scholarly journals The Drosophila insulin-degrading enzyme restricts growth by modulating the PI3K pathway in a cell-autonomous manner

2014 ◽  
Vol 25 (6) ◽  
pp. 916-924 ◽  
Author(s):  
Diego Galagovsky ◽  
Maximiliano J. Katz ◽  
Julieta M. Acevedo ◽  
Eleonora Sorianello ◽  
Alvaro Glavic ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Signaling ◽  
Pi3k Pathway ◽  
Cell Number ◽  
Loss Of Function ◽  
Insulin Degrading Enzyme ◽  
Diabetes Mellitus Type Ii ◽  
Degrading Enzyme ◽  
A Cell ◽  
Regulation Of Growth

Mammalian insulin-degrading enzyme (IDE) cleaves insulin, among other peptidic substrates, but its function in insulin signaling is elusive. We use the Drosophila system to define the function of IDE in the regulation of growth and metabolism. We find that either loss or gain of function of Drosophila IDE (dIDE) can restrict growth in a cell-autonomous manner by affecting both cell size and cell number. dIDE can modulate Drosophila insulin-like peptide 2 levels, thereby restricting activation of the phosphatidylinositol-3-phosphate kinase pathway and promoting activation of Drosophila forkhead box, subgroup O transcription factor. Larvae reared in high sucrose exhibit delayed developmental timing due to insulin resistance. We find that dIDE loss of function exacerbates this phenotype and that mutants display increased levels of circulating sugar, along with augmented expression of a lipid biosynthesis marker. We propose that dIDE is a modulator of insulin signaling and that its loss of function favors insulin resistance, a hallmark of diabetes mellitus type II.

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 Cell-Permeable, Small-Molecule Activators of the Insulin-Degrading Enzyme

2012 ◽  
Vol 17 (10) ◽  
pp. 1348-1361 ◽  
Author(s):  
Sayali S. Kukday ◽  
Surya P. Manandhar ◽  
Marissa C. Ludley ◽  
Mary E. Burriss ◽  
Benjamin J. Alper ◽  
...  
Keyword(s):  
Small Molecules ◽  
Biologically Active ◽  
Small Peptides ◽  
Insulin Degrading Enzyme ◽  
Potential Therapeutic Target ◽  
Aβ Peptides ◽  
Degrading Enzyme ◽  
Enzyme Substrate ◽  
A Cell

The insulin-degrading enzyme (IDE) cleaves numerous small peptides, including biologically active hormones and disease-related peptides. The propensity of IDE to degrade neurotoxic Aβ peptides marks IDE as a potential therapeutic target for Alzheimer disease. Using a synthetic reporter based on the yeast a-factor mating pheromone precursor, which is cleaved by multiple IDE orthologs, we identified seven small molecules that stimulate rat IDE activity in vitro. Half-maximal activation of IDE by the compounds is observed in vitro in the range of 43 to 198 µM. All compounds decrease the Km of IDE. Four compounds activate IDE in the presence of the competing substrate insulin, which disproportionately inhibits IDE activity. Two compounds stimulate rat IDE activity in a cell-based assay, indicating that they are cell permeable. The compounds demonstrate specificity for rat IDE since they do not enhance the activities of IDE orthologs, including human IDE, and they appear specific for a-factor–based reporters since they do not enhance rat IDE-mediated cleavage of Aβ-based reporters. Our results suggest that IDE activators function in the context of specific enzyme-substrate pairs, indicating that the choice of substrate must be considered in addition to target validation in IDE activator screens.

Abstract 12189: Molecular Mechanisms Underlying Fasting Modulated Liver Insulin Sensitivity and Metabolism in Male Lipodystrophic Bscl2/Seipin-Deficient Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Weiqin Chen ◽  
Hongyi Zhou ◽  
Pradip Saha ◽  
Luge Li ◽  
Lawrence Chan
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Liver Lipid ◽  
De Novo Lipogenesis ◽  
Hepatic Insulin Signaling ◽  
A Cell

Bscl2–/– mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip Congenital Lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatomegly, hepatic steatosis and insulin resistance. The mechanisms that underlie hepatic steatosis and insulin resistance in Bscl2–/– mice are poorly understood. To address this issue, we performed hyperinsulinemic-euglycemic clamp on Bscl2–/– and wild-type mice after an overnight (16-h) fast, and found that Bscl2–/– actually displayed increased hepatic insulin sensitivity. Interestingly, liver in Bscl2–/– mice after a short term (4-h) fast had impaired acute insulin signaling, a defect that disappeared after a 16-h fast. Notably, fasting dependent hepatic insulin signaling in Bscl2–/– mice was not associated with liver diacylglyceride and ceramide contents, but could be attributable in part to the expression of hepatic insulin signaling receptor and substrates. Meanwhile, increased de novo lipogenesis and decreased β-oxidation led to severe hepatic steatosis in fed or short fasted Bscl2–/– mice while liver lipid accumulation and metabolism in Bscl2–/– mice was markedly impacted by prolonged fasting. Furthermore, mice with liver-specific inactivation of Bscl2 manifested no hepatic steatosis even under high fat diet, suggesting Bscl2 does not play a cell autonomous role in regulating liver lipid homeostasis. Overall, our results offered new insights into the metabolic adaptations of liver in response to fasting and uncovered a novel fasting-dependent regulation of hepatic insulin signaling in a mouse model of human BSCL2.

scholarly journals Immunohistochemical evidence of ubiquitous distribution of the metalloendoprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cell lines

2008 ◽  
Vol 389 (11) ◽  
Author(s):  
Gregor Weirich ◽  
Karin Mengele ◽  
Christina Yfanti ◽  
Apostolos Gkazepis ◽  
Daniela Hellmann ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Striated Muscle ◽  
Tumor Cell Lines ◽  
Trophoblast Cells ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
A Cell ◽  
Organ Tissue ◽  
Immunohistochemical Evidence

Abstract Immunohistochemical evidence of ubiquitous distribution of the metalloprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cells is presented. Immunohistochemical staining was performed on a multi-organ tissue microarray (pancreas, lung, kidney, central/peripheral nervous system, liver, breast, placenta, myocardium, striated muscle, bone marrow, thymus, and spleen) and on a cell microarray of 31 tumor cell lines of different origin, as well as trophoblast cells and normal blood lymphocytes and granulocytes. IDE protein was expressed in all the tissues assessed and all the tumor cell lines except for Raji and HL-60. Trophoblast cells and granulocytes, but not normal lymphocytes, were also IDE-positive.

scholarly journals Partial Loss-of-Function Mutations in Insulin-Degrading Enzyme that Induce Diabetes also Impair Degradation of Amyloid β-Protein

2004 ◽  
Vol 164 (4) ◽  
pp. 1425-1434 ◽  
Author(s):  
Wesley Farris ◽  
Stefan Mansourian ◽  
Malcolm A. Leissring ◽  
Elizabeth A. Eckman ◽  
Lars Bertram ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Loss Of Function ◽  
Insulin Degrading Enzyme ◽  
Partial Loss ◽  
Degrading Enzyme ◽  
Β Protein
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