Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperglycemia is considered a key causal factor in the development of diabetic vascular complications and can mediate its adverse effects through multiple pathways. This was confirmed for microangiopathy in the Diabetes Control and Complications Trial study for type 1 diabetes and corroborated for type 2 diabetes by the United Kingdom Prospective Diabetes Study published in 1998. Prevention of diabetic complications requires at least control of glycemia. This article briefly summarizes the evidence that strongly supports the role of hyperglycemia in vascular complications. After outlining the role of the polyol pathway, protein kinase C, and oxidative stress, the author focuses on one of the key biochemical mechanisms for this pathologic process: the direct deleterious action of glucose and other sugars on proteins, known as glycation or nonenzymatic glycosylation. Results of animal studies and phase III clinical trials reveal that the inhibition of this process attenuates the development of a range of these complications.
 ...
PMID:Glycation as the glucose link to diabetic complications. 1110 51

Diabetic Nephropathy (DN) is the commonest cause of end-stage renal failure (ESRF) in the Western world. Diabetic nephropathy follows a well outline clinical course, starting with microalbuminuria through proteinuria, azotaemia and culminating in ESRF. Before the onset of overt proteinuria, there are various renal functional changes including renal hyperfiltration, hyperperfusion, and increasing capillary permeability to macromolecules. Basement-membrane thickening and mesangial expansion have long been recognized as pathological hallmark of diabetes. It has been postulated that DN occurs as a result of the interplay of metabolic and hemodynamic factors in the renal microcirculation. There is no doubt that there is a positive relationship between hyperglycaemia, which is necessary but not sufficient, and microvascular complications. The accumulation of advanced glycosylated end-products (AGEs), the activation of isoform(s) of protein kinase C (PKC) and the acceleration of the aldose reductase pathway may explain how hyperglycemia damages tissue. PKC is one of the key signaling molecules in the induction of the vascular pathology of diabetes. The balance between extracellular matrix production and degradation is important in this context. Transforming growth factor-beta (TGF-beta) appears to play a pivotal role in accumulation in the diabetic kidney. Hemodynamic disturbances are believed to be directly responsible for the development of glomerulosclerosis and its attendant proteinuria. There is familial clustering of diabetic kidney disease. A number of gene loci have been investigated to try to explain the genetic susceptibility to diabetic nephropathy. The genes coding for components of renin-angiotensin system have drawn special attention, due to the central role that this system plays in the regulation of blood pressure, sodium metabolism, and renal hemodynamics. Endothelial dysfunction is closely associated with the development of diabetic retinopathy, nephropathy and atherosclerosis, both in IDDM and in NIDDM. The pathogenesis of diabetic nephropathy is not clarified completely yet.
 ...
PMID:Pathogenesis of diabetic nephropathy. 1146 May 89

Diabetic nephropathy is characterized functionally by glomerular hyperfiltration and albuminuria and histologically by the expansion of glomerular mesangium. We and others have found that protein kinase C (PKC) is activated through an increase in de novo synthesis of diacylglycerol (DAG) from glucose in glomerular mesangial cells cultured under high glucose conditions and in glomeruli of diabetic rats. The activation of PKC could activate further various intracellular signal transduction systems, such as extracellular regulated kinase (ERK). The activation of the DAG-PKC-ERK pathway is considered to be one of the important molecular mechanisms of the development and progression of diabetic nephropathy. To prove this hypothesis, we examined whether the inhibition of the DAG-PKC-ERK pathway could prevent the development of glomerular dysfunction in diabetic animals. First, we found that thiazolidinedione compounds could inhibit PKC activation by activating DAG kinase. Thiazolidinedione compounds were able to prevent glomerular hyperfiltration, albuminuria, and excessive production of extracellular matrix proteins in glomeruli in streptozotocin-induced diabetic rats, a model for type 1 diabetes. Second, we tried to inhibit PKC directly by oral administration of PKC beta inhibitor. PKC beta inhibitor could prevent albuminuria and mesangial expansion in db/db mice, a model for type 2 diabetes. These results confirmed the importance of the activation of the DAG-PKC-ERK pathway in the development of glomerular dysfunction in diabetes.
 ...
PMID:Cellular mechanisms in the development and progression of diabetic nephropathy: activation of the DAG-PKC-ERK pathway. 1157 50

