The newly inbred Cohen diabetic rat is an exceptional experimental model of diet-induced type 2 diabetes mellitus that is the result of secondary inbreeding nearly 30 years after it originally had been established. Animals from the original colony were selectively inbred by stringent criteria for 10 additional generations, bringing overall inbreeding to >50 generations. The metabolic phenotypes of the resulting contrasting strains, designated as the Cohen diabetic-sensitive (CDs) and -resistant (CDr) rats, were characterized. The phenotype of the CDs strain that was fed a regular diet consisted of fasting normoglycemia, normal glucose tolerance to intraperitoneal glucose loading, normal fasting insulin levels, and a normal insulin response to glucose loading. In contrast, CDs rats that were fed a custom-prepared high-sucrose low-copper diabetogenic diet became overtly diabetic: fasting glucose levels were normal or elevated, and the blood glucose insulin response to glucose loading was markedly abnormal. CDr rats that were fed a regular or diabetogenic diet did not develop diabetes and maintained normal glucose tolerance and insulin secretion. A striking sex difference was observed in CDs rats that were fed a diabetogenic diet: males had a lower growth rate and a more severe glucose intolerance pattern than females. Gonadectomy shortly after weaning did not prevent the development of the diabetic phenotype in its early phase in either sex but markedly attenuated its expression in males at a later phase, abolishing the sex differences. Alternate-day feeding, as opposed to daily feeding, also attenuated the metabolic phenotype in males. The development of the diabetic phenotype in CDs rats that were fed a diabetogenic diet was not accompanied by obesity or hyperlipidemia. The genetic profile of the strains was established using 550 microsatellite markers evenly distributed throughout the rat genome. The rate of homozygosity within strain was >96%. The rate of polymorphism between the contrasting strains was 43%. We conclude that the metabolic phenotypes of the rebred colony of CDs and CDr rats and their genetic makeup render the Cohen diabetic rat a useful experimental model that is highly suitable for studying the interaction between nutritional-metabolic environmental factors and genetic susceptibility (sensitivity and resistance) for the development of type 2 diabetes. The model is also distinctively useful for investigating the effect of sex on the expression of the diabetic phenotype.

I . Two strains of rabbits have been bred with marked differences in their cardiac baroreflex sensitivity (BRS). The difference in cardiac BRS was attenuated by naloxone. We compared the sympathetic responses to a pressor stimulus in these two strains, by measuring the changes in plasma catecholamines in the presence and absence of naloxone.2. Cardiac BRS was assessed in eight rabbits of each group by the steady-state method. Two weeks later, both ear arteries and one ear vein were cannulated. Mean arterial pressure (MAP) and heart rate (HR) were recorded from one artery and blood samples ( 5 mL) for plasma catecholamines (CA) taken before, and during the peak of the pressor response to intravenous phenylephrine (PE, 20 pg/kg) from the other. The experiment was repeated 2-3 weeks later in rabbits with high BRS (Group I) after injection of naloxone 0.1 mg/kg, i.v.3. Resting MAP and HR did not differ in the two groups. The mean gains of the cardiac baroreflex were 23.3 -t 2.2 ms/mmHg in Group I and 6.3 k I . 1 ms/mmHg in Group 11. After PE, MAP rose by 54.5 * 1.8 mmHg in Group I1 and 40.3 t 3.6 mmHg in Group I (Pt0.02). The pressor response was associated with a 3 I % reduction in plasma noradrenaline (NA) in Group I and a 34% increase in Group 11. The reduction in NA was significantly correlated with the degree of bradycardia in Group I (r=0.72, Pt0.05) and with BRS in both groups (r=0.78, PtO.01). Naloxone reduced BRS in Group I to 8.2 f 1.0 ms/mmHg and virtually abolished the fall in plasma NA in response to PE. 4. We suggest that stimulation of cardiopulmonary afferents by a strong pressor stimulus in Group I rabbits results in sympathetic inhibition which involves the mediation of opioid peptides.