A time-course study was carried out of the levels of submandibular kallikrein, serum insulin and blood glucose of rats rendered diabetic by alloxan or streptozotocin. The permanent hyperglycemia seen one day after treatment and the subsequent relative changes in the levels of blood glucose recorded over the following nine days were in agreement with previous observations. A significant reduction in the concentration of submandibular kallikrein did not become apparent until ten days following the injection of alloxan or streptozotocin. Thus the enzyme would not appear to have played either a causal or a preventative role in the production of the hyperglycemic state. Furthermore, in disagreement with previous speculation, the submandibular gland had not compensated for the deficiency of insulin with an increase in production of kallikrein. The fall in the level of serum insulin had preceded the decrease in submandibular kallikrein. However, administration of exogenous insulin over a period of three days did not bring about an increase in the concentration of submandibular kallikrein of the diabetic rats. Thus insulin would not seem to be involved in controlling the level of kallikrein in the submandibular gland.
Administration of the compound M&B 39890A lowered serum glucose levels significantly (p less than 0.001) in genetically obese mice, while no effect on serum insulin levels was observed. In in vitro experiments with isolated rat islets of Langerhans M&B 39890A inhibited arginine-stimulated glucagon release at all concentrations tested (0.5, 5.0 and 50 mumol/l). Insulin secretion was not inhibited by M&B 39890A (0.5 and 5.0 mumol/l), but was slightly decreased at 50 mumol/l. M&B 39890A (5 mumol/l) also inhibited glucagon secretion in vitro in the presence of 2 mmol/l, 6 mmol/l and 20 mmol/l glucose, while exerting no effect on insulin secretion. These results suggest that the hypoglycaemic action of M&B 39890A may be due to its direct and selective effect on glucagon secretion; this appears to operate by a mechanism different to that of glucose.
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