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)

The molecular mechanism responsible for obesity-associated insulin resistance has been partially clarified: increased fatty acid levels in muscle fibers promote diacylglycerol synthesis, which activates certain isoforms of protein kinase C (PKC). This in turn triggers a kinase cascade which activates both IkappaB kinase-beta (IKK-beta) and c-Jun N-terminal kinase (JNK), each of which can phosphorylate a key serine residue in IRS-1, rendering it a poor substrate for the activated insulin receptor. Heat shock proteins Hsp27 and Hsp72 have the potential to prevent the activation of IKK-beta and JNK, respectively; this suggests that induction of heat shock proteins may blunt the adverse impact of fat overexposure on insulin function. Indeed, bimoclomol--a heat shock protein co-inducer being developed for treatment of diabetic neuropathy--and lipoic acid--suspected to be a heat shock protein inducer--have each demonstrated favorable effects on the insulin sensitivity of obese rodents, and parenteral lipoic acid is reported to improve the insulin sensitivity of type 2 diabetics. Moreover, there is reason to believe that heat shock protein induction may have a favorable impact on the microvascular complications of diabetes, and on the increased risk for macrovascular disease associated with diabetes and insulin resistance syndrome. Heat shock protein induction may also have potential for preventing or treating neurodegenerative disorders, controlling inflammation, and possibly even slowing the aging process. The possible complementarity of bimoclomol and lipoic acid for heat shock protein induction should be assessed, and further efforts to identify well-tolerated agents active in this regard are warranted.
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PMID:Induction of heat shock proteins may combat insulin resistance. 1630 49

The insulin-regulated glucose transporter GLUT4 is a key modulator of whole body glucose homeostasis, and its selective loss in adipose tissue or skeletal muscle causes insulin resistance and diabetes. Here we report an RNA interference-based screen of protein kinases expressed in adipocytes and identify four negative regulators of insulin-responsive glucose transport: the protein kinases PCTAIRE-1 (PCTK1), PFTAIRE-1 (PFTK1), IkappaB kinase alpha, and MAP4K4/NIK. Integrin-linked protein kinase was identified as a positive regulator of this process. We characterized one of these hits, MAP4K4/NIK, and found that it is unique among mitogen-activated protein (MAP) kinases expressed in cultured adipocytes in attenuating hexose transport. Remarkably, MAP4K4/NIK suppresses expression of the adipogenic transcription factors C/EBPalpha, C/EBPbeta, and PPARgamma and of GLUT4 itself in these cells. RNA interference-mediated depletion of MAP4K4/NIK early in differentiation enhances adipogenesis and triglyceride deposition, and even in fully differentiated adipocytes its loss up-regulates GLUT4. Conversely, conditions that inhibit adipogenesis such as TNF-alpha treatment or depletion of PPARgamma markedly up-regulate MAP4K4/NIK expression in cultured adipocytes. Furthermore, TNF-alpha signaling to down-regulate GLUT4 is impaired in the absence of MAP4K4/NIK, indicating that MAP4K4 expression is required for optimal TNF-alpha action. These results reveal a MAP4K4/NIK-dependent signaling pathway that potently inhibits PPARgamma-responsive gene expression, adipogenesis, and insulin-stimulated glucose transport.
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PMID:An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPARgamma, adipogenesis, and insulin-responsive hexose transport. 1646 67

