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)

A coordinated functional genomics program was implemented to identify secreted polypeptides with therapeutic applications in the treatment of diabetes. Secreted factors were predicted from a diverse expressed-sequence tags (EST) database, representing >1,000 cDNA libraries, using a combination of bioinformatic algorithms. Subsequently, approximately 8,000 human proteins were screened in high-throughput cell-based assays designed to monitor key physiological transitions known to be centrally involved in the physiology of type 2 diabetes. Bone morphogenetic protein-9 (BMP-9) gave a positive response in two independent assays: reducing phosphoenolpyruvate carboxykinase (PEPCK) expression in hepatocytes and activating Akt kinase in differentiated myotubes. Purified recombinant BMP-9 potently inhibited hepatic glucose production and activated expression of key enzymes of lipid metabolism. In freely fed diabetic mice, a single subcutaneous injection of BMP-9 reduced glycemia to near-normal levels, with maximal reduction observed 30 hours after treatment. BMP-9 represents the first hepatic factor shown to regulate blood glucose concentration. Using a combination of bioinformatic and high-throughput functional analyses, we have identified a factor that may be exploited for the treatment of diabetes.
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PMID:An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis. 1261 May 67

Thiazolidinediones are used to treat type 2 diabetes mellitus because they decrease plasma glucose, insulin, triglyceride, and fatty acid levels. Thiazolidinediones are agonists for peroxisome proliferator-activated receptor gamma, a nuclear receptor that is highly expressed in fat tissue. We identify glyceroneogenesis as a target of thiazolidinediones in cultured adipocytes and fat tissues of Wistar rats. The activation of glyceroneogenesis by thiazolidinediones occurs mainly in visceral fat, the same fat depot that is specifically implicated in the progression of obesity to type 2 diabetes. The increase in glyceroneogenesis is a result of the induction of its key enzyme, phosphoenolpyruvate carboxykinase, whose gene expression is peroxisome proliferator-activated receptor gamma-dependent in adipocytes. The main role of this metabolic pathway is to allow the re-esterification of fatty acids via a futile cycle in adipocytes, thus lowering fatty acid release into the plasma. The importance of such a fatty acid re-esterification process in the control of lipid homeostasis is highlighted by the existence of a second thiazolidinedione-induced pathway involving glycerol kinase. We show that glyceroneogenesis accounts for at least 75% of the whole thiazolidinedione effect. Because elevated plasma fatty acids promote insulin resistance, these results suggest that the glyceroneogenesis-dependent fatty acid-lowering effect of thiazolidinediones could be an essential aspect of the antidiabetic action of these drugs.
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PMID:Thiazolidinediones block fatty acid release by inducing glyceroneogenesis in fat cells. 1264 61

The regulation of hepatic gluconeogenesis is an important process in the adjustment of the blood glucose level, and pathological changes in the glucose production of the liver are a central characteristic in type 2 diabetes. The pharmacological intervention in signaling events that regulate the expression of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and the catalytic subunit glucose-6-phosphatase (G-6-Pase) is regarded as a potential strategy for the treatment of metabolic aberrations associated with this disease. However, such intervention requires a detailed understanding of the molecular mechanisms involved in the regulation of this process. Glucagon and glucocorticoids are known to increase hepatic gluconeogenesis by inducing the expression of PEPCK and G-6-Pase. The coactivator protein PGC-1 has been identified as an important mediator of this regulation. In contrast, insulin is known to suppress both PEPCK and G-6-Pase gene expression by the activation of PI 3-kinase. However, PI 3-kinase-independent pathways can also lead to the inhibition of gluconeogenic enzymes. This review focuses on signaling mechanisms and nuclear events that transduce the regulation of gluconeogenic enzymes.
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PMID:Novel concepts in insulin regulation of hepatic gluconeogenesis. 1295 35

