Diabetes, Vol 43, Issue 4 511-517, Copyright © 1994 by American Diabetes Association

ARTICLES

What beta-cell defect could lead to hyperproinsulinemia in NIDDM? Some clues from recent advances made in understanding the proinsulin-processing mechanism

CJ Rhodes and C Alarcon
E.P. Joslin Research Laboratory, Joslin Diabetes Center, Brigham and Women's Hospital, Boston, Massachusetts 02215.

Pancreatic beta-cell dysfunction is a characteristic of non-insulin-dependent diabetes mellitus (NIDDM). An aspect of this dysfunction is that an increased proportion of proinsulin is secreted, but an actual beta-cell defect that leads to hyperproinsulinemia is unknown. Nevertheless, an impairment in beta-cell proinsulin conversion mechanism has been suggested as the most likely cause. Insulin is produced from its precursor molecule, proinsulin, by limited proteolytic cleavage at two dibasic sequences (Arg31, Arg32 and Lys64, Arg65). Two endopeptidase activities catalyze this cleavage: PC2 and PC3. PC2 endopeptidase cleaves predominately at Lys64, Arg65, and PC3 endopeptidase cleaves at Arg31, Arg32. The recent identification and characterization of these endopeptidases has enabled a better understanding of the human proinsulin-processing mechanism. In particular, experimental evidence suggests that the majority of human proinsulin processing is sequential. PC3 cleaves proinsulin first to generate a proinsulin conversion intermediate that is the preferred substrate of PC2. Both PC2 and PC3 activities are influenced by Ca2+ and pH, but the more stringent Ca2+ and pH requirements of PC3 suggest it as the most likely enzyme to regulate proinsulin conversion, as well as initiate it. When an increased demand is placed on the proinsulin-processing mechanism by a glucose-stimulated increase in proinsulin biosynthesis, there is a coordinate increase in PC3 biosynthesis (but not in PC2). This supports PC3 as the key endopeptidase that regulates proinsulin processing. In this perspective, the current concepts of the enzymology and regulation of proinsulin conversion at a molecular level are reviewed.(ABSTRACT TRUNCATED AT 250 WORDS)
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D.-J. Kim and E. Barrett-Connor Association of serum proinsulin with hormone replacement therapy in nondiabetic older women: the rancho bernardo study. Diabetes Care, March 1, 2006; 29(3): 618 - 624. [Abstract] [Full Text] [PDF]

				K. Huang, J. Dong, N. B. Phillips, P. R. Carey, and M. A. Weiss Proinsulin Is Refractory to Protein Fibrillation: TOPOLOGICAL PROTECTION OF A PRECURSOR PROTEIN FROM CROSS-{beta} ASSEMBLY J. Biol. Chem., December 23, 2005; 280(51): 42345 - 42355. [Abstract] [Full Text] [PDF]

				M. E. Roder and S. E. Kahn Suppression of Beta-Cell Secretion by Somatostatin Does Not Fully Reverse the Disproportionate Proinsulinemia of Type 2 Diabetes Diabetes, December 1, 2004; 53(suppl_3): S22 - S25. [Abstract] [Full Text] [PDF]

				B. Zethelius, C. N. Hales, H. O. Lithell, and C. Berne Insulin Resistance, Impaired Early Insulin Response, and Insulin Propeptides as Predictors of the Development of Type 2 Diabetes: A population-based, 7-year follow-up study in 70-year-old men Diabetes Care, June 1, 2004; 27(6): 1433 - 1438. [Abstract] [Full Text] [PDF]

				L. Marzban, G. Trigo-Gonzalez, X. Zhu, C. J. Rhodes, P. A. Halban, D. F. Steiner, and C. B. Verchere Role of {beta}-Cell Prohormone Convertase (PC)1/3 in Processing of Pro-Islet Amyloid Polypeptide Diabetes, January 1, 2004; 53(1): 141 - 148. [Abstract] [Full Text] [PDF]

