When β-cells fail: lessons from dedifferentiation.
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.
Department of Medicine and Berrie Diabetes Center, Columbia University, New York, New York. da230@cumc.columbia.edu.
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Accili
Department of Medicine and Berrie Diabetes Center, Columbia University, New York, New York.
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Talchai
Department of Medicine and Berrie Diabetes Center, Columbia University, New York, New York.
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Kim-Muller
Department of Medicine and Berrie Diabetes Center, Columbia University, New York, New York.
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Cinti
Department of Medicine and Berrie Diabetes Center, Columbia University, New York, New York.
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Ishida
Department of Medicine and Berrie Diabetes Center, Columbia University, New York, New York.
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Ordelheide
Department of Medicine and Berrie Diabetes Center, Columbia University, New York, New York.
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Kuo
Department of Medicine and Berrie Diabetes Center, Columbia University, New York, New York.
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Fan
Department of Medicine and Berrie Diabetes Center, Columbia University, New York, New York.
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D000818:Animals; D054337:Cell Dedifferentiation; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice
D051858:Forkhead Transcription Factors; D007328:Insulin
aldehyde dehydrogenase; biomarker; genetics; human disease; lineage marker; progenitor cells; regeneration; therapeutic failure