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)

Excessive hepatic glucose production is a contributing factor to fasting hyperglycemia in diabetes. Insulin suppresses hepatic glucose production by inhibiting the expression of two gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase). The forkhead transcription factor Foxo1 has been implicated as a mediator of insulin action in regulating hepatic gluconeogenesis, and a Foxo1 mutant (Foxo1-Delta256), devoid of its carboxyl domain, has been shown to interfere with Foxo1 function and inhibit gluconeogenic gene expression in cultured cells. To study the effect of Foxo1-Delta256 on glucose metabolism in animals, the Foxo1-Delta256 cDNA was delivered to the livers of mice by adenovirus-mediated gene transfer. Hepatic Foxo1-Delta256 production resulted in inhibition of gluconeogenic activity, as evidenced by reduced PEPCK and G-6-Pase expression in the liver. Mice treated with the Foxo1-Delta256 vector exhibited significantly reduced blood glucose levels. In contrast, blood glucose levels in control vector-treated animals remained unchanged, which coincided with the lack of alterations in the expression levels of PEPCK and G-6-Pase. When tested in diabetic db/db mice, hepatic production of Foxo1-Delta256 was shown to reduce fasting hyperglycemia. Furthermore, we showed that hepatic Foxo1 expression was deregulated as a result of insulin resistance in diabetic mice and that Foxo1-Delta256 interfered with Foxo1 function via competitive binding to target promoters. These results demonstrated that functional inhibition of Foxo1, caused by hepatic expression of its mutant, is associated with reduced hepatic gluconeogenic activity and improved fasting glycemia in diabetic mice.
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PMID:Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. 1278 75

Brown adipose tissue (BAT) glyceroneogenesis was evaluated in rats either fasted for 48 h or with streptozotocin-diabetes induced 3 days previously or adapted for 20 days to a high-protein, carbohydrate-free (HP) diet, conditions in which BAT glucose utilization is reduced. The three treatments induced an increase in BAT glyceroneogenic activity, evidenced by increased rates of incorporation of [1-14C]pyruvate into triacylglycerol (TAG)-glycerol in vitro and a marked, threefold increase in the activity of BAT phosphoenolpyruvate carboxykinase (PEPCK). BAT glycerokinase activity was not significantly affected by fasting or diabetes. After unilateral BAT denervation of rats fed either the HP or a balanced diet, glyceroneogenesis activity increased in denervated pads, evidenced by increased rates of nonglucose carbon incorporation into TAG-glycerol in vivo (difference between 3H2O and [14C]glucose incorporations) and of [1-14C]pyruvate in vitro. PEPCK activity was not significantly affected by denervation. The data suggest that BAT glyceroneogenesis is not under sympathetic control but is sensitive to hormonal/metabolic factors. In situations of reduced glucose use there is an increase in BAT glyceroneogenesis that may compensate the decreased generation of glycerol-3-phosphate from the hexose.
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PMID:Control of glyceroneogenic activity in rat brown adipose tissue. 1279 97

Insulin rapidly and completely inhibits expression of the hepatic insulin-like growth factor binding protein-1 (IGFBP-1), phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) genes. This inhibition is mediated through a phosphatidyl inositol 3-kinase-dependent regulation of a DNA element, termed the thymine-rich insulin response element, found within the promoters of each of these genes. This has led to the conclusion that these three promoters are regulated by insulin using the same molecular mechanism. However, we recently found that the regulation of the IGFBP1 but not the PEPCK or G6Pase genes by insulin was sensitive to rapamycin, an inhibitor of mTOR. Here, we present further evidence that different regulatory pathways mediate the insulin regulation of these promoters. Importantly, we identify a protein phosphatase activity in the pathway connecting mTOR to the IGFBP-1 promoter. These data have major implications for the development of molecular therapeutics for the treatment of insulin-resistant states such as diabetes and hypertension.
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PMID:Different mechanisms are used by insulin to repress three genes that contain a homologous thymine-rich insulin response element. 1291 28

