Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes

Cinti, Francesca; Bouchi, Ryotaro; Kim-Muller, Ja Young; Ohmura, Yoshiaki; Sandoval, P. Rodrigo; Masini, Matilde; Marselli, Lorella; Suleiman, Mara; Ratner, Lloyd E.; Marchetti, Piero; Accili, Domenico

doi:10.1210/jc.2015-2860

Cited by 495 publications

(531 citation statements)

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“…Similarly to loss of Nkx2.2 in adult mouse β cells, inactivation of NKX2.2 in human islets predominantly led to the upregulation of SST ( Figure 7D). Interestingly, the predominance of insulin-and SST-coexpressing cell populations has been described in several recent studies reporting the presence of polyhormonal cells in islets derived from diabetic individuals (33,35).…”

Section: Discussionmentioning

confidence: 84%

Pancreatic β cell identity requires continual repression of non–β cell programs

Gutiérrez¹,

Bender²,

Cirulli³

et al. 2016

Journal of Clinical Investigation

112

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from alternative islet cell fates. Furthermore, β cells appeared to transdifferentiate to acquire other non-β cell endocrine identities. Deletion of Nkx2.2 in fully differentiated adult β cells also resulted in the very rapid onset of diabetes, and the islets of these mice were also characterized by a loss of β cell identity and the acquisition of δ cell characteristics, confirming the importance of NKX2.2 ration and/or function, we generated mouse models that allowed constitutive and inducible deletion of the Nkx2.2 gene. Disruption of Nkx2.2 in maturing β cells resulted in the rapid development of diabetes, with a significant decrease in insulin expression and content. Strikingly, the loss of genes associated with β cell identity and function was accompanied by increased expression of genes ΔBeta compared with control mice at 4 weeks of age. The white boxes indicate regions of the islet that are shown in higher magnification in E and F. (G) Ad libitum blood glucose levels in 2-week-old male Nkx2.2ΔBeta mice compared with controls (n = 3-16), in 3-week-old mice (n = 5-22), and in 11-week-old mice (n = 6-18). **P ≤ 0.01, ***P ≤ 0.001; 2-tailed Student's t test. Each control genotype was examined separately to ensure that the individual Cre and floxed alleles did not cause metabolic phenotypes. (H) Higher fasting blood glucose levels are evident in 11-week-old Nkx2.2ΔBeta mice compared with controls (3-week-old mice: n = 6-23; 11-week-old mice: n = 8-21). *P ≤ 0.05; 2-tailed Student's t test. (I) Glucose intolerance is observed in Nkx2.2ΔBeta male mice compared with controls at 3 weeks of age (n = 6-23). *P ≤ 0.05, ***P ≤ 0.001; 2-tailed Student's t test. (J) Glucose intolerance becomes more severe at 11 weeks of age in Nkx2.2ΔBeta male mice compared with control mice (n = 8-21). *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001; 2-tailed Student's t test.

show abstract

Section: Discussionmentioning

confidence: 84%

Pancreatic β cell identity requires continual repression of non–β cell programs

Gutiérrez¹,

Bender²,

Cirulli³

et al. 2016

Journal of Clinical Investigation

112

View full text Add to dashboard Cite

show abstract

“…While increased β cell apoptosis may be responsible for the majority of decreased β cell mass in advanced T2DM patients (42,43), recently it has been suggested that an additional mechanism may exist. Thus, accumulation of dedifferentiated/ immature β cells, which express markers of both α and β cells, has been reported in mouse models of diabetes as well as in human T2DM islets (4,32,(43)(44)(45). While the origin of these dedifferentiated/immature β cells is still controversial in humans (32,43), it is plausible that strategies to suppress β cell apoptosis and/or increase β cell differentiation/maturation would be effective at improving β cell function.…”

Section: Discussionmentioning

confidence: 99%

Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function

Riopel

Seo

Bandyopadhyay

et al. 2018

Journal of Clinical Investigation

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“…They may include, for example, a switch from expression of insulin to expression of glucagon or somatostatin, indicating that β cell plasticity is largely confined to the islet program. The potential of metabolically stressed β cells to dedifferentiate and then redifferentiate into non-β cell fates was proposed as a novel mechanism underlying reversible β cell failure in diabetes (8,(10)(11)(12)(13). Plasticity between α and β cell fates is supported by the remarkably similar epigenetic states of the 2 cell types (14).…”

Section: Introductionmentioning

confidence: 99%