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)

Leucine performs a signaling role to enhance protein synthesis by phosphorylating eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and 70-kDa ribosomal protein S6 kinase (S6K1), two key regulatory proteins involved in the initiation of mRNA translation. The purpose of the current study was to assess whether the phosphorylation of 4E-BP1 and S6K1 was increased in skeletal muscle and liver by an oral administration of leucine to diabetic rats and to determine the in vivo contribution of insulin to a leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation. Food-deprived (18 h) normal and diabetic rats were orally administered 135 mg/ 100 g body weight L-leucine and sacrificed at 1 h after administration. Leucine administration resulted in enhanced phosphorylation of 4E-BP1 and S6K1 in skeletal muscle and in liver of nondiabetic rats. The stimulatory action of leucine on the phosphorylation of 4E-BP1 and S6K1 in skeletal muscle was not abolished in rats with streptozotocin-induced diabetes. In contrast, leucine administration did not stimulate the phosphorylation of 4E-BP1 and S6K1 in the liver of diabetic rats. These findings suggest that in skeletal muscle, leucine functions as a nutritional signaling molecule that independently regulates the phosphorylation states of 4E-BP1 and S6K1. In contrast to skeletal muscle, insulin is essential in mediating the leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation in liver. leucine, 4E-BP1, S6K1, translation initiation, diabetes
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PMID:Oral administration of leucine stimulates phosphorylation of 4E-bP1 and S6K 1 in skeletal muscle but not in liver of diabetic rats. 1202 90

Ser/Thr phosphorylation of insulin receptor substrate-1 (IRS-1) is a negative regulator of insulin signaling. One potential mechanism for this is that Ser/Thr phosphorylation decreases the ability of IRS-1 to be tyrosine-phosphorylated by the insulin receptor. An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. Ser/Thr phosphorylation of IRS-1 correlates with IRS-1 degradation, yet the details of how this occurs are still unknown. In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. First, we found that inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin block the degradation. Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide-dependent kinase-1, were found to be deficient in the insulin-stimulated degradation of IRS-1. Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. Third, concurrent with the decrease in IRS-1 degradation, the inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin also blocked the insulin-stimulated increase in Ser(312) phosphorylation. Most important, an IRS-1 mutant in which Ser(312) was changed to alanine was found to be resistant to insulin-stimulated IRS-1 degradation. Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser(312) phosphorylation yet completely blocked insulin-stimulated c-Jun phosphorylation. Further, insulin-stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser(312) in response to insulin. In summary, our results indicate that the insulin-stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser(312) phosphorylation of IRS-1.
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PMID:Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. 1251 59

Type 1 diabetic patients depend on insulin replacement therapy. However, chronic hyperglycemia due to failure to maintain proper glycemic control leads to microvascular, macrovascular, and neurological complications. Increased glucose disposal by tissues engineered to overexpress key regulatory genes in glucose transport or phosphorylation can reduce diabetic hyperglycemia. Here we report that differentiated myoblast cells expressing the glucose-phosphorylating enzyme glucokinase (GK) showed a glucose-dependent increase in glucose uptake and utilization in vitro. Transplantation of GK-expressing myotubes into healthy mice did not alter blood glucose levels and recipient mice maintained normoglycemia. After streptozotocin treatment, mice transplanted with GK-expressing myotubes counteracted hyperglycemia, polydipsia, and polyphagia, whereas mice transplanted with control myotubes developed diabetes. Similarly, diabetic mice transplanted with control myotubes remained hyperglycemic. In contrast, transplantation of GK-expressing myotubes into diabetic mice lowered hyperglycemia. These results suggest that the use of genetically engineered muscle cells to express glucokinase may provide a glucose-regulated approach to reduce diabetic hyperglycemia.
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PMID:Glucose-regulated glucose uptake by transplanted muscle cells expressing glucokinase counteracts diabetic hyperglycemia. 1254 44

The aim of the present study was to investigate whether diabetic embryopathy may be associated with the inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) resulting from an excess of reactive oxygen species (ROS) in the embryo. Recent demonstrations of enhanced ROS production in mitochondria of bovine aortic endothelial cells exposed to high glucose have supported the idea that the pathogenesis of diabetic complications may involve ROS-induced GAPDH inhibition. We investigated whether a teratogenic diabetic environment also inhibits embryonic GAPDH activity and alters GAPDH gene expression and whether antioxidants diminish such GAPDH inhibition. In addition, we determined whether the inhibition of GAPDH with iodoacetate induces dysmorphogenesis, analogous to that caused by high glucose concentration, and whether antioxidants modulated the putative teratogenic effect of such direct GAPDH inhibition. We found that embryos from diabetic rats and embryos cultured in high glucose concentrations showed decreased activity of GAPDH (by 40-60%) and severe dysmorphogenesis on gestational days 10.5 and 11.5. GAPDH mRNA was decreased in embryos of diabetic rats compared to control embryos. Supplementing the high-glucose culture with the antioxidant N-acetylcysteine (NAC) increased GAPDH activity and diminished embryonic dysmorphogenesis. Embryos cultured with iodoacetate showed both decreased GAPDH activity and dysmorphogenesis; supplementing the culture with NAC increased both parameters toward normal values. In conclusion, dysmorphogenesis caused by maternal diabetes is correlated with ROS-induced inhibition of GAPDH in embryos, which could indicate that inhibition of GAPDH plays a causal role in diabetic embryopathy.
Diabetes 2003 May
PMID:Maternal diabetes in vivo and high glucose in vitro diminish GAPDH activity in rat embryos. 1271 56

