Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-degrading enzyme (IDE) plays a principal role in the proteolysis of several peptides in addition to insulin and is encoded by IDE, which resides in a region of chromosome 10q that is linked to type 2 diabetes. Two recent studies presented genetic association data on IDE and type 2 diabetes (one positive and the other negative), but neither explored the fundamental question of whether polymorphism in IDE has a measurable influence on insulin levels in human populations. To address this possibility, 14 single nucleotide polymorphisms (SNPs) from a linkage disequilibrium block encompassing IDE have been genotyped in a sample of 321 impaired glucose tolerant and 403 nondiabetic control subjects. Analyses based on haplotypic genotypes (diplotypes), constructed with SNPs that differentiate common extant haplotypes extending across IDE, provided compelling evidence of association with fasting insulin levels (P = 0.0009), 2-h insulin levels (P = 0.0027), homeostasis model assessment of insulin resistance (P = 0.0001), and BMI (P = 0.0067), with effects exclusively evident in men. The strongest evidence for an effect of a single marker was obtained for rs2251101 (located near the 3' untranslated region of IDE) on 2-h insulin levels (P = 0.000023). Diplotype analyses, however, suggest the presence of multiple interacting trait-modifying sequences in the region. Results indicate that polymorphism in/near IDE contributes to a large proportion of variance in plasma insulin levels and correlated traits, but questions of sex specificity and allelic heterogeneity will need to be taken into consideration as the molecular basis of the observed phenotypic effects unfolds.
Diabetes 2004 Aug
PMID:Quantitative trait loci near the insulin-degrading enzyme (IDE) gene contribute to variation in plasma insulin levels. 1527 98

The goal of this study was to further explore potential mechanisms through which diabetogenic dietary conditions that result in promotion of insulin resistance (IR), a feature of non-insulin dependant diabetes mellitus (type-2 diabetes), may influence Alzheimer's disease (AD). Using genome-wide array technology, we found that connective tissue growth factor (CTGF), a gene product described previously for its involvement in diabetic fibrosis, is elevated in brain tissue in an established mouse model of diet-induced IR. With this evidence we continued to explore the regulation of CTGF in postmortem AD brain tissue and found that CTGF expression correlated with the progression of AD clinical dementia and amyloid neuritic plaque (NP) neuropathology, but not neurofibrillary tangle (NFT) deposition. Consistent with this evidence, we also found that exposure of Tg2576 mice (a model AD-type amyloid neuropathology) to a diabetogenic diet that promotes IR results in a ~2-fold elevation in CTGF steady-state levels in the brain, coincident with a commensurate promotion of AD-type amyloid plaque burden. Finally, using in vitro cellular models of amyloid precursor protein (APP)-processing and Abeta generation/clearance, we confirmed that human recombinant (hr)CTGF may increase Abeta1-40 and Abeta1-42 peptide steady-state levels, possibly through a mechanism that involves gamma-secretase activation and decreased insulin-degrading enzyme (IDE) steady-state levels in a MAP kinase (MAPK)/ phosphatidylinositol 3-kinase (PI-3K)/protein kinase-B (AKT)1-dependent manner. The findings in this study tentatively suggest that increased CTGF expression in the brain might be a novel biological predicative factor of AD clinical progression and neuropathology in response to dietary regimens promoting IR conditions.
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PMID:Connective tissue growth factor (CTGF) expression in the brain is a downstream effector of insulin resistance- associated promotion of Alzheimer's disease beta-amyloid neuropathology. 1618 74

The insulin-degrading enzyme is responsible for the intracellular proteolysis of insulin. Its gene IDE is located on chromosome 10, in an area with suggestive linkage to type 2 diabetes and related phenotypes. Due to the impact of genetic variants of this gene in rodents and the function of its protein product, it has been proposed as a candidate gene for type 2 diabetes. Various groups have explored the role of the common genetic variation of IDE on insulin resistance and reported associations of various single nucleotide polymorphisms (SNPs) and haplotypes on both type 2 diabetes and glycemic traits. We sought to characterize the haplotype structure of IDE in detail and replicate the association of common variants with type 2 diabetes, fasting insulin, fasting glucose, and insulin resistance. We assessed linkage disequilibrium, selected single-marker and multimarker tags, and genotyped these markers in several case-control and family-based samples totalling 4,206 Caucasian individuals. We observed no statistically significant evidence of association between single-marker or multimarker tests in IDE and type 2 diabetes. Nominally significant differences in quantitative traits are consistent with statistical noise. We conclude that common genetic variation at IDE is unlikely to confer clinically significant risk of type 2 diabetes in Caucasians.
Diabetes 2006 Jan
PMID:High-density haplotype structure and association testing of the insulin-degrading enzyme (IDE) gene with type 2 diabetes in 4,206 people. 1638 Apr 85

