Hypoglycaemic effect of metformin in genetically obese (fa/fa) rats results from an increased utilization of blood glucose by intestine.
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ABSTRACT:
SUBMITTER: Penicaud L
PROVIDER: S-EPMC1133356 | biostudies-other | 1989 Sep
REPOSITORIES: biostudies-other
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Project description:1. The glucose metabolism of conscious lean and obese rats of the Zucker strain was studied by using doubly labelled glucose ([6-3H,U-14C]glucose) given by intravenous injection as a single dose. Fed animals were used, allowing the study to be made in conditions favouring active lipogenesis. 2. At any given prior food intake (consumption during preceding 24 h), the irreversible glucose replacement rate, R0, was considerably higher in the growing obese rat (4-6 months old) when both of these variables were scaled in terms of the total body water of the animals. 3. When scaled in a similar way, the minimal mass of glucose (Mmin.) was also larger in the obese rats. The mean transit time, t, through the pool did not differ significantly between the two groups, but there was a tendency for this to be shorter in obese rats. 4. There was no difference in the proportion of 14C (derived from metabolized labelled glucose) that recycled as [14C]-glucose after passing through the pyruvate pool in the two groups of rats if the rate of recycling of radioactivity (Rc) was expressed as a percentage of R0.
| S-EPMC1161515 | biostudies-other
Project description:Increased hepatic glucose production has been reported to occur in the insulin-resistant genetically obese fa/fa rats. The possible existence of an increased basal gluconeogenesis in obese rats was investigated, upon comparing the metabolic fate of glycerol and alanine in liver of fed anaesthetized lean and genetically obese (fa/fa) rats. Glycerol turnover rate in obese animals was 3 times that of the lean. This increase in glycerol turnover rate was associated with an increase in blood glycerol levels in obese animals. The contribution of glycerol to glucose production was significantly increased in obese animals. In contrast, the contribution of alanine to the hepatic glucose production was similar to lean and obese animals. A higher incorporation of glucose, glycerol and alanine into hepatic lipids was observed in obese animals than in controls. It is concluded that in fed genetically obese (fa/fa) rats the high blood glycerol concentrations is a major driving force for the increased basal hepatic conversion of this substrate into glucose.
| S-EPMC1131804 | biostudies-other
Project description:The obese (ob) gene has recently been isolated through a positional cloning approach, the mutation of which causes a marked hereditary obesity and diabetes mellitus in mice. In the present study, we isolated rat ob cDNA and examined the tissue distribution of the ob gene expression in rats. We also studied the gene expression in genetically obese Zucker fatty (fa/fa) rats. The rat ob gene product, a 167 amino acid protein with a putative signal sequence, was 96 and 83% homologous to the mouse and human ob proteins, respectively. Northern blot analysis using the rat ob cDNA probe identified a single mRNA species of 4.5 kb in size in the adipose tissue, while no significant amount of ob mRNA was present in other tissues in rats. The ob gene was expressed in the adipose tissue with region specificities. The rank order of the ob mRNA level in the adipose tissue was epididymal, retroperitoneal, and pericardial white adipose tissue > mesenteric and subcutaneous white adipose tissue > or = interscapular brown adipose tissue. The ob gene expression occurred in mature adipocytes rather than in stromalvascular cells isolated from the rat adipose tissue. Expression of the ob gene was markedly augmented in all the adipose tissue examined in Zucker fatty (fa/fa) rats at the stage of established obesity. The present study leads to the better understanding of the physiologic and pathophysiologic roles of the ob gene.
| S-EPMC185791 | biostudies-other
Project description:Glucokinase (EC 2.7.1.2) activity of B-cells was measured in extracted pancreatic islets isolated from lean and obese fa/fa Zucker rats and maintained in primary culture overnight. Formation of [14C]glucose phosphoric esters from D-[U-14C]glucose was measured in the presence of unlabelled glucose from 0.05 to 0.50 mM for hexokinase (EC 2.7.1.1) activity, and 8.0-16.0 mM unlabelled glucose for glucokinase activity. Eadie-Hofstee analysis revealed that hexokinase kinetic parameters (Vmax and Km) for [14C]glucose phosphoric ester formation were similar in lean- and fa/fa-rat islets. For glucokinase, there was no difference in Vmax. between phenotypes. A non-significant tendency to increased sensitivity to glucose was noted in the fa/fa-rat islets (P = 0.13). In lean-rat islets, the glucokinase inhibitor mannoheptulose (3 mM) decreased Vmax. by 80% and increased the apparent Km from 3.3 +/- 0.7 mM to 12.2 +/- 2.0 mM (P < 0.05). There was no difference in Km or Vmax. in mannoheptulose-treated versus control islets from fa/fa rats. This lack of effect was consistent with reported effects of mannoheptulose on insulin secretion from fa/fa-rat islets [Chan, MacPhail and Mitton (1993) Can. J. Physiol. Pharmacol. 71, 34-39]. The data from glucose and mannoheptulose experiments support the hypothesis that glucokinase function is altered in fa/fa Zucker rats and may contribute to fasting hyperinsulinaemia in vivo in these animals.
