Total or near-total loss of insulin-producing β-cells is a situation found in diabetes (Type 1, T1D) 1,2. Restoration of insulin production in T1D is thus a major medical challenge. We previously observed in mice in which β-cells are completely ablated that the pancreas reconstitutes new insulin-producing cells in absence of autoimmunity 3. The process involves the contribution of islet non-β-cells; specifically, glucagon-producing α-cells begin producing insulin by a process of reprogramming (transdifferentiation) without proliferation 3. Here we studied the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through adulthood, and also in aged individuals, even a long-time after β-cell loss. In contrast, prior to puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery; it occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The younglings display “somatostatin-to-insulin” δ-cell conversion, involving de-differentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon combined action of FoxO1 and downstream effectors. Restoration of insulin producing-cells from non-β-cell origins is thus enabled throughout life via δ- or α-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, thus offering new perspectives.

Aims/hypothesis Glycogen synthase kinase 3β (GSK-3β) is an enzyme that is suppressed by insulin and when elevated results in insulin resistance in skeletal muscle and diabetes.

The mechanisms restricting regeneration and maintaining cell identity following injury are poorly characterized in higher vertebrates. Upon β-cell loss, 1–2% of the glucagon-producing α-cells spontaneously engage in insulin production in mice. Here we explore the mechanisms inhibiting α-cell plasticity. We show that the adaptive α-cell identity changes are constrained by intra-islet Insulin- and Smoothened-mediated signaling, among others. The combination of β-cell loss, or insulin signaling inhibition, with Smoothened inactivation in α- or δ-cells, stimulates insulin production in more α-cells. These findings suggest that removing constitutive “brake signals” is crucial for neutralizing the refractoriness to adaptive cell-fate changes. It appears that cell identity maintenance is an active process mediated by repressive signals, released by neighbor cells, curbing an intrinsic trend of differentiated cells to change.

Type 2 diabetes (T2D) is characterized by β-cell dysfunction and the subsequent depletion of insulin production, usually in a context of increased peripheral insulin resistance. T2D patients are routinely treated with oral antidiabetic agents such as sulfonylureas or dipeptidyl peptidase-4 antagonists, which promote glucose- and incretin-dependent insulin secretion, respectively. Interestingly, insulin secretion may also be induced by neural stimulation. Here we report the expression of Nogo-A in β-cells. Nogo-A is a membrane protein that inhibits neurite outgrowth and cell migration in the central nervous system. We observed that Nogo-A–deficient mice display improved insulin secretion and glucose clearance. This was associated with a stronger parasympathetic input and higher sensitivity of β-cells to the cholinergic analog carbachol. Insulin secretion was also improved in diabetic db/db mice treated with neutralizing antibody against Nogo-A. Together, these findings suggest that promoting the vagal stimulation of insulin secretion through the selective inhibition of Nogo-A could be a novel therapeutic approach in T2D.

No abstract