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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Low birth weight in humans is predictive of insulin resistance and diabetes in adult life. The molecular mechanisms underlying this link are unknown but fetal exposure to excess glucocorticoids has been implicated. The fetus is normally protected from the higher maternal levels of glucocorticoids by feto-placental 11beta-hydroxysteroid dehydrogenase type-2 (11beta-HSD2) which inactivates glucocorticoids. We have shown previously that inhibiting 11beta-HSD2 throughout pregnancy in rats reduces birth weight and causes hyperglycemia in the adult offspring. We now show that dexamethasone (a poor substrate for 11beta-HSD2) administered to pregnant rats selectively in the last week of pregnancy reduces birth weight by 10% (P < 0.05), and produces adult fasting hyperglycemia (treated 5.3+/-0.3; control 4.3+/-0.2 mmol/ liter, P = 0.04), reactive hyperglycemia (treated 8.7+/-0.4; control 7.5+/-0.2 mmol/liter, P = 0.03), and hyperinsulinemia (treated 6.1+/-0.4; control 3.8+/-0.5 ng/ml, P = 0.01) on oral glucose loading. In the adult offspring of rats exposed to dexamethasone in late pregnancy, hepatic expression of glucocorticoid receptor (GR) mRNA and phosphoenolpyruvate carboxykinase (PEPCK) mRNA (and activity) are increased by 25% (P = 0.01) and 60% (P < 0.01), respectively, while other liver enzymes (glucose-6-phosphatase, glucokinase, and 11beta-hydroxysteroid dehydrogenase type-1) are unaltered. In contrast dexamethasone, when given in the first or second week of gestation, has no effect on offspring insulin/glucose responses or hepatic PEPCK and GR expression. The increased hepatic GR expression may be crucial, since rats exposed to dexamethasone in utero showed potentiated glucose responses to exogenous corticosterone. These observations suggest that excessive glucocorticoid exposure late in pregnancy predisposes the offspring to glucose intolerance in adulthood. Programmed hepatic PEPCK overexpression, perhaps mediated by increased GR, may promote this process by increasing gluconeogenesis.
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PMID:Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. 959 73

Microsomes prepared from three rat tissues were examined for their ability to import glucose-6-phosphate (G-6-P). Microsomes from liver, which possess a high level of glucose-6-phosphatase activity, were compared with those from cerebral cortex and cardiac muscle, which are not involved in the export of glucose and in which glucose-6-phosphatase activity is relatively low. In all three, a selective permeability to G-6-P was detected by light scattering. However, the sugar-phosphate specificity of the transport process differed. G-6-P was able to enhance ATP-dependent Ca2+ sequestration in all three types of microsomes. In addition, enzymatic detection of G-6-P after the rapid filtration of microsomes determined that, in the absence of Ca2+ and ATP, a level of intramicrosomal G-6-P approaching a passive equilibrium with the extramicrosomal G-6-P concentration was rapidly achieved in all three tissues. However, under conditions in which Ca2+ was being actively accumulated, the intramicrosomal levels of G-6-P exceeded the equilibrium value by three- to fourfold. This enhanced sequestration was not observed in the presence of Ca2+ or ATP alone or in the presence of a Ca2+ ionophore or an inhibitor of the microsomal Ca2+ ATPase. These data are consistent with a selective import pathway into the endoplasmic/sarcoplasmic reticulum for G-6-P independent of glucose-6-phosphatase activity. In addition, they suggest an alternate explanation for the enhanced sequestration of Ca2+ by the endoplasmic/sarcoplasmic reticulum of intact cells seen when extracellular glucose is increased.
Diabetes 1998 Jun
PMID:Glucose-6-phosphate and Ca2+ sequestration are mutually enhanced in microsomes from liver, brain, and heart. 960 62