Exposure of pancreatic beta-cells to cytokines, such as interleukin-1beta (IL-1beta), is thought to contribute to the beta-cell apoptosis that underlies the onset of type 1 diabetes. One important event triggered by IL-1beta is induction of nitric oxide synthase (iNOS), an enzyme that catalyzes intracellular generation of the cytotoxic free radical NO. We recently described a novel requirement for the protein kinase C (PKC) isozyme PKCdelta in this process. Our current aim, therefore, was to assess whether PKCdelta also plays a role in beta-cell apoptosis. As assessed by either annexin V staining or DNA fragmentation, IL-1beta caused INS-1 cells to undergo apoptosis. This was completely blocked by adenoviral overexpression of a dominant-negative, kinase-dead (KD) PKCdelta mutant. The corresponding PKCalpha virus was without effect. However, apoptosis caused by the cytotoxic agent streptozotocin (STZ), which acts independent of iNOS, was also inhibited by overexpression of PKCdeltaKD. STZ was additionally shown to activate the proteolytic enzyme caspase-3, a key biochemical effector of end-stage apoptosis. Moreover, STZ caused a caspase-dependent cleavage of PKCdelta, thereby releasing a COOH-terminal fragment corresponding to the kinase catalytic domain. Thus, proteolytic activation of PKCdelta seems to be important in the distal apoptotic pathway induced by STZ. That IL-1beta also activated caspase-3 and promoted PKCdelta cleavage suggests that this distal pathway also contributes in the apoptotic response to the cytokine. These data therefore support a dual role for PKCdelta in IL-1beta-mediated cell death: it is required for efficient NO generation through regulation of iNOS levels but also contributes to apoptotic pathways downstream of caspase activation.
 ...
PMID:Inhibition of protein kinase C delta protects rat INS-1 cells against interleukin-1beta and streptozotocin-induced apoptosis. 1181 38

Poorly controlled or untreated type I diabetes mellitus is characterized by hyperglycemia and is associated with decreased bone mass and osteoporosis. We have demonstrated that osteoblasts are sensitive to hyperglycemia-associated osmotic stress and respond to elevated extracellular glucose or mannitol by increasing c-jun and collagen I expression. To determine whether MAPKs are involved in this response, MC3T3-E1 osteoblasts were treated with 16.5 mm glucose, mannitol, or contrast dye for 1 h. Immunoblotting of phosphorylated p38 demonstrated activation of p38 MAPK by hyperosmotic stress in vitro and in vivo. Activation peaked at 20 min, remained detectable after 24 h, and was protein kinase C-independent. Activating transcription factor-2 (ATF-2) activation followed the same pattern as phospho-p38. Transactivation of cAMP response element (CRE)- and c-jun promoter (containing a CRE-like element)-reporter constructs increased following hyperosmotic treatment. SB 203580 (a p38 MAPK inhibitor) blocked ATF-2 phosphorylation, CRE transactivation, and c-jun promoter activation. Hyperosmotic activation of collagen I promoter activity was also inhibited by SB 203580, consistent with the involvement of c-jun in collagen I up-regulation. Therefore, we propose that hyperglycemia-induced increases in p38 MAPK activity and ATF-2 phosphorylation contribute to CRE activation and modulation of c-jun and collagen I expression in osteoblasts.
 ...
PMID:P38 and activating transcription factor-2 involvement in osteoblast osmotic response to elevated extracellular glucose. 1214 42

Abnormal activation of protein kinase C-beta isoforms in the diabetic state has been implicated in the development of diabetic nephropathy. It is thus plausible that DNA sequence differences in the protein kinase C-beta1 gene (PRKCB1), which encodes both betaI and betaII isoforms, may influence susceptibility to nephropathy. Nine single-nucleotide polymorphisms (SNP) in PRKCB1 were tested for association with diabetic nephropathy in type I diabetes mellitus, by using both case-control and family-study designs. Allele and genotype distributions of two SNP in the promoter (--1504C/T and --546C/G) differed significantly between case patients and control patients (P < 0.05). These associations were particularly strong with diabetes mellitus duration of <24 yr (P = 0.002). The risk of diabetic nephropathy was higher among carriers of the T allele of the --1504C/T SNP, compared with noncarriers (odds ratio, 2.54; 95% confidence interval, 1.39 to 4.62), and among carriers of the G allele of the --546C/G SNP (odds ratio, 2.45; 95% confidence interval, 1.37 to 4.38). Among individuals with diabetes mellitus duration of >/==" BORDER="0">24 yr, these two SNP were not associated with diabetic nephropathy. These positive findings were confirmed by using the family-based transmission disequilibrium test. The T-G haplotype, with both risk alleles, was transmitted more frequently than expected from heterozygous parents to offspring who developed diabetic nephropathy during the first 24 yr of diabetes mellitus. It is concluded that DNA sequence differences in the promoter of PRKCB1 contribute to diabetic nephropathy susceptibility in type I diabetes mellitus.
 ...
PMID:Identification of a common risk haplotype for diabetic nephropathy at the protein kinase C-beta1 (PRKCB1) gene locus. 1287 55

