Insulin Secretory Function Is Impaired in Isolated Human Islets Carrying the Gly972→Arg IRS-1 Polymorphism
- Piero Marchetti1,
- Roberto Lupi1,
- Massimo Federici2,
- Lorella Marselli1,
- Matilde Masini4,
- Ugo Boggi4,
- Silvia Del Guerra1,
- Giovanni Patanè1,
- Salvatore Piro3,
- Marcello Anello3,
- Ettore Bergamini4,
- Francesco Purrello3,
- Renato Lauro2,
- Franco Mosca4,
- Giorgio Sesti5 and
- Stefano Del Prato1
- 1Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
- 2Department of Internal Medicine, University of Rome “Tor Vergata,” Rome, Italy
- 3Department of Endocrinology, University of Catania, Catania, Italy
- 4Department of General Pathology, University of Pisa, Pisa, Italy
- 5Department of Clinical and Experimental Medicine, University of Catanzaro “Magna Graecia,” Catanzaro, Italy
Abstract
Type 2 (non–insulin-dependent) diabetes results from decreased insulin action in peripheral target tissues (insulin resistance) and impaired pancreatic β-cell function. These defects reflect both genetic components and environmental risk factors. Recently, the common Gly972→Arg amino acid polymorphism of insulin receptor substrate 1 (Arg972 IRS-1) has been associated with human type 2 diabetes. In this study, we report on some functional and morphological properties of isolated human islets carrying the Arg972 IRS-1 polymorphism. Insulin content was lower in variant than control islets (94 ± 47 vs. 133 ± 56 μU/islet; P < 0.05). Stepwise glucose increase (1.7 to 16.7 mmol/l) significantly potentiated insulin secretion from control islets, but not Arg972 IRS-1 islets, with the latter also showing a relatively lower response to glyburide and a significantly higher response to arginine. Proinsulin release mirrored insulin secretion, and the insulin-to-proinsulin ratio in response to arginine was significantly lower from Arg972 IRS-1 islets than from control islets. Glucose utilization and oxidation did not differ in variant and wild-type islets at both low and high glucose levels. Electron microscopy showed that Arg972 IRS-1 β-cells had a severalfold greater number of immature secretory granules and a lower number of mature granules than control β-cells. In conclusion, Arg972 IRS-1 islets have reduced insulin content, impaired insulin secretion, and a lower amount of mature secretory granules. These alterations may account for the increased predisposition to type 2 diabetes in individuals carrying the Gly972→Arg amino acid polymorphism of IRS-1.
Footnotes
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Address correspondence and reprint requests to Piero Marchetti, MD, Department of Endocrinology and Metabolism, Metabolic Unit, Ospedale Cisanello, via Paradisa 2, 56100 - Pisa, Italy. E-mail: marchant{at}immr.med.unipi.it.
Received for publication 26 June 2001 and accepted in revised form 14 January 2002.
HBSS, Hanks’ balanced salt solution; IRS-1, insulin receptor substrate 1; PC 1/3, prohormone convertase 1/3; PDX-1, pancreatic duodenal homeobox 1; PI, phosphatidylinositol.
- DIABETES