There is a growing body of evidence for the role of inflammation in type 2 diabetes. In addition to the evidence presented elsewhere, evidence is emerging that many drugs that have apparent "anti-inflammatory" properties may reduce the incidence and/or delay the onset of type 2 diabetes. Statins have been found to lower inflammatory markers, and a post hoc analysis of the West of Scotland Coronary Prevention Study (WOSCOPS) suggested that pravastatin may reduce the risk of developing diabetes, although the Lipid Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) found no statistically significant effect of atorvastatin on risk of developing diabetes. Fibrates have been found to lower some markers of inflammation, and a prospective trial found that bezafibrate reduces risk of developing diabetes. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers appear to reduce some markers of inflammation, and a meta-analysis concluded that ACE inhibitors and angiotensin receptor blockers reduce risk of developing type 2 diabetes. Metformin is known to reduce the risk of developing diabetes, and more recent evidence suggests it also lowers C-reactive protein, in part because of its modest weight-reducing effect. Thiazolidinediones reduce risk of developing diabetes, and consistently lower inflammatory markers independent of adiposity effects. High-dose aspirin inhibits cyclooxygenase and IkappaB kinase-beta and reduces fasting plasma glucose concentration, although there has not, as yet, been a large-scale trial to examine the effect of aspirin on the risk of developing diabetes. We conclude that although many drugs with potential anti-inflammatory properties reduce the risk of developing diabetes, it is difficult to prove that such anti-inflammatory properties contribute to their diabetes prevention since nearly all drugs have other, often more pronounced, actions. Studies with more specific inhibitors of inflammatory pathways (e.g., interleukin- 6 blockers) and mendelian randomization (genetic studies) will help determine whether targeting the inflammation axis is a fertile mechanism to treat or prevent type 2 diabetes.
Diabetes Technol Ther 2006 Feb
PMID:"Anti-inflammatory" drugs and their effects on type 2 diabetes. 1647 47

The diabetes-prone biobreeding (BB-DP) rat contains the lyp mutation which results in lymphopenia and promotes the progression of a T cell-mediated autoimmune attack of the pancreas in certain rat strains. This mutation has been mapped to a gene which bears homology to human Gimap5/Ian5 and results in the truncation and loss of activity of this protein. The lymphopenic state induced by the loss of this protein has led to the proposal that Gimap5 has an anti-apoptotic function. Previously we described an additional phenotype of incomplete activation mediated by the loss of Gimap5 function. Here we further characterize this incomplete activation phenotype and map a potential signal transduction pathway leading to activation. We show that CD5 expression on peripheral T cells is elevated in Gimap5 animals, while thymocyte expression remains similar between the two strains. Additionally, we show that NF-kappaB but not NFAT is activated in unstimulated Gimap5 mutant T cells as compared to unstimulated wild type T cells. Mapping this activation to its upstream source we show that activation of NF-kappaB is correlated with an activation of IKK. Using a variety of kinase inhibitors we further map this increase in IKK to an increase in MEK activation. Finally, to counter the possibility that activation is an indirect consequence of the lymphopenic environment, we created bone marrow chimeras in which Gimap5 mutant T cells developed in a normal environment and show that these cells retain their activated phenotype. Together, we interpret these data as demonstrating that the activation caused by loss of Gimap5 is a cell intrinsic phenomenon caused, in part, by a MEK-dependent activation of IKK. This, in turn, would suggest that Gimap5 functions to promote both T cell survival and quiescence and that these pathways are biochemically linked.
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PMID:Loss of a gimap/ian gene leads to activation of NF-kappaB through a MAPK-dependent pathway. 1658 74

Type 2 diabetes is a heterogeneous disease characterized by hyperglycemia and insulin resistance in peripheral tissues such as adipose tissue and skeletal muscle. This review focuses on obesity as one of the major environmental factors contributing to the development of diabetes. It has become evident that adipose tissue represents an active secretory organ capable of releasing a variety of cytokines such as TNFalpha, IL-6, adiponectin and other still unknown factors that might constitute the missing link between adipose tissue and insulin resistance. In fact, adipocyte-derived factors are significantly increased in obesity and represent good predictors of the development of type 2 diabetes. The negative crosstalk between adipocytes and skeletal muscle cells leads to disturbances in muscle cell insulin signalling and insulin resistance involving major pathways in inflammation, cellular stress and mitogenesis. Positive regulators of insulin sensitivity include the adipocyte hormone adiponectin and inhibitors of inflammatory pathways such as JNK-, IKK- and ERK-inhibitors. In summary, a better knowledge of intracellular and intercellular mechanisms by which adipose tissue affects skeletal muscle cell physiology may help to develop new strategies for diabetes treatment.
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PMID:Pathways leading to muscle insulin resistance--the muscle--fat connection. 1693 52

