Diabetic neuropathy is a major complication of diabetes mellitus affecting skeletal muscle and peripheral nerve. Electrophysiological and histochemical investigations have shown that the changes which occur in muscle resemble those observed in the denervated state. There is, however, some question as to whether skeletal muscle alterations in diabetic neuropathy are due to: (1) denervation by disturbance of motor innervation or (2) direct effects on muscle by insulin deficiency and generalized hormone and metabolic imbalance. Denervated skeletal muscle demonstrates plasma membrane alterations. Studies I have completed show biochemical alterations in the sarcolemma to include: decreased membrane density, increased sialoglycoprotein and acetylcholine receptor content, and decreased catecholamine ad guanylyl nucleotide activated adenyl cyclase activity. In an attempt to gain insight on the origin of skeletal muscle dysfunction in diabetes, I plan to investigate sarcolemmal membrane biochemical alterations in diabetic rats. The immediate objective will be to detect membrane alterations prior to demonstrable changes in axonal conduction velocity and amplitude of the action potential. Biochemical studies will emphasize characterization of the insulin and catecholamine receptor and activation of adenyl cyclase activity. Modulation of adenyl cyclase activity by the guanylyl nucleotides and possible inhibition by insulin will be assessed. This work will be complemented by studies on sarcolemmal structural constituents to ascertain alterations in membrane protein-lipid composition which may eventually be related to abnormal receptor-effector enzyme function in the diabetic state. The overall results of these studies will provide information on the: (1) possible early myopathic factors operating at the membrane level in diabetic neuropathy and (2) plasma membrane alterations in disease processes of excitable tissue.