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 receptor substrate (IRS) proteins are important intracellular molecules that mediate insulin receptor tyrosine kinase signaling. A decreased content of IRS proteins has been found in insulin-resistant states in animals, humans, and cultured cells under various conditions. However, the molecular mechanism that controls cellular levels of IRS proteins is unknown. We report that chronic insulin treatment induces the degradation of IRS-1, but not IRS-2, protein in cultured cells. The insulin-induced degradation of IRS-1 can be prevented by pretreatment with lactacystin, a specific inhibitor for proteasome degradation. These data demonstrate, for the first time, that insulin-induced degradation of IRS-1 is mediated by the proteasome degradation pathway. IRS-2 can escape from the insulin-induced proteasome degradation, suggesting the existence of specific structural requirements for this degradation process.
Diabetes 1999 Jul
PMID:Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway. 1038 39

It is assumed that increased oxidative stress contributes to the development of complications in diabetes. In this study, several markers of protein structural modifications directly induced by free radicals were investigated in the liver and kidney cytosolic fractions of rats with streptozotocin-induced diabetes. Sulfydryl residue and side-chain amino group analyses, as well as immunoblotting and chromatographic measurements of protein-bound carbonyl, suggest that protein oxidative modification is not increased by diabetes, with the exception of sulfydryl groups in renal cytosol. The levels of the glycation-derived carbonyl N epsilon-fructosyl-lysine are significantly increased by diabetes. Furthermore, unchanged proteolytic activity against in vivo-oxidized proteins, significant decreases both in activity against H2O2-modified proteins and in proteasome activity, measured by the degradation of a specific fluorogenic substrate, suggest that the unchanged oxidative protein modification in the diabetic state cannot be attributed to an increased cytosolic proteolytic activity in these tissues. These results provide evidence against a generalized increase in protein oxidative damage and demonstrate a diabetes-induced alteration in cytosolic proteolytic pathways, suggesting that proteasome activity may be impaired in these organs.
Diabetes 1999 Nov
PMID:Diabetes induces an impairment in the proteolytic activity against oxidized proteins and a heterogeneous effect in nonenzymatic protein modifications in the cytosol of rat liver and kidney. 1053 57

Insulin deficiency (e.g., in acute diabetes or fasting) is associated with enhanced protein breakdown in skeletal muscle leading to muscle wasting. Because recent studies have suggested that this increased proteolysis is due to activation of the ubiquitin-proteasome (Ub-proteasome) pathway, we investigated whether diabetes is associated with an increased rate of Ub conjugation to muscle protein. Muscle extracts from streptozotocin-induced insulin-deficient rats contained greater amounts of Ub-conjugated proteins than extracts from control animals and also 40-50% greater rates of conjugation of (125)I-Ub to endogenous muscle proteins. This enhanced Ub-conjugation occurred mainly through the N-end rule pathway that involves E2(14k) and E3alpha. A specific substrate of this pathway, alpha-lactalbumin, was ubiquitinated faster in the diabetic extracts, and a dominant negative form of E2(14k) inhibited this increase in ubiquitination rates. Both E2(14k) and E3alpha were shown to be rate-limiting for Ub conjugation because adding small amounts of either to extracts stimulated Ub conjugation. Furthermore, mRNA for E2(14k) and E3alpha (but not E1) were elevated 2-fold in muscles from diabetic rats, although no significant increase in E2(14k) and E3alpha content could be detected by immunoblot or activity assays. The simplest interpretation of these results is that small increases in both E2(14k) and E3alpha in muscles of insulin-deficient animals together accelerate Ub conjugation and protein degradation by the N-end rule pathway, the same pathway activated in cancer cachexia, sepsis, and hyperthyroidism.
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PMID:Ubiquitin conjugation by the N-end rule pathway and mRNAs for its components increase in muscles of diabetic rats. 1056 3

Catabolic conditions such as uremia, cancer, insulin-dependent diabetes and sepsis are associated with muscle atrophy resulting from activation of the ubiquitin-proteasome proteolytic pathway. Evidence for the activation of this pathway includes an increase in both proteolytic activity and capacity, as demonstrated by increased protein degradation and a higher rate of gene transcription in muscle yielding increased levels of mRNAs encoding components of the pathway. Glucocorticoids are critical but other hormones and cytokines interact to regulate the activity of this proteolytic pathway.
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PMID:Mechanisms stimulating protein degradation to cause muscle atrophy. 1056 34

