β-Cell Fate in Human Insulin Resistance and Type 2 Diabetes: A Perspective on Islet Plasticity

Abstract

Although it is well established that type 2 diabetes (T2D) is generally due to the progressive loss of β-cell insulin secretion against a background of insulin resistance, the actual correlation of reduced β-cell mass to its defective function continues to be debated. There is evidence that a compensatory increase in β-cell mass, and the consequent insulin secretion, can effectively cope with states of insulin resistance, until hyperglycemia supervenes. Recent data strongly indicate that the mechanisms by which islets are able to compensate in response to insulin resistance in peripheral tissues is secondary to hyperplasia, as well as the activation of multiple cellular machineries with diverse functions. Importantly, islet cells exhibit plasticity in altering their endocrine commitment; for example, by switching from secretion of glucagon to secretion of insulin and back (transdifferentiation) or from an active secretory state to a nonsecretory quiescent state (dedifferentiation) and back. Lineage tracing (a method used to track each cell though its differentiation process) has demonstrated these potentials in murine models. A limitation to drawing conclusions from human islet research is that most studies are derived from human autopsy and/or organ donor samples, which lack in vivo functional and metabolic profiling. In this review, we specifically focus on evidence of islet plasticity in humans-from the normal state, progressing to insulin resistance to overt T2D-to explain the seemingly contradictory results from different cross-sectional studies in the literature. We hope the discussion on this intriguing scenario will provide a forum for the scientific community to better understand the disease and in the long term pave the way for personalized therapies.

Figure 1

Schematic representation of the hypothetical scenario of islet plasticity. Islet plasticity is the capacity of the islet to modify its morphology and function according to different metabolic conditions. A potential explanation of the present scenario is as follows: when insulin resistance increases insulin demand, islet plasticity guarantees a twofold increase in β-cells, whose origins are still debated but some hypotheses are transdifferentiation from centroacinar and duct cells (duct red cells and centroacinar violet cells), replication (red cell Ki67⁺), and neogenesis from an unknown source (white to red cell); a twofold increase in the α-cells transdifferentiated into insulin-producing cells (yellow double-positive cells); and a fivefold increase in the α-cells via neogenesis, with a consequent increase of a potential GLP-1 source (white to green cell). As with any compensatory mechanism, in a chronic condition, it is bound to fail. The exhausted β-cells undergo dedifferentiation (Dedif) (a resting state, red to gray cells), the double-positive cell switches back into the original α-cell (yellow cells to green cells), and the overstressed β-cells transdifferentiate into α-cells (red cell to green cell).