A 59-year-old man with type 1 diabetes mellitus presented with severe resistance to subcutaneously injected insulin. Histological analysis of the injection sites, demonstrated foreign body type granulomas surrounding areas of amyloidosis. It is suggested that the granulomas were the source of an insulin-degrading enzyme (IDE) which simultaneously degraded amyloidogenic precursors into localized amyloid deposits. These findings may add insight into the role of insulin-degrading enzymes in the etiology of subcutaneous insulin resistance syndromes.
Diabetes Res Clin Pract 2007 Mar
PMID:Severe insulin resistance associated with subcutaneous amyloid deposition. 1693 Jul 58

HIV-1 protease inhibitors have revolutionized the treatment of HIV infection, but their use has been associated with lipodystrophy and insulin resistance. One suggestion for this has been the inhibition of insulin-degrading enzyme (IDE). We have previously demonstrated that insulin, through IDE, can inhibit the proteasome, thus decreasing cytosolic protein degradation. We examined whether the protease inhibitor nelfinavir inhibited IDE and its effect on protein degradation both in vitro and in whole cells. 125I-Insulin degradation was measured by trichloroacetic acid precipitation. Proteasome activities were measured using fluorogenic peptide substrates. Cellular protein degradation was measured by prelabelling cells with 3H-leucine and determining the release of TCA-soluble radioactivity. Nelfinavir inhibited IDE in a concentration-dependent manner with 50% inhibition at the maximal concentration tested, 100 microm. Similarly, the chymotrypsin-like and trypsin-like activities of the proteasome were decreased with an IC50 of approximately 3 microm. The ability of insulin to inhibit the proteasome was abrogated by nelfinavir. Treatment of HepG2 cells with 50 microm nelfinavir decreased 125I-insulin degradation and increased cell-associated radioactivity. Insulin alone maximally decreased protein degradation by 15%. Addition of 50 microm nelfinavir inhibited cellular protein degradation by 14% and blunted the effect of insulin. These data show that nelfinavir inhibits IDE, decreases insulin's ability to inhibit protein degradation via the proteasome and provides another possible mechanism for the insulin resistance seen in protease inhibitor-treated HIV patients.
Diabetes Obes Metab 2006 Nov
PMID:Effect of nelfinavir on insulin metabolism, proteasome activity and protein degradation in HepG2 cells. 1702 90

The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.
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PMID:Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. 1746 49

C-peptide is a substance that the pancreas releases into the circulation in equimolar amounts to insulin and has demonstrated important physiological effects which relate to the vascular field, in particular the microcirculation. For this analysis, we included 321 full and 36 half sibling pairs affected with type 2 diabetes (T2D) from West Africa. A genome-wide panel of 390 tri-nucleotide and tetra-nucleotide repeats with an average distance of 8.9 cM was performed on a total of 691 persons. Variance components based on multipoint linkage approach as implemented in SOLAR were performed for log C-peptide. Significant linkage evidences were observed on 10q23 at D10S2327 with a LOD score of 4.04 (nominal p-value=0.000008, empirical p-value=0.0004); and on 4p15 at D4S2632 with a LOD score of 3.48 (nominal p-value=0.000031, empirical p-value=0.0013). Other suggestive evidence of linkage were observed on 15q14 at D15S659 with a LOD score 2.41 (nominal p-value=0.000435, empirical p-value=0.0068), and on 18p11 near D18S976 with a LOD score 2.18 (nominal p-value=0.000771 and empirical p-value=0.0094). Interestingly, five positional candidate genes for diabetes and related complications are located in our linkage region (the pituitary adenylate cyclase activating polypeptide (PACAP in 18p11); the peroxisome proliferator-activated receptor gamma coactivator 1 (PPARGC1 in 4p15); PTEN, PPP1R5, and IDE located in 10q23. In conclusion, we identified four major genetic loci (10q23, 4p15, 15q14, and 18p11) influencing C-peptide concentration in West Africans with T2D.
Diabetes Res Clin Pract 2007 Dec
PMID:Genome-wide search for susceptibility genes to type 2 diabetes in West Africans: potential role of C-peptide. 1754 23

