UMLS:C0011849 - FACTA Search

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 2 diabetes, a major risk factor for atherosclerosis, is associated with a cluster of lipid risk factors, many of which can be mechanistically linked with underlying dysregulated fatty acid metabolism and elevated plasma non-esterified fatty acids (NEFA). Thus, we tested the hypothesis that elevated NEFA dysregulates lipid metabolism at the levels of lipid synthesis and gene expression in THP-1 monocyte derived macrophages (MDM). THP-1 MDM incubated with oleic acid (OA) and a BODIPY-conjugated NEFA, accumulate, respectively, intracellular inclusions that are positive for oil red O and BODIPY-labeling. Parallel studies with [(14)C]OA show dose-dependent accumulation of intracellular (14)C-labeled neutral lipid, almost exclusively as triglyceride; the rate of [(3)H]OA uptake increases as THP-1 MDM convert to foam cells. Preincubation of THP-1 MDM with higher concentrations of OA (1.8mM versus 0.2mM) was associated with enhanced uptake of Ac-LDL, and increased expression of adipocyte fatty acid binding protein, FAT/CD36, and cyclooxygenase-2 (COX-2); COX-2 mass and activity also increased. These observations suggest a mechanistic link between sustained elevations in albumin-bound NEFA and foam cell formation that may be mediated by enhanced adipogenesis, increased uptake of modified LDL, and upregulated formation of eicosanoids, which may be proinflammatory.
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PMID:Sustained elevations in NEFA induce cyclooxygenase-2 activity and potentiate THP-1 macrophage foam cell formation. 1687 Jan 93

Type 2 diabetes mellitus is characterized by insulin resistance of peripheral tissues and dysfunction of pancreatic beta-cells. Furthermore, the number of pancreatic beta-cells decreases as a secondary effect of advanced type 2 diabetes, although the molecular mechanism has not been elucidated. Recently, it has been shown that hyperglycemic conditions induce the expression of cyclooxygenase-2 in pancreatic islets and increase the downstream product prostaglandin E(2) (PGE(2)). To investigate whether high glucose-induced PGE(2) has an adverse effect on pancreatic beta-cells, we generated transgenic mice (RIP-C2mE) that express cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in their beta-cells using the rat insulin-2 gene promoter (RIP). The homozygous RIP-C2mE (Tg/Tg) mice showed severe hyperglycemia from six weeks of age. Although the heterozygous RIP-C2mE (Tg/-) mice showed normal blood glucose levels throughout their lifetime, this level increased significantly compared with that of wild-type mice when glucose was loaded. The relative number of beta-cells to the total islet cell number was reduced to 54 and 14% in the RIP-C2mE (Tg/-) and (Tg/Tg) mice, respectively, whereas that in the wild-type mice was 84%. Importantly, the proliferation rate in the islets of the RIP-C2mE (Tg/Tg) mice at four weeks of age decreased significantly in comparison to that in the wild-type mice. Because beta-cells replicate not only during the postnatal period but also in the adult pancreas at a basal level, it is possible that increased PGE(2) signaling thus contributes to the reduction of the pancreatic beta-cell mass through inhibition of proliferation, thereby aggravating diabetes further.
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PMID:Destruction of pancreatic beta-cells by transgenic induction of prostaglandin E2 in the islets. 1687 78