Glucokinase (GCK) is a key regulatory enzyme in the pancreatic beta-cell and catalyzes the rate-limiting step for beta-cell glucose metabolism. We report two novel GCK mutations (T65I and W99R) that have arisen de novo in two families with familial hypoglycemia. Insulin levels, although inappropriately high for the degree of hypoglycemia, remain regulated by fluctuations in glycemia, and pancreatic histology was normal. These mutations are within the recently identified heterotropic allosteric activator site in the theoretical model of human beta-cell glucokinase. Functional analysis of the purified recombinant glutathionyl S-transferase fusion proteins of T65I and W99R GCK revealed that the kinetic changes result in a relative increased activity index (a measure of the enzyme's phosphorylating potential) of 9.81 and 6.36, respectively, compared with wild-type. The predicted thresholds for glucose-stimulated insulin release using mathematical modeling were 3.1 (T65I) and 2.8 (W99R) mmol/l, which were in line with the patients' fasting glucose. In conclusion, we have identified two novel spontaneous GCK-activating mutations whose clinical phenotype clearly differs from mutations in ATP-sensitive K(+) channel genes. In vitro studies confirm the validity of structural and functional models of GCK and the putative allosteric activator site, which is a potential drug target for the treatment of type 2 diabetes.
Diabetes 2003 Sep
PMID:Insights into the biochemical and genetic basis of glucokinase activation from naturally occurring hypoglycemia mutations. 1294 86

The 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism is implicated in extracellular matrix (ECM) synthesis, but its role in podocytes has not been studied. This study tested whether 12-LO induction by diabetes or by high glucose (HG) in cultured podocytes alters glomerular basement membrane by activating signal transduction pathways culminating in ECM synthesis. Sprague-Dawley rats received an injection of diluent (control [C]) or streptozotocin 65 mg/kg (DM) and were killed at 1 or 4 mo. Glomerular 12-LO mRNA and protein levels were higher in DM than in C glomeruli at 1 and 4 mo, and 12-LO localized predominantly in podocytes. Glomerular p38 mRNA and protein were higher in DM at months 1 and 4, but phospho-p38 mitogen-activated protein (MAPK) was increased only at month 1. Glomerular collagen alpha5(IV)/glutaraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA ratio was increased in DM at month 1 but not at month 4, whereas collagen alpha5(IV) protein was higher at both 1 and 4 mo. Mouse podocytes were cultured in media with 25 mM glucose (HG) with or without the 12-LO inhibitor cinnamyl-3,4-dihydroxy-cyanocinnamate (CDC) or with 5.5 mM glucose + 19.5 mM mannitol (low glucose [LG+M]) for 10 d at 37 degrees C. 12-LO mRNA and protein levels were higher in HG than in LG+M as was the p38 MAPK/GAPDH mRNA ratio. Phospho-p38 MAPK protein but not total p38 MAPK was higher in HG compared with LG+M. Collagen alpha5(IV)/GAPDH mRNA ratio and protein were higher in HG than in LG+M. 12-LO inhibition by CDC decreased HG-induced phospho-p38 MAPK and the phospho-p38/total p38 MAPK ratio, collagen alpha5(IV)/GAPDH mRNA ratio, and collagen alpha5(IV) protein expression. In summary, diabetes in vivo and exposure of podocytes to HG in vitro stimulated 12-LO, p38 MAPK, and collagen alpha5(IV) mRNA and (activated) protein. 12-LO inhibition by CDC diminished the expression of podocyte phospho-p38 MAPK and collagen alpha5(IV) mRNA and protein. These findings implicate 12-LO and the p38 MAPK signaling pathway in the mediation of ECM synthesis by podocytes in diabetes.
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PMID:Role of 12-lipoxygenase in the stimulation of p38 mitogen-activated protein kinase and collagen alpha5(IV) in experimental diabetic nephropathy and in glucose-stimulated podocytes. 1463 16

