Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerosis is a long-term chronic inflammatory disease associated with increased concentrations of inflammatory hepatic markers, such as CRP and fibrinogen, and of peripheral origin, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. Peroxisome proliferator-activated receptor (PPAR-)-alpha is a ligand-activated transcription factor that regulates expression of key genes involved in lipid homeostasis and modulates the inflammatory response both in the vascular wall and the liver. PPAR-alpha is activated by natural ligands, such as fatty acids, as well as the lipid-lowering fibrates. PPAR-alpha agonists impact on different steps of atherogenesis: (1) early markers of atherosclerosis, such as vascular wall reactivity, are improved, (2) however, reduced expression of adhesion molecules on the surface of endothelial cells, accompanied by decreased levels of inflammatory cytokines, such as TNF-alpha, IL-1, and IL-6, leads to a decreased leukocyte recruitment into the arterial wall; (3) in later stages of the atherosclerotic process, PPAR-alpha agonists may promote plaque stabilization and reduce cardiovascular events, via effects on metalloproteinases, such as MMP9. Moreover, PPAR-alpha activation by fibrates also impairs proinflammatory cytokine-signaling pathways in the liver resulting in the modulation of the acute phase response reaction via mechanisms independent of changes in lipoprotein levels. Effective coronary artery disease (CAD) prevention requires the use of agents that act beyond low-density lipoprotein cholesterol-lowering. PPAR-alpha agonists appear to comprehensively address some of the abnormalities of the most common clinical phenotypes of the high CAD risk patient of the 21st century such as in the metabolic syndrome and type 2 diabetes: low high-density lipoprotein cholesterol, high triglycerides, small, dense low-density lipoprotein, and a proinflammatory, procoagulant state.
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PMID:Modulation of hepatic inflammatory risk markers of cardiovascular diseases by PPAR-alpha activators: clinical and experimental evidence. 1642 52

Aging is due to a complex interaction of genetic, epigenetic, and environmental factors, but a strong genetic component appears to have an impact on survival to extreme ages. In order to identify "longevity genes" in humans, different strategies are now available. In our laboratory, we performed association studies on a variety of "candidate" polymorphisms in Italian centenarians. Many genes/polymorphisms gave negative results, while others showed a positive association with human longevity and a sometimes-positive association with unsuccessful aging (myocardial infarction, Alzheimer's disease, and type 2 diabetes). Results regarding genes involved in inflammation (IL-1 cluster, IL-6, IL-10, TNF-alpha, TGF-beta, TLR-4, PPARgamma), insulin/IGF-1 signaling pathway and lipid metabolism (apolipoproteins, CETP, PON1), and oxidative stress (p53, p66(shc)) will be described. In addition, a strong role of the interaction between nuclear and mitochondrial genomes (mtDNA haplogroups and the C150T mutation) emerged from our findings. Thus, the genetics of human longevity appears to be quite peculiar in a context where antagonistic pleiotropy can play a major role and genes can have a different biological role at different ages.
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PMID:The genetics of human longevity. 1680 95

The exact factors contributing to the pathogenesis of type 2 diabetes remain elusive. Lately, it was suggested that inflammation and activation of the innate immune system could be linked to type 2 diabetes pathogenesis and also to the development of common diabetic complications, mainly atherosclerosis. The aim of this study was to investigate the role of monocytes in this sub-clinical inflammatory state and test 1,25-dihydroxyvitamin D(3), the active form of Vitamin D, as an anti-inflammatory agent. For this purpose, monocytes from type 2 diabetic patients were compared to monocytes from healthy controls and type 1 diabetic patients. The expression profile of inflammatory markers in freshly isolated and immune-stimulated monocytes was measured by quantitative real-time RT-PCR. Type 2 diabetic patients showed significantly higher expression levels of TNF-alpha, IL-6, IL-1, IL-8, COX-2, ICAM-1 and B7-1 compared to controls and type 1 diabetic patients. 1,25-Dihydroxyvitamin D(3) was able to down-regulate the expression of TNF-alpha, IL-6, IL-1, and IL-8, confirming its immunomodulatory properties. From these data we concluded that monocytes from type 2 diabetic patients have a pro-inflammatory profile. In addition, 1,25-dihydroxyvitamin D(3) was able to modulate inflammation in these monocytes.
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PMID:Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-Dihydroxyvitamin D(3) works as anti-inflammatory. 1711 20