The mRNA and the activity of glucose-6-phosphatase (Glc-6-Pase) were present in the liver, kidney, and small intestine of 15-day-old suckling rats, but were absent from the stomach, colon, lung, white and brown adipose tissues, muscle, heart, brain, and spleen. The mRNA encoding Glc-6-Pase was present in the liver of 21-day-old fetal rats and increased markedly immediately after birth. From 5 days after birth to the end of the suckling period, it returned to 50% of the level found in the liver of 48-h starved adult rats. When rats were weaned at 21 days onto a high-carbohydrate, low-fat (HCLF) diet, the concentration of liver Glc-6-Pase mRNA was markedly increased. In the fetal rat jejunum, the activity and mRNA of Glc-6-Pase were very low. It increased during the 5 days after birth and then declined to reach very low levels. Neither mRNA nor activity of Glc-6-Pase was present in the fetal kidney. They appeared and increased slowly during the suckling period to reach maximal levels 15 days after birth and then remained constant. Weaning onto the HCLF diet did not change the Glc-6-Pase gene expression, neither in the jejunum nor in the kidney. The regulation of Glc-6-Pase gene expression by hormones and nutrients was studied in cultured hepatocytes from 20-day-old rat fetuses. Bt2cAMP stimulated the Glc-6-Pase gene expression in a dose-dependent manner. This probably resulted from an increased gene transcription since the half-life of the transcript was not affected by dibutyryl cAMP (Bt2cAMP). The Bt2cAMP-induced Glc-6-Pase mRNA accumulation was antagonized by insulin in a dose-dependent manner. Long-chain fatty acids (LCFAs), but not medium-chain fatty acids, induced the accumulation of Glc-6-Pase mRNA and the stabilization of the transcript. The peroxisome proliferator, clofibrate, induced a threefold increase in Glc-6-Pase mRNA concentration. Both stimulation of Glc-6-Pase mRNA by LCFAs and clofibrate were inhibited by insulin. Increasing concentrations of glucose (from 0 to 20 mmol/l) did not affect the Bt2cAMP-induced Glc-6-Pase gene expression. By contrast, high glucose concentration (25 mmol/l) markedly induced the Glc-6-Pase gene expression in fed adult rat hepatocytes. The difference in the response to glucose between fetal and adult rat hepatocytes is discussed. We conclude that the rapid increase in hepatic Glc-6-Pase mRNA levels that accompanies the fetal-to-neonatal transition in the rat is triggered by the reciprocal change in circulating insulin and LCFA concentrations, coupled to the rise in liver cAMP concentration.
Diabetes 1998 Jun
PMID:Development and regulation of glucose-6-phosphatase gene expression in rat liver, intestine, and kidney: in vivo and in vitro studies in cultured fetal hepatocytes. 960 63

Glucose-6-phosphatase catalyzes the terminal step in the gluconeogenic and glycogenolytic pathways. Transcription of the gene encoding the glucose-6-phosphatase catalytic subunit (G6Pase) is stimulated by cAMP and glucocorticoids whereas insulin strongly inhibits both this induction and basal G6Pase gene transcription. Previously, we have demonstrated that the maximum repression of basal G6Pase gene transcription by insulin requires two distinct promoter regions, designated A (from -271 to -199) and B (from -198 to -159). Region B contains an insulin response sequence because it can confer an inhibitory effect of insulin on the expression of a heterologous fusion gene. By contrast, region A fails to mediate an insulin response in a heterologous context, and the mutation of region B within an otherwise intact promoter almost completely abolishes the effect of insulin on basal G6Pase gene transcription. Therefore, region A is acting as an accessory element to enhance the effect of insulin, mediated through region B, on G6Pase gene transcription. Such an arrangement is a common feature of cAMP and glucocorticoid-regulated genes but has not been previously described for insulin. A combination of fusion gene and protein-binding analyses revealed that the accessory factor binding region A is hepatocyte nuclear factor-1. Thus, despite the usually antagonistic effects of cAMP/glucocorticoids and insulin, all three agents are able to use the same factor to enhance their action on gene transcription. The potential role of G6Pase overexpression in the pathophysiology of MODY3 and 5, rare forms of diabetes caused by hepatocyte nuclear factor-1 mutations, is discussed.
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PMID:Hepatocyte nuclear factor-1 acts as an accessory factor to enhance the inhibitory action of insulin on mouse glucose-6-phosphatase gene transcription. 968 59

