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)

Insulin resistance is central to the pathophysiology of type 2 diabetes. It has been known for some time that down-regulation and reduced kinase activity of the insulin receptor play a role in insulin resistance; however, it has recently emerged that defects in the intracellular responses to insulin are also very important. We studied the molecular basis of insulin resistance in mice in which injection with gold thioglucose led to the development of hyperphagia, obesity and insulin resistance over a 4-month period. We found that the insulin-stimulated activation of MAP kinase was defective in obese, insulin-resistant mice. Similarly, we investigated insulin-stimulated PI3-kinase activation in the isolated soleus muscle of lean and obese mice, and found a marked reduction in the PI3-kinase activation of obese animals. The magnitude of the effect was greater than the reduction in insulin receptor activation, suggesting that impairment of PI3-kinase activation is a very important element in the development of insulin resistance in obese mice. In keeping with this, we found that the defect in PI3-kinase activation developed in young obese mice before the emergence of overt insulin resistance. We investigated different mechanisms by which defects in the components of the insulin signalling cascade could emerge, including down-regulation and abnormal phosphorylation of signal molecules. In adipocytes from young obese mice in which insulin resistance had not yet developed, we found that there were already marked defects in IRS-1 tyrosine phosphorylation. Increased IRS-1 phosphorylation on serine and threonine residues affects tyrosine phosphorylation. Such a process could contribute to the defective IRS-1 tyrosine phosphorylation in insulin-resistant animals. We found that brief exposure of 3T3-L1 adipocytes to platelet-derived growth factor led to IRS-1 serine/threonine phosphorylation through a PI3-kinase-dependent pathway, and that this prevented phosphorylation of the tyrosine residues of IRS-1. Such a mechanism, induced by growth factors, TNF-alpha or some other agent, may play an important role in the development of insulin resistance in obese mice.
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PMID:Molecular mechanisms of insulin action in normal and insulin-resistant states. 1032 50

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.
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PMID:Use of topical recombinant human platelet-derived growth factor-BB (becaplermin) in healing of chronic mixed arteriovenous lower extremity diabetic ulcers. 1055 55

Type 2 diabetes mellitus is a polygenic disorder with complicated biochemical alterations. Numerous investigators have examined the implication of receptor abnormalities in the pathogenesis of the disorder. The authors review the potential roles of some important receptors, such as the insulin receptor, beta 3-adrenergic receptor, leptin receptor and peroxisome proliferator-activated receptor gamma, in the pathogenesis of human type 2 diabetes. They emphasize the significance of effective glycemic control by examining the evidence that strongly suggests the association of chronic complications of type 2 diabetes with abnormalities of receptors for the advanced glycation end products, transforming growth factor-beta and platelet-derived growth factor. The molecular understanding of receptor abnormalities and alterations in postreceptor signalling pathways may not only clarify the pathogenesis of human type 2 diabetes and the development of chronic complications in the disorder but also provide insight into more efficacious drug regimens that target these receptors.
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PMID:The roles of receptor abnormalities in the pathogenesis and chronic complications of type 2 diabetes mellitus. 1041 Aug 31

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.
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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

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.
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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

This prospective, multicenter, open-label study assessed the efficacy and tolerability of recombinant human platelet-derived growth factor BB (becaplermin) in the treatment of chronic ulcers of the lower extremities in 73 patients with and without type 2 diabetes mellitus. Becaplermin gel .01% was applied once daily for 12 weeks. Efficacy was assessed in terms of progression to healing (100% epithelialization); the secondary efficacy endpoint was time to complete healing. Safety was assessed in terms of incidence of adverse events. Ninety-five percent of all ulcers were completely healed at week 9; only 5% remained incompletely healed at week 12 and were considered treatment failures. Healing time did not differ between diabetic and nondiabetic patients. The major adverse events were pain, burning sensation, and pruritus at the ulcer site, with an overall incidence of 10%. No patients dropped out because of adverse events. Becaplermin gel .01% was safe and well tolerated. Further studies are necessary to assess the durability of healing with this treatment.
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PMID:Treatment of chronic ulcers in the lower extremities with topical becaplermin gel .01%: a multicenter open-label study. 1118 57

