Parenteral nutrition with lipid or glucose suppresses liver growth and response to GH in adolescent male rats.

Our aim was to investigate the effects of modifying the carbohydrate-to-lipid ratio of parenteral nutrition (PN) on body composition and the anabolic actions of insulin-like growth factor I (IGF-I) and growth hormone (GH). Adolescent male Sprague-Dawley rats were randomized to receive 7 days of GH, IGF-I (3.5 mg. kg(-1). day(-1) for both) or placebo while receiving high-carbohydrate PN (CHO-PN), high-lipid PN (L-PN), or an oral diet (chow) (the PN protocols were isonitrogenous and isocaloric). PN impaired muscle growth, which was reversed by GH in the CHO-PN group only (P < 0.03). PN increased carcass lipid (P < 0.02), the effect being greater in the L-PN than in the CHO-PN group (P < 0.001). Visceral lean tissue growth was significantly impaired by PN (P < 0.001). IGF-I reversed this impairment, but GH had no effect. PN impaired the normal increase in hepatic protein and DNA (P < 0.001) and produced liver steatosis (P < 0.001). However, this steatosis was less in L-PN than in CHO-PN (P < 0.001). Serum IGF-I and the acid-labile subunit (ALS) were decreased by PN (P < 0.001) and were not affected by GH during PN treatment. However, GH significantly increased serum ALS concentrations in the chow-fed rats (P = 0.032). In conclusion, modifying the CHO-to-L ratio of PN had no significant effect on IGF-I action, but CHO-PN increased the peripheral effect of GH. L-PN increased carcass lipid significantly and decreased hepatic steatosis. Nevertheless, PN caused significant liver steatosis and profound impairment of hepatic cell growth, which was associated with relative hepatic GH resistance.

Effect of a series of novel sulphonylthioureas on glucose tolerance in the obese fa/fa Zucker rat.

1. The recent development of a series of novel KATP channel modulators, namely sulphonylthioureas and sulphonylureas, is thought to make improvements in potency and tissue selectivity compared with current sulphonylureas, such as glibenclamide, which shares a similar structure to the novel compounds. 2. These novel compounds were first examined for their effect on hyperglycaemia and glucose tolerance during an oral glucose tolerance test following 5 days administration in the lean fa/- and obese fa/fa Zucker rat (a model of insulin resistance). Comparisons with present antidiabetic agents, metformin and glibenclamide were performed. 3. Several compounds showed improvements in glucose tolerance compared with control and the primary structural prerequisites for the maintenance of this activity were investigated. Of most interest was compound 3-15 ((N-[(4-methylphenylsulphonyl]-N'-(2-ethoxypyrid-4-yl)thiourea; 0.1 mg/kg per day), which significantly improved glucose tolerance following 5 days administration in the fa/fa Zucker rat. This paralleled the improvement seen in metformin (300 mg/kg per day)-treated fa/fa rats, but compound 3-15 was up to 3000-fold more potent than metformin. 4. Obese fa/fa Zucker rats were then treated with compound 3-15 for 28 days to determine whether glycaemic control could be maintained over the longer term. 5. Compound 3-15 showed a significant improvement in glucose clearance and reduction in insulin concentration following 28 days treatment during an intravenous glucose tolerance test compared with untreated rats, without any change in the rate of weight gain. 6. The novel sulphonylthiourea 3-15 appears to improve glucose clearance during acute and chronic treatment in the fa/fa Zucker rat with no effect on the rate of weight gain. It is thought that compound 3-15 may be eliciting its actions by improving insulin sensitivity, but its effects on insulin secretion are still to be elucidated.

Parenteral amino acid intake alters the anabolic actions of insulin-like growth factor I in rats.

The anabolic properties of insulin-like growth factor (IGF) I are attenuated by oral diets that are low in protein. However, it is not known whether parenteral nutrition (PN) providing a low amino acid (AA) input will influence IGF-I action. With the use of a rat model, this study examined the interaction between AA input (1.27 and 0.62 g N. kg body wt(-1). 24 h(-1), AA and 1/2AA groups, respectively) and recombinant human IGF-I (rhIGF-I, 2.5 mg. kg body wt(-1). 24 h(-1)) infusion on the composition of the carcass and organs and on plasma insulin, IGF-I, IGF-binding protein 1 (IGFBP-1), and acid-labile subunit (ALS) concentrations. Carcass protein deposition only occurred in the AA groups (P < 0.003) and was not influenced by administration of rhIGF-I. However, visceral protein loss persisted in the AA group but was prevented by rhIGF-I infusion. The changes in water content of the carcass and the organs were generally in the expected proportion of normal lean tissue. The accumulation of lipid that follows the infusion of the AA-deficient PN was prevented by rhIGF-I infusion, which may indicate an improved energy utilization. Neither serum insulin nor ALS concentrations were influenced by the level of AA infusion but were reduced by rhIGF-I administration. However, plasma IGF-I levels were elevated by higher AA infusion and by IGF-I administration. Also, IGFBP-1 concentrations were reduced by the higher AA infusion and increased with rhIGF-I administration. Interestingly, there was a significant interaction effect between both of these influences. It is concluded that free IGF-I concentration, which may be regulated by IGFBP-1 through a direct effect of AAs on the liver, may have an important role in regulating anabolism in visceral and possibly skeletal tissue during PN.

Epidural analgesia reduces the release of amino acids from peripheral tissues in the ebb phase of the metabolic response to major upper abdominal surgery.

The purpose of this prospective cohort study was to compare metabolic effects of epidural or patient controlled analgesia (PCA) in patients undergoing major upper abdominal surgery. Seventeen patients undergoing major upper abdominal surgery were included: 10 received perioperative epidural analgesia (Group I) and the remainder received morphine via a PCA device for postoperative analgesia (Group II). A number of measures compared between one day preoperatively (day 1) and day 2 postoperatively included femoral arterial and venous blood concentrations of glucose, lactate, pyruvate and amino acids. In addition, the relevant flux values were measured from the products of the respective arteriovenous substrate concentration differences and calf blood flow. The efflux of lactate from peripheral tissues was greater in Group II than in Group I (P < 0.01): glucose and pyruvate efflux did not differ between groups. There was no difference between groups in mean individual and total flux of amino acids on day-1. However increased efflux between day-1 and day 2 was found for alanine, valine, isoleucine, leucine, phenylalanine, lysine, arginine in both groups, and for serine, glycine, tyrosine and histidine in Group II (P < 0.05). The efflux of glycine, methionine, amino benzoic acid, alanine, and lysine was less in Group I than Group II on day 2 (P < 0.05). There was a significant difference in the total amino acid flux on day 2 (Group I = -1.2 mumol. (100 ml tissue)-1.min-1 cf Group II = -2.5 mumol. (100 ml tissue)-1.min-1; P = 0.04). In conclusion, perioperative epidural analgesia was associated with a reduced postoperative amino acid efflux two days following major upper abdominal surgery.