Summary Glucose production and utilization and activities of key enzymes involved in liver and muscle glucose metabolism were studied in post-absorptive streptozotocin-diabetic rats after 12h of severe hyperglycaemia (17.5 + 0.5 mmol/1) and insulinopenia (5 + 1 ~tU/ml). Basal glucose production was increased: 36.6 + 3.0 mg. kg. min -1, vs 24.4 + 2.5 in controls (p < 0.05); liver glycogen concentration was decreased by 40 % (p < 0.05); liver phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities were increased by 375 and 156 %, respectively (/7 < 0.001 and < 0.01). During a euglycaemic clamp at a plasma insulin level of 200 ~U/ml, glucose production was totally suppressed in controls, but persisted at 20 % of basal in diabetic rats. In these rats, glucose production was suppressed at a plasma insulin level of 2500 ~tU/ml. Basal whole body glucose utilization rate, 2-deoxy-l-[3H]-D-glucose ([3H]-2DG) uptake by muscles and muscle glycogen concentrations were similar in both groups, as well as total and active forms of pyruvate dehydrogenase and glycogen synthase activities. During the euglycaemic clamp, the total body glucose utilization rates and [3H]-2DG uptake by muscles were similar in control and diabetic rats at a plasma insulin level of 200 ~tU/ ml, but lower in diabetic rats at a plasma insulin level of 2500 ~tU/ml. We conclude 1) in recent-onset severely insulinopenic rats, an excessive glucose production via gluconeogenesis prevailed, mainly accounting for the concomitant hyperglycaemia. This excess glucose output cannot be attributed to liver insulin resistance: the gluconeogenic pathway is physiologically less sensitive than glycogenolysis to the inhibition by insulin. 2) Glucose utilization was apparently normal under hyperglycaemic conditions and at a lower insulin plateau of the euglycaemic clamp but suboptimal in the presence of maximal insulin concentrations, suggesting an early appearance of peripheral insulin resistance. [Diabetologia (1995) 38: 283-290]

Fatty acid synthase (FAS) expression is low in liver and adipose tissue of suckling rats and increases markedly after weaning on to a high-carbohydrate low-fat diet. It has been shown previously that glucose alone, via an increase in intracellular glucose-6-phosphate level, stimulated the accumulation of FAS mRNA in cultured white adipose tissue of suckling rats. The regulation of FAS expression by glucose and hormones (insulin, dexamethasone and triiodothyronine) was studied in cultured hepatocytes from suckling rats. In hepatocytes cultured for 48 h in the absence of hormones and glucose, FAS mRNA, as well as glucokinase mRNA, levels remained undetectable. Glucose alone was unable to stimulate FAS expression. The combination of hormones, in the absence of glucose, has a marginal effect on FAS mRNA levels. However, FAS mRNA levels were increased in the presence of both glucose and the combination of hormones. This demonstrated that the hormonal induction of FAS mRNA was dependent on the presence of glucose in the culture medium. We have then investigated if glucokinase expression could be a prerequisite for the stimulation of FAS expression in response to glucose. Hepatocytes were cultured for 48 h in the absence of glucose but in the presence of insulin, dexamethasone and triiodothyronine. In these conditions, glucokinase mRNA and activity were markedly increased but there was no accumulation of FAS mRNA. When these hepatocytes were then exposed to various levels of glucose, FAS mRNA rapidly accumulated. Glucose stimulation of FAS expression was observed only in hepatocytes which expressed glucokinase activity. The importance of glucokinase expression for the induction of FAS mRNA by glucose is supported by the striking correlation between glucose-6-phosphate concentrations and the levels of FAS mRNA. This study clearly demonstrates that: (a) glucose metabolism is directly involved in the regulation of FAS gene expression; (b) the effect of hormones is partly due to their capacity to induce in the hepatocytes the capacity for glucose phosphorylation.Keywords. Fatty acid synthase ; glucokinase ; hepatocyte ; suckling rat; gene expression.Fatty acid synthase (FAS) plays a central role in de novo lipogenesis in mammals by catalyzing the synthesis of saturated long-chain fatty acids from acetyl-CoA and malonyl-CoA. FAS activity is not known to be regulated by allosteric effectors or covalent modifications. In the liver, the activity of FAS, the level of its mRNA and the rate of gene transcription change during development [l-31 and in response to alterations in nutritional and hormonal environment (review in [4]). The activity of FAS and the level of its mRNA are low during the suckling period and markedly increase after weaning onto a high-carbohydrate diet [l-31. They are Iow in adult rats starved or fed a high-fat diet and they are increased in rodents fed a high-carbohydrate diet [5 -81. In diabetic rodents, liver FAS expression was markedly reduced and was rapidly restored by administration of insulin [8, 91 ...