Whereas NF-kappaB has potent antiapoptotic function in most cell types, it was reported that in pancreatic beta cells it serves a proapoptotic function and may contribute to the pathogenesis of autoimmune type 1 diabetes. To investigate the role of beta cell NF-kappaB in autoimmune diabetes, we produced transgenic mice expressing a nondegradable form of IkappaBalpha in pancreatic beta cells (RIP-mIkappaBalpha mice). beta cells of these mice were more susceptible to killing by TNF-alpha plus IFN-gamma but more resistant to IL-1beta plus IFN-gamma than normal beta cells. Similar results were obtained with beta cells lacking IkappaB kinase beta, a protein kinase required for NF-kappaB activation. Inhibition of beta cell NF-kappaB accelerated the development of autoimmune diabetes in nonobese diabetic mice but had no effect on glucose tolerance or serum insulin in C57BL/6 mice, precluding a nonphysiological effect of transgene expression. Development of diabetes after transfer of diabetogenic CD4(+) T cells was accelerated in RIP-mIkappaBalpha/nonobese diabetic mice and was abrogated by anti-TNF therapy. These results suggest that under conditions that resemble autoimmune type 1 diabetes, the dominant effect of NF-kappaB is prevention of TNF-induced apoptosis. This differs from the proapoptotic function of NF-kappaB in IL-1beta-stimulated beta cells.
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PMID:NF-kappa B prevents beta cell death and autoimmune diabetes in NOD mice. 1726

Obesity is associated with insulin resistance and a state of abnormal inflammatory response. The Toll-like receptor (TLR)4 has an important role in inflammation and immunity, and its expression has been reported in most tissues of the body, including the insulin-sensitive ones. Because it is activated by lipopolysaccharide and saturated fatty acids, which are inducers of insulin resistance, TLR4 may be a candidate for participation in the cross-talk between inflammatory and metabolic signals. Here, we show that C3H/HeJ mice, which have a loss-of-function mutation in TLR4, are protected against the development of diet-induced obesity. In addition, these mice demonstrate decreased adiposity, increased oxygen consumption, a decreased respiratory exchange ratio, improved insulin sensitivity, and enhanced insulin-signaling capacity in adipose tissue, muscle, and liver compared with control mice during high-fat feeding. Moreover, in these tissues, control mice fed a high-fat diet show an increase in IkappaB kinase complex and c-Jun NH(2)-terminal kinase activity, which is prevented in C3H/HeJ mice. In isolated muscles from C3H/HeJ mice, protection from saturated fatty acid-induced insulin resistance is observed. Thus, TLR4 appears to be an important mediator of obesity and insulin resistance and a potential target for the therapy of these highly prevalent medical conditions.
Diabetes 2007 08
PMID:Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. 2720 24

Protein transduction domains (PTDs), both naturally occurring and synthetic, have been increasingly employed to deliver biologically active agents to a variety of cell types in vitro and in vivo. In addition to the previously characterized arginine-rich PTDs, including Tat (transactivator of transcription), Antp (Antennapedia) and PTD-5, we have demonstrated that lysine and ornithine, as well as arginine, homopolymers are able to mediate transduction of a wide variety of agents. To screen for optimal PTDs, we have used as a therapeutic cargo a peptide derived from IKK {IkappaB [inhibitor of NF-kappaB (nuclear factor kappaB)] kinase} beta, able to bind to the IKK regulatory subunit [NEMO (NF-kappaB essential modulator)], preventing formation of an active kinase complex. This peptide, termed NBD, is able to block activation of NF-kappaB, but not basal activity. We demonstrate that PTD-mediated delivery of NBD using certain PTDs, in particular 8K (octalysine), is therapeutic following systemic delivery in murine models of inflammatory bowel disease, diabetes and muscular dystrophy. In addition, we have developed a peptide phage display library screening method for novel transduction peptides able to facilitate tissue-specific internalization of marker protein complexes. Using this approach, we have identified transduction peptides that are able to facilitate internalization of large protein complexes into tumours, airway epithelia, synovial fibroblasts, cardiac tissue and HEK-293 (human embryonic kidney) cells in culture and/or in vivo.
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PMID:Protein transduction: identification, characterization and optimization. 1763 54

