Diabetic rats and mice are resistant to porcine and human insulin: flawed experimental models for testing islet xenografts

Pepper AR, Gall C, Mazzuca DM, Melling CWJ, White DJG. Diabetic rats and mice are resistant to porcine and human insulin: flawed experimental models for testing islet xenografts. Xenotransplantation 2009; 16: 502–510. © 2009 John Wiley & Sons A/S. : Background: Islet transplantation is potentially a promising therapy for the restoration of carbohydrate control to diabetic patients. However, the global application of islet transplantation requires a ubiquitous source of β cells. The xenotransplantation of porcine islets would provide such a source. Success in porcine islet xenografting has been achieved in diabetic primates. However, there are few reports of reversal of diabetes with porcine islet xenografts in rodent models of diabetes, relative to the number of successful rodent experiments performed as allografts. Here we report for the first time the inability of porcine (and human) insulin to control blood glucose levels in diabetic rodents determined by a series of dose escalating studies. Methods: Insulin was administered intravenously to streptozotocin induced diabetic Lewis rats, Balb/c and athymic Balb/c mice (n = 5 per group) at the following doses: Group I “physiological dose” (pd) of 0.16 U/kg for a total dose of 40 mU to a 250 g rat. Group II received 0.64 U/kg (4xpd), group III 1.6 U/kg (10xpd) and group IV 6.4 U/kg (40xpd). Blood glucose levels were monitored in each animal at seven time points: 0 (pre‐injection), 10 min, 20 min, 30 min, 45 min, 1 h, 1.5 h, 2 h and 3 h post‐injection. Serum insulin levels were also determined. Results: Diabetic Lewis rats achieved a maximum reduction in blood glucose from 22.1 ± 1.8mmol/l to 8.0 ± 3.1 mmol/l (a 63.7% reduction), 90 minutes post‐injection of 6.4 U/kg dose of porcine insulin (40xpd). Human insulin was less effective at reducing blood glucose levels in rats than porcine insulin (P