| S-EPMC1134612 | biostudies-other
Project description:The use of rapamycin to extend lifespan and delay age-related disease in mice is well-established despite its potential to impair glucose metabolism which is driven partially due to increased hepatic gluconeogenesis. We tested whether a combination therapeutic approach using rapamycin and metformin could diminish some of the known metabolic defects caused by rapamycin treatment in mice. In genetically heterogeneous HET3 mice, we found that chronic administration of encapsulated rapamycin by diet caused a measurable defect in glucose metabolism in both male and female mice as early as 1 month after treatment. In female mice, this defect was alleviated over time by simultaneous treatment with metformin, also by diet, such that females treated with both drugs where indistinguishable from control mice during glucose tolerance tests. While rapamycin-mediated glucose intolerance was unaffected by metformin in males, we found metformin prevented rapamycin-mediated reduction in insulin and leptin concentrations following 9 months of co-treatment. Recently, the Interventions Testing Program showed that mice treated with metformin and rapamycin live at least as long as those treated with rapamycin alone. Together, our data provide compelling evidence that the pro-longevity effects of rapamycin can be uncoupled from its detrimental effects on metabolism through combined therapeutic approaches.
| S-EPMC5892694 | biostudies-literature
Project description:To investigate the effects of the somatostatin analogue, octreotide, on maltose and sucrase activities and expression of glucose transporter type 2 (GLUT2) in obese rat intestinal mucosa.We divided 49 Sprague-Dawley rats into a group of 31 high fat diet-induced obese rats and a group of 18 normal controls. The obese rats were separated into an octreotide treated group of 16 rats and an obese group of 15. The intervention group was injected with octreotide at 40 ?g/kg body weight every 12 h for 8 d. Rat body weight was measured weekly to calculate Lee's index. After euthanization, maltase and sucrase activities in the small intestine were measured by activity assays, and the fasting plasma glucose level was measured. The expression of GLUT2 in small intestinal mucosa was analyzed by immunohistochemistry, reverse transcriptase polymerase chain reaction and Western blotting assays.Body weight, Lee's index, fasting plasma glucose level, maltase activity in small intestinal mucosa, mucosa and apical GLUT2, GLUT2 mRNA and protein expression levels were all significantly higher in the obese group than in the normal control group (605.61 ± 141.00 vs 378.54 ± 111.75, 337.61 ± 10.82 vs 318.73 ± 20.10, 8.60 ± 1.38 vs 7.33 ± 0.70, 156.01 ± 58.81 vs 50.43 ± 30.49, 390 744.2 ± 62 469.21 vs 170 546.50 ± 50 646.14, 26 740.18 ± 3809.60 vs 354.98 ± 57.19, 0.26 ± 0.11 vs 0.07 ± 0.02, and 2.08 ± 0.59 vs 1.27 ± 0.38, respectively, all P < 0.01). Sucrase activity did not differ between the two groups. Octreotide intervention significantly decreased the body weight and fasting plasma glucose level of obese rats (508.27 ± 94.39 vs 605.61 ± 141.00, 7.58 ± 1.51 vs 8.60 ±1.38, respectively, all P < 0.05). The intestinal mucosa and apical GLUT2, expression of GLUT2 mRNA and protein were also significantly lower in the octreotide intervention group than in the obese group (269 975.2 ± 53 730.94 vs 390 744.2 ± 62 469.21, 3758.06 ±364.51 vs 26 740.18 ± 3809.60, 0.08 ± 0.02 vs 0.26 ±0.11, and 1.31 ± 0.27 vs 2.08 ± 0.59, respectively, all P < 0.01).High fat diet-induced obesity is associated with elevated intestinal maltase activity, GLUT2 expression, and permanent apical GLUT2 in the small intestinal mucosa of rats. Octreotide can inhibit these effects.
| S-EPMC3218159 | biostudies-literature
Project description:Analysis of the gene signature of steatosis associated to obesity in hepatocytes of Zucker fa/fa obese rats and their controls; identifying target genes linked to steatosis progression. or Obesity and insulin resistance-associated steatosis can be a non-inflammatory condition affecting hepatocytes or progress to steatohepatitis: a condition that can result in end-stage liver disease. Although molecular events leading to accumulation of lipid droplets in the liver have been identified individually, the complexity of the condition suggested that emergent target would be uncovered by a more comprehensive examination. Then, this study was aimed at establishing a gene signature of steatosis in hepatocytes and at identifying target genes linked to steatosis progression. Using Affymetrix oligonucleotide arrays, we compared transcriptomes of hepatocytes isolated from Zucker "fa/fa" obese rats with three different age-related grades of steatosis with those of their counterpart non-steatotic cells.