The effect of sun ginseng (SG, heat-processed Panax ginseng C. A. MEYER at 120 degrees C) on diabetic renal damage was investigated using streptozotocin-induced diabetic rats. The diabetic rats showed loss of body weight gain, and increases in food and water intake and urine volume, while the oral administration of SG at a dose of 50 or 100 mg/kg body weight/d for 15 d attenuated water intake and urine excretion induced by diabetes. In addition, the diabetic rats given SG at a dose of 100 mg/kg body weight showed significant decreases in serum glucose, serum glycosylated protein and urinary protein levels, suggesting that SG improves the abnormal conditions that lead to oxidative stress. Furthermore, SG significantly reduced advanced glycation endproduct (AGE) formation and thiobarbituric acid-reactive substance levels elevated in the kidneys of diabetic rats. This implies that SG would alleviate the oxidative stress under diabetes through the inhibition of lipid peroxidation. SG also reduced the overexpression of cyclooxygenase-2 and inducible nitric oxide synthase in the kidney induced by hyperglycemia via deactivation the activation of nuclear factor-kappa B. Furthermore, treatment with SG decreased the levels of 3-nitrotyrosine, carboxymethyllysine and receptors for AGE which increase under diabetes. These findings indicate that oxidative stress is increased in the diabetic rat kidney and that SG can prevent renal damage associated with diabetes by attenuating the oxidative stress.
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PMID:Protective effect of sun ginseng against diabetic renal damage. 1688 Jun 25

Based on findings of experimental models of diabetes mellitus (DM) showing increased expression of vascular cyclooxygenase-2 (COX-2), we hypothesized that in patients with DM changes in COX-2-dependent prostaglandin synthesis affect vasomotor responses of coronary arterioles. Arterioles were dissected from the right atrial appendages obtained at the time of cardiac surgery of patient with DM(+) or without documented diabetes DM(-). Isolated arterioles (89+/-15 microm in diameter) were cannulated and pressurized (at 80 mm Hg), and changes in diameter were measured with video microscopy. After spontaneous tone developed [DM(-): 32+/-7%; DM(+): 37+/-5%; P=NS], arteriolar responses to bradykinin were investigated. Dilations to bradykinin (0.1 nmol/L to 1 micromol/L) were significantly (P<0.05) greater in DM(+) than DM(-) patients (10 nmol/L: 77+/-10% versus 38+/-14%). In both groups, dilations were similar to the NO-donor, sodium nitroprusside. In arterioles of DM(+), but not those of DM(-), patients' bradykinin-induced dilations were reduced by the nonselective COX inhibitor indomethacin or by the selective COX-2 inhibitor NS-398 (DM(+) at 10 nmol/L: to 20+/-4% and 29+/-7%, respectively). Correspondingly, a marked COX-2 immunostaining was detected in coronary arterioles of DM(+), but not in those of DM(-) patients. We conclude that in coronary arterioles of diabetic patients bradykinin induces enhanced COX-2-derived prostaglandin-mediated dilation. These findings are the first to show that in humans diabetes mellitus increases COX-2 expression and dilator prostaglandin synthesis in coronary arterioles, which may serve to increase dilator capacity and maintain adequate perfusion of cardiac tissues.
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PMID:Increased cyclooxygenase-2 expression and prostaglandin-mediated dilation in coronary arterioles of patients with diabetes mellitus. 1691 94

Diabetes is associated with enhanced inflammatory responses and cardiovascular complications such as atherosclerosis. However, it is unclear whether similar responses are present in cells derived from experimental animal models of diabetes. We examined our hypothesis that macrophages and short-term cultured vascular smooth muscle cells (VSMCs) derived from obese, insulin-resistant, and diabetic db/db mice would exhibit increased proatherogenic responses relative to those from control db/+ mice. We observed that macrophages from db/db mice exhibit significantly increased expression of key inflammatory cytokines and chemokines as well as arachidonic acid-metabolizing enzymes cyclooxygenase-2 and 12/15-lipoxygenase that generate inflammatory lipids. Furthermore, VSMCs derived from db/db mice also showed similar enhanced expression of inflammatory genes. Expression of inflammatory genes was also significantly increased in aortas derived from db/db mice. Both macrophages and VSMCs from db/db mice demonstrated significantly increased oxidant stress, activation of key signaling kinases, and transcription factors cAMP response element-binding protein and nuclear factor-kappaB, involved in the regulation of atherogenic and inflammatory genes. Interestingly, VSMCs from db/db mice displayed enhanced migration as well as adhesion to WEHI mouse monocytes relative to db/+. Thus, the diabetic milieu and a potential hyperglycemic memory can induce aberrant behavior of vascular cells. These new results demonstrate that monocyte/macrophages and VSMCs derived from db/db mice display a "preactivated" and proinflammatory phenotype associated with the pathogenesis of diabetic vascular dysfunction and atherosclerosis.
Diabetes 2006 Sep
PMID:Enhanced proatherogenic responses in macrophages and vascular smooth muscle cells derived from diabetic db/db mice. 1693 11

