title: Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes.
abstract: Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in beta-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m(2); 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m(2); 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative beta-cell volume, frequency of beta-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative beta-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 beta-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of beta-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 beta-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 beta-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased beta-cell apoptosis. Since the major defect leading to a decrease in beta-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and beta-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.
authors.affiliation: Division of Endocrinology and Diabetes, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Butler
authors.forename: Juliette
authors.initials: J
authors.lastname: Janson
authors.forename: Susan
authors.initials: S
authors.lastname: Bonner-Weir
authors.forename: Robert
authors.initials: R
authors.lastname: Ritzel
authors.forename: Robert A
authors.initials: RA
authors.lastname: Rizza
authors.forename: Peter C
authors.initials: PC
authors.lastname: Butler
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000682:Amyloid / Q000378:metabolism; D017209:Apoptosis; D016923:Cell Death; D002455:Cell Division; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D010179:Pancreas / Q000473:pathology; D010183:Pancreatic Ducts / Q000378:metabolism
chemical_list: D000682:Amyloid; D007328:Insulin