Insulin and insulin-like growth factor 1 antagonize the stimulation of ob gene expression by dexamethasone in cultured rat adipose tissue.

The ob gene, specifically expressed in fat cells, encodes leptin, a hormone that induces satiety and increases energy expenditure. In this study, we investigated the interactions between glucocorticoids and insulin on ob gene expression in cultured explants of rat adipose tissue. Only low levels of ob mRNA were detected when adipose tissue from fasted rats was cultured for 12-24 h in minimal essential medium. However, the addition of dexamethasone to the medium increased ob gene expression in a concentration-dependent manner (EC50 10 nM). With 1 microM dexamethasone, ob mRNA levels were similar to those in fresh fat pads from fed rats, reaching a maximum after 12 h. The effect of dexamethasone was blocked by actinomycin D, which indicates an action on transcription. This effect was increased when a minimum amount of fuel (glucose or a mixture of lactate and pyruvate) was supplied in the medium. Unlike dexamethasone, insulin, even when combined with high glucose concentrations, did not induce ob expression, although it strongly increased the accumulation of mRNA species for fatty acid synthase (FAS), the insulin-sensitive glucose transporter GLUT4 and the gamma isoform of peroxisome proliferator-activated receptor (PPARgamma). Unexpectedly, insulin dose-dependently inhibited dexamethasone-induced ob mRNA accumulation. This effect was observed at low concentrations of insulin (IC50 1 nM) and was delayed in onset, beginning after 6-9 h of culture. It was mimicked by insulin-like growth factor 1 (IGF-1) (100 nM). The inhibition by insulin was only detectable when fuels were present and/or when a critical level of ob expression was reached. As this inhibitory effect was reversed by cycloheximide, this suggests that it required ongoing protein synthesis. In conclusion, unlike dexamethasone, insulin had no direct stimulatory effect on ob gene expression. On the other hand, insulin (and IGF-1) even inhibited the dexamethasone-induced accumulation of ob mRNA. The underlying mechanism involved ongoing synthesis of an inhibitory protein by insulin, which is in keeping with its delayed effect. Moreover, the expression of genes for FAS, GLUT4 and PPARgamma may be inversely related to that of ob.

Improvement of glucose and lipid metabolism in diabetic rats treated with molybdate.

Molybdenum mimics certain insulin actions in vitro. We have investigated the effects of oral administration of Na2MoO4 (Mo) for 8 wk on carbohydrate and lipid metabolism in streptozotocin-diabetic rats. Mo decreased hyperglycemia and glucosuria by 75% and corrected the elevation of plasma nonesterified fatty acids. Tolerance to glucose loads was improved, and glycogen stores were replenished. These effects were not due to a rise of insulinemia. In liver, Mo restored the blunted mRNA and activity of glucokinase and pyruvate kinase and decreased to normal phosphoenolpyruvate carboxykinase values. Finally, Mo totally reversed the low expression and activity of acetyl-CoA carboxylase and fatty acid synthase in liver, but not in white adipose tissue. In conclusion, Mo exerts a marked blood glucose-lowering effect in diabetic rats by an insulin-like action. This effect results in part from a restoration of hepatic glucose metabolism and is associated with a tissue-specific correction of lipogenic enzyme gene expression, both processes being essentially mediated by reversal of impaired pretranslational regulatory mechanisms. These observations raise new therapeutic perspectives in diabetes, particularly in the insulin-resistant condition.

Long term improvement of glucose homeostasis by vanadate in obese hyperinsulinemic fa/fa rats.

The trace element vanadium (V) exerts insulin-like effects in vitro and lowers blood glucose in streptozotocin-diabetic rats. The present study examined whether V can also improve glucose homeostasis in genetically obese, insulin-resistant rats. Na3VO4 was administered for 3 months in water and food to Zucker fa/fa rats. Since these V rats reduced their food intake by about 30% compared to controls (C), one group of untreated rats was pair-fed (P-F) with V rats. In the fed state, the insulin/glucose ratio was lower in V rats than in P-F or C rats, merely because of a decrease (approximately 50%) in plasma insulin levels. Tolerance to oral glucose was improved in V rats only; the integrated glucose response was 30% lower than that in P-F or C rats. Insulin levels were also lower in V rats, but the integrated response was not consistently decreased. During an iv glucose tolerance test, the glucose disappearance rate was 50% higher in V rats than in the other two groups. An iv arginine test clearly showed that B-cell responsiveness was not increased in V rats. Insulin sensitivity, assessed by insulin-induced hypoglycemia, was similar in V and P-F rats and slightly better than that in C rats. In conclusion, oral vanadate produces a sustained improvement of glucose homeostasis by an insulin-like, largely body weight-independent mechanism in genetically insulin-resistant rats.

