{beta}-Cell mass dynamics and islet cell plasticity in human type 2 diabetes.
Studies of long-standing type 2 diabetes (T2D) report a deficit in beta-cell mass due to increased apoptosis, whereas neogenesis and replication are unaffected. It is unclear whether these changes are a cause or a consequence of T2D. Moreover, whereas islet morphogenetic plasticity has been demonstrated in vitro, the in situ plasticity of islets, as well as the effect of T2D on endocrine differentiation, is unknown. We compared beta-cell volume, neogenesis, replication, and apoptosis in pancreata from lean and obese (body mass index > or = 27 kg/m(2)) diabetic (5 +/- 2 yr since diagnosis) and nondiabetic cadaveric donors. We also subjected isolated islets from diabetic (3 +/- 1 yr since diagnosis) and nondiabetic donors to an established in vitro model of islet plasticity. Differences in beta-cell volume between diabetic and nondiabetic donors were consistently less pronounced than those reported in long-standing T2D. A compensatory increase in beta-cell neogenesis appeared to mediate this effect. Studies of induced plasticity indicated that islets from diabetic donors were capable of epithelial dedifferentiation but did not demonstrate regenerative potential, as was seen in islets from nondiabetic donors. This deficiency was associated with the overexpression of Notch signaling molecules and a decreased neurogenin-3(+) cell frequency. One interpretation of these results would be that decreased beta-cell volume is a consequence, not a cause, of T2D, mediated by increased apoptosis and attenuated beta-cell (re)generation. However, other explanations are also possible. It remains to be seen whether the morphogenetic plasticity of human islets, deficient in vitro in islets from diabetic donors, is a component of normal beta-cell mass dynamics.
Hanley
Stephen C
SC
M.Eng., Montréal General Hospital C9-128, 1650 Cedar Avenue, Montréal, Québec, Canada H3G 1A4.
Austin
Emily
E
Assouline-Thomas
Béatrice
B
Kapeluto
Jordanna
J
Blaichman
Jason
J
Moosavi
Mandana
M
Petropavlovskaia
Maria
M
Rosenberg
Lawrence
L
D000704:Analysis of Variance; D017209:Apoptosis; D002452:Cell Count; D049109:Cell Proliferation; D048430:Cell Shape; D048429:Cell Size; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000032:analysis; D050417:Insulin-Secreting Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007328:Insulin