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Processing of Pro-Islet Amyloid Polypeptide in the Constitutive and Regulated Secretory Pathways of ß Cells

Department of Pathology and Laboratory Medicine & British Columbia Research Institute for Children’s and Women’s Health, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4

Address all correspondence and requests for reprints to: Dr. C. Bruce Verchere, British Columbia Research Institute for Children’s and Women’s Health, 3084-950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4. E-mail: verchere{at}interchange.ubc.ca.

Islet amyloid is a pathologic characteristic of the pancreas in type 2 diabetes comprised mainly of the ß-cell peptide islet amyloid polypeptide (IAPP; amylin). We used a pulse-chase approach to investigate the kinetics of processing and secretion of the IAPP precursor, proIAPP, in ß cells. By only 20 min after synthesis, a COOH-terminally processed proIAPP intermediate (6 kDa) was already present in ß cells. Formation of this NH₂-terminally extended intermediate was not prevented by arresting secretory pathway transport at the trans-Golgi network (TGN) by either brefeldin A or temperature blockade, suggesting that this initial cleavage step occurs in the TGN before entry of (pro)IAPP into granules. Mature IAPP (4 kDa) was not detected until 60 min of chase, suggesting that NH₂-terminal cleavage occurs in granules. Cells chased in low glucose without Ca²⁺ or with diazoxide, to block regulated release, secreted both proIAPP (8 kDa) and a partially processed form (6 kDa) via the constitutive secretory pathway. Stimulation of regulated secretion resulted in secretion primarily of mature IAPP as well as low levels of both unprocessed (8 kDa) and partially processed (6 kDa) proIAPP. We conclude that normal processing of proIAPP is a two-step process initiated by cleavage at its COOH terminus (likely by prohormone convertase 1/3 in the TGN) followed by cleavage at its NH₂ terminus (by prohormone convertase 2 in granules) to form IAPP. Both proIAPP and its NH₂-terminally extended intermediate appear to be normal secretory products of the ß cell that can be released via either the regulated or constitutive secretory pathways.

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