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) has been proposed as a new target for type 2 diabetes drugs. The aim of the present study was to assess the effects of inhibition of 11 beta-HSD1 on blood glucose levels, glucose tolerance, and insulin sensitivity in mouse models of type 2 diabetes. BVT.2733 is an isoform-selective inhibitor of mouse 11 beta-HSD1. Hyperglycemic and hyperinsulinemic ob/ob, db/db, KKAy, and normal C57BL/6J mice were orally administered BVT.2733 (200 mg/kg.d, twice daily). In hyperglycemic, but not in normal mice, BVT.2733 lowered circulating glucose (to 50-88% of control) and insulin (52-65%) levels. In oral glucose tolerance tests in ob/ob and KKAy mice, glucose concentrations were 65-75% of vehicle values after BVT.2733 treatment, and in KKAy mice insulin concentrations were decreased (62-74%). Euglycemic, hyperinsulinemic clamps demonstrated decreased endogenous glucose production (21-61%). Analysis of hepatic mRNA in KKAy mice showed reduced phosphoenolpyruvate carboxykinase mRNA (71%). A slight reduction in food intake was observed in ob/ob and KKAy mice. Cholesterol, triglycerides, and free fatty acid levels were decreased to 81-86% in KKAy mice after a 4-h fast. The results support previous suggestions that selective 11 beta-HSD1 inhibitors lower blood glucose levels and improve insulin sensitivity in different mouse models of type 2 diabetes.
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PMID:Selective inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains. 1296 99

Recent studies brought adipocyte glyceroneogenesis back to the fore as an important pathway in fatty acid homeostasis and underlined the key role played by cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) in this pathway. The present review analyses the mechanisms by which a series of hormones and nutrients affect PEPCK-C gene transcription and glyceroneogenesis and describes evidence for disregulation of this pathway in type 2 diabetes.
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PMID:Regulation of glyceroneogenesis and phosphoenolpyruvate carboxykinase by fatty acids, retinoic acids and thiazolidinediones: potential relevance to type 2 diabetes. 1473 73

Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) is the key enzyme in glyceroneogenesis, an important metabolic pathway in adipocytes for reesterification of fatty acids during fasting. Dysregulation of glyceroneogenesis could play a role in the increase in plasma non-esterified fatty acids that accompanies type 2 diabetes. In rodent adipocyte transcription of the PEPCK-C gene is induced by thiazolidinediones (TZDs) through an element, named PCK2, in its promoter. PCK2 binds a peroxisome proliferator activated receptor gamma (PPARgamma), retinoid X receptor alpha (RXRalpha) heterodimer. We demonstrated that in cultured human subcutaneous adipose tissue explants, PEPCK-C specific activity and mRNA were induced by 1 microM of the TZD rosiglitazone, respectively, about twofold in 8 h and fivefold in 5 h. Using gel shift experiments, we show that this effect is likely to involve the human PCK2 (hPCK2) element, which binds a protein complex that contains PPARgamma and RXRalpha. We analyzed hPCK2 (position -1031 to -1015 base pairs) and nearby sequences in the PEPCK-C promoter in 403 subjects with type 2 diabetes and 123 non-diabetic controls. The sequence of hPCK2 was not polymorphic, but we detected two C/T single nucleotide polymorphisms (SNPs), in complete linkage disequilibrium, at positions -1097 and -967 bp. Allele and genotype frequencies were not significantly different in patients and controls. However, our results suggest co-dominant effects of C and T-alleles on fasting plasma glucose and glycosylated hemoglobin A1c levels in obese type 2 diabetic patients.
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PMID:Expression of phosphoenolpyruvate carboxykinase gene in human adipose tissue: induction by rosiglitazone and genetic analyses of the adipocyte-specific region of the promoter in type 2 diabetes. 1473 78

We sequenced the promoter and coding regions of PCK1 encoding cytosolic phosphoenolpyruvate carboxykinase from genomic DNA of subjects with type 2 diabetes mellitus (DM). We found nine single nucleotide polymorphisms (SNPs) that were present with varying allele frequencies and pairwise linkage disequilibrium relationships in different ethnic groups. The -232C-->G promoter SNP was within a cis-acting element required for basal and cAMP-mediated PCK1 gene transcription. The expression of a luciferase reporter construct containing -232G in three different cell lines showed significantly increased basal expression with no down-regulation by insulin compared with a construct containing -232C. The odds ratios for type 2 DM among subjects with one or two copies of -232G compared with -232C/C homozygotes were 1.9 (95% confidence interval, 1.2-3.0) in a Canadian aboriginal sample and 2.8 (95% confidence interval, 1.7-4.7) in a Caucasian sample. Thus, we report a promoter SNP in PCK1 that was resistant to down-regulation by insulin in vitro and was associated with type 2 DM in two independent study samples.
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PMID:Promoter polymorphism in PCK1 (phosphoenolpyruvate carboxykinase gene) associated with type 2 diabetes mellitus. 1476 11

