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High Glucose Causes Apoptosis in Cultured Human Pancreatic Islets of Langerhans

A Potential Role for Regulation of Specific Bcl Family Genes Toward an Apoptotic Cell Death Program

¹ Department of Internal Medicine, University of Rome "Tor Vergata," Rome
² Unit for Metabolic Diseases, Scientific Institute for Research and Cure (IRCCS), Hospital San Raffaele, Milan
³ IDI-IRCCS Biochemistry Lab c/o the Department of Experimental Medicine, University of Rome "Tor Vergata," Rome
⁴ National Research Center (CNR), Centro per lo Studio della Farmacologia Cellulare e Molecolare, Milano
⁵ Department of Surgical Pathology, Università dell’Insubria, Varese; Departments of
⁶ Surgery
⁷ Medicine, and
⁸ Cardiology, IRCCS HS Raffaele, Milan
⁹ Department of Endocrinology and Metabolism, University of Pisa, Pisa
¹⁰ Department of Internal Medicine, University of Milan, Milan
¹¹ Department of Clinical and Experimental Medicine, University of Catanzaro, Catanzaro
¹² Institute of Neurobiology and Molecular Medicine, CNR, Rome, Italy

Type 2 diabetes is characterized by insulin resistance and inadequate insulin secretion. In the advanced stages of the disease, ß-cell dysfunction worsens and insulin therapy may be necessary to achieve satisfactory metabolic control. Studies in autopsies found decreased ß-cell mass in pancreas of people with type 2 diabetes. Apoptosis, a constitutive program of cell death modulated by the Bcl family genes, has been implicated in loss of ß-cells in animal models of type 2 diabetes. In this study, we compared the effect of 5 days’ culture in high glucose concentration (16.7 mmol/l) versus normal glucose levels (5.5 mmol/l) or hyperosmolar control (mannitol 11 mmol/l plus glucose 5 mmol/l) on the survival of human pancreatic islets. Apoptosis, analyzed by flow cytometry and electron and immunofluorescence microscopy, was increased in islets cultured in high glucose (HG5) as compared with normal glucose (NG5) or hyperosmolar control (NG5+MAN5). We also analyzed by reverse transcriptase–polymerase chain reaction and Western blotting the expression of the Bcl family genes in human islets cultured in normal glucose or high glucose. The antiapoptotic gene Bcl-2 was unaffected by glucose change, whereas Bcl-xl was reduced upon treatment with HG5. On the other hand, proapoptotic genes Bad, Bid, and Bik were overexpressed in the islets maintained in HG5. To define the pancreatic localization of Bcl proteins, we performed confocal immunofluorescence analysis on human pancreas. Bad and Bid were specifically expressed in ß-cells, and Bid was also expressed, although at low levels, in the exocrine pancreas. Bik and Bcl-xl were expressed in other endocrine islet cells as well as in the exocrine pancreas. These data suggest that in human islets, high glucose may modulate the balance of proapoptotic and antiapoptotic Bcl proteins toward apoptosis, thus favoring ß-cell death.

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