The activity of glucose-6-phosphatase (G-6-Pase) in isolated rat microsomes was inhibited by a new selective inhibitor of the multi-subunit G-6-Pase system, 1-[2-(4-chloro-phenyl)-cyclopropylmethoxy]-3,4-dihydroxy-5-(3-imid azo[4,5-b]pyridin-1-yl-3-phenyl-acryloyloxy)-cyclohexanecarboxylic acid (compound A) with a 50% inhibitory concentration (IC50) of approximately 10 nmol/l. Compound A (500 nmol/l) inhibited the uptake of [14C]glucose-6-phosphate (G-6-P) into intact isolated rat microsomes, confirming that this agent blocks G-6-P translocation, as suggested by previous studies using intact and permeabilized microsomes. The inhibition of microsomal G-6-P transport by compound A was associated with inhibition of the rate of glucose output from rat hepatocytes incubated in the presence of 25 nmol/l glucagon (IC50 approximately 320 nmol/l.) Compound A (1 micromol/l) also inhibited the basal rate of glucose production by rat hepatocytes by 47%. Intraperitoneal administration of compound A to fasted mice lowered circulating plasma glucose concentrations dose-dependently at doses as low as 1 mg/kg. This effect was comparatively short-lived; glucose lowering was maximal at 30 min after dosing with 100 mg/kg compound A (-71%) and declined thereafter, being reversed within 3 h. A similar time course of glycemic response was observed in fasted rats; glucose lowering was maximal 30 min after dosing with 100 mg/kg compound A (-36%) and declined until the effect was fully reversed by 3 h postdose. In rats subjected to compound A treatment, liver glycogen content was increased. G-6-P and lactate levels were maximally elevated 30 min after dosing and declined thereafter. Cumulatively, these results suggest that the mechanism of glucose lowering by compound A was via inhibition of G-6-Pase activity, mediated through inhibition of the T1 subunit of the microsomal G-6-Pase enzyme system. Drug levels measured over the same time course as that used to assess in vivo efficacy peaked within 30 min of administration, then declined, which is consistent with the transient changes in plasma glucose and liver metabolites.
Diabetes 1998 Oct
PMID:Plasma glucose levels are reduced in rats and mice treated with an inhibitor of glucose-6-phosphate translocase. 975 3

The terminal step in hepatic gluconeogenesis is catalyzed by glucose-6-phosphatase, an enzyme activity residing in the endoplasmic reticulum and consisting of a catalytic subunit (glucose-6-phosphatase (G6Pase)) and putative accessory transport proteins. We show that Zucker diabetic fatty rats (fa/fa), which are known to exhibit impaired suppression of hepatic glucose output, have 2.4-fold more glucose-6-phosphatase activity in liver than lean controls. To define the potential contribution of increased hepatic G6Pase to development of diabetes, we infused recombinant adenoviruses containing the G6Pase cDNA (AdCMV-G6Pase) or the beta-galactosidase gene into normal rats. Animals were studied by one of three protocols as follows: protocol 1, fed ad libitum for 7 days; protocol 2, fed ad libitum for 5 days, fasted overnight, and subjected to an oral glucose tolerance test; protocol 3, fed ad libitum for 4 days, fasted for 48 h, subjected to oral glucose tolerance test, and then allowed to refeed overnight. Hepatic glucose-6-phosphatase enzymatic activity was increased by 1.6-3-fold in microsomes isolated from AdCMV-G6Pase-treated animals in all three protocols, and the resultant metabolic profile was similar in each case. AdCMV-G6Pase-treated animals exhibited several of the abnormalities associated with early stage non-insulin-dependent diabetes mellitus, including glucose intolerance, hyperinsulinemia, decreased hepatic glycogen content, and increased peripheral (muscle) triglyceride stores. These animals also exhibited significant decreases in circulating free fatty acids and triglycerides, changes not normally associated with the disease. Our studies show that overexpression of G6Pase in liver is sufficient to perturb whole animal glucose and lipid homeostasis, possibly contributing to the development of metabolic abnormalities associated with diabetes.
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PMID:Perturbation of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats. 981 78