Recently, rapid and transient cardiac pacing was shown to induce preconditioning in animal models. Whether the electrical stimulation per se or the concomitant myocardial ischemia affords such a protection remains unknown. We tested the hypothesis that chronic pacing of a cardiac preparation maintained in a normoxic condition can induce protection. Hearts of 4-day-old chick embryos were electrically paced in ovo over a 12-h period using asynchronous and intermittent ventricular stimulation (5 min on-10 min off) at 110% of the intrinsic rate. Sham (n ϭ 6) and paced hearts (n ϭ 6) were then excised, mounted in vitro, and subjected successively to 30 min of normoxia (20% O2), 30 min of anoxia (0% O2), and 60 min of reoxygenation (20% O2). Electrocardiogram and atrial and ventricular contractions were simultaneously recorded throughout the experiment. Reoxygenation-induced chrono-, dromo-, and inotropic disturbances, incidence of arrhythmias, and changes in electromechanical delay (EMD) in atria and ventricle were systematically investigated in sham and paced hearts. Under normoxia, the isolated heart beat spontaneously and regularly, and all baseline functional parameters were similar in sham and paced groups (means Ϯ SD): heart rate (190 Ϯ 36 beats/min), P-R interval (104 Ϯ 25 ms), mechanical atrioventricular propagation (20 Ϯ 4 mm/s), ventricular shortening velocity (1.7 Ϯ 1 mm/s), atrial EMD (17 Ϯ 4 ms), and ventricular EMD (16 Ϯ 2 ms). Under anoxia, cardiac function progressively collapsed, and sinoatrial activity finally stopped after ϳ9 min in both groups. During reoxygenation, paced hearts showed 1) a lower incidence of arrhythmias than sham hearts, 2) an increased rate of recovery of ventricular contractility compared with sham hearts, and 3) a faster return of ventricular EMD to basal value than sham hearts. However, recovery of heart rate, atrioventricular conduction, and atrial EMD was not improved by pacing. Activity of all hearts was fully restored at the end of reoxygenation. These findings suggest that chronic electrical stimulation of the ventricle at a near-physiological rate selectively alters some cellular functions within the heart and constitutes a nonischemic means to increase myocardial tolerance to a subsequent hypoxia-reoxygenation. chick embryo; hypoxia-reoxygenation; preconditioning; arrhythmias; excitation-contraction coupling IN THE ADULT HEART, it is well established that the deleterious consequences of prolonged ischemia can be minimized if this condition is preceded by a short episode(s) of ischemia, the so-called classical preconditioning (30). Cardioprotection is measured in terms of a decrease in infarct size, a delay in ultrastructural damage, a reduction in myocardial stunning, and a diminution in incidence and severity of ischemia-reperfusion-induced arrhythmias. Preconditioning can also be induced by numerous nonischemic stimuli, such as exercise, heat stress, endotoxins or cytokines, catecholamines, pharmacological agents, adenosine, reactive oxygen species (ROS), and nitric ...

Acarbose is a potent intestinal glucosidase inhibitor which could have an anti-obesity property by reducing postprandial plasma glucose and insulin levels, potentially responsible for high rates of lipid synthesis in adipose tissue. We have tested this hypothesis by studying rats during the weaning period, when the lipogenic capacity of the adipose tissue develops. Rats were treated from age 19 days onwards with acarbose (10 mg/100 g diet) and studied at age 30 days. Acarbose was efficient in reducing postprandial excursions of both blood glucose and plasma insulin. Acarbose-treated rats behave like rats continuously infused with glucose with no metabolic signs of carbohydrate deprivation since gluconeogenesis was not activated. There was no massive caecal fermentation of carbohydrate since volatile fatty acids did not significantly increase in the portal blood. One of the most striking features of the acarbose-treated rats was the reduction of adipose tissue weight due to a reduced adipocyte size. This was concomitant with a reduced lipogenic capacity from glucose in isolated adipocytes under insulin stimulation. The activity of fatty acid synthase and acetyl-CoA carboxylase was decreased concomitantly with a reduced expression of their specific mRNA. This study allows the conclusion that postprandial hyperinsulinaemia and hyperglycaemia have a major role in the control of expression of lipogenic enzymes and thus on adipose tissue lipogenic capacity.

Total pyruvate dehydrogenase complex activity is low in white adipose tissue during the suckling period and increases markedly at weaning on to a high-carbohydrate diet. This is concomitant with an increase in the E1 alpha, E1 beta and E2 subunit protein concentration and their respective mRNAs, suggesting a pretranslational control of this phenomenon. The most marked change is seen for the E1 alpha subunit (17-fold increase in protein concentration). The changes in pyruvate dehydrogenase complex activity and subunit abundance induced by weaning on to a high-carbohydrate diet are precluded if the animals are weaned on to a high-fat diet, suggesting that the nutritional and/or related hormonal changes rather than a developmental stage are responsible for the observed adipose-tissue pyruvate dehydrogenase complex pattern.