The hormones glucagon and insulin delicately regulate the concentration of blood glucose. When patients become resistant to the effects of insulin or produce too little of it to properly regulate glucose concentrations, then diabetes can result. Unfortunately, not all patients with insulin-resistant, type 2 diabetes mellitus respond to drugs that improve insulin sensitivity. However, there is reason to be hopeful. A new molecule that targets glucokinase (GK), the enzyme responsible for phosphorylating glucose in pancreatic beta cells and hepatic cells, acts to significantly reduce blood glucose concentrations in rodents. The GK activator RO-28-1675 increased the glucose affinity and Vmax of GK, and rats treated with RO-28-1675 had improved glucose tolerance and elevated glucose uptake in liver. These results provide the basis for improved drug design that may alleviate diabetes mellitus and the disorders that accompany it in patients.
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PMID:Two birds with one stone: novel glucokinase activator stimulates glucose-induced pancreatic insulin secretion and augments hepatic glucose metabolism. 1499 57

AMP-activated protein kinase (AMPK) is considered as a cellular energy sensor that regulates glucose and lipid metabolism by phosphorylating key regulatory enzymes. Despite the major role of adipose tissue in regulating energy partitioning in the organism, the role of AMPK in this tissue has not been addressed. In the present study, we subjected AMPKalpha2 knockout (KO) mice to a high-fat diet to examine the effect of AMPK on adipose tissue formation. Compared with the wild type, AMPKalpha2 KO mice exhibited increased body weight and fat mass. The increase in adipose tissue mass was due to the enlargement of the preexisting adipocytes with increased lipid accumulation. However, we did not observe any changes in adipocyte marker expression, such as peroxisome proliferator-activated receptor-gamma, CCAAT/enhancer-binding protein alpha (C/EBPalpha) and adipocyte fatty acid-binding protein (aFABP/aP2), or total cell number. Unlike impaired glucose homeostasis observed on normal diet feeding, when fed a high-fat diet AMPKalpha2 KO mice did not show differences in glucose tolerance and insulin sensitivity compared with wild-type mice. Our results suggest that the increase in lipid storage in adipose tissue in AMPKalpha2 KO mice may have protected these mice from further impairment of glucose homeostasis that normally accompanies high-fat feeding. Our study also demonstrates that lack of AMPKalpha2 subunit may be a factor contributing to the development of obesity.
Diabetes 2004 Sep
PMID:Induced adiposity and adipocyte hypertrophy in mice lacking the AMP-activated protein kinase-alpha2 subunit. 1533 33

In the present study we report results on the possible mechanism of inhibition of tryptophan-5-hydroxylase activity induced by insulin-dependent diabetes mellitus (IDDM). Kinetic experiments were done with different L-tryptophan (L-Trp) concentrations in the rat brain at different days of evolution of the disease. Additionally, different activation conditions of the enzyme were evaluated, to gain information on the mechanism of the activity changes. Diabetes state was induced in normal male rats, by the administration of 75 mg/kg body weight of streptozotocin (STZ). The results showed an increase of the Km value and a decrease in the Vmax in the diabetic's brain as compared to controls. Interestingly, in the diabetic group, the response capacity to phosphorylation is significantly reduced. These shifts in the activity of tryptophan-5-hydroxylase developed during IDDM may not be explained only by a decrease of L-Trp, but also by a possible change in the enzyme itself, reflected in a diminished affinity for the substrate and a decreased response to phosphorylating conditions.
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PMID:Inhibition and kinetic changes of brain tryptophan-5-hydroxylase during insulin-dependent diabetes mellitus in the rat. 1590 68

The glucokinase regulatory protein (GRP) plays a pivotal role in the regulation of metabolic flux in liver by the glucose-phosphorylating enzyme glucokinase. Random peptide phage display library screening for binding partners of GRP allowed the identification of an asparagine-leucine consensus motif. Asparagine-leucine motifs of glucokinase located in the hinge region, as well as in the large domain, were changed by site-directed mutagenesis. The L58R/N204Y and the L309R/N313Y glucokinase mutants showed a significantly reduced interaction with GRP. The L355R/N350Y mutant had a fivefold-higher binding affinity for GRP than wild-type glucokinase. Imaging of glucokinase and GRP fluorescence fusion proteins revealed that the L58R/N204Y glucokinase mutant lacked glucose-dependent translocation by GRP, whereas the L355R/N350Y glucokinase mutant was trapped in the nucleus due to high affinity for GRP. The results indicate that the L58/N204 motif in the hinge region confers binding to GRP, while the L355/N350 motif may modulate the binding affinity for GRP. This latter motif is part of the alpha10 helix of glucokinase and accessible to GRP in the free and complex conformation.
Diabetes 2005 Oct
PMID:Interaction of glucokinase with the liver regulatory protein is conferred by leucine-asparagine motifs of the enzyme. 1618 82


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