Neonatal STZ model of type II diabetes mellitus in the Fischer 344 rat: characteristics and assessment of the status of the hepatic adrenergic receptors

The Fischer 344 rat was found to be extremely sensitive to the diabetogenic effects of neonatally injected streptozotocin (STZ): injection of 40-100 m g/kg STZ at 1.5 days postnatal produced in the adult graded levels of hyper glycemia in males but not the females. The optimal dose in the 1.5 day old male was 80 mg/kg: it produced hyperglycemia without affecting growth or th yroid status in the adult. The neonatally STZ-injected adult rat displayed characteristics consistent with type II diabetes: mild hyperglycemia accent uated by fasting or consumption of a high fat diet; little change in insuli n levels; slight elevation in glucagon levels; no alterations in ketones. U sing radioligand binding techniques to isolated rat liver plasma membranes, compared to the control state, the type II diabetic state was found to hav e: no effect on either alpha(2)- or beta-adrenergic receptor binding; a dec rease in the major dominant alpha(1)-adrenergic receptor, reflecting a decr ease in receptor numbers but not their affinity; an increase in the plasma membrane calcium transport system, potentially depleting intracellular calc ium stores essential for producing an alpha(1)-adrenergic receptor response . Since the alpha(1)-adrenergic receptor-calcium effector system is critica l for the actions of catecholamines in the rat, these results suggest that the liver in the type II diabetic state may be refractory to the actions of catecholamines. We propose that the diabetes-evoked decrease in the domina nt adrenergic receptor-effector system through which catecholamines act may be the cellular expression of defective glucocounrerregulation in the diab etic stale. (C) 2000 Elsevier Science Ltd. All rights reserved.