Insulin secretion and glucose tolerance were studied in 20-week-old male and female offspring of rat dams maintained on an isocaloric 20% or 8% protein diet during pregnancy and lactation after transfer to the same diet at weaning. Protein-restricted male and female offspring were also weaned onto a 20% protein diet. In males, post-absorptive insulin concentrations were suppressed by protein restriction from conception to adulthood (by 41%; P<0·001); however, basal insulin levels were 2·6-fold higher (P<0·001) if protein restriction was limited to gestation and lactation. Post-absorptive insulinaemia in females was unaffected by early or sustained protein restriction, but was lower than for males in the control group and the group exposed to protein restriction during early life alone (by 40% (P<0·001) and 52% (P<0·001) respectively). Plasma insulin/blood glucose ratios were higher in males compared with females in both control and early protein-restricted groups (1·6-fold (P<0·05) and 2·3-fold (P<0·001) respectively). A positive linear relationship existed between mean ambient insulin and glucose concentrations in males (r=1·0) and females (r=0·9), but the gradient was 12·4-fold greater (P<0·01) in males.-Cell function was evaluated after intravenous glucose challenge. In males, the acute insulin response and the suprabasal 30-min area under the insulin curve were dramatically higher in rats exposed to protein restriction during gestation and lactation alone (2·6-and 2·8-fold respectively; P<0·001). In contrast, these parameters were lowered by extending the exposure to protein restriction to adulthood in males, and by either early or prolonged exposure to protein restriction in females. The insulin resistance index was increased (2·5-fold; P<0·001) in male, but not female, rats exposed to protein restriction during gestation and lactation alone, and was not increased by extending the period of protein restriction to adulthood in either sex. Thus the data have demonstrated genderspecific lowering of insulin sensitivity due to protein restriction during early life only. The insulinogenic index (insulin response in relation to prevailing glycaemia) was increased in male, but not female, rats exposed to protein restriction during gestation and lactation alone (3·0-fold; P<0·001). A modest decline in insulin secretion in the female groups exposed to protein restriction until either the end of lactation or adulthood was compensated by increased insulin sensitivity, as demonstrated by significant decreases in the insulin resistance index in both groups (by 48% and 52% respectively; P<0·05). Glucose disappearance rates did not differ between the male and female control or early protein-restricted groups but were higher in both male (31%; P<0·05) and female groups (46%; P<0·001) exposed to protein restriction from conception to adulthood. Marked gender differences in glucosestimulated insulin secretion were not associated with gender differences with respect to glucose tolerance. Our data therefore demonstrated...

Fuel metabolism is highly regulated to ensure adequate energy for cellular function. The contribution of the major metabolic fuels - glucose, lactate and fatty acids (FAs) - often reflects their circulating levels. In addition, regulatory crosstalk and fuel-induced hormone secretion ensures appropriate and co-ordinate fuel utilization. Because its activity can either determine or reflect fuel preference (carbohydrate versus fat), the pyruvate dehydrogenase complex (PDC) occupies a pivotal position in fuel cross-talk. Active PDC permits glucose oxidation and allows the formation of mitochondrially derived intermediates (e.g. malonyl-CoA and citrate) that reflect fuel abundance. FA oxidation suppresses PDC activity. PDC inactivation by phosphorylation is catalysed by pyruvate dehydrogenase kinases (PDKs) 1–4, which are regulated differentially by metabolite effectors. Most tissues contain at least two and often three of the PDK isoforms. We develop the hypothesis that PDK4 is a ‘lipid status’-responsive PDK isoform facilitating FA oxidation and signalling through citrate formation. Substrate interactions at the level of gene transcription extend glucose-FA interactions to the longer term. We discuss potential targets for substrate-mediated transcriptional regulation in relation to selective PDK isoform expression and the influence of altered PDK isoform expression in fuel sensing, selection and utilization.

