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

Diabetes (type I and type II) affects approximately 13 million people in the United States. Delayed and incomplete healing of wounds can be a major problem for diabetic patients. Macrophages are an important cell in the complex process of wound repair representing the major source of cytokines throughout the wound-healing process. Cytokines mediate many of the cellular responses critical to timely wound repair. It has been suggested that diabetes impairs wound healing through disruption of local cytokine production. Our previous in vivo studies in rats demonstrated that diabetes-induced and diet-induced hyperlipidemia cause changes in macrophage phenotype and function (Iacopino 1995; Doxey et al. 1998), suggesting that alterations in macrophage cytokine profiles represent the cellular/molecular mechanism responsible for delayed wound healing. The purpose of this study was to investigate how monocyte maturation/differentiation and cytokine production were altered by serum lipids in an in vitro system using human cells. Commercially prepared purified human monocytes were cultured and exposed to serum lipids. Phenotypic analysis of differentiated macrophages was then performed by flow cytometry and fluorescent microscopy using surface antigens specific for various macrophage subsets. Selected cytokines in conditioned medium were assayed using commercial human enzyme-linked immunosorbent assay (ELISA) kits. We demonstrate that serum lipids cause an increase in monocytic differentiation leading to an inflammatory macrophage phenotype rather than a reparative/proliferative phenotype. We also show that serum lipids cause a generalized decrease in macrophage cytokine production using interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), platelet-derived growth factor (PDGF), and transforming growth factor beta 1 (TGF-beta 1) as marker cytokines. Our present in vitro results using human cells confirm our previous in vivo studies in the rat and support the hypothesis that diabetes-induced hyperlipidemia alters the monocyte differentiation process resulting in changes of macrophage subsets and cytokine release at the wound site, ultimately impairing the wound-healing process.
 ...
PMID:In vitro alteration of macrophage phenotype and function by serum lipids. 1038 75

Lower extremity ulcers cause significant morbidity and mortality in patients with diabetes. The primary factors that contribute to the development of this type of ulcer are peripheral neuropathy and peripheral vascular disease, which are often accompanied by infection. Lower extremity diabetic ulcers are chronic and difficult to treat, in part due to underlying pathologic conditions in individuals with diabetes that can contribute to impaired wound healing. This article reports the author's experience with treatment of chronic lower extremity ulcers of mixed etiologies with recombinant human platelet-derived growth factor--BB [rhPDGF-BB, REGRANEX (becaplermin) Gel 0.01%] in a patient with multiple risk factors including long-standing insulin-dependent type 2 diabetes.
 ...
PMID:Use of topical recombinant human platelet-derived growth factor-BB (becaplermin) in healing of chronic mixed arteriovenous lower extremity diabetic ulcers. 1055 55

Altered growth of renal cells is one of the early abnormalities detected after the onset of diabetes. Cell culture studies whereby renal cells are exposed to high glucose concentrations have provided a considerable amount of insight into mechanisms of growth. In the glomerular compartment, there is a very early and self-limited proliferation of mesangial cells with subsequent hypertrophy, whereas proximal tubular cells primarily undergo hypertrophy. There is overwhelming evidence from in vivo and cell culture studies that induction of the transforming growth factor-beta (TGF-beta) system mediates the actions of high ambient glucose and that this system is pivotal for the hypertrophy of mesangial and tubular cells. Other factors such as hemodynamic forces, protein glycation products, and several mediators (for example, angiotensin II, endothelin-1, thromboxane, and platelet-derived growth factor) may further amplify the synthesis of TGF-beta and/or the expression of its receptors in the diabetic state. Cellular hypertrophy can be characterized by cell cycle arrest in the G1 phase. The molecular mechanism arresting mesangial cells in the G1 phase of the cell cycle is the induction of cyclin-dependent kinase (CdK) inhibitors such as p27Kip1 and p21, which bind to and inactivate cyclin-CdK complexes responsible for G1-phase exit. High-glucose-induced activation of protein kinase C and stimulated TGF-beta expression appear to be essential for stimulated expression of p27Kip1. In addition, a decreased turnover of protein caused by the inhibition of proteases contributes to hypertrophy. The development of irreversible renal changes in diabetes mellitus such as glomerulosclerosis and tubulointerstitial fibrosis is always preceded by the early hypertrophic processes in the glomerular and the tubular compartments. It may still be debated whether diabetic renal hypertrophy will inevitably lead to irreversible fibrotic changes in the absence of other factors such as altered intraglomerular hemodynamics and genetic predisposition. Nevertheless, understanding cellular growth on a molecular level may help design a novel therapeutic approach to prevent or treat diabetic nephropathy effectively.
 ...
PMID:Molecular mechanisms of diabetic renal hypertrophy. 1043 77

