Prevention of Postprandial Hyperglycemia by Ophthalmic Nanoparticles Based on Protamine Zinc Insulin in the Rabbit

Postprandial hyperglycemia, a so-called blood glucose spike, is associated with enhanced risks of diabetes mellitus (DM) and its complications. In this study, we attempted to design nanoparticles (NPs) of protamine zinc insulin (PZI) by the bead mill method, and prepare ophthalmic formulations based on the PZI-NPs with (nPZI/P) or without polyacrylic acid (nPZI). In addition, we investigated whether the instillation of the newly developed nPZI and nPZI/P can prevent postprandial hyperglycemia in a rabbit model involving the oral glucose tolerance test (OGTT). The particle size of PZI was decreased by the bead mill to a range for both nPZI and nPZI/P of 80–550 nm with no observable aggregation for 6 d. Neither nPZI nor nPZI/P caused any noticeable corneal toxicity. The plasma INS levels in rabbits instilled with nPZI were significantly higher than in rabbits instilled with INS suspensions (commercially available formulations, CA-INS), and the plasma INS levels were further enhanced with the amount of polyacrylic acid in the nPZI/P. In addition, the rapid rise in plasma glucose levels in OGTT-treated rabbits was prevented by a single instillation of nPZI/P, which was significantly more effective at attenuating postprandial hyperglycemia (blood glucose spike) in comparison with nPZI. In conclusion, we designed nPZI/P, and show that a single instillation before OGTT attenuates the rapid enhancement of plasma glucose levels. These findings suggest a better management strategy for the postprandial blood glucose spike, which is an important target of DM therapy.

Prospective evaluation of a protocol for transitioning porcine lente insulin-treated diabetic cats to human recombinant protamine zinc insulin

Objectives The objective was to evaluate a nadir-led protocol for transitioning porcine lente insulin suspension (PLIS)-treated diabetic cats onto human recombinant protamine zinc insulin (PZIR). Methods Recently diagnosed (<5 months) diabetic cats, treated with PLIS q12h for ⩾6 weeks, were recruited. Fructosamine, 24 h blood glucose curve (BGC), quality of life assessment (DIAQoL-pet score) and Diabetic Clinical Score (DCS) were assessed at enrolment (PLIS-treated) and 2, 4 and 12 weeks after transitioning to PZIR (starting dose 0.2–0.7 U/kg q12h). Short duration of insulin action was defined as <9 h. Linear mixed effects modelling assessed for change in fructosamine, mean blood glucose (MBG) during BGCs, DIAQoL-pet score, DCS and q12h insulin dose. McNemar’s tests compared the proportion of cats with hypoglycaemia at week 0 (PLIS-treated) and week 4 (PZIR-treated). Results Twenty-two cats were recruited. Median PLIS dose at enrolment was 0.5 U/kg (interquartile range 0.3–0.7 U/kg) q12h, equalling median PZIR starting dose (0.5 U/kg; interquartile range 0.3–0.7 U/kg q12h). Transitioning was followed by significant decreases in fructosamine ( P = 0.00007), insulin dose ( P = 0.02), DCS ( P = 8.1 × 10−8) and DIAQoL-pet score ( P = 0.003), indicating improved quality of life. MBG did not alter significantly ( P = 0.1). Five cats (22.7%) achieved remission. Hypoglycaemia was recorded in 30/190 12 h BGCs (15.8%) and five cats experienced clinical hypoglycaemia. The proportion of cats with hypoglycaemia did not differ between PLIS (week 0) and PZIR (week 4) ( P = 1.0). Duration of action was analysed in 19 cats. Six cats (31.6%) showed short duration of action on PLIS, compared with two cats (10.5%) after 4 weeks on PZIR. All six cats with short PLIS duration showed duration of ⩾9 h on PZIR. Conclusions and relevance Used alongside a low-carbohydrate diet, transitioning to PZIR was associated with significantly improved clinical signs and quality of life, with some cats achieving remission. Transition to PZIR should be considered for cats with short duration of action on PLIS.

Obesity in Osborne-Mendel and S 5B/Pl rats: effects of sucrose solutions, castration, and treatment with estradiol or insulin

S 5B/Pl rats were tested for their susceptibility to develop obesity when 1) ovariectomized, 2) given injections of insulin, and 3) given a sucrose solution to drink instead of water. The results obtained in Osborne-Mendel rats susceptible to dietary obesity when fed a high-fat diet were compared to those obtained in the S 5B/Pl rats not susceptible to dietary obesity. When tested at the end of 10 wk, ovariectomized rats of both strains had gained 22% more weight than sham-operated controls. Replacement estradiol injections suppressed food intake in both strains with a concomitant loss in body weight. Osborne-Mendel rats tolerated at least 40 U of U-100 protamine zinc insulin/day and rapidly gained weight whereas S 5B/Pl rats given more than 2 U U-100 protamine zinc insulin/day died. Compared to female Osborne-Mendel rats drinking water, rats drinking a sucrose solution accumulated more body fat and had higher levels of serum immunoreactive insulin and lower levels of serum free fatty acids. The substitution of a sucrose solution for plain drinking water suppressed weight gain in S 5B/Pl rats.