Angiotensin converting enzyme inhibitors in diabetes: experimental and human experience

Peripheral glucose metabolism was studied during the influence of elevated systemic kinin levels by either application of exogenous bradykinin (BK) or inhibition of endogenous kinin degradation by angiotensin converting enzyme inhibitors (ACEI). In infusion experiments in streptozotocin-diabetic rats, both BK (0.3 micrograms/min) and ACEI (300 micrograms captopril/100 g) showed a significant reduction of elevated blood glucose levels. In man, non-insulin dependent diabetics (NIDD) and healthy subjects in postoperative (POP) stress were examined. Peripheral insulin-sensitivity and muscular glucose balance were determined using the glucose clamp technique and the forearm technique. In NIDD as well as in POP subjects, impaired peripheral insulin responsiveness, as evaluated by whole body glucose consumption, was improved up to 50% by application of BK (80 micrograms/h i.v.) or ACEI (25 mg captopril p.o.), respectively. This was most probably due to accelerated muscular glucose uptake which was assessed in the same experiment and found to be increased 2- to 3-fold under these conditions. As a molecular basis for the observed effects on muscular glucose uptake, phosphofructokinase was found to be markedly stimulated by BK (8 X 10(-10)mol/l) in the isolated perfused rat heart, suggesting accelerated glycolytic flux. It may be concluded that ACEI increase muscular insulin responsiveness, thus being beneficial in insulin-resistant states as well as in hypertension. This metabolic effect is most probably due to elevated systemic kinin levels. Further investigations are required to evaluate the clinical relevance of these findings.