Decreased hepatic glycogen content and accelerated response to starvation in rats with carbon tetrachloride-induced cirrhosis

Effect of chromium supplementation and copper status on glucose and lipid metabolism in Angus and Simmental beef cows

Chromium propionate in turkeys: effects on insulin sensitivity

Progressive decrease in tissue glycogen content in rats with long-term cholestasis

Liver and skeletal muscle glycogen metabolism were investigated in rats 1 and 4 weeks after bile duct ligation (BDL) and in pair–fed, sham– operated control rats. Livers were subjected to morphometric analysis to express glycogen content and enzyme activities per mL hepatocytes. One week after BDL, the hepatic glycogen content was 28.8 ± 13.8 versus 38.6 ± 16.4 mg/mL hepatocyte in BDL and control rats, respectively. Total activity of glycogen synthase (50.2 ± 7.0 vs. 63.5 ± 9.4 mU/mL hepatocytes) and glycogen phosphorylase (59.4 ± 12.9 vs. 90.8 ± 18.9 U/mL) were significantly reduced in BDL whereas the active fraction of glycogen synthase (27 ± 6 vs. 38 ± 5%) but not of glycogen phosphorylase was reduced. The skeletal muscle glycogen content was not different between BDL and control rats. Four weeks after BDL, hepatic glycogen content was further reduced (20.5 ± 14.2 vs. 52.9 ± 6.4 mg/mL). Total activity of glycogen synthase (38.8 ± 12.1 vs. 60.1 ± 4.6 mU/mL hepatocytes) and glycogen phosphorylase (127 ± 19 vs. 178 ± 33 U/mL hepatocytes) were both reduced in BDL rats as were their corresponding active fractions (30 ± 18 vs. 66 ± 8% and 58 ± 10 vs. 76 ± 10). At this time point, the glycogen content in soleus muscle was decreased by 64% in BDL. The glucagon plasma concentration was increased in BDL rats at both time points. There were positive correlations between the volume fraction and both hepatic glycogen content and total activity of hepatic glycogen synthase. Plasma glucagon and the active fraction of hepatic glycogen synthase were negatively correlated. The current studies show a progressive decrease in the hepatic and skeletal muscle glycogen content in BDL rats. The observed decrease in the activities of glycogen synthase and phosphorylase suggest that reduced glycogen synthesis is the major mechanism leading to the reduction in the hepatic glycogen content in BDL rats.

A polymorphism in FABP2 that results in an alanine-to-threonine substitution at amino acid 54 of the intestinal fatty acid-binding protein (IFABP) is associated with insulin resistance in Pima Indians. In vitro, the threonine form (Thr54) has a higher binding affinity for long-chain fatty acids than does the alanine form (Ala54). We tested whether this polymorphism affected metabolic responses to dietary fat, in vivo. Eighteen healthy Pima Indians, half homozygous for the Thr54 form of IFABP and half homozygous for the Ala54 form, were studied. The groups were matched for sex, age, and body mass index. Plasma triglyceride, nonesterified fatty acid (NEFA), glucose, and insulin responses were measured after a mixed meal (35% of daily energy requirements, 50 g of fat) and after a high fat challenge (1362 kcal, 129 g of fat). NEFA concentrations were approximately 15% higher after the mixed meal and peaked earlier and were approximately 20% higher at 7 h in response to the high fat test meal in Thr54 homozygotes compared with Ala54 homozygotes. Insulin responses to the test meals tended to be higher in Thr54 homozygotes, but glucose and triglyceride responses were not different.The results of this study suggest that the Thr54 form of IFABP is associated with higher and prolonged NEFA responses to dietary fat in vivo. Higher NEFA concentrations may contribute to insulin resistance and hyperinsulinemia in individuals with this allele.

Glucose 6-phosphate (Glc-6-P) produced in cultured hepatocytes by direct phosphorylation of glucose or by gluconeogenesis from dihydroxyacetone (DHA) was equally effective in activating glycogen synthase (GS). However, glycogen accumulation was higher in hepatocytes incubated with glucose than in those treated with DHA. This difference was attributed to decreased futile cycling through GS and glycogen phosphorylase (GP) in the glucose-treated hepatocytes, owing to the partial inactivation of GP induced by glucose. Our results indicate that the gluconeogenic pathway and the glucokinase-mediated phosphorylation of glucose deliver their common product to the same Glc-6-P pool, which is accessible to liver GS. As observed in the treatment with glucose, incubation of cultured hepatocytes with DHA caused the translocation of GS from a uniform cytoplasmic distribution to the hepatocyte periphery and a similar pattern of glycogen deposition. We hypothesize that Glc-6-P has a major role in glycogen metabolism not only by determining the activation state of GS but also by controlling its subcellular distribution in the hepatocyte.

