Loss of β-cell identity occurs in type 2 diabetes and is associated with islet amyloid deposits

TY - JOUR

T1 - Loss of β-cell identity occurs in type 2 diabetes and is associated with islet amyloid deposits

AU - Spijker, H Siebe

AU - Song, Heein

AU - Ellenbroek, Johanne H

AU - Roefs, Maaike M

AU - Engelse, Marten A

AU - Bos, Erik

AU - Koster, Abraham J

AU - Rabelink, Ton J

AU - Hansen, Barbara C

AU - Clark, Anne

AU - Carlotti, Françoise

AU - de Koning, Eelco J P

N1 - © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

PY - 2015/4/27

Y1 - 2015/4/27

N2 - 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 loss of β-cell identity also occurs in vivo and whether it is related to the presence of (pre)diabetes in humans and non-human primates. We observed an 8x increased frequency of insulin(+) cells co-expressing glucagon in diabetic donors. Up to 5% of the cells that were Nkx6.1(+) but insulin(-) co-expressed glucagon, which represents a 5x increased frequency compared to 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 diabetic macaques and humans was correlated with the presence and extent of islet amyloidosis. These data indicate that 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.

AB - 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 loss of β-cell identity also occurs in vivo and whether it is related to the presence of (pre)diabetes in humans and non-human primates. We observed an 8x increased frequency of insulin(+) cells co-expressing glucagon in diabetic donors. Up to 5% of the cells that were Nkx6.1(+) but insulin(-) co-expressed glucagon, which represents a 5x increased frequency compared to 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 diabetic macaques and humans was correlated with the presence and extent of islet amyloidosis. These data indicate that 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.

U2 - 10.2337/db14-1752

DO - 10.2337/db14-1752

M3 - Article

C2 - 25918235

SN - 0012-1797

JO - Diabetes

JF - Diabetes

ER -