Differences between renal tubular processing of glucagon and insulin

Renal processing of glucagon and insulin was compared. Iodinated glucagon (mol wt 3,674, linear molecule) or insulin (mol wt 6,000, two chains with disulfide bonds) was microinfused into surface nephrons of the rat kidney, and the radiolabel recovered in the urine was quantified and characterized. Proximal but not distal reabsorption of both peptides was observed, and uptake varied similarly as a function of tubular length. After proximal microinfusion, [125I]glucagon was largely degraded to [125I]tyrosine in the urine, but remained intact after distal infusion. [125I]Insulin was recovered as intact peptide following both proximal and distal microinfusion. Prolonged tubular sequestration of 125I label was observed following proximal microinfusion of [125I]insulin, with efflux requiring longer than 1 h for completion. No measurable cellular sequestration of [125I]glucagon was observed. Incubation of both peptides with rabbit renal microvilli membranes resulted in enzymatic hydrolysis of [125I]glucagon but relatively little or no degradation of [125I]insulin. It is concluded that glucagon and insulin are reabsorbed in the proximal tubule by predominantly different mechanisms.