Insulin-degrading enzyme (IDE) is a zinc metalloprotease that hydrolyzes amyloid-beta (Abeta) and insulin, which are peptides associated with Alzheimer disease (AD) and diabetes, respectively. Our previous structural analysis of substrate-bound human 113-kDa IDE reveals that the N- and C-terminal domains of IDE, IDE-N and IDE-C, make substantial contact to form an enclosed catalytic chamber to entrap its substrates. Furthermore, IDE undergoes a switch between the closed and open conformations for catalysis. Here we report a substrate-free IDE structure in its closed conformation, revealing the molecular details of the active conformation of the catalytic site of IDE and new insights as to how the closed conformation of IDE may be kept in its resting, inactive conformation. We also show that Abeta is degraded more efficiently by IDE carrying destabilizing mutations at the interface of IDE-N and IDE-C (D426C and K899C), resulting in an increase in Vmax with only minimal changes to Km. Because ATP is known to activate the ability of IDE to degrade short peptides, we investigated the interaction between ATP and activating mutations. We found that these mutations rendered IDE less sensitive to ATP activation, suggesting that ATP might facilitate the transition from the closed state to the open conformation. Consistent with this notion, we found that ATP induced an increase in hydrodynamic radius, a shift in electrophoretic mobility, and changes in secondary structure. Together, our results highlight the importance of the closed conformation for regulating the activity of IDE and provide new molecular details that will facilitate the development of activators and inhibitors of IDE.
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PMID:Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE. 1761 31

Insulin-degrading enzyme (IDE) is a metalloproteinase which degrades insulin and terminates its action. Homologous deletion of IDE gene resulted in hyperinsulinemia and glucose intolerance in a rat model of type 2 diabetes mellitus. Several genetic association studies examined IDE as a susceptibility gene for type 2 diabetes in European descents. Here we investigated the genetic association of IDE polymorphisms with the risk of type 2 diabetes and its related phenotypes in the Korean population. Among six single nucleotide polymorphisms analyzed, g.-179T>C (OR=1.73, P=0.04), and g.IVS18+99G>A (OR=1.23, P=0.02) revealed borderline association with increased risk of type 2 diabetes. Combining our results with previous data obtained from the European population, g.-179T>C (OR=1.11, P=0.03), and g.IVS24-64A>T (OR=1.18, P=0.005) showed significant association with type 2 diabetes. Haplotype consisting of common alleles of the six polymorphisms was associated with decreased risk of type 2 diabetes (OR=0.82, P=0.02). However, none of the polymorphisms was significantly associated with metabolic phenotypes. We can conclude that variations in IDE might contribute to diabetes susceptibility in the Korean population.
Diabetes Res Clin Pract 2008 Feb
PMID:Association of polymorphisms in the insulin-degrading enzyme gene with type 2 diabetes in the Korean population. 1791 78

Internally quenched fluorogenic substrates are commonly used for measuring enzyme activity in biological samples and allow high sensitivity and continuous real-time measurement that is well suited for high throughput analysis. We describe the development and optimisation of an immunocapture-based assay that uses the fluorogenic peptide substrate (Mca-RPPGFSAFK(Dnp)) and allows the specific measurement of insulin-degrading enzyme (IDE) activity in brain tissue homogenates. This fluorogenic substrate can be cleaved by a number of enzymes including neprilysin (NEP), endothelin-converting enzyme-1 (ECE-1) and angiotensin-converting enzyme (ACE), as well as IDE, and we have previously shown that discrimination between these individual enzymes is not readily achieved in tissue homogenates, even in the presence of selective inhibitors and pH conditions. We tested a panel of IDE antibodies to isolate and capture IDE from brain tissue homogenates and found that immunocapture with antibody to the inactive domain of IDE prior to the addition of fluorogenic substrate allows sensitive (linear at 156-2500ng/ml) and specific measurement of IDE activity and negligible cross-reactivity with NEP, ACE or ECE-1. This assay should allow the measurement of IDE enzyme levels in a variety of biological tissues and may be useful in study of diseases such as Alzheimer's disease and insulin-dependent diabetes.
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PMID:Immunocapture-based fluorometric assay for the measurement of insulin-degrading enzyme activity in brain tissue homogenates. 1822 86


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