When β-cells fail: lessons from dedifferentiation

Abstract

Diabetes is caused by a combination of impaired responsiveness to insulin and reduced production of insulin by the pancreas. Until recently, the decline of insulin production had been ascribed to β-cell death. But recent research has shown that β-cells do not die in diabetes, but undergo a silencing process, termed "dedifferentiation." The main implication of this discovery is that β-cells can be revived by appropriate treatments. We have shown that mitochondrial abnormalities are a key step in the progression of β-cell dysfunction towards dedifferentiation. In normal β-cells, mitochondria generate energy required to sustain insulin production and its finely timed release in response to the body's nutritional status. A normal β-cell can adapt its mitochondrial fuel source based on substrate availability, a concept known as "metabolic flexibility." This capability is the first casualty in the progress of β-cell failure. β-Cells lose the ability to select the right fuel for mitochondrial energy production. Mitochondria become overloaded, and accumulate by-products derived from incomplete fuel utilization. Energy production stalls, and insulin production drops, setting the stage for dedifferentiation. The ultimate goal of these investigations is to explore novel treatment paradigms that will benefit people with diabetes.

Keywords: aldehyde dehydrogenase; biomarker; genetics; human disease; lineage marker; progenitor cells; regeneration; therapeutic failure.

Figure 1. Changes to Foxo sub-cellular localization during diabetes progression

Transcription factor Foxo1 translocates from the cytoplasm to the nucleus of the β-cell in response to changes in glucose, lipid, and cytokine levels in the environment. Nuclear translocation is associated with the activation of a stress response that aims to maintain mitochondrial function and β-cell identity. Nuclear Foxo1 is more rapidly degraded; thus, if hyperglycemia is not reversed, Foxo1 gradually fall, paving the way for β-cell dysfunction.

Figure 2. Model of Foxo (1, 3a, 4) role in physiologic β-cell function

In the early phases of diabetes, Foxo nuclear translocation mediates the effects of glucose on gene expression through MODY gene networks, allowing glucose flux into mitochondria for ATP production (thick arrows), while limiting the contributions by lipids and amino acids (thin dotted arrows). This situation likely prevents the generation of toxic metabolic intermediates that can be detrimental to β-cell health.

Figure 3. Model of β-cell dysfunction and role of Foxo in pathophysiologic conditions

As Foxo become functionally exhausted, β-cells are transcriptionally blindsided to the effects of glucose, increasing lipid and amino acid flux. MODY genes are suppressed, and Pparα increased, consistent with the role of Foxo to suppress Pparα in liver [67]. Interestingly, pathway analysis of RNA sequencing data indicates that the decrease in Foxo levels also leads to increased Pparγ. These data could be interpreted to suggest that Foxo promotes lipogenesis to prevent excessive mitochondrial fat oxidation [68]. PC: Pyruvate carboxylase; GDH: glutamate dehydrogenase; Cpt1: carnitine palmitoyltransferase-1.