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.

Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function

“…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.…”

“…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. Interestingly, chronic FKN-Fc administration enhanced GSIS and decreased β cell apoptosis.…”

“…These experiments revealed that FKN inhibits K ATP channel activity through an ERK-dependent and ATP-independent mechanism, without effects on VDCC activity. It is known that glucose triggers the insulin secretory pathway by increasing the β cell ATP/ADP ratio and inhibiting K ATP channel activity (21,32). This leads to membrane depolarization with opening of VDCCs, leading to a rise in intracellular Ca 2+ levels and exocytosis of insulin secretory granules (21).…”

“…This is consistent with the literature that shows that increased intracellular Ca 2+ levels induced by voltage-gated L-type Ca 2+ channel (VDCC) activator treatment, K + overload, K ATP channel inhibitor treatment, or arginine treatment are not sufficient to stimulate insulin secretion, if not accompanied by increased β cell metabolism or other events normally induced by glucose (33)(34)(35)(36). In T2DM, it has been suggested that decreased β cell glucose responsiveness is associated with lower mitochondrial ATP production capacity, leading to incomplete inhibition of K ATP channel activity (21,23,32,37,38). Therefore, it is reasonable to suggest that the action of FKN to inhibit basal K ATP channel conductance may compensate for lower mitochondrial ATP production in type 2 diabetic β cells and, thus, enhance GSIS.…”

Diabetes Research and Care Through the Ages

“…With regard to the latter feature, brilliant work has recently discovered "hubs" of b-cells that serve the function of synchronizing insulin discharge across the islet (74), a sort of specific conduction system analogous to that of the heart. The fundamental discovery of b-cell plasticity will add important details to the processes of dedifferentiation and redifferentiation of a-and b-cells (75)(76)(77)(78). By way of example, an antimalarial drug class, the artemisinins, facilitate transdifferentiation of a-to b-cells in a pathway involved in active GABA A receptor signaling in neurons (79).…”