P. Ferre

Effect of anesthesia on glucose production and utilization in rats.

This study was undertaken to determine the effects of pentobarbital anesthesia (50 mg/kg ip) on glucose kinetics and individual tissue glucose utilization in vivo, in chronically catheterized rats. Glucose turnover studies were carried out using [3-3H]glucose as tracer. A transient hyperglycemia and an increased glucose production were observed 3 min after induction of anesthesia. However, 40 min after induction of anesthesia, glycemia returned to the level observed in awake animals, whereas glucose turnover was decreased by 30% as compared with unanesthetized rats. These results are discussed with regard to the variations observed in plasma insulin, glucagon, and catecholamine levels. Glucose utilization by individual tissues was studied by the 2-[1-3H]deoxyglucose technique. A four- to fivefold decrease in glucose utilization was observed in postural muscles (soleus and adductor longus), while in other nonpostural muscles (epitrochlearis, tibialis anterior, extensor digitorum longus, and diaphragm) and other tissues (white and brown adipose tissues) anesthesia did not modify the rate of glucose utilization. A decrease in glucose utilization was also observed in the brain.

Glucose Metabolism in Pregnancy

Pregnancy is characterized by a number of maternal metabolic modifications in order to meet the energy requirements of the growing fetus. A progressive alteration of maternal glucose homeostasis develops throughout gestation and becomes maximal during the last trimester. A relative hypoglycemia is observed during the postabsorptive period despite an elevated plasma insulin concentration and an enhanced hepatic glucose production. In addition, the glucose utilization rate by peripheral maternal tissues is lowered in late gestation indicating that the mother supplies glucose to the fetus at the expense of her own tissues. Concomitantly, an insulin-resistant state develops in the mother to help sparing glucose for the pregnant uterus. It involves both glucose-producing (liver) and glucose-utilizing tissues. So far, the factor(s) responsible for the development of pregnancy-induced insulin resistance has not been identified although a number of circulating hormones are known to counteract insulin effects.

Hormonal control of specific gene expression in the rat liver during the suckling-weaning transition

In the rat, the suckling-weaning transition is accompanied by marked changes in nutrition. During the suckling period, the pups are fed with milk which is a high-fat low-carbohydrate diet. At weaning, milk is progressively replaced by the rat chow which is a high-carbohydrate low-fat diet. This is accompanied by considerable hormonal modifications: an increase in plasma insulin and a decrease in plasma glucagon concentrations, as well as by marked changes in metabolic pathways in liver: decrease in hepatic gluconeogenesis, increase in lipogenesis, and appearance of liver glucokinase. Most of the data concerning these changes are related to maximal activity of enzymes. The recent availability of specific cDNA probes for phosphoenolpyruvate carboxykinase, acetyl-CoA carboxylase, fatty acid synthase and glucokinase has allowed study of the role of pancreatic hormones and of nutrition in the changes of the expression of these genes at weaning in the rat.

Hormonal regulation of liver phosphoenolpyruvate carboxykinase and glucokinase gene expression at weaning in the rat

During the suckling period, the rats are fed continuously with milk, which is a high-fat low-carbohydrate diet (HF). At weaning, milk is progressively replaced by the rats laboratory chow which is a high-carbohydrate low-fat diet (HCHO), and this is accompanied by large hormonal modifications: an increase in plasma insulin and a decrease in plasma glucagon concentrations, and by marked changes in metabolic pathways in liver: decrease in hepatic gluconeogenesis and increase in glycolysis and lipogenesis. Most of the data concerning these changes are related to maximal activity of enzymes. The recent availability of specific cDNA probes for phosphoenolpyruvate carboxykinase (PEPCK), and glucokinase (GK) has allowed the study of the role of pancreatic hormones and nutrition in the changes of the expression of these genes at weaning in the rat. Regarding phosphoenolpyruvate carboxykinase gene transcription, the concentration of mRNA as well as the activity of PEPCK are elevated in the liver of suckling rat until the onset of weaning, 21 d after delivery. After weaning to a HCHO diet, both mRNA and activity of PEPCK rapidly decrease to a very low level. In contrast, weaning on an HF diet, which maintains high plasma glucagon and low plasma insulin levels, does not decrease in plasma glucagon concentration and a 90% decrease in PEPCK gene transcription and PEPCK mRNA concentration in 1 h. Regarding glucokinase gene transcription, the concentration of mRNA as well as the activity of GK are not detectable before 15 d after birth in the liver of the rat. They markedly increase when the newborn are weaned on an HCHO diet but not when they are weaned on an HF diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of feeding pattern on the sensitivity of hepatic carnitine palmitoyl-transferase to inhibition by malonyl-CoA in the rat

1. The feeding pattern influences the inhibitory effects of malonyl-CoA on carnitine palmitoyltransferase-I. 2. The sensitivity of liver carnitine palmitoyltransferase-I to malonyl-CoA is increased in rats meal-fed when compared to rats fed ad libitum. 3. Moreover, liver carnitine palmitoyltransferase-I of meal-fed rats remains more sensitive to inhibition by malonyl-CoA during a 24 hour fast than liver carnitine palmitoyltransferase-I of rats previously fed ad libitum.

