The effects of insulin and Syzygium aromaticum-derived oleanolic acid containing dermal patches on kidney function and renal expression of glucose transporters in streptozotocin-induced diabetic rats.

Introduction The tight glycaemic control required to attenuate chronic complications in type 1 diabetes mellitus requires multiple daily injections of bolus insulin which have been reported to be associated with Na+ retention resulting in hyperinsulinaemic oedema and hypertension. Current research on insulin delivery methods include buccal, oral, nasal, and transdermal delivery systems. Transdermal delivery system is of great interest as this offers sustained controlled release of insulin into the systemic circulation. We have previously reported that transdermal application of pectin hydrogel insulin (PI) matrix patches sustain controlled insulin delivery into the bloodstream of STZ-induced diabetic rats to perhaps ameliorate diabetic complications. Since we have previously reported that STZ-induced diabetic rats retain Na+ following hypotonic saline challenge, this study investigated whether insulin-containing dermal patches can avert and improve the impaired renal fluid and electrolyte handling of STZ-induced diabetic rats. We have also shown that oral administration of OA in addition to possessing hypoglycaemic effects, improves kidney function STZ-induced diabetic rats. The study therefore also investigated whether OA-containing dermal patches can improve kidney function STZ-induced diabetic rats. Materials and methods Pectin insulin (PI)-containing dermal patches of various doses (3.99, 9.57, 16.80 μg/kg) and pectin oleanolic acid (P-OA) containing dermal patches of various doses (21, 42, 84 mg/kg) were prepared by dissolving pectin/insulin or pectin/OA in deionized water and solidified with CaCl2. Short-term (5 weeks) effects on renal function of thrice daily treatments with PI and P-OA patches 8 hours apart were assessed in diabetic animals. Rats sham treated with the pectin drug free patch and insulin (175 μg/kg sc) acted as negative and positive controls, respectively. Daily urine volume, urinary glucose, Na+, K+ and creatinine excretion rates were monitored over 5-weeks. Blood was collected 6 h following treatments for insulin determination. Blood and kidney samples were also collected after 5 weeks for hormonal analysis and measurement of selected biochemical parameters. Results Untreated STZ-induced diabetic rats exhibited elevated weekly urinary glucose, K+ outputs and depressed urinary Na+ outputs throughout the 5-week compared to non-diabetic control animals. Application of PI-containing dermal patches significantly increased urinary Na+ output and reduced urine volume and urinary outputs of glucose and K+ in weeks 4 and 5. Plasma AVP concentrations of untreated STZ-induced diabetic rats were significantly low at end of the 5-week experimental period by comparison with control non-diabetic animals while plasma aldosterone levels were significantly elevated. The highest dose of the insulin-containing dermal patch (16.80 μg/kg) significantly (p < 0.05) elevated plasma AVP concentrations while decreasing plasma aldosterone concentrations of STZ-induced rats by comparison to untreated STZ-diabetic rats. …