The worldwide increase in prevalence of type 2 diabetes has resulted in a parallel increase in diabetic foot ulcers--a pervasive and significant problem associated with this disease [2]. Currently, an estimated 10.3 million people have been diagnosed with diabetes, while an additional estimated 5.4 million people with diabetes remain undiagnosed, representing a sixfold increase in the incidence of diabetes over the past four decades [9]. Approximately 15% (more than 2 million individuals, based on these estimates) of all people with diabetes will develop a lower-extremity ulcer during the course of the disease [10-12]. While most of these ulcers can be treated successfully on an outpatient basis, some will persist and become infected. Ultimately, between 14% and 20% of patients with lower-extremity diabetic ulcers will require amputation of the affected limb [13-15]. Diabetic foot ulcers can result in staggering financial burdens for both the healthcare system and the patient. For example, analysis of the 1995 Medicare claims revealed that lower-extremity ulcer care accounted for $1.45 billion in Medicare costs and contributed substantially to the high cost of care for diabetics, compared with Medicare costs for the general population [5]. Therapies that promote rapid and complete healing and reduce the need for expensive surgical procedures would impact these costs substantially. Results of this analysis suggest that becaplermin may ultimately be more cost-effective for the treatment of chronic diabetic foot ulcers than other treatment modalities, despite its higher initial dollar cost. This finding may be attributed to a combination of factors. First, expenses incurred in more prolonged treatment, such as office visits and the need for additional dressings, can be avoided when healing completes in a shorter period. Second, rapid and complete ulcer healing may reduce the incidence of significant morbidities (such as amputation or infection) and premature mortality; consequently, the financial burden associated with these complications would be reduced. Finally, the value of improved quality of life in patients with healed ulcers and the reduction in financial burden for patients who return to work cannot be ignored. These promising results warrant further investigation in larger controlled clinical studies to define more clearly the cost-effectiveness of becaplermin in this patient population.
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PMID:Cost-effective management of recalcitrant diabetic foot ulcers. 1247 56

Diabetic retinopathy develops in patients with both type 1 and type 2 diabetes and is the major cause of vision loss and blindness in the working population. In diabetes, damage to the retina occurs in the vasculature, neurons and glia resulting in pathological angiogenesis, vascular leakage and a loss in retinal function. The renin-angiotensin system is a causative factor in diabetic microvascular complications inducing a variety of tissue responses including vasoconstriction, inflammation, oxidative stress, cell hypertrophy and proliferation, angiogenesis and fibrosis. All components of the renin-angiotensin system including the angiotensin type 1 and angiotensin type 2 receptors have been identified in the retina of humans and rodents. There is evidence from both clinical and experimental models of diabetic retinopathy and hypoxic-induced retinal angiogenesis that the renin-angiotensin system is up-regulated. In these situations, retinal dysfunction has been linked to angiotensin-mediated induction of growth factors including vascular endothelial growth factor, platelet-derived growth factor and connective tissue growth factor. Evidence to date indicates that blockade of the renin-angiotensin system can confer retinoprotection in experimental models of diabetic retinopathy and ischemic retinopathy. This review examines the role of the renin-angiotensin system in diabetic retinopathy and the potential of its blockade as a treatment strategy for this vision-threatening disease.
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PMID:Angiotensin and diabetic retinopathy. 1616 93

We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice. Introgression of a 7-Mb segment of the B6 chromosome 19 into the BTBR background (strain 1339A) replicated the reduced insulin linked to T2dm2. The 1339A mice have markedly impaired insulin secretion in vivo and disrupted islet morphology. We used subcongenic strains derived from 1339A to localize the T2dm2 quantitative trait locus (QTL) to a 242-kb segment comprising the promoter, first exon and most of the first intron of the Sorcs1 gene. This was the only gene in the 1339A strain for which we detected amino acid substitutions and expression level differences between mice carrying B6 and BTBR alleles of this insert, thereby identifying variation within the Sorcs1 gene as underlying the phenotype associated with the T2dm2 locus. SorCS1 binds platelet-derived growth factor, a growth factor crucial for pericyte recruitment to the microvasculature, and may thus have a role in expanding or maintaining the islet vasculature. Our identification of the Sorcs1 gene provides insight into the pathway underlying the pathophysiology of obesity-induced type 2 diabetes mellitus.
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PMID:Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus. 1668 71

Glucagon-like peptide-1 is a hormone secreted by L cells of the small intestine and stimulates glucose-dependent insulin response. Glucagon-like peptide-1 receptor agonists such as exendin-4 are currently used in type 2 diabetes, and considered to have beneficial effects on the cardiovascular system. To further elucidate the effect of glucagon-like peptide-1 receptor agonists on cardiovascular diseases, we investigated the effects of exendin-4 on intimal thickening after endothelial injury. Under continuous infusion of exendin-4 at 24 nmol/kg/day, C57BL/6 mice were subjected to endothelial denudation injury of the femoral artery. Treatment of mice with exendin-4 reduced neointimal formation at 4weeks after arterial injury without altering body weight or various metabolic parameters. In addition, in vitro studies of isolated murine, rat and human aortic vascular smooth muscle cells showed the expression of GLP-1 receptor. The addition of 10nM exendin-4 to cultured smooth muscle cells significantly reduced their proliferation induced by platelet-derived growth factor. Our results suggested that exendin-4 reduced intimal thickening after vascular injury at least in part by the suppression of platelet-derived growth factor-induced smooth muscle cells proliferation.
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PMID:Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury. 2121 53


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