Short term (48 h) in vivo administration of either T3 or T4 was associated with an increase in hepatic glycogen synthase activity in the rat. Administration of 0.25 mg T3/kg BW 48, 24, and 2 h before enzyme preparation increased the total glycogen synthase activity by approximately 50% and increased the percentage of synthase in the I or active form from 19 +/- 1% to 63 +/- 3%. These effects of thyroid hormones on glycogen synthase were rapid (expressed within 24 h) and dose dependent with respect to T3 or T4. Fasting rats for 24 h increased hepatic glycogen synthase levels in control but not thyroid hormone-treated rats. Total glycogen synthase activity of rats administered thyroid hormone and fasted for 24 h remained 1.4-fold greater than that of their fasted euthyroid controls. The percentage of synthase in the I form was 79 +/- 4% for the fasted T3-treated rats compared to 51 +/- 2% for their fasted euthyroid counterparts. Thus, both total hepatic glycogen synthase activity and the percentage of synthase in the I form are increased by short term administration of thyroid hormones in vivo.

The objective was to evaluate the impact of nutritional changes after artificial insemination (AI) on plasma metabolites, steroid hormones, and uterine histotroph. Beef heifers (n = 50) were randomly assigned to a post-AI dietary treatment (High=161.5% or Low=77.45% of maintenance energy) until uteri were flushed for embryo recovery (d14). Blood samples were collected on d -3, 0 (AI), 3, 6, 9, 12, and 14 for analysis of plasma non-esterified fatty acid (NEFA), total protein (protein), glucose, cholesterol, and progesterone concentrations. Uterine flushes (UF) were analyzed for concentrations of Mg, P, S, K, Ca, Cu, Zn, Se, Mn, Co, B, Cr, and Fe. Plasma NEFA, protein, glucose, cholesterol, and progesterone concentrations were analyzed as repeated measures in SAS (PROC MIXED). Mineral concentrations in UF were analyzed using the MIXED procedures in SAS. Diet influenced plasma NEFA concentrations, with Low heifers having elevated concentrations (P < 0.01); however, diet did not influence plasma protein, glucose, cholesterol, or progesterone concentrations (P > 0.10). Plasma NEFA, glucose, and progesterone concentrations changed over time (P < 0.05), but protein and cholesterol did not differ over time (P > 0.10). Diet by time interactions influenced plasma NEFA, protein, and cholesterol concentrations (P < 0.05), but glucose and progesterone concentrations were not different (P > 0.10). Presence of a recovered embryo by time interaction influenced plasma protein concentrations (P < 0.04), but NEFA, glucose, cholesterol, and progesterone concentrations were not affected by the interaction (P > 0.10). Embryo recovery and diet by embryo recovery by time did not impact plasma NEFA, protein, glucose, cholesterol and progesterone concentrations (P > 0.10). When an embryo was recovered, Mg (P = 0.02) and S (P = 0.02) were decreased in UF. Diet and diet by embryo recovery did not affect UF mineral concentrations (P>0.10). In conclusion, post-AI nutrition influenced plasma NEFA, protein, glucose, cholesterol, and progesterone concentrations. Additionally, uterine histotroph mineral concentrations were affected by presence of an embryo.

L-tryptophan administration promotes the reversion of pre-established chronic liver injury in rats treated with carbon tetrachloride

Although an increased plasma non-esterified fatty acid (NEFA) concentration has been shown to increase insulin resistance (Randle cycle), decrease insulin secretion and increase hepatic gluconeogenesis, the effect of NEFA on the deterioration of glucose tolerance has not been studied prospectively in Caucasian subjects. Therefore, we investigated whether plasma NEFA may be regarded as predictors of deterioration of glucose tolerance in subjects with normal (NGT, n = 3671) or impaired (IGT, n = 418) glucose tolerance who were participants in the Paris Prospective study. The subjects were first examined between 1967 and 1972 and underwent two 75-g oral glucose tolerance tests 2 years apart with measurements of plasma glucose, insulin and NEFA concentrations. Glucose tolerance deteriorated from NGT to IGT or non-insulin-dependent diabetes (NIDDM) in 177 subjects and from IGT to NIDDM in 32 subjects. In multivariate analysis, high fasting plasma NEFA in NGT subjects and high 2-h plasma NEFA and low 2-h plasma insulin concentrations in IGT subjects were significant independent predictors of deterioration along with older age, high fasting and 2-h plasma glucose concentrations and high iliac to thigh ratio. When subjects were divided by tertiles of plasma NEFA concentration at baseline, there was an increase in 2-h glucose concentration with increasing NEFA in the subjects who did not deteriorate, but no effect of plasma NEFA in those who deteriorated. In subjects with IGT who deteriorated compared with those who did not 2-h plasma insulin concentration was lower but there was no evidence that this resulted from an effect of plasma NEFA. Our data suggest that a high plasma NEFA concentration is a risk marker for deterioration of glucose tolerance independent of the insulin resistance or the insulin secretion defect that characterize subjects at risk for NIDDM.

