Pharmacological induction of pancreatic islet cell transdifferentiation: relevance to type I diabetes

Abstract

Type I diabetes (T1D) is an autoimmune disease in which an immune response to pancreatic β-cells results in their loss over time. Although the conventional view is that this loss is due to autoimmune destruction, we present evidence of an additional phenomenon in which autoimmunity promotes islet endocrine cell transdifferentiation. The end result is a large excess of δ-cells, resulting from α- to β- to δ-cell transdifferentiation. Intermediates in the process of transdifferentiation were present in murine and human T1D. Here, we report that the peptide caerulein was sufficient in the context of severe β-cell deficiency to induce efficient induction of α- to β- to δ-cell transdifferentiation in a manner very similar to what occurred in T1D. This was demonstrated by genetic lineage tracing and time course analysis. Islet transdifferentiation proceeded in an islet autonomous manner, indicating the existence of a sensing mechanism that controls the transdifferentiation process within each islet. The finding of evidence for islet cell transdifferentiation in rodent and human T1D and its induction by a single peptide in a model of T1D has important implications for the development of β-cell regeneration therapies for diabetes.

Increased Hormone-Negative Endocrine Cells in the Pancreas in Type 1 Diabetes

“…The finding reported here that the abundance and pattern of distribution of these cells is comparable in type 1 and 2 diabetes has several implications. First, the relatively high abundance of degranulated ␤-cells (ϳ50% of ␤-cells) reported in mouse models of type 1 and 2 diabetes far exceeds that in humans with type 1 or 2 diabetes (3%) (17,18). Therefore, the proposal that ␤-cell loss in type 1 and type 2 diabetes may be in large part an artifact due to degranulation of ␤-cells may be valid in mice, but is not the case for humans.…”

“…Therefore, the proposal that ␤-cell loss in type 1 and type 2 diabetes may be in large part an artifact due to degranulation of ␤-cells may be valid in mice, but is not the case for humans. Second, the fact that changes in ␤-cell identity (degranulation and mixed identity) have been reported in both type 1 and 2 diabetes suggests that these changes are secondary to diabetes rather than primary drivers of ␤-cell dysfunction (18,19). In both type 1 and 2 diabetes there are well characterized and specific inducers of ␤-cell stress, cytokines delivered by autoreactive immune cells and misfolded islet amyloid polypeptide toxic oligomers respectively (20,21).…”

Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx

“…Bi-hormonal human pancreatic cells including Glucagon + Insulin + cells in subjects with diabetes (Piran et al, 2014; Yoneda et al, 2013) or in cultured islets (Bramswig et al, 2013) have been documented. However the molecular or regulatory features underlying development of these abnormal Glucagon + cells in T1D has not been described, reflecting inherent difficulties of pancreas procurement in humans with specific diseases.…”

Lack of glucagon receptor signaling and its implications beyond glucose homeostasis

“…Such situations include extreme b-cell loss, increased expression of Pax4 in a-cells, forced PDX1 expression, epigenomic manipulation, or the use of the peptide caerulein after treatment with alloxan (Collombat et al 2009, Liu & Habener 2009, Thorel et al 2010, Yang et al 2011, Bramswig et al 2013, Piran et al 2014.…”