Obesity and insulin resistance are independent risk factors for metabolic syndrome, diabetes, and cardiovascular disease. Adipose tissue samples from nonobese (NO), insulin-sensitive obese (ISO), and insulin-resistant obese (IRO) subjects from subcutaneous (SC) and omental (OM) adipose tissue (n = 28) were analyzed by microarray and confirmed by real-time PCR. Insulin signaling gene expression changes were greater in OM than in SC tissue and were related to insulin resistance rather than to obesity; few genes correlated with body mass index. Insulin receptor and insulin receptor substrate 1 (IRS-1) increased in the IRO versus pooled insulin-sensitive (NO+ISO) subjects. In glucose transport, PI3Kalpha and PDK2 decreased in IRO subjects, whereas PI3Kgamma, Akt2, GLUT4, and GLUT1 increased. IRS-1 regulators Jnk and IKK increased in IRO (P < 0.01 and P < 0.001 respectively). In protein synthesis, most genes examined were downregulated in IRO subjects, including mTor, Rheb, and 4EBP and eIF members (all P < 0.05). In proliferation, SHC, SOS, and Raf1 (P < 0.05) were increased, whereas Ras and MEK1/2 kinase 1 (P < 0.05) were decreased, in IRO subjects. Finally, in differentiation, PPARgamma, CEBPalpha, and CEBPbeta decreased, whereas PPARdelta, CEBPgamma, and CEBPepsilon increased, in IRO subjects (P < 0.05). Together, microarray and real-time PCR data demonstrate that insulin resistance rather than obesity is associated with altered gene expression of insulin signaling genes, especially in OM adipose tissue.
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PMID:Influence of obesity and insulin sensitivity on insulin signaling genes in human omental and subcutaneous adipose tissue. 1798 14

Advanced glycation end products (AGEs) could be implicated in insulin resistance. However, the molecular mechanisms underlying this are not fully understood. Since pigment epithelium-derived factor (PEDF) blocks the AGE-signaling pathways, we examined here whether and how PEDF improves insulin resistance in AGE-exposed hepatoma cells, Hep3B cells. Proteins were extracted from Hep3B cells, immunoprecipitated with or without insulin receptor substrate-1 (IRS-1) antibodies, and subjected to Western blot analysis. Glycogen synthesis was measured using [ (14)C]-d-glucose. AGE induced Rac-1 activation and increased phosphorylation of IRS-1 at serine-307 residues, JNK, c-JUN, and IkappaB kinase in association with decreased IkappaB levels in Hep3B cells. PEDF or overexpression of dominant negative Rac-1 blocked these effects of AGE on Hep3B cells. Further, AGEs decreased tyrosine phosphorylation of IRS-1, and subsequently reduced the association of p85 subunit of phosphatidylinositol 3-kinase with IRS-1 and glycogen synthesis in insulin-exposed Hep3B cells, all of which were inhibited by PEDF. Our present study suggests that PEDF could improve the AGE-elicited insulin resistance in Hep3B cells by inhibiting JNK- and IkappaB kinase-dependent serine phosphorylation of IRS-1 via suppression of Rac-1 activation. PEDF may play a protective role against hepatic insulin resistance in diabetes.
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PMID:Pigment epithelium-derived factor (PEDF) ameliorates advanced glycation end product (AGE)-induced hepatic insulin resistance in vitro by suppressing Rac-1 activation. 1879 73


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