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Insulin Secretory Function Is Impaired in Isolated Human Islets Carrying the Gly⁹⁷²Arg IRS-1 Polymorphism

¹ Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
² Department of Internal Medicine, University of Rome "Tor Vergata," Rome, Italy
³ Department of Endocrinology, University of Catania, Catania, Italy
⁴ Department of General Pathology, University of Pisa, Pisa, Italy
⁵ Department of Clinical and Experimental Medicine, University of Catanzaro "Magna Graecia," Catanzaro, Italy

Type 2 (non–insulin-dependent) diabetes results from decreased insulin action in peripheral target tissues (insulin resistance) and impaired pancreatic ß-cell function. These defects reflect both genetic components and environmental risk factors. Recently, the common Gly⁹⁷²Arg 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 ß-cells had a severalfold greater number of immature secretory granules and a lower number of mature granules than control ß-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 Gly⁹⁷²Arg amino acid polymorphism of IRS-1.

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