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Diabetes 52:102-110, 2003
© 2003 by the American Diabetes Association, Inc.
ß-Cell Deficit and Increased ß-Cell Apoptosis in Humans With Type 2 Diabetes
1 Division of Endocrinology and Diabetes, Keck School of Medicine, University of Southern California, Los Angeles, California
2 Karolinska Institute, Stockholm, Sweden
3 Joslin Diabetes Center, Boston, Massachusetts
4 Division of Endocrinology, Mayo Clinic, Rochester, Minnesota
Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in ß-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m2; 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m2; 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative ß-cell volume, frequency of ß-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative ß-cell volume was increased in obese versus lean nondiabetic cases (P = 0.05) through the mechanism of increased neogenesis (P < 0.05). Obese humans with IFG and type 2 diabetes had a 40% (P < 0.05) and 63% (P < 0.01) deficit and lean cases of type 2 diabetes had a 41% deficit (P < 0.05) in relative ß-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of ß-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of ß-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group (P < 0.05). We conclude that ß-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased ß-cell apoptosis. Since the major defect leading to a decrease in ß-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and ß-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia.
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