Chronic elevation of proinflammatory markers in type 2 diabetes (T2D) is well defined, but the role of anti-inflammatory cytokines in T2D is less clear. In this study, we report that normal IL-4-dependent elaboration of IL-1 receptor antagonist (IL-1RA) requires IRS-2-mediated PI3K activity in primary macrophages. We also show that macrophages isolated from obese/diabetic db/db mice have impaired IRS-2-mediated PI3K activity and constitutively overexpress suppressor of cytokine signaling (SOCS)-3, which impairs an important IL-4 anti-inflammatory function. Peritoneal proinflammatory cytokine levels were examined in diabese (db/db) mice, and IL-6 was found to be nearly 7-fold higher than in nondiabese (db/+) control mice. Resident peritoneal macrophages were isolated from db/db mice and were found to constitutively overexpress IL-6 and were unable to elaborate IL-1RA in response to IL-4-like db/+ mouse macrophages. Inhibition of PI3K with wortmannin or blockage of IRS-2/PI3K complex formation with a cell permeable IRS-2-derived tyrosine phosphopeptide inhibited IL-4-dependent IL-1RA production in db/+ macrophages. Examination of IL-4 signaling in db/db macrophages revealed that IL-4-dependent IRS-2/PI3K complex formation and IRS-2 tyrosine phosphorylation was reduced compared with db/+ macrophages. SOCS-3/IL-4 receptor complexes, however, were increased in db/db mouse macrophages compared with db/+ mice macrophages as was db/db mouse macrophage SOCS-3 expression. These results indicate that in the db/db mouse model of T2D, macrophage expression of SOCS-3 is increased, and impaired IL-4-dependent IRS-2/PI3K formation induces a state of IL-4 resistance that disrupts IL-4-dependent production of IL-1RA.
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PMID:Type 2 diabetes impairs insulin receptor substrate-2-mediated phosphatidylinositol 3-kinase activity in primary macrophages to induce a state of cytokine resistance to IL-4 in association with overexpression of suppressor of cytokine signaling-3. 1751 37

Interleukin-1 receptor antagonist (IL-1Ra) expression is reduced in islets of patients with type 2 diabetes. 70 patients with type 2 diabetes were randomized to treatment with anakinra (IL-1Ra) or placebo for 13 weeks. Following treatment glycated hemoglobin was 0.46 percent lower, C-peptide secretion was enhanced, and systemic IL-6 and C-reactive protein levels were reduced in the anakinra group compared to the placebo group. Insulin resistance remained unchanged. Blocking IL-1 activity improved glycemia and b-cell secretory function and reduced markers of systemic inflammation.
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PMID:[Interleukin-1 receptor antagonist-treatment of patients with type 2 diabetes]. 1742 83

The impressive correlation between cardiovascular disease and alterations in glucose metabolism has raised the likelihood that atherosclerosis and type 2 diabetes may share common antecedents. Inflammation is emerging as a conceivable etiologic mechanism for both. Interleukins are regulatory proteins with ability to accelerate or inhibit inflammatory processes, and matrixins are prepro enzymes responsible for the timely breakdown of extracellular matrix. Interleukins (ILs) are classified based on their role in diabetes and atherosclerosis, hypothesizing that each interleukin acts on both diseases in the same direction - regardless if harmful, favorable or neutral. They are clustered into three groups: noxious (the 'bad', 8 members), comprising IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL-17 and IL-18; protective (the 'good', 5 members), comprising IL-4, IL-10, IL-11, IL-12 and IL-13; and 'aloof' , comprising IL-5, IL-9, IL-14, IL-16 and IL-19 through IL-29 (15 members). Each group presented converging effects on both diseases. IL-3 was reluctant to clustering and IL-30 through 33 were not included due to the scarce available data. It may be seen that (1) favorable effects of a given interleukin on either diabetes or atherosclerosis predicts similar effects on the other; (2) equally, harmful interleukin effects on one disease can be extrapolated to the other, and (3) absence of influence of a given interleukin on one of these diseases forecasts lack of effects on the other. Matrixins seem to present a similar pathophysiological pattern. These facts further support the unifying etiologic theory of diabetes and heart disease, emphasizing the importance of a cardiovascular diabetologic approach to these cytokines for future research. A pharmacologic simultaneous targeting of interleukins and matrixins might provide an effective means to concurrently control both atherosclerosis and diabetes.
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PMID:Biomarkers in cardiovascular diabetology: interleukins and matrixins. 1823 Sep 55

Subclinical inflammation is a recently discovered phenomenon in type 2 diabetes. Elevated cytokines impair beta-cell function and survival. A recent clinical trial shows that blocking IL-1beta signaling by IL-1 receptor antagonist (IL-1Ra) improves beta-cell secretory function in patients with type 2 diabetes. In the present study, we provide further mechanisms of the protective role of IL-1Ra on the beta-cell. IL-1Ra prevented diabetes in vivo in C57BL/6J mice fed a high-fat/high-sucrose diet (HFD) for 12 wk; it improved glucose tolerance and insulin secretion. High-fat diet treatment increased serum levels of free fatty acids and of the adipokines resistin and leptin, which were reduced by IL-1Ra treatment. In addition, IL-1Ra counteracted adiponectin levels, which were decreased by high-fat feeding. Studies on isolated islets revealed that IL-1Ra specifically acted on the beta-cell. IL-1Ra protected islets from HFD treated animals from beta-cell apoptosis, induced beta-cell proliferation, and improved glucose-stimulated insulin secretion. Insulin mRNA was reduced in islets from mice fed a HFD but normalized in the IL-1Ra group. Our results show that IL-1Ra improves beta-cell survival and function, and support the potential role for IL-1Ra in the treatment of diabetes.
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PMID:The antiinflammatory cytokine interleukin-1 receptor antagonist protects from high-fat diet-induced hyperglycemia. 1823 70