The effects of the adipocyte-derived hormone leptin on glucose metabolism in hepatocytes were investigated. Incubation of hepatocytes from Wistar rats with leptin for 16 h caused a dose-dependent increase in incorporation of [14C]glucose into glycogen, with a maximal effect at 30 nmol/l leptin. This effect of leptin was observed over a range of glucose concentrations (10-25 mmol/l) and was associated with stimulation of net glycogen deposition. It was not counteracted by mercaptopicolinate, an inhibitor of phosphoenolpyruvate carboxykinase, indicating that it is not due to increased gluconeogenic flux. Leptin also enhanced the short-term stimulation of glycogen synthesis by insulin. These effects of leptin were associated with inhibition of phosphorylase a, which occurred after 4 h of exposure to leptin. Culture with leptin for 16 h did not affect the activities of glucose-6-phosphatase or glucokinase or the activation state of glycogen synthase. Leptin did not affect glycolysis determined from the detritiation of [3-(3)H]glucose. The inhibitory effects of leptin on phosphorylase a were counteracted by short-term incubation with glucagon but were additive with the inhibitory effects of insulin and also with the inhibition caused by resorcinol (25 pmol/l), which inhibits phosphorylase kinase by a mechanism analogous to the antidiabetic drug proglycosyn. These results show that leptin has additive effects with insulin in inhibiting phosphorylase and stimulating glycogen storage in hepatocytes, indicating that these hormones act by separate but convergent mechanisms. It is concluded that the primary action of leptin in hepatocytes is to enhance glycogen storage. This may be an important compensatory mechanism for the inhibition of insulin secretion.
Diabetes 1999 Jan
PMID:Leptin enhances glycogen storage in hepatocytes by inhibition of phosphorylase and exerts an additive effect with insulin. 989 17

We directly examined whether visceral fat (VF) modulates hepatic insulin action by randomizing moderately obese (body wt approximately 400 g) Sprague-Dawley rats to either surgical removal of epididymal and perinephric fat pads (VF-; n = 9) or a sham operation (VF+; n = 11). Three weeks later, total VF was fourfold increased (8.5 +/- 1.2 vs. 2.1 +/- 0.3 g, P < 0.001) in the VF+ compared with the VF- group, but whole-body fat mass (determined using 3H2O) was not significantly different. The rates of insulin infusion required to maintain plasma glucose levels and basal hepatic glucose production in the presence of hepatic-pancreatic clamp were markedly decreased in VF- compared with VF+ rats (0.57 +/- 0.02 vs. 1.22 +/- 0.19 mU x kg(-1) x min(-1), P < 0.001). Similarly, plasma insulin levels were more than twofold higher in the VF+ group (P < 0.001). The heightened hepatic insulin sensitivity is supported by the decrease in gene expression of both glucose-6-phosphatase and PEPCK and by physiological hyperinsulinemia in VF- but not VF+ rats. The improvement in hepatic insulin sensitivity in VF- rats was also supported by a approximately 70% decrease in the plasma levels of insulin-like growth factor binding protein-1, a marker of insulin's transcription regulation in the liver. The removal of VF pads also resulted in marked decreases in the gene expression of tumor necrosis factor-alpha (by 72%) and leptin (by 60%) in subcutaneous fat. We conclude that visceral fat is a potent modulator of insulin action on hepatic glucose production and gene expression.
Diabetes 1999 Jan
PMID:Surgical removal of visceral fat reverses hepatic insulin resistance. 989 27

The transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) is enriched in liver and adipose tissue and controls the expression of a wide variety of genes coding for important metabolic pathways, including gluconeogenesis and lipid synthesis. To investigate the role of C/EBPbeta on glucose homeostasis, we studied mice with a targeted deletion of the gene for C/EBPbeta-/- mice. Adult C/EBPbeta-/- mice have hypoglycemia after an 18-hour fast, accompanied by lower hepatic glucose production (40% of that of wild-type mice), with no change in plasma insulin and a lower concentration of plasma free fatty acids (FFA). Glucagon infusion during a pancreatic clamp acutely stimulated hepatic glucose production by 38% in wild-type animals, with no change detected in C/EBPbeta-/- mice. Unexpectedly, both the basal and glucagon-stimulated hepatic cyclic adenosine monophosphate (cAMP) levels were lower in C/EBPbeta-/- mice, indicating an essential role for C/EBPbeta in controlling proximal signal transduction. Fasting hypoglycemia was associated with normal levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene expression, however net liver glycogenolysis was impaired in C/EBPbeta-/- mice. FFA release from isolated adipose tissue in response to epinephrine was 68% lower in C/EBPbeta-/- mice than in control animals; however, N6,O2'-dibutyryladenosine (Bt2) cAMP stimulated a twofold increase in FFA release in C/EBPbeta-/- compared with no further increase in wild-type mice. Because a deletion in the gene for C/EBPbeta reduces blood glucose and circulating FFA, it could be an important therapeutic target for the treatment of non-insulin-dependent diabetes and possibly obesity, based on designing antagonists that decrease C/EBPbeta activity.
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PMID:Hypoglycemia and impaired hepatic glucose production in mice with a deletion of the C/EBPbeta gene. 991 32

A pancreatic islet-specific glucose-6-phosphatase-related protein (IGRP) was cloned using a subtractive cDNA expression cloning procedure from mouse insulinoma tissue. Two alternatively spliced variants that differed by the presence or absence of a 118-bp exon (exon IV) were detected in normal balb/c mice, diabetic ob/ob mice, and insulinoma tissue. The longer, 1901-bp full-length cDNA encoded a 355-amino acid protein (molecular weight 40,684) structurally related (50% overall identity) to the liver glucose-6-phosphatase and exhibited similar predicted transmembrane topology, conservation of catalytically important residues, and the presence of an endoplasmic reticulum retention signal. The shorter transcript encoded two possible open reading frames (ORFs), neither of which possessed His174, a residue thought to be the phosphoryl acceptor (Pan CJ, Lei KJ, Annabi B, Hemrika W, Chou JY: Transmembrane topology of glucose-6-phosphatase. J Biol Chem 273:6144-6148, 1998). Northern blot and reverse transcription-polymerase chain reaction analysis showed that the mRNA was highly expressed in pancreatic islets and expressed more in beta-cell lines than in an alpha-cell line. It was notably absent in tissues and cell lines of non-islet neuroendocrine origin, and no other major tissue source of the mRNA was found. During development, it was expressed in parallel with insulin mRNA. The mRNA was efficiently translated and glycosylated in an in vitro translation/membrane translocation system and readily transcribed into COS 1, HIT, and CHO cells using cytomegalovirus or Rous sarcoma virus promoters. Whereas the liver glucose-6-phosphatase showed activity in these transfection systems, the IGRP failed to show glucose phosphotransferase or phosphatase activity with p-nitrophenol phosphate, inorganic pyrophosphate, or a range of sugar phosphates hydrolyzed by the liver enzyme. While the metabolic function of the enzyme is not resolved, its remarkable tissue-specific expression warrants further investigation, as does its transcriptional regulation in conditions where glucose responsiveness of the pancreatic islet is altered.
Diabetes 1999 Mar
PMID:Molecular cloning of a pancreatic islet-specific glucose-6-phosphatase catalytic subunit-related protein. 1007 53


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