Effect of weaning on different diets on hepatic gluconeogenesis in the rat.

The capacity of gluconeogenesis from lactate (10 mmol/l) was studied on isolated hepatocytes in 15-day-old suckling and in 28-day-old rats weaned at the age of 19 days on various diets. Weaning on a high-fat carbohydrate-free diet allowed to maintain a high gluconeogenic rate. By contrast, as soon as the carbohydrate content of the weaning diet was sufficient to meet the glucose needs of the newborn, the gluconeogenic capacity was reduced. The amount of fat in the weaning diet had no influence on the gluconeogenic capacity. Changes in the hepatic gluconeogenic rate at weaning were inversely correlated with the plasma insulin/glucagon molar ratio.

Intramitochondrial factors controlling hepatic fatty acid oxidation at weaning in the rat

Fatty acid oxidation was studied in isolated liver mitochondria of rats during the suckling‐weaning transition. The oxidation rate of oleyl‐CoA and palmitoylcarnitine was reduced 2.5‐fold in rats weaned on a high‐carbohydrate diet compared to suckling rats, when acetyl‐CoA produced by β‐oxidation was directed towards ketone‐body synthesis. Weaning on a high‐fat diet minimized this change. Channeling of acetyl‐CoA towards citrate synthesis doubled the oxidation rate of both substrates in HC‐weaned rats. Thus, in addition to changes in carnitine palmitoyltransferase I activity, the β‐hydroxymethylglutaryl‐CoA synthase pathway is also involved in the decreased fatty acid oxidation at weaning. This was confirmed by measurement of β‐hydroxymethylglutaryl‐CoA synthase pathway activity.

Normal insulin sensitivity during the phase of glucose intolerance but insulin resistance at the onset of diabetes in the spontaneously diabetic BB rat.

SummaryIn diabetes-prone BB rats, 30 to 50% of animals undergo autoimmune destruction of the pancreatic B-cells leading to a short period of glucose intolerance, followed by an abrupt onset of diabetes. We have examined whether the glucose intolerance period and the onset of diabetes are associated with changes in insulin sensitivity, using the euglycaemic hyperinsulinaemic clamp coupled with [3-3H] glucose infusion. Glucose intolerant rats were detected by a transient glycosuria one hour after an oral glucose load performed every four days. Insulin sensitivity studied in these rats the day following their detection was normal. Other diabetes-prone BB rats were tested daily and studied on the first day of glycosuria. In the basal state, glucose production was increased in diabetic rats (11.3±1.1 vs 7.1±0.8mg·min−1·kg−1, p<0.05). Tissue glucose utilization was similar in diabetic and control rats (8.3±0.5 vs 7.1±0.8mg·min−1·kg−1) despite a three fold higher glycaemia in the diabetic rats. During the hyperinsulinaemic clamps, glycaemia was clamped at 6.1–6.6 mmol/l in diabetic and control rats. A decreased insulin sensitivity was observed in diabetic rats at submaximal (200 μU/ml) and maximal (1500 μU/ml) insulin concentrations for both inhibition of hepatic glucose production and stimulation of glucose utilization. No autoantibodies against insulin could be detected in the plasma of diabetic rats. Plasma concentrations of glucagon, catecholamines, ketone bodies and fatty acids were similar in control and diabetic rats during the clamp studies. Our results suggest that the decrease of basal insulin concentration is responsible for the insulin resistance in the diabetic BB rat at onset of diabetes, either directly or through the increased glycaemia.

Alanine Turnover Rate and Its Hepatic Metabolism Are Increased in Midpregnant Rat

At mid pregnancy (12th day) fed rats exhibit a drop of blood alanine level when the weight of the fetoplacental unit is still negligible. A primed infusion A-V method was used to measure alanine kinetics in fed midpregnant rats and virgin controls, using L-[2,3-3H]alanine as a tracer. Alanine turnover and metabolic clearance rates were higher on day 12 than in virgin controls. The increase in alanine turnover rate was accounted for by an increase in alanine degradation. Since the liver is the main site of alanine degradation, alanine uptake was studied in isolated hepatocytes. Hepatocytes isolated from midpregnant rats utilized 50% more alanine than those from virgin controls. This increase was mainly due to metabolism rather than incorporation into proteins. In conclusion, the alanine turnover rate and its hepatic metabolism are increased in fed midpregnant rats, resulting in the decrease in blood alanine.

Evidence that hepatic mitochondrial mass decreases during the first sixteen hours following birth in starved newborn rats

Fatty acid oxidation increases in newborn rats between 0 and 16 h after birth. We have tested the hypothesis that such a rise might be due to an increase in hepatic mitochondrial mass. The ratio total activity/specific activity for cytochrome c oxidase and citrate synthase was used as an index that reflected the changes in mitochondrial mass. This ratio was decreased by about 25% 16 h after delivery, indicating that hepatic mitochondrial mass was lower 16 h after birth than at birth in starved rats. We conclude that changes in the mitochondrial mass are not responsible for the increase in liver capacity to oxidize fatty acids.