Loss of β-Cell Identity Occurs in Type 2 Diabetes and Is Associated With Islet Amyloid Deposits.
Loss of pancreatic islet β-cell mass and β-cell dysfunction are central in the development of type 2 diabetes (T2DM). We recently showed that mature human insulin-containing β-cells can convert into glucagon-containing α-cells ex vivo. This loss of β-cell identity was characterized by the presence of β-cell transcription factors (Nkx6.1, Pdx1) in glucagon(+) cells. Here, we investigated whether the loss of β-cell identity also occurs in vivo, and whether it is related to the presence of (pre)diabetes in humans and nonhuman primates. We observed an eight times increased frequency of insulin(+) cells coexpressing glucagon in donors with diabetes. Up to 5% of the cells that were Nkx6.1(+) but insulin(-) coexpressed glucagon, which represents a five times increased frequency compared with the control group. This increase in bihormonal and Nkx6.1(+)glucagon(+)insulin(-) cells was also found in islets of diabetic macaques. The higher proportion of bihormonal cells and Nkx6.1(+)glucagon(+)insulin(-) cells in macaques and humans with diabetes was correlated with the presence and extent of islet amyloidosis. These data indicate that the loss of β-cell identity occurs in T2DM and could contribute to the decrease of functional β-cell mass. Maintenance of β-cell identity is a potential novel strategy to preserve β-cell function in diabetes.
Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
H Siebe
HS
Spijker
Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Heein
H
Song
Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
Johanne H
JH
Ellenbroek
Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
Maaike M
MM
Roefs
Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
Marten A
MA
Engelse
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
Erik
E
Bos
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
Abraham J
AJ
Koster
Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
Ton J
TJ
Rabelink
Departments of Internal Medicine and Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL.
Barbara C
BC
Hansen
Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, U.K.
Anne
A
Clark
Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
Françoise
F
Carlotti
Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands Hubrecht Institute, Utrecht, the Netherlands e.dekoning@lumc.nl.
Eelco J P
EJ
de Koning
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology
D007328:Insulin; D005934:Glucagon