We investigated the effects of Chinese prescription Kangen-karyu on high glucose-induced oxidative stress using LLC-PK(1) cells, renal tubular cells, which are the most vulnerable renal tissue to oxidative stress. High-concentration glucose (30mM) treatment induced LLC-PK(1) cell death, but Kangen-karyu, at a concentration of 5, 10 or 50 microg/ml, significantly inhibited high glucose-induced cytotoxicity. In addition, the intracellular reactive oxygen species level was increased by 30mM glucose treatment, but it was concentration-dependently inhibited by Kangen-karyu treatment. Moreover, 30mM glucose treatment induced high levels of superoxide anion, nitric oxide and peroxynitrite. However, Kangen-karyu treatment significantly reduced the radical overproduction induced by high glucose, suggesting Kangen-karyu has radical-scavenging activity that would protect against oxidative stress induced by high glucose. Kangen-karyu also reduced the overexpression of inducible nitric oxide synthase and cyclooxygenase-2 proteins induced by high glucose. Furthermore, treatment with Kangen-karyu, at a concentration of 50mug/ml, inhibited the nuclear translocation of nuclear factor-kappa B induced by 30mM glucose in LLC-PK(1) cells. These findings indicate that Kangen-karyu is a potential therapeutic agent that will reduce the damage caused by hyperglycemia-induced oxidative stress associated with diabetes.
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PMID:Protective effect of the Chinese prescription Kangen-karyu against high glucose-induced oxidative stress in LLC-PK1 cells. 1694 79

We aimed to clarify whether grape seed polyphenols (GSPs) are candidates therapeutic agents against diabetes mellitus, and to determine what degree of GSP oligomerization has the most potent efficacy. We studied the protective effects of various molecular weight GSPs (monomer, oligomer, polymer, and oligonol) on high glucose-induced cytotoxicity. In the present study, a high concentration of glucose (30 mM) induced cytotoxicity and oxidative stress (reactive oxygen species and nitric oxide) in cultured LLC-PK1 cells, but treatment with GSPs, especially oligomer GSPs, had potent protective effects against high glucose-induced oxidative stress. In addition, high glucose induced nuclear translocation of nuclear factor-kappa B, and increased expression of cyclooxygenase-2, inducible nitric oxide synthase, and bax, but GSP treatment inhibited them. These results indicate that GSPs have protective effects against high glucose-induced cytotoxicity, and among them, oligomer GSPs have more potent effects than other GSPs (monomer, polymer, and oligonol) on high glucose-induced renal cell damage.
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PMID:Protective effect of grape seed polyphenols against high glucose-induced oxidative stress. 1696 Mar 88