Influence of low- and high-protein diets on glucose homeostasis in the rat.

1. The influence of the protein content of the diet on glucose homeostasis was studied in the rat. Rats of 28 d of age received ad lib. a control diet containing (g/kg) 150 protein (P15), or a diet containing 50 protein (P5) or 450 protein (P45). Since P5 rats spontaneously reduced their food intake, a fourth group of rats (P25) received the same amount of energy as P5 rats and the same amount of protein as P15 rats. 2. After 12-13 weeks on these diets, plasma glucose and insulin levels were similar in fed P45, P25 and control P15 rats, but were lower in P5 rats. In fasted animals, plasma glucose and insulin levels were also decreased in P5 rats, whereas plasma glucose levels were increased in both P45 and P25 animals. 3. During an oral glucose tolerance test, the glucose rise was only slightly larger in P5 than in P15 rats in spite of a considerably smaller increase in insulin levels. P45 rats displayed a normal tolerance to glucose with a normal insulin response, whereas tolerance to glucose was slightly poorer in P25 rats in spite of a normal insulin response. 4. Pancreatic insulin stores were lower in P5 than in control P15 rats, not only because of the smaller size of their pancreas, but also because of a decrease in the insulin concentration in the gland. A much smaller decrease was also observed in P25 rats, whereas insulin reserves were not altered in P45 rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose homeostasis in magnesium-deficient rats.

Glucose homeostasis was studied in rats fed diets containing 750,200, or 100 mg/kg Mg for 6 to 8 weeks, from the age of 4 weeks. Weight gain of the rats receiving 200 and 100 mg/kg diets was decreased. This resulted from both a lower food intake and reduced effectiveness of the ingested food. Fed or fasting plasma glucose levels were similar in the three groups. During an intravenous glucose tolerance test, the rate of glucose disappearance was higher in Mg 100 rats than in controls. By contrast, during an oral glucose tolerance test, the rise in plasma glucose was greater and more sustained in Mg 100 rats. During both tests, the insulin response was markedly lower in Mg-deficient rats than in controls. This could be partially due to the reduced insulin content of the pancreas of these animals. The impairment of tolerance to oral glucose was corrected by 5 weeks on a high-Mg diet. After intravenous injection of insulin, the fall in plasma glucose levels was also slightly more pronounced in Mg 100 rats. During no test did we observe a significant difference between glucose or insulin responses in Mg 200 or Mg 750 rats. These results, thus, show that chronic Mg deficiency alters several parameters of glucose homeostasis in the rat.

Glucose homeostasis in rats treated acutely and chronically with quinine.

Glucose homeostasis in normal rats was studied after chronic or acute administration of quinine. Male rats received a daily dose of 10-30 mg/kg of quinine in the drinking water for 20 weeks. The high dose caused a slight decrease in food intake and weight gain. Though basal plasma insulin levels were increased in treated rats, their plasma glucose levels were only slightly and not consistently decreased. After oral or intravenous administration of glucose, the plasma insulin levels were higher and the disappearance rate of glucose was greater in rats receiving quinine than in the controls. The insulin content of the pancreas was not affected by quinine treatment. Intraperitoneal injection of a high dose of quinine (30 mg/kg) transiently increased plasma glucose and insulin levels. The insulin response was increased during a subsequent administration of glucose but the glucose levels were not modified. This study shows that chronic administration of quinine increases plasma insulin levels, accelerates disposal of oral or intravenous glucose but does not cause hypoglycaemia in normal rats.

Glucose homeostasis in rats acutely and chronically treated with chloroquine.

Glucose homeostasis of normal rats was studied after chronic or acute administration of chloroquine. Male rats received, in drinking water, a daily dose of 5-20 mg chloroquine/kg, for 20 weeks. The high dose caused a slight decrease in food intake and weight gain. In these animals, plasma glucose levels were somewhat lower than in controls after an overnight fast and after oral administration of glucose or intravenous administration of insulin, but not after intravenous administration of glucose. Their insulin response to oral or intravenous glucose was normal. The insulin content of their pancreas was decreased by about 15%. Electron microscopy revealed the presence of myeloid bodies and numerous lysosomes in B cells. Acute intraperitoneal administration of chloroquine was without effect on glucose tolerance and insulin release. This study shows that chloroquine, at plasma concentrations similar to those reached in treated patients, does not impair glucose homeostasis in normal rats.