Abstract
Hypoglycemia caused by palmitic-acid modified exendin-4 (Pal-Ex4) administered via the pulmonary route was evaluated and compared with that caused by native Ex4. Pal-Ex4 and Ex4 in solution (each 50μl) were administered using a microsprayer directly into the trachea of type 2 diabetic db/db mice at 75 or 150nmol/kg. The lung depositions of Cy5.5-labeled Ex4 or Pal-Ex4 were monitored using an infrared imaging system after administration. The hypoglycemia caused by Pal-Ex4 was found to be 3.4 and 2.3 times greater than that caused by native Ex4 at 75 and 150nmol/kg, respectively. Furthermore, time to blood glucose level (BGL) rebound to >150mg/dl for Pal-Ex4 was 3.5 times greater than that of Ex4 (18.1h vs. 5.2h at 150nmol/kg). In particular, the time taken for Pal-Ex4 to reach a BGL nadir was significantly greater than that of Ex4 (~8h versus 4h). Furthermore, lung deposition images clearly showed that Pal-Ex4 was slowly absorbed from lungs and barely distributed into kidneys until 8h post-administration. It is likely that the prolonged hypoglycemia exhibited by Pal-Ex4 was due to; (i) delayed absorption in the lungs and (ii) albumin-binding in the circulation. The study demonstrates that palmitic acid-modified exendin-4 should be viewed as a long-acting inhalation candidate for the treatment of type 2 diabetes.
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