Absorption and efficiency of insulin after oral administration of insulin-loaded nanocapsules in diabetic rats.

Poly(isobutylcyanoacrylate) nanocapsules have been shown to decrease the blood glucose level after oral administration to streptozotocin-induced diabetic fasted rats after 2 days [Diabetes 37 (1988) 246]. Yet, the absorption of insulin in the blood of rats has not been characterised. The aim of this work was to evaluate the biological activity of insulin given orally as nanocapsules. Humalog-loaded nanocapsules (50 IU/kg) were administered by gavage to streptozotocin-induced diabetic rats. Thirty minutes to 1 h after oral administration, significant levels of human insulin were detected in rat plasma. However, the concentrations were very heterogenous from one rat to another and no decrease of glycemia could be observed. In addition, parenteral injection of insulin in solution showed that high levels of the protein are necessary to decrease blood glucose concentration in diabetic rats. These concentrations were not reached after oral administration. The same dose of insulin decreased glycemia by 50% in normal rats and by only 25% in diabetics. This suggested that an insulino-resistance was developed by streptozotocin-induced diabetic rats.

The inhibitory effect of glucose on phosphoenolpyruvate carboxykinase gene expression in cultured hepatocytes is transcriptional and requires glucose metabolism.

Phosphoenolpyruvate carboxykinase (PEPCK) is the rate-limiting enzyme of gluconeogenesis in the liver. PEPCK gene expression is controlled at the transcriptional level and is mainly regulated by hormones that are involved in glucose homeostasis. In this study, we have investigated the role of glucose on PEPCK gene expression in cultured hepatocytes. We demonstrate that glucose counteracts the stimulatory effect of glucocorticoids and cAMP on PEPCK expression. Glucose must be metabolized through glucokinase to have its inhibitory effect. The effect of glucose is mainly transcriptional and the region responsible for glucose inhibition is localized in the first 490 bp of the promoter.