Body weight homeostasis is regulated by central and peripheral mechanisms, in which cytokines appear to have an important role.The circulating levels of the cytokines interleukin 1 (IL-1) and interleukin 18 (IL-18), and of inflammatory mediators such as prostaglandin E2 (PGE2), amongst others, are elevated in obese individuals. The low-grade inflammation associated with obesity may contribute to the development of insulin resistance, impaired glucose tolerance and type 2 diabetes. This review highlights results of studies in mice which indicate important roles for these proinflammatory cytokines during the development of obesity and insulin resistance, and in the treatment of type 2 diabetes.
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PMID:Insights into the roles of the inflammatory mediators IL-1, IL-18 and PGE2 in obesity and insulin resistance. 1885 49

Peroxisome proliferators activated receptors (PPAR) are ligand-inducible nuclear transacting factors comprising three subtypes, PPARalpha, PPARbeta/delta and PPARgamma, which play a key role in lipids and glucose homeostasis. All PPAR subtypes have been identified in joint or inflammatory cells and their activation resulted in a transcriptional repression of pro-inflammatory cytokines (IL-1, TNFalpha), early inflammatory genes (NOS(2), COX-2, mPGES-1) or matrix metalloproteases (MMP-1, MMP-13), at least for the gamma subtype. PPAR full agonists were also shown to stimulate IL-1 receptor antagonist (IL-1Ra) production by cytokine-stimulated articular cells in a subtype-dependent manner. These anti-inflammatory and anti-catabolic properties were confirmed in animal models of joint diseases where PPAR agonists reduced synovial inflammation while preventing cartilage destruction or inflammatory bone loss, although many effects required much higher doses than needed to restore insulin sensitivity or to lower circulating lipid levels. However, these promising effects of PPAR full agonists were hampered by their ability to reduce the growth factor-dependent synthesis of extracellular matrix components or to induce chondrocyte apoptosis, by the possible contribution of immunosuppressive properties to their anti-arthritic effects, by the increased adipocyte differentiation secondary to prolonged stimulation of PPARgamma, and by a variable contribution of PPAR subtypes depending on the system. Clinical data are scarce in rheumatoid arthritis (RA) patients whereas thousands of patients worldwilde, treated with PPAR agonists for type 2 diabetes or dyslipidemia, are paradoxically prone to suffer from osteoarthritis (OA). Whereas high dosage of full agonists may expose RA patients to cardiovascular adverse effects, the proof of concept that PPAR agonists have therapeutical relevance to OA may benefit from an epidemiological follow-up of joint lesions in diabetic or hyperlipidemic patients treated for long periods of time with glitazones or fibrates. Additionally, cellular and animal studies are required to assess whether partial agonists of PPAR (SPPARMs) may preserve therapeutical properties with potentially less safety concern.
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PMID:[Pathophysiological relevance of peroxisome proliferators activated receptors (PPAR) to joint diseases - the pro and con of agonists]. 1909 28

In the past few years, several interleukins (ILs) attracted considerable attention as potential effectors in the pathology and physiology of insulin resistance associated with type 2 diabetes mellitus (T2DM) and obesity. IL-1, a major proinflammatory cytokine, is present at increased levels in patients with diabetes mellitus, and could promote beta-cell destruction and alter insulin sensitivity. The effects of IL-1 are likely to be counteracted by IL-1 receptor antagonist protein (IL-1ra), as suggested by interventional studies in patients with T2DM who were treated with a recombinant form of this protein. However, studies in IL-1ra-deficient mice provided controversial results on the exact effect of the IL-1 signaling pathway on insulin secretion, insulin sensitivity and accumulation of adipose tissue. Likewise, IL-6 has been suggested to be involved in the development of obesity-related and T2DM-related insulin resistance. The action of IL-6 on glucose homeostasis is also complex and integrates central and peripheral mechanisms. Both experimental and clinical studies now converge to show that several ILs contribute to the pathology and physiology of T2DM through their interaction with insulin signaling pathways and beta-cell function.
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PMID:The role of interleukins in insulin resistance and type 2 diabetes mellitus. 1939 17


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