Diabetes is a condition that develops when the body does not produce or use a hormone called insulin effectively. Insulin helps fat and muscle cells absorb glucose from the blood, and so diabetes can result in high levels of blood glucose, which can cause strokes, blindness, and heart disease.

In healthy individuals, beta cells in the pancreas (a large gland located behind the stomach) produce insulin. The beta cells develop from endocrine progenitor cells, which are unspecialised cells that can either duplicate themselves or ‘differentiate’ to form one of the specialised cell types found in the pancreas.

In diabetic patients, however, certain stresses (such as an immune attack in type-1 diabetics or insulin-resistance due to obesity, pregnancy, or ageing in type-2 diabetics) can cause mature beta cells to lose their identity in a process known as ‘de-differentiation’. This means that beta cells either revert back to an earlier stage in their development or adopt a new dysfunctional identity. When this occurs, the body loses beta cells and is unable to produce insulin.

It was not known whether de-differentiated beta cells in diabetic patients can recover to form mature beta cells that are capable of producing insulin. Additionally, the drugs currently used to treat diabetes are able to lower blood glucose levels, but these drugs do not replace the lost beta cells.

Blum et al. now show that mice stop expressing a gene called Urocortin 3 when beta cells first start to de-differentiate. Only functional beta cells express Urocortin 3, so this gene is a useful ‘marker’ that can be used to tell if a cell is a mature, functional beta cell or not. Using this system, Blum et al. found that if de-differentiated cells are transplanted into a non-diabetic mouse, they are able to revert back into mature beta cells that can produce insulin. This happens even if the cells have been de-differentiated for a long time.

Blum et al. then used this system to investigate ways of protecting against or reversing beta cell de-differentiation. Using small molecules to block the activity of a protein called TGF beta receptor 1 was found to protect against beta cell de-differentiation and to restore the identity of mature beta cells. The findings of Blum et al. represent a first step towards the possible development of new drugs to prevent or even restore the loss of healthy, mature beta cells in diabetic patients.

Dysfunction or death of pancreatic β cells underlies all types of diabetes. In the case of Type 1 diabetes, it is unknown whether the initiating cause of β cell destruction is an immune attack or a β cell pathology that instigates autoimmunity. β cell failure in type 2 diabetes (T2D) is thought to begin as a compensatory response to peripheral insulin resistance and eventually results in the loss of a mature β cell phenotype, without necessarily leading to β cell death (Weir and Bonner-Weir, 2004; Weir et al., 2013). The loss of a mature β cell phenotype, sometimes called de-differentiation, can result from exposure to high levels of glucose, lipids, and inflammatory cytokines (Accili et al., 2010). De-differentiation of β cells in the context of diabetes has been shown in vivo with the genetic disruption of key transcription factors, including FoxO1 (Talchai et al., 2012) and NeuroD (Gu et al., 2010), and is also seen in isolated islets cultured in vitro on an adherent substrate (Gershengorn et al., 2004; Weinberg et al., 2007; Russ et al., 2008; Bar-Nur et al., 2011; Bar et al., 2012; Negi et al., 2012). In both the FoxO1 knockout mice and obese diabetic (Lepr^Db/Db) mice, de-differentiating β cells gradually lose insulin expression and begin to express progenitor-cell markers including Ngn3 and Sox9 (Talchai et al., 2012). Oxidative stress, also associated with T2D, inactivates the β cell specific transcription factors MafA, Nkx6.1, and Pdx1, again leading to the loss of mature β cell identity (Guo et al., 2013). β cell de-differentiation may represent a reversal of the normal ontogeny of β cells, or follow a different pathway, but it is clear that de-differentiation depletes the pool of functionally mature β cells in T2D patients (Weir and Bonner-Weir, 2004; Weir et al., 2013). It is not known whether there are stages of de-differentiation at which the cells can recover or re-differentiate back into fully mature β cells. The commonly used T2D drugs act by suppressing glucose production in the liver (e.g., Metformin), by enhancing peripheral insulin sensitivity (e.g., Rosiglitazone and other thiazolidinediones), or by forcing the secretion of more insulin from the already-stressed β cells (e.g., sulfonylureas such as Glyburide). There is no evidence that any of these drugs reverse β cell de-differentiation or restore the functionally mature β cell mass after β cell de-differentiation has occurred (Kahn et al., 2006; Accili et al., 2010). The availability of markers for early β cell stress (Akirav et al., 2011; Mahdi et al., 2012; Erener et al., 2013) allows one to test whether dysfunctional, stressed β cells can be revived or re-differentiated.