The nonobese diabetic (NOD) mouse is an animal model of human type I diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) of the genome. We have identified in NOD lymphocytes a specific proteasome defect that results from the lack of the LMP2 subunit. The pronounced proteasome defect results in defective production and activation of the transcription factor NF-kappaB, which plays an important role in immune and inflammatory responses as well as in preventing apoptosis induced by tumor necrosis factor alpha. The defect in proteasome function in NOD mouse splenocytes was evident from impaired NF-kappaB subunit p50 and p52 generation by proteolytic processing and impaired degradation of the NF-kappaB-inhibitory protein IkappaBalpha. An obligatory role of MHC-linked proteasome subunits in transcription factor processing and activation has been established in a spontaneous-disease model and mutant cells similarly lacking the MHC-encoded subunit. These data suggest that NOD proteasome dysfunction is due to a tissue- and developmental-stage-specific defect in expression of the MHC-linked Lmp2 gene, resulting in altered transcription factor NF-kappaB activity, and that this defect contributes to pathogenesis in NOD mice. These observations are consistent with the diverse symptomatology of type I diabetes and demonstrate clear sex-, tissue-, and age-specific differences in the expression of this error which parallel the initiation and disease course of insulin-dependent (type I) diabetes mellitus.
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PMID:NOD mice are defective in proteasome production and activation of NF-kappaB. 1056 88

In uremia, accelerated muscle protein degradation results from activation of the ATP-ubiquitin proteasome proteolytic pathway. Like uremia, other conditions (e.g., acidosis and diabetes) activate this pathway in rat muscles and are associated with excess glucocorticoids (GC) and impaired insulin action. To define the stimuli responsible for muscle wasting in IDDM, the roles of glucocorticoids, insulinopenia and acidosis in streptozotocin (STZ) - induced diabetes were studied. Proteolysis in isolated epitrochlearis muscles from acutely (3d) diabetic rats was 52% higher than pair-fed, sham-injected rats; this increase was eliminated by an inhibitor of the proteasome or by blocking ATP synthesis. In muscles of STZ-diabetic rats, the levels of ubiquitin-conjugated proteins and mRNAs encoding ubiquitin, the ubiquitin-carrier protein, E2(14k) and the C3, C5 and C9 proteasome subunits were increased. Transcription of ubiquitin and C3 proteasome subunit genes in muscle was also increased by IDDM. Oral NaHCO(3) eliminated acidemia but did not prevent accelerated muscle proteolysis. Corticosterone excretion was higher in IDDM rats and adrenalectomy (ADX) prevented these catabolic responses; physiologic doses of glucorcoticoids restored the excessive protein catabolism in ADX-STZ rats. Giving IDDM rats replacement insulin also normalized protein degradation in muscles. In conclusion, reduced insulin together with physiologic levels of glucocorticoids activate the ubiquitin-proteasome pathway by a mechanism that includes enhancing ubiquitin conjugation and proteolysis by the proteasome. The balance between these stimuli could regulate muscle proteolysis in uremia.
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PMID:The balance between glucocorticoids and insulin regulates muscle proteolysis via the ubiquitin-proteasome pathway. 1068 43

Decreased muscle mass in patients with chronic renal failure (CRF) can be caused by mechanisms that activate the ubiquitin-proteasome proteolytic system. This system accelerates the degradation of muscle protein. Concurrent with muscle protein breakdown, there is an increase in transcription of genes encoding components of this pathway, including ubiquitin and subunits of the proteasome. Potential activating signals include metabolic acidosis which stimulates proteolysis in CRF patients and in muscle of rats with CRF by a mechanism involving glucocorticoids. In CRF patients, there is insulin resistance and high circulating levels of tumor necrosis factor and other cytokines. As the ubiquitin-proteasome proteolytic system is activated in acute diabetes and in catabolic conditions associated with high levels of circulating cytokines, these factors could also activate this pathway. Consequently, we examined whether the transcription factor activated by certain cytokines, NF-kappaB, is involved in the transcriptional regulation of subunits of the 26S proteasome complex. The results suggest that cytokines may be involved in the regulation of muscle protein degradation in uremia.
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PMID:Mechanisms causing muscle proteolysis in uremia: the influence of insulin and cytokines. 1068 42

