Effects of the dual PPAR-α/γ agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat.

AIMS: To evaluate the effects of aleglitazar, a dual peroxisome proliferator-activated receptor-α/γ agonist, on the development of diabetes-related organ dysfunction, in relation to glycaemic and lipid changes, in Zucker diabetic fatty (ZDF) rats. METHODS: Six-week-old, male ZDF rats received aleglitazar 0.3 mg/kg/day or vehicle as food admix for 13 weeks (n = 10 per group). Age-matched male Zucker lean rats served as non-diabetic controls. Plasma and renal markers were measured at several time points. Histopathology and quantitative immunohistochemistry were performed at 13 weeks. RESULTS: Glycated haemoglobin (5.4 vs. 9.2%) and blood glucose (8.3 ± 0.3 vs. 26.1 ± 1.0 mmol/l) were significantly reduced at 12 weeks with aleglitazar versus vehicle-treated ZDF rats (both p < 0.01), while aleglitazar preserved near-normal plasma insulin levels. Aleglitazar prevented the development of hypertriglyceridaemia (1.4 ± 0.1 vs. 8.5 ± 0.9 mmol/l) and reduced plasma non-esterified fatty acids (0.09 ± 0.02 vs. 0.26 ± 0.04 mmol/l) relative to vehicle-treated animals (both p < 0.01). Urinary glucose and protein concentrations were significantly reduced at 13 weeks with aleglitazar versus vehicle-treated rats (both p < 0.01). Consistent with its effect on glycaemic control, aleglitazar protected ß-cell morphology, as evidenced by preservation of islet integrity, and reduction of ß-cell apoptosis and islet fibrosis. Aleglitazar prevented renal glomerular hypertrophy, podocyte degeneration, glomerulosclerosis, tubulo-interstitial lesions and development of cataracts. CONCLUSIONS: Aleglitazar strongly improved glycaemic and lipid parameters while protecting key tissues, including the pancreas, kidneys and eyes, against diabetes-associated structural and functional changes in the ZDF rat.

Of mice and mutations: phenotypic effects of the diabetic db/db and ob/ob mutations on the skull and teeth of mice.

AIM: To compare the phenotypic appearance of the skull bones and teeth of wild type C57BL/6J mice with that of diabetic leptin-deficient (ob/ob) and diabetic leptin receptordeficient (db/db) mice used as models for diabetes. STUDY DESIGN AND METHODS: Skulls were extracted from the carcasses of mice belonging to wild-type C57B/6J mice, db/db mice on a C57BLKS/J background, and ob/ob mice on a C57B/6J background. After removal of overlying tissue, the skulls and mandibles were then left to dehydrate and examined for phenotypic variations in structure and wear. RESULTS: Bone surfaces of the skulls of wild type mice had a whiter and smoother surface compared with a yellowish colour with a grainy texture in the two mutant strains. The frontal, parietal and occipital bones were translucent in the two mutant strains. Breakages of the zygomatic arches and mandibles were more common in the ob/ob and db/db mice than in the wild type mice. Half of the teeth of the db/db mice and 90% teeth of the ob/ob mice showed considerable wear compared with marginal wear in the wild type mice. CONCLUSIONS: These observations suggested that the teeth of the two diabetic mutant strains are exhibiting considerable signs of hypomineralization with increased fragility and decreased bone thickness.

Enamel mineral concentration in diabetic rodents.

AIM: This was to use x-ray microtomography (XMT), to assess the mineral composition and 3-D structure of enamel and bone in the teeth and skulls of diabetic rodents. METHODS: Three-dimensional images of the skull were reconstructed using computer generated false colour to highlight different levels of mineralization in bone and enamel. RESULTS: These showed that diabetic rodents exhibited more wear in their teeth. Deformities were observed in the alveolar process of the mandible and maxilla. Regions of extensive hypomineralization were found in the calvarial bone of skulls. The maximum mineral concentrations and the time constants for diabetic rodents were similar to the controls. The diabetic mice appeared to have random regions of hypomineralization and one diabetic rat had areas of hypoplasia in the mandibular incisors. CONCLUSIONS: Diabetes may have a detrimental influence on the function of ameloblasts in laying down enamel.

Defective enamel ultrastructure in diabetic rodents.

We investigated six different types of diabetic rodents. Four expressed a genetic obesity resulting in diabetes. One developed diabetes induced by a diet-dependent obesity, and one with genetic diabetes received anti-diabetic medication. The tooth samples were examined under a scanning electron microscope and with an energy dispersive microanalysis (EDX). The electron micrographs showed severe, varying degrees of damage within the six different diabetic animal types, such as irregular crystallite deposition and prism perforations in genetically obese animals compared to less-disordered prism structures in diet-dependent obesity. Anti-diabetic medication resulted in normal enamel ultrastructure. The EDX analysis revealed a reduction in the amount of calcium and phosphorus in all regions affected by diabetes. Based on these animal studies, we suggest that both juvenile diabetes type I (in infants) and adult diabetes type II (in pregnant mothers, affecting the developing foetus) may affect the normal development of teeth in humans.