Amitraz is a formamidine insecticide/acaricide widely used to treat mange in animals and to spray orchards. Amitraz poisonings in humans as well as animals have been reported. Hyperglycemia due to inhibition of insulin release is the most frequently detected toxic effect of amitraz in dogs. Because dogs are a good animal model for human diabetes, humans may develop hyperglycemia when exposed to amitraz. Patients with non-insulin-dependent diabetes mellitus (NIDDM, Type II), i.e., individuals who have impaired insulin secretion and/or utilization should be particularly at risk. There are at least 10 million such patients in the U.S. The chances that these patients may be affected by amitraz are real and must not be overlooked. The results of proposed studies will: 1) provide information which is essential in elucidating the mechanism(s) by which amitraz inhibits insulin release, and 2) serve to establish an in vitro model to define preventive measures and treatment for patients, particularly those with NIDDM, who are exposed to this pesticide. Our working hypothesis is that 1) amitraz (including its metabolites), inhibits insulin release by decreasing Ca 2+ """"""""influx through voltage-dependent Ca 2+ """"""""channels into the beta-cells of the pancreatic islet, and 2) the inhibition of insulin release by amitraz is mediated by alpha2-adrenergic receptors in the plasma membrane via guanine-nucleotide binding proteins (G-proteins). Hamster insulin-secreting tumor (HIT) cells will be used in these studies to determine the effects of amitraz and its metabolites on: 1) insulin release, 2) cytosolic free calcium concentrations ([Ca 2+]i), 3) Ca 2 + currents associated with voltage-dependent Ca 2+' channels, and 4) K efflux. An increase in K+ efflux could indirectly activate voltage-dependent Ca 2+, channels by causing hyperpolarization of the plasma membrane.