Peroxisome proliferator-activated receptor-delta (PPARdelta) is a nuclear receptor implicated in lipid oxidation and the pathogenesis of obesity and diabetes. This study was designed to examine the potential effect of PPARdelta on human cholangiocarcinoma cell growth and its mechanism of actions. Overexpression of PPARdelta or activation of PPARdelta by its pharmacological ligand, GW501516, at low doses (0.5-50 nM) promoted the growth of three human cholangiocarcinoma cell lines (CCLP1, HuCCT1, and SG231). This effect was mediated by induction of cyclooxygenase-2 (COX-2) gene expression and production of prostaglandin E2 (PGE2) that in turn transactivated epidermal growth factor receptor (EGFR) and Akt. In support of this, inhibition of COX-2, EGFR, and Akt prevented the PPARdelta-induced cell growth. Furthermore, PPARdelta activation or PGE2 treatment induced the phosphorylation of cytosolic phospholipase A2alpha (cPLA2alpha), a key enzyme that releases arachidonic acid (AA) substrate for PG production via COX. Overexpression or activation of cPLA2alpha enhanced PPARdelta binding to PPARdelta response element (DRE) and increased PPARdelta reporter activity, indicating a novel role of cPLA2alpha for PPARdelta activation. Consistent with this, AA enhanced the binding of PPARdelta to DRE, in vitro, suggesting a direct role of AA for PPARdelta activation. In contrast, although PGE2 treatment increased the DRE reporter activity in intact cells, it failed to induce PPARdelta binding to DRE in cell-free system, suggesting that cPLA2alpha-mediated AA release is required for PGE2-induced PPARdelta activation. Taken together, these observations reveal that PPARdelta induces COX-2 expression in human cholangiocarcinoma cells and that the COX-2-derived PGE2 further activates PPARdelta through phosphorylation of cPLA2alpha. This positive feedback loop plays an important role for cholangiocarcinoma cell growth and may be targeted for chemoprevention and treatment.
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PMID:A novel positive feedback loop between peroxisome proliferator-activated receptor-delta and prostaglandin E2 signaling pathways for human cholangiocarcinoma cell growth. 2659 Feb 96

It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three salicylates inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in NF-kappaB DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three salicylates inhibited the diabetes-induced translocation of p50 (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. Sulfasalazine (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by NF-kappaB, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate. Salicylates, in doses administrated in our experiments, inhibited NF-kappaB and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy.
Diabetes 2007 Feb
PMID:Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. 1725 77

Pharmacologic treatment of diabetic retinopathy via eyedrops could have advantages but has not been successful to date. We explored the effect of topical Nepafenac, an anti-inflammatory drug known to reach the retina when administered via eyedrops, on the development of early stages of diabetic retinopathy and on metabolic and physiologic abnormalities that contribute to the retinal disease. Streptozotocin-induced diabetic rats were assigned to three groups (0.3% Nepafenac eyedrops, vehicle eyedrops, and untreated control) for comparison to age-matched nondiabetic control animals. Eyedrops were administered in both eyes four times per day for 2 and 9 months. At 2 months of diabetes, insulin-deficient diabetic control rats exhibited significant increases in retinal prostaglandin E(2), superoxide, vascular endothelial growth factor (VEGF), nitric oxide (NO), cyclooxygenase-2, and leukostasis within retinal microvessels. All of these abnormalities except NO and VEGF were significantly inhibited by Nepafenac. At 9 months of diabetes, a significant increase in the number of transferase-mediated dUTP nick-end labeling-positive capillary cells, acellular capillaries, and pericyte ghosts were measured in control diabetic rats versus nondiabetic controls, and topical Nepafenac significantly inhibited all of these abnormalities (all P < 0.05). Diabetes-induced activation of caspase-3 and -6 in retina was partially inhibited by Nepafenac (all P < 0.05). Oscillatory potential latency was the only abnormality of retinal function reproducibly detected in these diabetic animals, and Nepafenac significantly inhibited this defect (P < 0.05). Nepafenac did not have a significant effect on diabetes-induced loss of cells in the ganglion cell layer or in corneal protease activity. Topical ocular administration of Nepafenac achieved sufficient drug delivery to the retina and diabetes-induced alterations in retinal vascular metabolism, function, and morphology were inhibited. In contrast, little or no effect was observed on diabetes-induced alterations in retinal ganglion cell survival. Local inhibition of inflammatory pathways in the eye offers a novel therapeutic approach toward inhibiting the development of lesions of diabetic retinopathy.
Diabetes 2007 Feb
PMID:Topical administration of nepafenac inhibits diabetes-induced retinal microvascular disease and underlying abnormalities of retinal metabolism and physiology. 1725 81

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