Interaction of Insulin with Prokinetic Drugs in STZ-induced Diabetic Mice

Abstract

AIM: Prokinetic drugs have been used for gastroparesis in diabetic patients for a relatively long time already and some data about the interactions with insulin in the clinic should be available. To study the possible interactions of metoclopramide, domperidone or erythromycin in streptozotocin (STZ)-induced diabetic mice treated with insulin in different parameters. METHODS: Effects of the individual as well as combined drugs were studied in diabetic mice via estimation of the blood glucose and serum insulin levels, small intestinal transit, gastric emptying, xylose absorption and glucose tolerance tests. The groups included were normal control, diabetic control, insulin 2 IU/kg (s.c.), metoclopramide 20 mg/kg (p.o.), domperidone 20 mg/kg (p.o.) and erythromycin 6 mg/kg (p.o.) individually and in combination. The first set of experiments was carried out to investigate the subchronic effect of one week of daily dose of the tested drugs individually as well as the combination of insulin with each prokinetic drug in diabetic mice on blood glucose and serum insulin levels. The other five sets of experiments were carried out to investigate the acute effect of a single dose of each drug individually and in combination on blood glucose and serum insulin levels, small intestinal transit, gastric emptying, oral xylose absorption and glucose tolerance tests. RESULTS: The study included test prokinetic drugs i.e., metoclopramide (20 mg/kg), domperidone (20 mg/kg) and erythromycin (6 mg/kg), as well as insulin (2 IU/kg), which was individually effective in decreasing SIT, enhancing GE and increasing xylose absorption significantly (P<0.05) in diabetic mice.Erythromycin tended to decrease blood glucose level and increase serum insulin level after one week of daily dose administration in diabetic mice. Erythromycin potentiated the effect of insulin given on blood glucose level and serum insulin level where other prokinetic agents failed to do so after repeated dose administration in diabetic mice.Metoclopramide or erythromycin in combination with insulin significantly (P<0.05) decreased small intestinal transit in diabetic mice, which was less than that of insulin alone. Administration of test prokinetic drugs along with insulin antagonized the action of insulin on xylose absorption. These combinations also increased the rate of glucose absorbed from the gut. CONCLUSIONS: The present study suggests that prokinetic drugs could potentially improve glycemic control in diabetic gastroparesis by allowing a more predictable absorption of nutrients, matched to the action of exogenous insulin. The use of prokinetics i.e. erythromycin may be interesting in the clinic in order to decrease the need for insulin in diabetic patients. The dose of insulin may be safely decreased with erythromycin in chronic treatments.