A pathological feature of Type 2 diabetes is deposits in the pancreatic islets primarily composed of amylin (islet amyloid polypeptide). Although much attention has been paid to the expression and secretion of amylin, little is known about the enzymes involved in amylin turnover. Recent reports suggest that insulin-degrading enzyme (IDE) may have specificity for amyloidogenic proteins, and therefore we sought to determine whether amylin is an IDE substrate. Amylin-degrading activity co-purified with IDE from rat muscle through several chromatographic steps. Metalloproteinase inhibitors inactivated amylin-degrading activity with a pattern consistent with the enzymatic properties of IDE, whereas inhibitors of acid and serine proteases, calpains, and the proteasome were ineffective. Amylin degradation was inhibited by insulin in a dose-dependent manner, whereas insulin degradation was inhibited by amylin. Other substrates of IDE such as atrial natriuretic peptide and glucagon also competitively inhibited amylin degradation. Radiolabeled amylin and insulin were both covalently cross-linked to a protein of 110 kDa, and the binding was competitively inhibited by either unlabeled insulin or amylin. Finally, a monoclonal anti-IDE antibody immunoprecipitated both insulin- and amylin-degrading activities. The data strongly suggest that IDE is an amylin-degrading enzyme and plays an important role in the clearance of amylin and the prevention of islet amyloid formation.
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PMID:Degradation of amylin by insulin-degrading enzyme. 1097 71

Type 1 diabetes is believed to be caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells. The non-obese diabetic (NOD) mouse is a spontaneous model of Type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has now been identified in NOD mouse lymphocytes that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect both prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which plays an important role in immune and inflammatory responses, in addition to increasing the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor-alpha (TNF-alpha). The proteasome dysfunction is both tissue- and developmental stage-specific and likely contributes to disease pathogenesis and tissue targeting.
Diabetes Metab Res Rev
PMID:The role of the proteasome in autoimmunity. 1102 57

The ubiquitin-proteasome system is thought to play a major role in normal muscle protein turnover and to contribute to diabetes-induced protein wasting in skeletal muscle. However, its importance in cardiac muscle is not clear. We measured heart muscle mRNA for ubiquitin and for the C2 and C8 proteasomal subunits, the amount of free ubiquitin and the proteasome chymotrypsin-like proteolytic activity in control and diabetic rats. Results were compared to those in skeletal muscle (rectus). Heart ubiquitin, C2 and C8 subunit mRNA and proteolytic activity were significantly greater than in skeletal muscle (P </= 0.05). This suggests that the ubiquitin proteasomal pathway may also be important for normal heart muscle turnover. Diabetes increased ubiquitin mRNA by approximately 50% in heart (P < 0.03) and by approximately 100% in skeletal muscle (P < 0.005). It remained high after 3 days of insulin treatment in both tissues. C2 and C8 subunit mRNA did not change with diabetes or insulin treatment. Diabetes did not change the amount of free ubiquitin or the proteasomal (lactacystin-inhibitable) chymotrypsin-like peptidase activity in heart or skeletal muscle. In conclusions, gene expression for several components of the ubiquitin-proteasome proteolytic pathway is significantly higher in cardiac than in skeletal muscle, as is the proteasome chymotrypsin-like peptidase activity. Diabetes increases the expression of ubiquitin but not C2 or C8 subunit mRNA, nor does it significantly alter the amount of free ubiquitin or the proteasome chymotrypsin-like peptidase activity. The rate-limiting step of enhanced protein degradation in diabetic rat heart and skeletal muscle may be located at ubiquitin conjugation and/or its binding to proteasome, not at the ubiquitin availability or the proteasome itself.
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PMID:The ubiquitin-proteasome proteolytic pathway in heart vs skeletal muscle: effects of acute diabetes. 1102 19


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