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

Diabetic retinopathy is one of the most feared complications of diabetes. In addition to the severity of hyperglycemia, systemic factors also play an important role in its development. Another risk factor in the development of diabetic retinopathy is elevated levels of homocysteine, a non-protein amino acid, and hyperglycemia and homocysteine are shown to produce synergistic detrimental effects on the vasculature. Hyperhomocysteinemia is associated with increased oxidative stress, and in the pathogenesis of diabetic retinopathy, oxidative stress-mitochondrial dysfunction precedes the development of histopathology characteristic of diabetic retinopathy. Furthermore, homocysteine biosynthesis from methionine forms S-adenosyl methionine (SAM), and SAM is a co-substrate of DNA methylation. In diabetes, DNA methylation machinery is activated, and mitochondrial DNA (mtDNA) and several genes associated with mitochondrial homeostasis undergo epigenetic modifications. Consequently, high homocysteine, by further affecting methylation of mtDNA and that of genes associated with mtDNA damage and biogenesis, does not give any break to the already damaged mitochondria, and the vicious cycle of free radicals continues. Thus, supplementation of sensible glycemic control with therapies targeting hyperhomocysteinemia could be valuable for diabetic patients to prevent/slow down the development of this sight-threatening disease.
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PMID:Diabetic Retinopathy: Mitochondria Caught in a Muddle of Homocysteine. 3296 62

Hyperglycemic memory is associated with several complications of diabetes. Although there is some physiological evidence that this phenomenon occurs with diabetic bladder dysfunction (DBD), there have been no studies in bladder that provide evidence of hyperglycemic memory at the molecular/biochemical level. In the present studies, we determined the effects of long-term diabetes on the metabolome of bladder detrusor in a rat model of streptozotocin-induced type-1-diabetes and the ability of insulin treatment to normalize metabolic changes. These studies demonstrated that although insulin reversed a majority of the metabolic changes caused by diabetes, with long-term diabetes there was a persistent decrease in the methylation index (indicated by a reduced ratio of S-adenosylmethionine to S-adenosyl homocysteine) after insulin treatment. We confirmed a "hypomethylated environment" develops in diabetic detrusor by demonstrating an overall reduction in methylated detrusor DNA that is only partially reversed with glycemic control. Furthermore, we confirmed that this hypomethylated environment is associated with epigenetic changes in the detrusor genome, which are again mostly, but not completely, reversed with glycemic control. Overall our studies provide strong molecular evidence for a mechanism by which diabetes alters methylation status and gene expression in the detrusor genome, and that these epigenetic modifications contribute to hyperglycemic memory. Our work suggests novel treatment strategies for diabetic patients who have attained glycemic control but continue to experience DBD. For example, epigenomic data can be used to identify "actionable gene targets" for its treatment and would also support a rationale for approaches that target the hypomethylation index.
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PMID:Hyperglycemic memory in the rat bladder detrusor is associated with a persistent hypomethylated state. 3320 May 30

Diabetic nephropathy (DN) is a common microvascular complication of diabetes and the main cause of end-stage nephropathy (ESRD). Inflammation and fibrosis play key roles in the development and progression of diabetic nephropathy. By using in vivo and in vitro DN models, our laboratory has identified the protective role of carnosine (CAR) on renal tubules. Our results showed that carnosine restored the onset and clinical symptoms as well as renal tubular injury in DN. Furthermore, carnosine decreased kidney inflammation and fibrosis in DN mice. These results were consistent with high glucose (HG)-treated mice tubular epithelial cells (MTECs). Using web-prediction algorithms, cellular thermal shift assay (CETSA) and molecular docking, we identified glycine N-methyltransferase (GNMT) as a carnosine target. Importantly, we found that GNMT, a multiple functional protein that regulates the cellular pool of methyl groups by controlling the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), was down-regulated significantly in the serum of Type 1 DM patients and renal tissues of DN mice. Moreover, using cultured TECs, we confirmed that the increased GNMT expression by transient transfection mimicked the protective role of carnosine in reducing inflammation and fibrosis. Conversely, the inhibition of GNMT expression abolished the protective effects of carnosine. In conclusion, carnosine might serve as a promising therapeutic agent for DN and GNMT might be a potential therapeutic target for DN.
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PMID:Carnosine alleviates diabetic nephropathy by targeting GNMT, a key enzyme mediating renal inflammation and fibrosis. 3324 46


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