				S. H. Song, C. J. Rhodes, J. D. Veldhuis, and P. C. Butler Diazoxide Attenuates Glucose-Induced Defects in First-Phase Insulin Release and Pulsatile Insulin Secretion in Human Islets Endocrinology, August 1, 2003; 144(8): 3399 - 3405. [Abstract] [Full Text] [PDF]

				A. J. G. Hanley, G. McKeown-Eyssen, S. B. Harris, R. A. Hegele, T. M. S. Wolever, J. Kwan, and B. Zinman Cross-Sectional and Prospective Associations between Abdominal Adiposity and Proinsulin Concentration J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 77 - 83. [Abstract] [Full Text] [PDF]

				S. E. Kahn The Importance of {beta}-Cell Failure in the Development and Progression of Type 2 Diabetes J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4047 - 4058. [Full Text] [PDF]

				M. Stumvoll, A. Fritsche, N. Stefan, E. Hardt, and H. Häring Evidence against a Rate-Limiting Role of Proinsulin Processing for Maximal Insulin Secretion in Subjects with Impaired Glucose Tolerance and {beta}-Cell Dysfunction J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1235 - 1239. [Abstract] [Full Text]

				J. Wang, J. Xu, J. Finnerty, M. Furuta, D. F. Steiner, and C. B. Verchere The Prohormone Convertase Enzyme 2 (PC2) Is Essential for Processing Pro-Islet Amyloid Polypeptide at the NH2-Terminal Cleavage Site Diabetes, March 1, 2001; 50(3): 534 - 539. [Abstract] [Full Text]

				P. Houssa, B. Dinesen, M. Deberg, B. H. Frank, C. Van Schravendijk, F. Sodoyez-Goffaux, and J.-C. Sodoyez First direct assay for intact human proinsulin Clin. Chem., July 1, 1998; 44(7): 1514 - 1519. [Abstract] [Full Text] [PDF]

				Y. Zambre, Z. Ling, X. Hou, A. Foriers, B. Van Den Bogaert, C. Van Schravendijk, and D. Pipeleers Effect of Glucose on Production and Release of Proinsulin Conversion Products by Cultured Human Islets J. Clin. Endocrinol. Metab., April 1, 1998; 83(4): 1234 - 1238. [Abstract] [Full Text]

				M. Furuta, R. Carroll, S. Martin, H. H. Swift, M. Ravazzola, L. Orci, and D. F. Steiner Incomplete Processing of Proinsulin to Insulin Accompanied by Elevation of Des-31,32 Proinsulin Intermediates in Islets of Mice Lacking Active PC2 J. Biol. Chem., February 6, 1998; 273(6): 3431 - 3437. [Abstract] [Full Text] [PDF]

				M. E. Røder, D. Porte Jr., R. S. Schwartz, and S. E. Kahn Disproportionately Elevated Proinsulin Levels Reflect the Degree of Impaired B Cell Secretory Capacity in Patients with Noninsulin-Dependent Diabetes Mellitus J. Clin. Endocrinol. Metab., February 1, 1998; 83(2): 604 - 608. [Abstract] [Full Text]

				M. G. Warren-Perry, S. E. Manley, D. Ostrega, K. Polonsky, S. Mussett, P. Brown, and R. C. Turner A Novel Point Mutation in the Insulin Gene Giving Rise to Hyperproinsulinemia J. Clin. Endocrinol. Metab., May 1, 1997; 82(5): 1629 - 1631. [Abstract] [Full Text] [PDF]

				B Thorens and J Roth Intracellular targeting of GLUT4 in transfected insulinoma cells: evidence for association with constitutively recycling vesicles distinct from synaptophysin and insulin vesicles J. Cell Sci., January 6, 1996; 109(6): 1311 - 1323. [Abstract] [PDF]

				S. O'Rahilly, H. Gray, P. J. Humphreys, A. Krook, K. S. Polonsky, A. White, S. Gibson, K. Taylor, and C. Carr Impaired Processing of Prohormones Associated with Abnormalities of Glucose Homeostasis and Adrenal Function N. Engl. J. Med., November 23, 1995; 333(21): 1386 - 1391. [Full Text] [PDF]