Abnormal depletion or accumulation of islet lipid may be important for the development of pancreatic cell failure. Long-term lipid sensing by cells may be co-ordinated via peroxisome proliferator-activated receptors (PPARs). We investigated whether PPAR activation in vivo for 24 h affects basal and glucose-stimulated insulin secretion in vivo after intravenous glucose administration and ex vivo in isolated perifused islets. Insulin secretion after intravenous glucose challenge was greatly increased by high-fat feeding (4 weeks) but glucose tolerance was minimally perturbed, demonstrating insulin hypersecretion compensated for insulin resistance. The effect of high-fat feeding to enhance glucose-stimulated insulin secretion was retained in perifused islets demonstrating a stable, long-term effect of high-fat feeding to potentiate islet glucose stimulussecretion coupling. Treatment of high-fat-fed rats with WY14,643 for 24 h reversed insulin hypersecretion in vivo without impairing glucose tolerance, suggesting improved insulin action, and ex vivo in perfused islets. PPAR activation only affected hypersecretion of insulin since glucose-stimulated insulin secretion was unaffected by WY14,643 treatment in vivo in control rats or in perifused islets from control rats. Our data demonstrate that activation of PPAR for 24 h can oppose insulin hypersecretion elicited by high-fat feeding via stable long-term effects exerted on islet function. PPAR could, therefore, participate in ameliorating abnormal glucose homeostasis and hyperinsulinaemia in dietary insulin resistance via modulation of islet function, extending the established requirement for PPAR for normal islet lipid homeostasis.

In the rat, dexamethasone treatment during late pregnancy leads to intrauterine growth retardation and is used as a model of early programming of adult onset disease. The present study investigated whether pre-natal dexamethasone treatment modifies cardiac glucose transporter (GLUT) protein expression in adulthood and identified signalling pathways involved in the response. Dexamethasone (100 µg/kg body wt per day) administered via an osmotic pump to pregnant rats (day 15 to day 21; term=22 to 23 days) reduced fetal weight at day 21 and caused hypertension, hyperinsulinaemia and elevated corticosterone levels in the adult (24-week-old) male offspring. Cardiac GLUT1 protein expression was selectively up-regulated (2·5-fold; P<0·001), in the absence of altered cardiac GLUT4 protein expression, in adult male offspring of dexamethasone-treated dams. Maternal dexamethasone treatment did not influence cardiac GLUT1 protein expression during fetal or early post-natal life. We examined potential regulatory signalling proteins that might mediate up-regulation of cardiac GLUT1 protein expression in adulthood. We observed marked (2·2-fold; P<0·01) activation of Akt/protein kinase B (PKB), together with modest activation of the anti-apoptotic protein kinase C (PKC) isoforms PKC (88%, P<0·05) and PKC ε (56%, P<0·05) in hearts of the early-growth-retarded male offspring. These effects were, however, observed in conjunction with up-regulation of cardiac protein expression of PKC 1 (191%, P<0·01), PKC 2 (49%, P<0·05) and PKC (35%; P<0·01), effects that may have adverse consequences. Maternal dexamethasone treatment was without effect on cardiac extracellular signal-related kinase (ERK) 1 or ERK2 activity in adulthood. In conclusion, our data demonstrate an effect of maternal dexamethasone treatment to up-regulate cardiac GLUT1 protein expression in early-growth-retarded, hypertensive, hyperinsulinaemic adult male offspring, an effect observed in conjunction with activation of Akt/PKB.

We examined the long-term effects of nutritional status and the acute effects of changes in exogenous carbohydrate- and lipid-substrate supply and utilization on fructose 2,6-bisphosphate (Fru-2,6-P2) concentrations in heart, gastrocnemius and soleus. Starvation decreased Fru-2,6-P2 concentrations in all three muscles. The acute administration of insulin and glucose increased skeletal-muscle Fru-2,6-P2 in the fed, but not in the starved, state, but cardiac Fru-2,6-P2 was unchanged. Cardiac and skeletal-muscle Fru-2,6-P2 concentrations were unaffected by acute increases in fatty acid supply produced by the administration of corn oil plus heparin, or by acute decreases in fatty acid supply produced by inhibition of lipolysis. Differences in cardiac and skeletal-muscle Fru-2,6-P2 concentrations observed in response to starvation were not reversed by administration of glucose or glucose plus insulin, or by inhibition of lipolysis, even though changes in citrate (heart), acylcarnitine (heart) and glycogen (skeletal muscle) were observed. Concentrations remained low for at least 8 h after chow re-feeding, but the fed value was restored by 24 h.