At present, diabetic kidney disease affects about 15-25 % of patients with type 1 diabetes (T1D) and 30-40 % of patients with type 2 diabetes (T2D). Several decades of extensive research have elucidated various pathways to be implicated in the development of diabetic kidney disease. These include metabolic factors beyond blood glucose (e.g. advanced glycation endproducts (AGEs)), haemodynamic factors (e.g. the renin angiotensin system (RAS)), intracellular signaling molecule proteins (e.g. protein kinase C (PKC)) and growth factors/cytokines (e.g. growth hormone (GH), insulin-like growth factors (IGFs), transforming growth factor beta (TGF-beta) and vascular endothelial growth factor (VEGF)). This review focuses on the role of three of these growth factors, i.e. GH, IGFs and VEGF. A brief discussion of each system is followed by description of its expression in the normal kidney. Then, for each system, in vitro, experimental and clinical evidence addressing the role of the system in diabetic kidney disease is presented. The interplay of each system to other potential pathways will also be addressed. Finally, well-known and potential therapeutic strategies targeting the GH/IGF and VEGF systems in a specific or indirect way will discussed.
 ...
PMID:The involvement of growth hormone (GH), insulin-like growth factors (IGFs) and vascular endothelial growth factor (VEGF) in diabetic kidney disease. 1554 23

Alterations in the microvasculature seen early in type 1 diabetes appear to be related to glycemic control. The later abnormalities occur primarily in patients with incipient or overt nephropathy and are likely to represent a more generalized vascular dysfunction as indicated by the increased cardiovascular risk in these groups. The mechanisms involved may be related to genetic susceptibility in combination with impaired hemorheology, dyslipidemia, hypertension, or the toxic effects of hyperglycemia. Many of these effects may relate to a common final pathway such as activation of PKC or increased oxidative stress. Therapeutic interventions to inhibit either PKC effects or decrease oxidative stress have been effective in reducing microangiopathy in diabetic animals. Vitamin C or E supplementation may improve vascular function in type 1 diabetes. The results of ongoing trials of PKC inhibitors are awaited with interest. Whether such interventions will influence the course of microangiopathy remains to be determined.
 ...
PMID:The microvasculature in type 1 diabetes. 1622 92

Cytokines mediate pancreatic islet beta-cell apoptosis and necrosis, leading to loss of insulin secretory capacity and type 1 diabetes mellitus. The cytokines, IL-1beta and interferon-gamma, induced terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining of rat islet cells within 48 h by about 25-30%, indicative of apoptosis and/or necrosis. Sphingosine 1-phosphate (S1P) at nanomolar concentrations significantly reduced islet cell cytokine-induced TUNEL staining. Similar effects were observed in INS-1 cells. The dihydro analog of S1P also reduced the percentage of TUNEL stained islet and INS-1 cells, whereas the S1P receptor antagonist BML-241 blocked the protective effects. Pertussis toxin did not affect the S1P protective response. In the presence of a phospholipase C antagonist, U73122, there was significant inhibition of the S1P protective effects against apoptosis/necrosis. S1P stimulated INS-1 cell protein kinase C activity. Carbamylcholine chloride acting through muscarinic receptors also inhibited cytokine-induced TUNEL staining in pancreatic islet cells. S1P and/or dihydro-S1P also antagonized cytokine-induced increases in cytochrome c release from mitochondria and caspase-3 activity in INS-1 cells, which are indicative of cell apoptosis vs. necrosis. S1P failed to affect nitric oxide synthase activity after 48 h. Thus, the evidence suggests that S1P acting on S1P receptors coupled to G(q) mediates protective effects on islet beta-cells against cytokine-induced apoptosis.
 ...
PMID:Sphingosine 1-phosphate affects cytokine-induced apoptosis in rat pancreatic islet beta-cells. 1679 3

Endothelial dysfunction is one manifestation of the many changes induced in the arterial wall by the metabolic abnormalities accompanying diabetes and insulin resistance. In type 1 diabetes, endothelial dysfunction is most consistently found in advanced stages of the disease. In other patients, it is associated with nondiabetic insulin resistance and probably precedes type 2 diabetes. In obesity and insulin resistance, increased secretion of proinflammatory cytokines and decreased secretion of adiponectin from adipose tissue, increased circulating levels of free fatty acids, and postprandial hyperglycemia can all alter gene expression and cell signaling in vascular endothelium, cause vascular insulin resistance, and change the release of endothelium-derived factors. In diabetes, sustained hyperglycemia causes increased intracellular concentrations of glucose metabolites in endothelial cells. These changes cause mitochondrial dysfunction, increased oxidative stress, and activation of protein kinase C. Dysfunctional endothelium displays activation of vascular NADPH oxidase, uncoupling of endothelial nitric oxide synthase, increased expression of endothelin 1, a changed balance between the production of vasodilator and vasoconstrictor prostanoids, and induction of adhesion molecules. This review describes how these and other changes influence endothelium-dependent vasodilation in patients with insulin resistance and diabetes. The clinical utility of endothelial function testing and future therapeutic targets is also discussed.
 ...
PMID:Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes. 1717 29


<< Previous 1 2 3 4 5 Next >>