Metabolic Stress and Compromised Identity of Pancreatic Beta Cells

Abstract

Beta cell failure is a central feature of type 2 diabetes (T2D), but the molecular underpinnings of the process remain only partly understood. It has been suggested that beta cell failure in T2D involves massive cell death. Other studies ascribe beta cell failure to cell exhaustion, due to chronic oxidative or endoplasmic reticulum stress leading to cellular dysfunction. More recently it was proposed that beta cells in T2D may lose their differentiated identity, possibly even gaining features of other islet cell types. The loss of beta cell identity appears to be driven by glucotoxicity inhibiting the activity of key beta cell transcription factors including Pdx1, Nkx6.1, MafA and Pax6, thereby silencing beta cell genes and derepressing alternative islet cell genes. The loss of beta cell identity is at least partly reversible upon normalization of glycemia, with implications for the reversibility of T2D, although it is not known if beta cell failure reaches eventually a point of no return. In this review we discuss current evidence for metabolism-driven compromised beta cell identity, key knowledge gaps and opportunities for utility in the treatment of T2D.

Keywords: Pax6; beta cell failure; dedifferentiation; gastrin; ghrelin; oxidative stress; reprogramming; type 2 diabetes mellitus.

FIGURE 1

Models for beta cell failure in T2D. The illustration shows the architecture and endocrine cell composition of a normal pancreatic islet of Langerhans (top) and potential changes, distinguished by beta cell fate, that lead to beta cell failure in T2D (bottom). Different colors indicate different islet cell type. ε, ghrelin; G, gastrin, E, endocrine cell with empty granules (no hormone is produced).

FIGURE 2

Gastrin expression in islets of mice and humans with type 2 diabetes. Gastrin expression in the pancreas is normally limited to fetal life. Islets of healthy adult mice and humans normally do not express gastrin. Strikingly, gastrin-positive cells re-appear in islets of mice and humans with type 2 diabetes. In diabetic db/db mice, gastrin is induced in beta cells; in humans with T2D, gastrin is induced mostly in delta cells. Sections are immunostained for gastrin (red), insulin (green), and Pdx1 or Dapi (blue). White arrows point to the gastrin positive cells. Micrographs are from our recently published paper (Dahan et al., 2017).

FIGURE 3

Ghrelin expression following Pax6 loss in adult beta cells. Top, pancreatic islets with ghrelin expression following Pax6 deletion in adult beta cells. Bottom left, deletion of pax6 was combined with Cre-mediated permanent expression of a yellow fluorescent protein (YFP) reporter. Bottom right, ghrelin-expressing cells do not express insulin, yet expression of YFP proves that these were insulin+ beta cells prior to the deletion of Pax6. Micrographs were adjusted from our published paper (Swisa et al., 2017).

FIGURE 4

Transcriptional activation and repression in the regulation of beta cell identity. A model presenting the dual role of beta cell transcription factors as direct activators of beta cell genes and repressors of alternative islet cell genes. Pax6 activates the expression of key beta cell transcription factors such as Nkx6.1, Pdx1, and MafA and also interacts with these factors at the protein level, to execute the specific transcriptional outcome, activation or repression. We propose that the chromatin state and the other factors interacting in the transcriptional complex will determine the transcriptional activity.

FIGURE 5

Hyperglycemia-induced loss of beta cell identity. A model summarizing downstream components of glucose signaling required for beta cell expression of gastrin following hyperglycemia. Red arrows, induction of beta cell reprograming; Yellow arrows, prevention of beta cell reprograming demonstrated by genetic or pharmacological interventions.

FIGURE 6

Intra-islet cell identity transitions. Summary of genetic manipulations that were shown to lead to intra-islet cell identity transitions in adult mice, indicating high plasticity within the pancreatic endocrine lineage. Note the fetal or abnormal islet cell types, ε, ghrelin; G, gastrin; P, polyhormonal; E, endocrine with empty granule. In most of the examples, only dominant transitions are presented. References cited in this figure: (1) Al-Hasani et al., 2013; (2) Brereton et al., 2014; (3) Chera et al., 2014; (4) Courtney et al., 2013; (5) Dahan et al., 2017; (6) Gao et al., 2014; (7) Gutierrez et al., 2017; (8) Swisa et al., 2017; (9) Talchai et al., 2012; (10) Thorel et al., 2010; (11) Taylor et al., 2013; (12) Wang et al., 2014.