2008-07-31 | E-MEXP-1414 | biostudies-arrayexpress
Project description:Negative interactions with healthcare providers may lead patients to switch physicians or "doctor shop." We hypothesized that overweight and obese patients would be more likely to doctor shop, and as a result, have increased rates of emergency department (ED) visits and hospitalizations as compared to normal weight nonshoppers.We combined claims data from a health plan in one state with information from beneficiaries' health risk assessments. The primary outcome was "doctor shopping," which we defined as having outpatient claims with ?5 different primary care physicians (PCPs) during a 24-month period. The independent variable was standard NIH categories of weight by BMI. We performed multivariate logistic regression to evaluate the association between weight categories and doctor shopping. We conducted multivariate zero-inflated negative binominal regression to evaluate the association between weight-doctor shopping categories with counts of ED visits and hospitalizations.Of the 20,726 beneficiaries, the mean BMI was 26.3 kg m(-2) (SD 5.1), mean age was 44.4 years (SD 11.1) and 53% were female. As compared to normal weight beneficiaries, overweight beneficiaries had 23% greater adjusted odds of doctor shopping (OR 1.23, 95%CI 1.04-1.46) and obese beneficiaries had 52% greater adjusted odds of doctor shopping (OR 1.52, 95%CI 1.26-1.82). As compared to normal weight non-shoppers, overweight and obese shoppers had higher rates of ED visits (IRR 1.85, 95%CI 1.37-2.45; IRR 1.83, 95%CI 1.34-2.50, respectively), which persisted during within weight group comparisons (Overweight IRR 1.50, 95%CI 1.10-2.03; Obese IRR 1.54, 95%CI 1.12-2.11).Frequently changing PCPs may impair continuity and result in increased healthcare utilization.
| S-EPMC3742565 | biostudies-literature
Project description:The farnesoid X receptor (FXR) is a bile acid activated nuclear receptor. Zucker (fa/fa) rats, harboring a loss of function mutation of the leptin receptor, develop diabetes, insulin resistance, obesity, and liver steatosis. In this study, we investigated the effect of FXR activation by 6-ethyl-chenodeoxycholic acid, (6E-CDCA, 10 mg/kg) on insulin resistance and liver and muscle lipid metabolism in fa/fa rats and compared its activity with rosiglitazone (10 mg/kg) alone or in combination with 6E-CDCA (5 mg/kg each). In comparison to lean (fa/+), fa/fa rats on a normal diet developed insulin resistance and liver steatosis. FXR activation protected against body weight gain and liver and muscle fat deposition and reversed insulin resistance as assessed by insulin responsive substrate-1 phosphorylation on serine 312 in liver and muscles. Activation of FXR reduced liver expression of genes involved in fatty acid synthesis, lipogenesis, and gluconeogenesis. In the muscles, FXR treatment reduced free fatty acid synthesis. Rosiglitazone reduced blood insulin, glucose, triglyceride, free fatty acid, and cholesterol plasma levels but promoted body weight gain (20%) and liver fat deposition. FXR activation reduced high density lipoprotein plasma levels. In summary, FXR administration reversed insulin resistance and correct lipid metabolism abnormalities in an obesity animal model.
| S-EPMC2842143 | biostudies-literature
Project description:Proteins from different fish species and different raw materials such as fish fillets and by-products have shown promising cardioprotective effects in rodents and humans, including effects on cholesterol metabolism. Blue whiting is used mainly to produce fish meal for the feed industry and during this production, a water-soluble protein fraction, containing small peptides that are easily absorbed and may hold bioactive properties, is isolated. The effects of water-soluble fish protein on cholesterol metabolism were investigated in twelve male obese Zucker fa/fa rats. Rats were fed diets with water-soluble protein from blue whiting (BWW) as 1/3 of the total protein and the remaining 2/3 as casein (BWW group) or with casein as the sole protein source (control group). After 5 weeks intervention, the BWW group had lower serum total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol concentrations and lower cholesteryl ester concentration compared to controls. Hepatic concentrations of cholesterol, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and LDL receptors were also lower in the BWW group. The groups had a similar concentration of serum total bile acids and similar fecal excretions of cholesterol and bile acids. To conclude, the BWW diet led to lower concentrations of serum and liver cholesterol in obese Zucker fa/fa rats, probably due to lower hepatic cholesterol synthesis.
| S-EPMC5983280 | biostudies-literature