To assess the role of insulin receptor (IR) substrate (IRS)-2 in insulin action and resistance in the liver, immortalized neonatal hepatocyte cell lines have been generated from IRS-2(-/-), IRS-2(+/-), and wild-type mice. These cells maintained the expression of the differentiated liver markers albumin and carbamoyl phosphate synthetase, as well as bear a high number of IRs. The lack of IRS-2 did not result in enhanced IRS-1 tyrosine phosphorylation or IRS-1-associated phosphatidylinositol (PI) 3-kinase activity on insulin stimulation. Total insulin-induced PI 3-kinase activity was decreased by 50% in IRS-2(-/-) hepatocytes, but the translocation of PI-3,4,5-trisphosphate to the plasma membrane in these cells was almost completely abolished. Downstream PI 3-kinase, activation of Akt, glycogen synthase kinase (GSK)-3 (alpha and beta isoforms), Foxo1, and atypical protein kinase C were blunted in insulin-stimulated IRS-2(-/-) cells. Reconstitution of IRS-2(-/-) hepatocytes with adenoviral IRS-2 restored activation of these pathways, demonstrating that IRS-2 is essential for functional insulin signaling in hepatocytes. Insulin induced a marked glycogen synthase activity in wild-type and heterozygous primary hepatocytes; interestingly, this response was absent in IRS-2(-/-) cells but was rescued by infection with adenoviral IRS-2. Regarding gluconeogenesis, the induction of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase by dibutyryl cAMP and dexamethasone was observed in primary hepatocytes of all genotypes. However, insulin was not able to suppress gluconeogenic gene expression in primary hepatocytes lacking IRS-2, but when IRS-2 signaling was reconstituted, these cells recovered this response to insulin. Suppression of gluconeogenic gene expression in IRS-2-deficient primary hepatocytes was also restored by infection with dominant negative Delta 256Foxo1.
Diabetes 2003 Sep
PMID:Molecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes. 1294 62

We studied in rats the expression of genes involved in gluconeogenesis from glutamine and glycerol in the small intestine (SI) during fasting and diabetes. From Northern blot and enzymatic studies, we report that only phosphoenolpyruvate carboxykinase (PEPCK) activity is induced at 24 h of fasting, whereas glucose-6-phosphatase (G-6-Pase) activity is induced only from 48 h. Both genes then plateau, whereas glutaminase and glycerokinase strikingly rebound between 48 and 72 h. The two latter genes are fully expressed in streptozotocin-diabetic rats. From arteriovenous balance and isotopic techniques, we show that the SI does not release glucose at 24 h of fasting and that SI gluconeogenesis contributes to 35% of total glucose production in 72-h-fasted rats. The new findings are that 1) the SI can quantitatively account for up to one-third of glucose production in prolonged fasting; 2) the induction of PEPCK is not sufficient by itself to trigger SI gluconeogenesis; 3) G-6-Pase likely plays a crucial role in this process; and 4) glutaminase and glycerokinase may play a key potentiating role in the latest times of fasting and in diabetes.
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PMID:Induction of control genes in intestinal gluconeogenesis is sequential during fasting and maximal in diabetes. 1455 23

Glyceroneogenesis is the synthesis of 3-glycerol phosphate by an abbreviated version of gluconeogenesis. The research that led to the discovery of glyceroneogenesis in white adipose tissue is presented. This pathway is active during fasting in white and brown adipose tissue and in the liver as part of the triglyceride/fatty acid cycle. Glyceroneogenesis is critical for the extensive recycling of free fatty acid (FFA) back to triglyceride that occurs in mammals, including humans, after lipolysis, when up to 65% of the fatty acids are re-esterified back to triglyceride. The rate-limiting enzyme in this pathway is the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (4.1.1.32) (PEPCK-C). Transcription of this gene is induced in adipose tissue and liver during fasting. Ablation of expression of the gene for PEPCK-C in white adipose tissue of mice results in lipodsytrophy, while overexpression of the gene for this enzyme in adipose tissue causes obesity. The critical role of glyceroneogenesis in diabetes was suggested by experiments in which the gene for PEPCK-C is induced in white adipose tissue by rosiglitazone, a drug used to control diabetes in humans. This was accompanied by a marked decrease in FFA release from adipose tissue due to an induction in glyceroneogenesis in the tissue. Since the chronic release of FFA by adipose tissue is a critical factor in the development Type 2 diabetes, it is likely that rosiglitazone acts in part by stimulating transcription of the gene for PEPCK-C, thereby increasing rate of glyceroneogenesis and lowering the rate of FFA release from adipose tissue.
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PMID:Glyceroneogenesis revisited. 1473 71

Primary aldosteronism is associated with glucose intolerance and diabetes, which is due in part to impaired insulin release caused by reduction of potassium, although other possibilities remain to be elucidated. To evaluate the in vivo effects of aldosterone on glucose metabolism, a single dose of aldosterone was administered to mice, which resulted in elevation of the blood glucose level. In primary cultured mouse hepatocytes, the gene expression of gluconeogenic enzymes such as glucose-6-phosphatase (G6Pase), fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase increased in response to aldosterone in a dose-dependent manner even at a concentration similar to a physiological condition (10(-9) M). The inhibitory effect of insulin on G6Pase gene expression was partially suppressed by aldosterone. Furthermore, aldosterone enhanced G6Pase promoter activity in human hepatoma cell line HepG2, which was prevented by co-treatment with a glucocorticoid antagonist RU-486, but not a mineralocorticoid antagonist spironolactone. In contrast, aldosterone had no effects on major insulin signaling pathways including insulin receptor substrate-1, protein kinase B, and forkhead transcription factor. These results suggest that aldosterone may affect the inhibitory effect of insulin on hepatic gluconeogenesis through the glucocorticoid receptor, which may be one of the causes of impaired glucose metabolism in primary aldosteronism.
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PMID:Aldosterone stimulates gene expression of hepatic gluconeogenic enzymes through the glucocorticoid receptor in a manner independent of the protein kinase B cascade. 1511 77

