Rat Models of Human Type 1 Diabetes.

Rat models of human type 1 diabetes have been shown to be of great importance for the elucidation of the mechanisms underlying the development of autoimmune diabetes. The three major well-established spontaneous rat models are the BioBreeding (BB) diabetes-prone rat, the Komeda diabetes-prone (KDP) rat, and the IDDM (LEW.1AR1-iddm) rat. Their distinctive features are described with special reference to their pathology, immunology, and genetics and compared with the situation in patients with type 1 diabetes mellitus. For all three established rat models, a distinctive genetic mutation has been identified that is responsible for the manifestation of the diabetic syndrome in these rat strains.

Dietary copper supplementation restores ß-cell function of Cohen diabetic rats: a link between mitochondrial function and glucose-stimulated insulin secretion.

ß-Cell mitochondrial dysfunction as well as proinflammatory cytokines have been suggested to contribute to reduced glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. We recently demonstrated that Cohen diabetic sensitive (CDs) rats fed a high-sucrose, low-copper diet (HSD) developed hyperglycemia and reduced GSIS in association with peri-islet infiltration of fat and interleukin (IL)-1ß-expressing macrophages, whereas CD resistant (CDr) rats remained normoglycemic on HSD. We examined: 1) the correlation between copper concentration in the HSD and progression, prevention, and reversion of hyperglycemia in CDs rats, 2) the relationship between activity of the copper-dependent, respiratory-chain enzyme cytochrome c oxidase (COX), infiltration of fat, IL-1ß-expressing macrophages, and defective GSIS in hyperglycemic CDs rats. CDs and CDr rats were fed HSD or copper-supplemented HSD before and during hyperglycemia development. Blood glucose and insulin concentrations were measured during glucose tolerance tests. Macrophage infiltration and IL-1ß expression were evaluated in pancreatic sections by electron-microscopy and immunostaining. COX activity was measured in pancreatic sections and isolated islets. In CDs rats fed HSD, GSIS and islet COX activity decreased, while blood glucose and infiltration of fat and IL-1ß-expressing macrophages increased with time on HSD (P < 0.01 vs. CDr-HSD rats, all parameters, respectively). CDs rats maintained on copper-supplemented HSD did not develop hyperglycemia, and in hyperglycemic CDs rats, copper supplementation restored GSIS and COX activity, reversed hyperglycemia and infiltration of fat and IL-1ß-expressing macrophages (P < 0.01 vs. hyperglycemic CDs-HSD rats, all parameters, respectively). We provide novel evidence for a critical role of low dietary copper in diminished GSIS of susceptible CDs rats involving the combined consequence of reduced islet COX activity and pancreatic low-grade inflammation.

Diabetes prevention by immunomodulatory FTY720 treatment in the LEW.1AR1-iddm rat despite immune cell activation.

The prevention of diabetes by the immunomodulatory agent FTY720 (fingolimod) was studied in the LEW.1AR1-iddm (IDDM) rat, an animal model of human type 1 diabetes. Immune cell subtypes and cytokine profiles in pancreatic islets, secondary lymphoid tissue, and serum were analyzed for signs of immune cell activation. Animals were treated with FTY720 (1 mg/kg body weight) for 40 d starting on d 50 of life. Changes in gene and protein expression of cytokines, CD8 markers, monocyte chemoattractant protein-1, inducible NO synthase, and caspase 3 were evaluated. Treatment with FTY720 prevented diabetes manifestation and islet infiltration around d 60 of life, the usual time of spontaneous diabetes development. On d 120, 30 d after the end of FTY720 therapy, diabetes prevention persisted. However, six of 12 treated animals showed increased gene expression of IL-1beta, TNF-alpha, and CD8 markers in pancreas-draining lymph nodes, indicating immune cell activation. In parallel, serum concentrations of these proinflammatory cytokines were increased. These six animals also showed macrophage infiltration without proinflammatory cytokine expression in a small minority (2-3%) of islets. Interestingly, regulatory T lymphocytes were significantly increased in the efferent vessels of the pancreas-draining lymph nodes only in animals without signs of immune cell activation but not in the rats with immune cell activation. This provides an indication for a lack of protective capacity in the animals with activated immune cells. Thus, FTY720 treatment prevented the manifestation of diabetes by promoting the retention of activated immune cells in the lymph nodes, thereby avoiding islet infiltration and beta-cell destruction by proinflammatory cytokines.

Prevention of nutritionally induced diabetes by rosiglitazone in the gerbil Psammomys obesus.

BACKGROUND: Psammomys obesus is a desert gerbil developing hyperglycaemia, hyperinsulinaemia and insulin resistance when placed for 2 weeks on a high-energy (HE) diet. The mechanism underlying the antidiabetic effect of rosiglitazone (RG) treatment (20 mg/kg per day for 2 weeks) was studied. METHODS: The antidiabetogenic effect of RG treatment on serum insulin and metabolic parameters in serum and target tissues of insulin action was investigated in vivo and compared with the pancreatic beta cell protective effects of RG. RESULTS: Almost all RG-treated animals remained normoglycaemic compared to controls, but, at the same time, they were hyperinsulinaemic. RG had no effect on serum free fatty acid and serum and muscle triglyceride concentrations and did not appreciably affect body weight and fat depots. RG prevented a HE diet-induced reduction of GLUT 4 glucose transporter content in epididymal adipose tissue, but not in gastrocnemius muscle. The normoglycaemic effect was not associated with a suppression of liver PEPCK activity. Muscle PKCepsilon expression, known to be elevated in diabetic Psammomys and to inhibit insulin signalling, was only marginally decreased. However, RG treatment prevented the marked decrease in insulin immunostaining as well as the vacuolization of the beta cells and accelerated beta cell proliferation. CONCLUSIONS: These data indicate that the skeletal muscle is not the primary target of RG action, whereas the preservation of the insulin secretory capacity and the prevention of degenerative beta cell vacuolization in spite of persisting insulin resistance appear to be the basis for the anti-hyperglycaemic effect of RG in Psammomys.