Diabetes is now the most common cause of kidney failure. The pathogenesis of diabetic nephropathy in both type 1 and type 2 diabetes, however, is still incompletely understood. Two mechanisms postulated to contribute to the pathogenesis of progressive diabetic nephropathy are glomerular cell proliferation and glomerular visceral epithelial cell or podocyte injury. The aim of the current study was to determine whether the aggravation of mesangial cell injury or podocyte injury in isolation would induce progressive diabetic nephropathy. Specifically, we examined whether the administration of either platelet-derived growth factor (PDGF) or basic fibroblast growth factor (bFGF) in sub-nephritogenic doses might lead to an aggravation of kidney structural changes associated with hyperglycemia, resulting in progressive kidney damage in the Goto Kakizaki (GK) rat, which is a genetic model of non-obese non-insulin-dependent diabetes mellitus (NIDDM), in which progressive kidney disease does not develop spontaneously. The results demonstrate that the administration of PDGF to hyperglycemic GK rats led to acute mesangial cell proliferation and activation as assessed by 5-bromo-2'-deoxyuridine-positive nuclei and immunostaining for alpha-smooth muscle actin. Despite acute mesangial cell activation and proliferation, PDGF treatment had no long-term effect on either kidney structure or function. Similarly, treatment of GK rats with bFGF, despite the augmentation of podocyte injury as demonstrated by de novo expression of glomerular desmin expression, did not lead to the development of progressive diabetic nephropathy. In summary, the data in the current manuscript suggest that the additive effect of hyperglycemia and superimposed isolated mesangial cell or podocyte injury does not lead to progressive diabetic nephropathy. This further emphasises the multifactorial nature of the pathogenesis of progressive diabetic nephropathy.
 ...
PMID:Augmentation of kidney injury by basic fibroblast growth factor or platelet-derived growth factor does not induce progressive diabetic nephropathy in the Goto Kakizaki model of non-insulin-dependent diabetes. 1048 16

We have previously reported that high glucose stimulates osteopontin (OPN) expression through protein kinase C-dependent pathways as well as hexosamine pathways in cultured rat aortic smooth muscle cells. The finding prompted us to study in vivo expression of OPN in diabetes mellitus. In the present study, we found by immunohistochemistry that medial layers of the carotid arteries of streptozotocin-induced diabetic rats and the forearm arteries of diabetic patients stained positively for OPN antibodies, whereas the staining from arteries of control rats and nondiabetic patients was negative. We also found that OPN stimulated the migration and enhanced platelet-derived growth factor (PDGF)-mediated DNA synthesis of cultured rat aortic smooth muscle cells. OPN and PDGF synergistically activated focal adhesion kinase as well as extracellular signal-regulated kinase; this finding seems to explain the OPN-induced enhancement of PDGF-mediated DNA synthesis. Taken together, our present results raise a possibility that OPN plays a role in the development of diabetic vascular complications.
 ...
PMID:Enhanced expression of osteopontin in human diabetic artery and analysis of its functional role in accelerated atherogenesis. 1071 83

Diabetic foot ulcers are frequent: 12,000 Dutch diabetes patients have such an ulcer. The ulcers have a multifactorial aetiology: polyneuropathy, biomechanical stress, infection, deficient footwear and to a less extent ischaemia are the major factors. The principles of ulcer treatment are relief of pressure, restoration of skin perfusion, treatment of infection, intensive wound care, metabolic control, treatment of comorbidity, and instruction of the patient. Wound healing is slow. The impaired wound healing is probably caused by deficiencies in local growth factors, changes in the extracellular matrix, diminished fibroblast function, decreased antimicrobial activity of leukocytes and disturbances in the macro- and microcirculation. In recent years several new treatment strategies have been developed to stimulate wound healing in diabetic foot ulcers. These (partly experimental) treatments include: topical growth factors, extracellular matrix products, bioengineered human skin, granulocyte colony stimulating factor and hyperbaric oxygen therapy. In particular recombinant human platelet derived growth factor (becaplermin) has proved to be clinically effective in chronic neuropathic foot ulcer and has been approved in the Netherlands.
 ...
PMID:[New developments in the treatment of diabetic foot ulcers]. 1071 45

