content. More importantly, mice that were fed a cafeteria diet demonstrated reduced insulin clearance and decay rate as well as reduced insulin-degrading enzyme (IDE) protein and mRNA levels in liver and skeletal muscle compared with the control animals. Furthermore, the cafeteria diet reduced IDE expression and alternative splicing in the liver and skeletal muscle of mice. In conclusion, a cafeteria diet impairs glucose homeostasis by reducing insulin sensitivity, but it also reduces insulin clearance by reducing IDE expression and alternative splicing in mouse liver; however, whether this mechanism contributes to the glucose intolerance or helps to ameliorate it remains unclear.

Download Full-text

Differentiation of BC3H1 and primary skeletal muscle cells and the activity of their endogenous insulin-degrading enzyme are inhibited by the same metalloendoprotease inhibitors

Journal of Cellular Biochemistry ◽

10.1002/jcb.240440303 ◽

1990 ◽

Vol 44 (3) ◽

pp. 137-151 ◽

Cited By ~ 11

Author(s):

Celik Kayalar ◽

William T. Wong ◽

Lisa Hendrickson

Keyword(s):

Skeletal Muscle ◽

Muscle Cells ◽

Skeletal Muscle Cells ◽

Insulin Degrading Enzyme ◽

Degrading Enzyme ◽

Endogenous Insulin

Download Full-text

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

British Journal Of Nutrition ◽

10.1017/s0007114514001238 ◽

2014 ◽

Vol 112 (6) ◽

pp. 900-907 ◽

Cited By ~ 10

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.

Download Full-text

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

Scientific Reports ◽

10.1038/s41598-017-13974-0 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 8

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

Download Full-text

Targeting Insulin-Degrading Enzyme in Insulin Clearance

International Journal of Molecular Sciences ◽

10.3390/ijms22052235 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2235 ◽

Cited By ~ 1

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.

Download Full-text