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 mechanism of increased hepatic glucose production in obese non-insulin-dependent diabetic (NIDDM) patients is unknown. The New Zealand Obese (NZO) mouse, a polygenic model of obesity and NIDDM shows increased hepatic glucose production. To determine the mechanism of this phenomenon, we measured gluconeogenesis from U-14C-glycerol and U-14C-alanine and relevant gluconeogenic enzymes. Gluconeogenesis from glycerol (0.07 +/- 0.01 vs 0.21 +/- 0.02 micromol.min-1.body mass index (BMI)-1, p < 0.005) and alanine (0.57 +/- 0.07 vs 0.99 +/- 0.07 micromol.min-1.BMI-1, p < 0.005) was elevated in control mice NZO vs as was glycerol turnover (0.25 +/- 0.02 vs 0.63 +/- 0.09 micromol.min-1.BMI-1, p < 0.05). Fructose 1,6-bisphosphatase activity (44.2 +/- 1.9 vs 55.7 +/- 4.1 nmol.min-1.mg protein-1, p < 0.05) and protein levels (6.9 +/- 1.1 vs 16.7 +/- 2.3 arbitrary units, p < 0.01) were increased in NZO mouse livers, as was the activity of pyruvate carboxylase (0.12 +/- 0.01 vs 0.17 +/- 0.02 nmol.min-1.mg protein-1, p < 0.05). To ascertain whether elevated lipid supply is responsible for these biochemical changes in NZO mice, we fed lean control mice a 60% fat diet for 2 weeks. Fat-fed mice were hyperinsulinaemic (76.37 +/- 4.06 vs 98.00 +/- 7.07 pmol/l, p = 0.05) and had elevated plasma non-esterified fatty acid levels (0.44 +/- 0.05 vs 0.59 +/- 0.03 mmol/l, p = 0.05). Fructose 1,6-bisphosphatase activity (43.86 +/- 2.54 vs 52.93 +/- 3.09 nmol.min-1.mg protein-1, p = 0.05) and protein levels (33.03 +/- 0.96 vs 40.04 +/- 1.26 arbitrary units, p = 0.005) and pyruvate carboxylase activity (0.10 +/- 0.003 vs 0.14 +/- 0.01 nmol.min-1.mg protein-1, p < 0.05) were elevated in fat-fed mice. We conclude that in NZO mice increased hepatic glucose production is due to elevated lipolysis resulting from obesity.
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PMID:The biochemical basis of increased hepatic glucose production in a mouse model of type 2 (non-insulin-dependent) diabetes mellitus. 878 11

Fructose 1,6-bisphosphatase (FBPase) has been identified as a drug discovery target for lowering glucose in type 2 diabetes mellitus. In this study, a large series of 105 FBPase inhibitors were studied using a combinational method by 3D-QSAR, molecular docking and molecular dynamics simulations for a further improvement in potency. The optimal 3D models exhibit high statistical significance of the results, especially for the CoMFA results with r(ncv) (2), q(2) values of 0.986, 0.514 for internal validation, and r(pred) (2), r(m) (2) statistics of 0.902, 0.828 statistics for external validation. Graphic representation of the results, as contoured 3D coefficient plots, also provides a clue to the reasonable modification of molecules. (1) Substituents with a proper length and size at the C5 position of the thiazole core are required to enhance the potency; (2) A small and electron-withdrawing group at the C2 position linked to the thiazole core is likely to help increase the FBPase inhibition; (3) Substituent groups as hydrogen bond acceptors at the C2 position of the furan ring are favored. In addition, the agreement between 3D-QSAR, molecular docking and molecular dynamics simulation proves the rationality of the developed models. These results, we hope, may be helpful in designing novel and potential FBPase inhibitors.
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PMID:In silico identification of structure requirement for novel thiazole and oxazole derivatives as potent fructose 1,6-bisphosphatase inhibitors. 2217 57

Fructose 1,6-bisphosphatase (FBPase) has attracted substantial interest as a target associated with cancer and type 2 diabetes. Herein, we found that disulfiram and its derivatives can potently inhibit FBPase by covalently binding to a new C128 allosteric site distinct from the original C128 site in APO FBPase. Further identification of the allosteric inhibition mechanism reveals that the covalent binding of a fragment of 214 will result in the movement of C128 and the dissociation of helix H4 (123-128), which in turn allows S123 to more easily form new hydrogen bonds with K71 and D74 in helix H3 (69-72), thereby inhibiting FBPase activity. Notably, both disulfiram and 212 might moderately reduce blood glucose output in vivo. Therefore, our current findings not only identify a new covalent allosteric site of FBPase but also establish a structural foundation and provide a promising way for the design of covalent allosteric drugs for glucose reduction.
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PMID:Identification of the New Covalent Allosteric Binding Site of Fructose-1,6-bisphosphatase with Disulfiram Derivatives toward Glucose Reduction. 3237 78