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

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.

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

PLoS ONE ◽

10.1371/journal.pone.0160239 ◽

2016 ◽

Vol 11 (7) ◽

pp. e0160239 ◽

Cited By ~ 12

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

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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.

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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.

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Hyperinsulinemia caused by dexamethasone treatment is associated with reduced insulin clearance and lower hepatic activity of insulin-degrading enzyme

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/j.jsbmb.2015.09.020 ◽

2016 ◽

Vol 155 ◽

pp. 1-8 ◽

Cited By ~ 18

Author(s):

André Otávio Peres Protzek ◽

Luiz Fernando Rezende ◽

José Maria Costa-Júnior ◽

Sandra Mara Ferreira ◽

Ana Paula Gameiro Cappelli ◽

...

Keyword(s):

Insulin Clearance ◽

Dexamethasone Treatment ◽

Insulin Degrading Enzyme ◽

Degrading Enzyme

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Chromiumâ€“Insulin Reduces Insulin Clearance and Enhances Insulin Signaling by Suppressing Hepatic Insulin-Degrading Enzyme and Proteasome Protein Expression in KKAy Mice

Frontiers in Endocrinology ◽

10.3389/fendo.2014.00099 ◽

2014 ◽

Vol 5 ◽

Cited By ~ 4

Author(s):

Zhong Q. Wang ◽

Yongmei Yu ◽

Xian H. Zhang ◽

James Komorowski

Keyword(s):

Protein Expression ◽

Insulin Signaling ◽

Insulin Clearance ◽

Insulin Degrading Enzyme ◽

Degrading Enzyme ◽

Kkay Mice ◽

Proteasome Protein

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Dietary Curcumin Systemically Maintains Insulin Homeostasis in Diet-Induced Aged Obese Mice via Liver-Pancreas-Brain Axis

Current Developments in Nutrition ◽

10.1093/cdn/nzab033_029 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 29-29

Author(s):

Yoo Kim ◽

Caio Henrique Mazucanti ◽

Jennifer F. O'Connell ◽

Josephine M. Egan

Keyword(s):

Insulin Clearance ◽

Chow Diet ◽

Obese Mice ◽

High Fat ◽

Insulin Degrading Enzyme ◽

Insulin Levels ◽

High Sugar ◽

Insulin Homeostasis ◽

Normal Chow ◽

Normal Chow Diet

Abstract Objectives Aging is a condition in which we gradually lose the ability to maintain homeostasis due to dysfunction. There continues to be a knowledge gap in implicating how dietary intervention affects the mechanisms delaying or preventing aging-related chronic diseases. Although curcumin (CUR), a natural antioxidant, shows the putative therapeutic properties such as reinstating insulin homeostasis in obese mice, an aging-associated mechanism in which CUR regulates insulin levels largely remains unclear. Thus, the objective of this study is to determine effects of CUR on anti-aging under obese condition mediated by maintaining insulin homeostasis via cross-talk among liver, pancreas and brain. Methods We examine how dietary CUR improves insulin clearance and maintains a proper range of circulating insulin level in the aged diet-induced obesity (DIO) mouse model. Old male C57BL/6J mice were fed a normal chow diet (NCD) or a NCD containing 0.4% (w/w) curcumin (NCD + CUR), a high fat/high sugar diet (HFHSD) or a HFHSD + CUR (N = 7–9 per group) for 16 weeks. Results Old male C57BL/6J mice were fed a normal chow diet (NCD) or a NCD containing 0.4% (w/w) curcumin (NCD + CUR), a high fat/high sugar diet (HFHSD) or a HFHSD + CUR (N = 7–9 per group) for 16 weeks. Mice given HFHSD + CUR had reduced body weight gain (4.7 ± 1.8 vs 7.8 ± 1.6g) and had lower blood insulin levels (2.24 ± 0.3 vs. 1.53 ± 0.3 ng/ml) under fasting conditions compared to mice on HFHSD alone, resulting from significantly improved insulin clearance via upregulation of hepatic insulin-degrading enzyme (IDE) and circulating IDE levels in serum. On the other hand, the expression of IDE gene in hypothalamus was significantly lower in HFHSD + CUR mice (1.3 folds) than HFHSD animals. Obesity induces hyperglycemic condition in brain by higher IDE expression to excessively break down insulin. We also observed significantly smaller islets of Langerhans (4.53 ± 0.72 vs 7.90 ± 0.34 a.u.) in HFSD + CUR fed mice and increased glucagon contents compared to HFS fed mice, indicating less secretion of insulin in pancreas under obese condition. Conclusions The conclusion of this study is that curcumin is a potent, natural therapeutic agent that can systemically regulate insulin levels in a multifaceted manner to protect against insulin resistance in aged mice. Funding Sources Intramural Research Program of NIAThe OTTOGI HAM TAIHO Foundation

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