The mechanism of diabetic macroangiopathy was studied from the view point of phenotypic change of arterial smooth muscle cells (SMC). Otsuka Long-Evans Tokushima fatty (OLETF) rat, an animal model of non-insulin dependent diabetes mellitus (NIDDM), develops spontaneous persistent hyperglycemia after the age of 18 weeks. Medial SMC in OLETF rats expressed more platelet-derived growth factor (PDGF) beta-receptor and fibronectin at the protein level than those from control, Long-Evans Tokushima Otsuka (LETO) rats, not only after but also before the onset of diabetes mellitus. Cultured SMC from OLETF rats more strongly responded specifically to the mitogenic stimuli of PDGF-AB and PDGF-BB and also expressed PDGF beta-receptor more intensely compared with those from LETO rats. PDGF is known to be the main contributor to the intimal thickening induced by balloon catheter injury, which is one of several forms of arterial injuries. Intimal thickening of carotid arteries in OLETF rats after balloon catheter injury increased compared with that in LETO rats before the onset of diabetes mellitus. In in vitro culture system, fibronectin synthesis was stimulated by transforming growth factor-beta1(TGF-beta1) in SMC from OLETF rats, but not in those from LETO rats, suggesting that SMC from OLETF rats respond to TGF-beta1. These results indicate that overexpression of PDGF beta-receptor and fibronectin in medial SMC plays an important role in the accelerated intimal thickening before the onset of diabetes mellitus in OLETF rats.
 ...
PMID:Increased atherogenesis in Otsuka Long-Evans Tokushima fatty rats before the onset of diabetes mellitus: association with overexpression of PDGF beta-receptors in aortic smooth muscle cells. 1072 85

Platelet-derived growth factor (PDGF) was found to contribute to the pathophysiological process in the development and progression of glomerulosclerosis characterized by mesangial cell proliferation and accumulation of extracellular matrix. To examine the role of PDGF in the development of diabetic nephropathy, we conducted immunohistochemical analysis for PDGF B-chain (PDGF-B) and PDGF beta-receptor (PDGFR-beta) in the glomeruli of streptozotocin-induced diabetic rats. At 2, 4, and 12 weeks after the onset of diabetes, the expression of PDGF-B in glomeruli of diabetic rats was increased significantly as compared to control or diabetic rats treated with insulin. Similar changes were observed on PDGFR-beta immunostaining. The immunostaining of mirror sections revealed the existence of PDGF-B or PDGFR-beta not only in mesangial cells but also in visceral epithelial cells. Glomerular volume was significantly increased in diabetes. This early glomerular abnormality was prevented by an inhibition of PDGF system with trapidil as well as by the treatment of insulin. Our results suggest that the activation of the PDGF system in glomerular cells might play an important role in the development of early glomerular lesion in diabetes.
Diabetes Res Clin Pract 2000 May
PMID:Immunohistochemical characterization of glomerular PDGF B-chain and PDGF beta-receptor expression in diabetic rats. 1080 45

Previously, we have reported that the lipoprotein fraction containing intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) isolated from diabetics stimulates an atherogenic cytokine in cultured endothelial cells. To study which lipoprotein fraction isolated from diabetics can modulate the gene expression in endothelial cells, we isolated IDL and LDL fractions from 14 type 2 diabetics and seven age- and BMI- adjusted non-diabetics. We measured the effects of the lipoproteins on mRNA expression of atherogenic molecules in cultured endothelial cells. We found that the IDL fraction stimulated monocyte chemoattractant protein-1 (MCP-1) mRNA expression in endothelial cells as time- and dose-dependent fashions, while the LDL fraction was not effective. IDL isolated from diabetics also increased not only platelet-derived growth factor B-chain, but also intercellular adhesion molecule-1 mRNA contents. Furthermore, the HbA(1c) levels in diabetics were significantly correlated with their abilities of IDL to increase MCP-1 mRNA content in the cells and the increment coincided with the increase in MCP-1 protein release into culture media. These results indicate that qualitative as well as quantitative changes in IDL fraction in diabetes are atherogenic through stimulating gene expression of atherogenic molecules in endothelial cells.
Diabetes Res Clin Pract 2000 May
PMID:IDL can stimulate atherogenic gene expression in cultured human vascular endothelial cells. 1080 50

Topically applied recombinant human platelet-derived growth factor-BB (becaplermin) is a new pharmacologically active therapy for chronic, neuropathic, lower extremity diabetic ulcers. In previous studies, becaplermin gel was administered once daily but dressings were changed twice daily. In the present study of 134 patients with diabetes mellitus and full thickness lower extremity ulcers, dressings were changed only once per day, simplifying the treatment regimen. Efficacy criteria included the percentage of patients achieving complete healing within the 20-week treatment period, the time to achieve complete healing, the rate of ulcer recurrence during the 6-month period following healing, and treatment compliance. Complete healing of ulcers was achieved in 57. 5% of patients, with a mean time to closure of 63 days and a recurrence rate of 21% at 6 months. Of the potential factors affecting ulcer healing, only drug compliance (p < 0.001), dressing compliance (p < 0.01), the presence of infection (p < 0.01), baseline ulcer area (p < 0.05), and baseline total wound evaluation score (p < 0.05) were significantly associated with healing. Results of this study further confirm the efficacy and safety of becaplermin gel for the treatment of lower extremity diabetic ulcers.
 ...
PMID:Recombinant human platelet-derived growth factor-BB (becaplermin) for healing chronic lower extremity diabetic ulcers: an open-label clinical evaluation of efficacy. 1088 6


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>