Resistin is an adipocyte-secreted protein that circulates at increased levels in obesity. Acute administration of resistin impairs glucose tolerance, but the effects of chronic hyperresistinemia have not been established. Here we describe the generation and characterization of transgenic mice that have high circulating levels of resistin in the setting of normal weight. Fasted blood glucose was higher in resistin-transgenic mice than in their nontransgenic littermates, and glucose tolerance was impaired in the hyperresistinemic mice. Metabolic studies in the setting of a hyperinsulinemic-euglycemic clamp protocol revealed that chronically hyperresistinemic mice have elevated glucose production. This increase in glucose production may be partly explained by increased expression of hepatic phosphoenolpyruvate carboxykinase. Thus, chronic hyperresistinemia impairs normal glucose metabolism.
Diabetes 2004 Aug
PMID:Abnormal glucose homeostasis due to chronic hyperresistinemia. 1518 75

We examined the effects of subchronic exposure to malathion, an organophosphorous (OP) insecticide, on plasma glucose and hepatic enzymes of glycogenolysis and gluconeogenesis in rats in vivo. Malathion was administered orally at doses of 100, 200 and 400 ppm for 4 weeks. At the end of the specified treatment (18 h fasting after the last dose of malathion), the liver was removed. The activities of glycogen phosphorylase (GP) and phosphoenolpyruvate carboxykinase (PEPCK) were analyzed in the homogenate. Four weeks administration of malathion at doses of 100 ppm, 200 ppm, and 400 ppm increased plasma glucose concentrations by 25% (P < 0.01), 17% (P < 0.01), and 14% (P < 0.01) of control, respectively. Malathion also increased hepatic PEPCK activity by 25% (100 ppm, P < 0.01), 16% (200 ppm, P < 0.01), and 21% (400 ppm, P < 0.01) of control, respectively. In addition, malathion increased hepatic GP by 22% (100 ppm, P < 0.01), 41% (200 ppm, P < 0.01), and 32% (400 ppm, P < 0.01) of controls. We conclude that exposure of rats to malathion as a widely used OP in subchronic exposure, which resembles human exposure, may induce diabetes associated with stimulation of hepatic gluconeogenesis and glycogenolysis in favor of glucose release into the blood. The possible mechanisms including increased energy production to detoxification, depressed paraoxonase activity, and increased production of cyclic nucleotides are discussed.
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PMID:Hyperglycemia associated with increased hepatic glycogen phosphorylase and phosphoenolpyruvate carboxykinase in rats following subchronic exposure to malathion. 1522 52

We have shown that physical exercise enhances insulin sensitivity of skeletal muscle in diabetes-prone Psammomys-obesus. In this study, we examined the effect of physical exercise on the liver of these animals. Three groups of animals were exposed to a 4-week protocol; high-energy diet (CH), high-energy diet and exercising (EH), and low-energy diet (CL). Different groups were studied either in a fed state or after an overnight fast, 30 minutes after intraperitoneal (IP) injection of 1 U insulin. Hepatic phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) activity was measured. Insulin signaling response was examined after insulin injection in the fast state by analyzing tyrosine phosphorylation of insulin receptor (IR) and the association between insulin receptor substrate-1 (IRS-1) and IRS-2 with phosphatidylinositol 3 kinase (PI3-K). After 4 weeks, none of the EH animals became diabetic, whereas all the CH animals became diabetic. PEPCK activity in the fed state was higher in the CH group compared with the CL and EH groups (480 +/- 28 nmol/min/mg protein, 280 +/- 30 nmol/min/mg protein, and 208 +/- 13 nmol/min/mg protein, respectively) (P < .02). G6Pase activity was higher in the CH and EH groups compared with the CL group (261 +/- 54 nmol/min/mg protein, 251 +/- 34 nmol/min/mg protein, and 75 +/- 32 nmol/min/mg protein, respectively) (P < .01). After insulin administration in the fast state, tyrosine phosphorylation of IR and association of IRS-2 with PI3-K were higher in the EH and CL groups than in the CH group. We conclude that exercise improves in vivo hepatic insulin sensitivity in diabetes-prone Psammomys-obesus.
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PMID:Physical exercise enhances hepatic insulin signaling and inhibits phosphoenolpyruvate carboxykinase activity in diabetes-prone Psammomys obesus. 1525 73


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