Chromium propionate in broilers: effect on insulin sensitivity

In order to assess the ability of nicotinic acid to decrease plasma glucose concentration, normal individuals were given continuous four hour infusions of either nicotinic acid (NA), somatostatin (SRIF), NA + SRIF, or 0.9% NaCl (Saline). Plasma non-esterified fatty acid (NEFA) concentration decreased to about one-fourth of the basal value in response to either NA or NA + SRIF, associated with statistically significant decreases in plasma glucose concentration. The ability of NA and NA + SRIF to decrease plasma glucose concentration was seen despite the fact that plasma insulin concentrations also fell significantly during both infusions. Although plasma glucose concentration fell significantly in response to both NA and NA + SRIF, the effect of NA + SRIF was approximately twice as great as that seen with NA alone. The augmented hypoglycaemic effect of NA + SRIF as compared to NA alone was associated with a concomitant fall in plasma glucagon concentration. In contrast, plasma glucose concentration did not change following Saline, and was actually higher than baseline after the infusion of SRIF alone. These results provide evidence that NA can lower plasma glucose concentration in normal volunteers, and suggests that this is mediated by the NA-associated decrease in plasma NEFA concentration.

Long-term effects of fluoxetine on glycemic control in obese patients with non-insulin-dependent diabetes mellitus or glucose intolerance: Influence on muscle glycogen synthase and insulin receptor kinase activity

In an attempt to elucidate the role of fat-storing cells (FSCs) in liver fibrosis, we investigated the collagen synthesis by FSCs freshly isolated from rats treated with CCl4, with vitamin A, and from untreated rats. FSCs from CCl4-treated rats contained a small number of lipid droplets and an abundant rough endoplasmic reticulum (RER), while those from vitamin A-treated rats showed numerous large lipid droplets and scanty RER. The population doubling times of FSCs isolated from normal, CCl4-treated, and vitamin A-treated rats were 38 +/- 4.3, 24 +/- 2.5, and 48 +/- 6.3 hr, respectively. The rate of collagen synthesis by FSCs from CCl4-treated rats was four- to sixfold enhanced, while collagen synthesis by FSCs from vitamin A-treated rats was suppressed. The ratio of collagen type I to type III produced by FSCs from CCl4 rats was enhanced as compared with control rats (94.7:5.3 vs 87.6:12.4). Therefore, FSCs can be considered to play an important role in the pathogenesis of liver fibrosis.

Energy metabolism is abnormal in patients and experimental animals with liver cirrhosis. To help better understand the abnormalities, fuel homeostasis and carnitine metabolism were studied in fed and 24-hr-starved rats with secondary biliary cirrhosis induced by bile duct ligation for 4 wk. Plasma ketone body concentrations were decreased by 67% in starved, bile duct-ligated rats compared with control rats. In contrast, plasma nonesterified fatty acid concentrations were not different between bile duct-ligated and control rats in the fed or the fasted state. Plasma triglyceride concentrations showed the expected decrease with starvation in control rats, but were increased with starvation in bile duct-ligated rats. Urinary excretion of dicarboxylic acids was increased in both fed and fasted bile duct ligated-rats compared with the respective control groups. Compared with control rats, hepatic total carnitine content (per gram of liver) was increased by 24% in fed and by 36% in fasted, bile duct-ligated rats. Fed, bile duct-ligated rats had an increased short-chain acylcarnitine-to-carnitine ratio in liver, plasma and urine compared with control rats. Analysis of the hepatic coenzyme A pool showed decreased coenzyme A content in fed and fasted bile duct-ligated rats compared with control rats. Hepatic long-chain acylcarnitine and long-chain acyl-coenzyme A content increased with starvation both in control and bile duct-ligated rats. The rise in plasma nonesterified fatty acid concentration and hepatic long-chain acylcarnitine and long-chain acylcoenzyme A contents with starvation in bile duct-ligated rats are consistent with unaltered hepatic availability of fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)