We have previously reported that infection with Plasmodium yoelii, Plasmodium chabaudi, or injection of extracts from malaria-parasitized red blood cells induces hypoglycemia in normal mice and normalizes the hyperglycemia in streptozotocin (STZ)-diabetic mice. P yoelii glycosylphosphatidylinositols (GPIs) were extracted in chloroform:methanol:water (CMW) (10:10:3), purified by high-performance thin layer chromatography (HPTLC) and tested for their insulin-mimetic activities. The effects of P yoelii GPIs on blood glucose were investigated in insulin-resistant C57BL/ks-db/db diabetic mice. A single intravenous injection of GPIs (9 and 30 nmol/mouse) induced a significant dose-related decrease in blood glucose (P < .001), but insignificantly increased plasma insulin concentrations. A single oral dose of 2.7 micromol GPIs per db/db mouse significantly lowered blood glucose (P < .01). P yoelii GPIs in vitro (0.062 to 1 micromol/L) significantly stimulated lipogenesis in rat adipocytes in a dose-dependent manner both in the presence and absence of 10(-8) mol/L insulin (P < .01). P yoelii GPIs stimulated pyruvate dehydrogenase phosphatase (PDH-Pase) and inhibited both cyclic adenosine monophosphate (cAMP)-dependent protein kinase A and glucose-6-phosphatase (G6Pase). P yoelii GPIs had no effect on the activity of the gluconeogenic enzymes fructose-1,6-bisphosphatase (FBPase) and phosphoenolpyruvate carboxykinase (PEPCK). This is the first report of the hypoglycemic effect of P yoelii GPIs in murine models of type 2 diabetes. In conclusion, P yoelii GPIs demonstrated acute antidiabetic effects in db/db mice and in vitro. We suggest that P yoelii GPIs, when fully characterized, may provide structural information for the synthesis of new drugs for the management of diabetes.
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PMID:Improvement of glucose homeostasis in obese diabetic db/db mice given Plasmodium yoelii glycosylphosphatidylinositols. 1528 Oct 17

Dietary antioxidant compounds such as bioflavonoids may offer some protection against the early stage of diabetes mellitus and the development of complications. We investigated the effect of citrus bioflavonoids on blood glucose level, hepatic glucose-regulating enzymes activities, hepatic glycogen concentration, and plasma insulin levels, and assessed the relations between plasma leptin and body weight, blood glucose, and plasma insulin. Male C57BL/KsJ-db/db mice (db/db mice, 5 wk old), an animal model for type 2 diabetes, were fed a nonpurified diet for 2 wk and then were fed an AIN-76 control diet or the control diet supplemented with hesperidin (0.2 g/kg diet) or naringin (0.2 g/kg diet). Hesperidin and naringin supplementation significantly reduced blood glucose compared with the control group. Hepatic glucokinase activity and glycogen concentration were both significantly elevated in the hesperidin- and the naringin-supplemented groups compared with the control group. Naringin also markedly lowered the activity of hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase compared with the control group. Plasma insulin, C-peptide, and leptin levels in the db/db mice from the 2 bioflavonoid-supplemented groups were significantly higher than those of the control group. Furthermore, plasma leptin was positively correlated with plasma insulin level (r = 0.578, P < 0.01) and body weight (r = 0.541, P < 0.05), and was inversely correlated with the blood glucose level (r = -0.46, P < 0.05). The current results suggest that hesperidin and naringin both play important roles in preventing the progression of hyperglycemia, partly by increasing hepatic glycolysis and glycogen concentration and/or by lowering hepatic gluconeogenesis.
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PMID:The hypoglycemic effects of hesperidin and naringin are partly mediated by hepatic glucose-regulating enzymes in C57BL/KsJ-db/db mice. 1546 37

