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)

The AMP-activated protein kinase (AMPK) is an enzyme that is activated in situations where there are changes in the cellular energy status such as muscle contraction and hypoxia. AMPK can also be pharmacologically activated by the compound 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and the antidiabetic agent metformin. Several studies support the hypothesis that AMPK plays an important role in the stimulation of muscle glucose uptake by these physiological and pharmacological stimuli. In isolated rat muscles, activation of AMPK is associated with increases in glucose uptake through an insulin-independent mechanism. Studies done in rodents have shown that the activation of AMPK by AICAR is accompanied by decreases in blood glucose concentrations, in part due to enhanced muscle glucose uptake. Similar to exercise, AICAR not only directly stimulates glucose uptake into the skeletal muscle, but also enhances insulin sensitivity. The activation of AMPK and associated increases in muscle glucose uptake are affected by factors such as glycogen content, exercise training and fibre type. The effects of AMPK on muscle glucose uptake makes this protein a promising pharmacological target for the treatment of type 2 diabetes.
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PMID:AMP-activated protein kinase and muscle glucose uptake. 1286 38

Recent studies have shown that genes involved in oxidative phosphorylation (OXPHOS) exhibit reduced expression in skeletal muscle of diabetic and prediabetic humans. Moreover, these changes may be mediated by the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). By combining PGC-1alpha-induced genome-wide transcriptional profiles with a computational strategy to detect cis-regulatory motifs, we identified estrogen-related receptor alpha (Erralpha) and GA repeat-binding protein alpha as key transcription factors regulating the OXPHOS pathway. Interestingly, the genes encoding these two transcription factors are themselves PGC-1alpha-inducible and contain variants of both motifs near their promoters. Cellular assays confirmed that Erralpha and GA-binding protein a partner with PGC-1alpha in muscle to form a double-positive-feedback loop that drives the expression of many OXPHOS genes. By using a synthetic inhibitor of Erralpha, we demonstrated its key role in PGC-1alpha-mediated effects on gene regulation and cellular respiration. These results illustrate the dissection of gene regulatory networks in a complex mammalian system, elucidate the mechanism of PGC-1alpha action in the OXPHOS pathway, and suggest that Erralpha agonists may ameliorate insulin-resistance in individuals with type 2 diabetes mellitus.
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PMID:Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. 1510 Apr 10

Insulin resistance is pathogenic for type 2 diabetes and cardiovascular disease. Several inhibitors of insulin signaling have a role in human insulin resistance. The transmembrane glycoprotein ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1; also known as plasma cell membrane glycoprotein PC-1) interacts with the insulin receptor and inhibits subsequent signaling by decreasing its beta-subunit autophosphorylation. E-NPP1 is overexpressed in skeletal muscle, adipose tissue and cultured skin fibroblasts of insulin-resistant individuals who are not yet obese or diabetic, which indicates that excessive E-NPP1 expression is an early, intrinsic defect in human insulin resistance. Genetic studies also support a primary role of E-NPP1 in insulin resistance. Among other variants, a missense polymorphism, Lys121Gln, has been described. The Gln121 variant is a stronger inhibitor than Lys121 of insulin receptor function, and is associated with insulin resistance, type 2 diabetes and both cardiovascular and nephrovascular complications in diabetic patients. E-NPP1 is measurable in human serum, where it might represent a valuable biomarker of insulin resistance, but its relationship to tissue and systemic insulin resistance remains to be thoroughly elucidated. Understanding the mechanisms that regulate E-NPP1 expression and/or function might render this protein a new target for strategies to treat and prevent type 2 diabetes and cardiovascular disease.
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PMID:Mechanisms of disease: Ectonucleotide pyrophosphatase phosphodiesterase 1 as a 'gatekeeper' of insulin receptors. 1714 16

Uncoupling protein 3 (UCP3), is primarily expressed in skeletal muscle mitochondria and has been suggested to be involved in mediating energy expenditure via uncoupling, hereby dissipating the mitochondrial proton gradient necessary for adenosine triphosphate (ATP) synthesis. Although some studies support a role for UCP3 in energy metabolism, other studies pointed towards a function in fatty acid metabolism. Thus, the protein is up regulated or high when fatty acid supply to the mitochondria exceeds the capacity to oxidize fatty acids and down regulated or low when oxidative capacity is high or improved. Irrespective of the exact operating mechanism, UCP3 seems to protect mitochondria against lipid-induced oxidative stress, which makes this protein a potential player in the development of type 2 diabetes mellitus. Next to skeletal muscle, UCP3 is also expressed in cardiac muscle where its role is relatively unexplored. Interestingly, energy deficiency in cardiac muscle is associated to heart failure and UCP3 might contribute to this energy deficiency. It has been suggested that UCP3 decreases energy status via uncoupling of mitochondrial respiration, but the available data does not provide a unified answer. In fact, the results obtained regarding cardiac UCP3 are very similar as in skeletal muscle, implying that its physiological function can be extrapolated. Therefore, cardiac UCP3 can just as well serve to protect the heart against lipid-induced oxidative stress, similar to the function described for skeletal muscle UCP3. The present review will deal with the available literature on both skeletal muscle- and cardiac UCP3 to elucidate its physiological function in these tissues.
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PMID:Mitochondrial uncoupling protein 3 and its role in cardiac- and skeletal muscle metabolism. 1819 Nov 61