The effects of fasting on glucose metabolism in the conscious resting rat were studied. Fasting decreased whole-body glucose utilization by 40%. The fast induced a decrease in glucose utilization in muscles which are constantly working even in the resting state, i.e. heart, diaphragm and postural muscles. No modification was observed in other tissues.

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]

In vivo studies have shown that insulin resistance in late pregnancy results from a decreased sensitivity of liver and peripheral tissues. In the present study, measurements of the rates of glucose utilization by skeletal muscles (soleus, extensor digitorum longus, epitrochlearis, and diaphragm), white adipose tissue, and brain of virgin and 19-day pregnant rats were performed in the basal condition and during a euglycemic, hyperinsulinemic (400 microU/ml) clamp to quantify the partition of glucose utilization and to identify the tissues other than liver responsible for insulin resistance. Fetal and placental glucose utilization rates were also measured in pregnant rats. The fetal glucose utilization rate (22 mg/min/kg) was very high and was not stimulated by physiologic maternal hyperinsulinemia. By contrast, the placental glucose utilization rate (29 mg/min/kg) was increased by 30% during hyperinsulinemia. The glucose utilization rate of the conceptus represented 23% of the maternal glucose utilization rate in the basal state. Glucose utilization rates in the basal condition were not statistically altered by pregnancy in brain, skeletal muscles, and white adipose tissue. During hyperinsulinemia (400 microU/ml), glucose utilization rates in extensor digitorum longus, epitrochlearis, and white adipose tissue were 30-70% lower in pregnant than in virgin rats. Insulin sensitivity of glucose metabolism in all the tissues tested other than brain was 50% lower in pregnant than in virgin rats. We conclude that skeletal muscles and, to a smaller extent, adipose tissue are involved in the insulin resistance of late pregnancy.

GLUT-2, glucokinase (GK) and phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was studied in the liver of chronically catheterized diabetic rats during the 3 days after an intravenous injection of 65 mg of streptozotocin (STZ)/kg. At 6 h after the STZ injection, portal plasma insulin levels were 270 +/- 32 mu-units/ml and blood glucose was 1.4 +/- 0.4 mmol/l, owing to pancreatic beta-cell destruction. GLUT-2 and PEPCK mRNA concentrations were rapidly and dramatically decreased (> 90%), whereas GK mRNA was increased. After 30 h, plasma insulin concentrations were lower than 5 mu-units/ml and blood glucose was > 20 mmol/l. GLUT-2 and PEPCK mRNA concentrations increased 2-fold and GK mRNA disappeared progressively. In order to assess the relative roles of hyperglycaemia and insulinopenia, blood glucose was clamped at 6.4 +/- 0.5 mmol/l from 18 to 72 h after STZ injection by phlorizin infusion (0.5-2 g/day per kg) or at 6.6 +/- 0.3 mmol/l from 18 to 48 h after STZ injection by insulin infusion (0.25 unit/min per kg). GLUT-2 mRNA concentrations were 50% lower in phlorizin-infused than in untreated diabetic rats. The low levels of GK mRNA and the high levels of PEPCK mRNA were unaffected by normalization of hyperglycaemia in phlorizin-infused diabetic rats. In insulin-infused rats (portal plasma insulin levels of 40 mu-units/ml) GLUT-2 mRNA levels were 25% of those in untreated diabetic rats, and they increased rapidly 6 h after insulin infusion was stopped. Liver GLUT-2 protein concentration showed similar changes in response to STZ injection and to phlorizin or insulin treatment, but after a delay of several hours. From this work we conclude that GLUT-2 gene expression is dramatically and rapidly (< 6 h) decreased by portal hyperinsulinaemia and increased by hyperglycaemia.

In 12-day lactating rats blood glucose and plasma insulin were decreased by, respectively, 20 and 35% when compared with nonlactating rats, despite a 25% increase of their glucose turnover rate. Then, by using the euglycemic hyperinsulinemic clamp technique, dose-response curves for the effects of insulin on glucose production and utilization in lactating and nonlactating rats were performed. Glucose production rate was totally suppressed at 250 microU/ml of insulin in lactating rats and for plasma insulin concentrations higher than 500 microU/ml in nonlactating rats. Plasma insulin level inducing half-maximal inhibition of glucose production was decreased by 60% during lactation. The maximal effect of insulin on glucose utilization rate and glucose metabolic clearance rate was, respectively, increased 1.5- and 2.4-fold during lactation and was obtained for plasma insulin concentrations lower in lactating than in nonlactating rats (250 vs. 500 microU/ml). Insulin concentrations inducing half-maximal stimulation of glucose utilization and glucose metabolic clearance were decreased by 50% during lactation. In conclusion, this study has shown that insulin sensitivity and responsiveness of liver and peripheral tissues are improved at peak lactation in the rat.