Chronic hypoxia, viral infections/bacterial toxins, inflammation states, biochemical disorders, and genetic abnormalities are the most likely trigger of sudden infant death syndrome (SIDS). Autopsy studies have shown increased pulmonary density of macrophages and markedly more eosinophils in the lungs accompanied by increased T and B lymphocytes. The elevated levels of immunoglobulins, about 20% more muscle in the pulmonary arteries, increased airway smooth muscle cells, and increased fetal hemoglobin and erythropoietin are evidence of chronic hypoxia before death. Other abnormal findings included mucosal immune stimulation of the tracheal wall, duodenal mucosa, and palatine tonsils, and circulating interferon. Low normal or higher blood levels of cortisol often with petechiae on intrathoracic organs, depleted maternal IgG antibodies to endotoxin core (EndoCAb) and early IgM EndoCAb triggered, partial deletions of the C4 gene, and frequent IL-10-592*A polymorphism in SIDS victims as well as possible hypoxia-induced decreased production of antiinflammatory, antiimmune, and antifibrotic cytokine IL-10, may be responsible for the excessive reactions to otherwise harmless infections. In SIDS infants, during chronic hypoxia and times of infection/inflammation, several proinflammatory cytokines are released in large quantities, sometimes also representing a potential source of tissue damage if their production is not sufficiently well controlled, eg, by pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP). These proinflammatory cytokines down-regulate gene expression of major cytochrome P-450 and/or other enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity, thus affecting metabolism of several endogenous lipophilic substances, such as steroids, lipid-soluble vitamins, prostaglandins, leukotrienes, thromboxanes, and exogenous substances. In SIDS victims, chronic hypoxia, TNF-alpha and other inflammatory cytokines, and arachidonic acid (AA) as well as n-3 polyunsaturated fatty acids (FA), stimulated and/or augmented superoxide generation by polymorphonuclear leukocytes, which contributed to tissue damage. Chronic hypoxia, increased amounts of nonheme iron in the liver and adrenals of these infants, enhanced activity of CYP2C9 regarded as the functional source of reactive oxygen species (ROS) in some endothelial cells, and nicotine accumulation in tissues also intensified production of ROS. These increased quantities of proinflammatory cytokines, ROS, AA, and nitric oxide (NO) also resulted in suppression of many CYP450 and other enzymes, eg, phosphoenolpyruvate carboxykinase (PEPCK), an enzyme important in the metabolism of FA during gluconeogenesis and glyceroneogenesis. PEPCK deficit found in SIDS infants (caused also by vitamin A deficiency) and eventually enhanced by PACAP lipolysis of adipocyte triglycerides resulted in an increased FA level in blood because of their impaired reesterification to triacylglycerol in adipocytes. In turn, the overproduction and release of FA into the blood of SIDS victims could lead to the metabolic syndrome and an early phase of type 2 diabetes. This is probably the reason for the secondary overexpression of the hepatic CYP2C8/9 content and activity reported in SIDS infants, which intensified AA metabolism. Pulmonary edema and petechial hemorrhages often present in SIDS victims may be the result of the vascular leak syndrome caused by IL-2 and IFN-alpha. Chronic hypoxia with the release of proinflammatory mediators IL-1alpha, IL-1beta and IL-6, and overloading of the cardiovascular and respiratory systems due to the narrowing airways and small pulmonary arteries of these children could also contribute to the development of these abnormalities. Moreover, chronic hypoxia of SIDS infants induced also production of hypoxia-inducible factor 1alpha (HIF-1alpha), which stimulated synthesis and release of different growth factors by vascular endothelial cells and intensified subclinical inflammatory reactions in the central nervous system, perhaps potentiated also by PACAP and VIP gene mutations. These processes could lead to the development of brainstem gliosis and disorders in the release of neuromediators important for physiologic sleep regulation. All these changes as well as eventual PACAP abnormalities could result in disturbed homeostatic control of the cardiovascular and respiratory responses of SIDS victims, which, combined with the nicotine effects and metabolic trauma, finally lead to death in these often genetically predisposed children.
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PMID:Possible pathomechanisms of sudden infant death syndrome: key role of chronic hypoxia, infection/inflammation states, cytokine irregularities, and metabolic trauma in genetically predisposed infants. 1554 94


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