The gene Urocortin 3 (Ucn3) is a marker for functionally mature β cells, cells capable of glucose stimulated insulin secretion (Blum et al., 2012). Ucn3 expression appears relatively late in postnatal mouse development and its expression levels correlates with functional β cell maturation in mice, and with the maturation of human pluripotent stem cell-derived β cells after transplantation (Blum et al., 2012; van der Meulen et al., 2012; Hua et al., 2013; van der Meulen and Huising, 2014). We hypothesized that Ucn3 expression may be lost or reduced early during β cell de-differentiation in T2D and if so, could be used to investigate the first steps of stress-induced β cell de-differentiation.

The response of β cells to the progression of T2D begins with an adaptive stage, in which the cells compensate for insulin resistance by over-production and over-secretion of insulin, as well as increasing β cell replication (Weir and Bonner-Weir, 2004; Guo et al., 2013; Yi et al., 2013). This adaptation is reversible, as can be seen when β cell function returns with the remission from T2D after bariatric surgery (Bradley et al., 2012). However, if the metabolic stress persists, β cells succumb to the metabolic overload and de-differentiation occurs. De-differentiation begins with translocation of the transcription factor FoxO1 to the nucleus, and continues with an inactivation of β cell-specific transcription factors including MafA, Nkx6.1, and Pdx1 and consequently, a reduction in insulin production and secretion. All together, these changes result in the escalation of the disease and eventually to a non-recoverable loss of a functionally mature β cell mass (Weir and Bonner-Weir, 2004; Talchai et al., 2012; Guo et al., 2013).

Our results put the loss of Ucn3 expression as an early event in β cell stress, occurring at the compensatory stage, before reduction in insulin expression and deterioration to frank diabetes. Ucn3 protein and mRNA were dramatically down regulated even in mildly diabetic mice, some of which had blood glucose levels that were just slightly above normal. This is further demonstrated by the loss of Ucn3 in S961-treated mice, exposed to insulin resistance and hyperglycemia for only a week. In severely diabetic mice, we observed a dramatic reduction in insulin expression indicative of advanced β cell de-differentiation, and the expression of Ucn3 mRNA was almost completely abolished.

Ucn3 is a small neuropeptide hormone, expressed mainly in the Islets of Langerhans (where, in the mouse, it is restricted to β cells), the small intestine, the skin, and specific brain regions such as the hypothalamus, amygdala, and brainstem (Lewis et al., 2001; Li et al., 2003; Benner et al., 2014; van der Meulen and Huising, 2014). Ucn3 has been suggested to regulate GSIS in response to high blood glucose (Li et al., 2007) and was linked to peripheral glucose homeostasis and food intake behavior (Kuperman and Chen, 2008; Kuperman et al., 2010; Jamieson et al., 2011). The precise role of Ucn3 in the pancreatic islets is not yet clear, but the expression of its receptors in mouse and human islets suggests an islet-autonomous autocrine and/or paracrine action (Huising et al., 2011). It is noteworthy, however, that loss of expression of Ucn3 per se is not a driver of diabetes, but is rather caused by it, as mice homozygous for a Ucn3-null allele are not diabetic, and even show slightly better glucose tolerance under high-fat feeding and aging (Li et al., 2007).

To utilize the finding that Ucn3 is an early marker of β cell de-differentiation, we developed triple-transgenic mice, in which a sensitive Ucn3-regulated GFP reporter is combined with β cell lineage tracing. This genetic system allows one to trace β cells even after profound de-differentiation. Using this system, we show that β cell de-differentiation can be reversed after 1 week of S961 treatment in vivo or after 1 week of adherent culture in vitro. A screen for pathways that can rescue β cells from de-differentiation identified three growth factors that restored Ucn3-GFP expression, namely BMP9, TGFβ sRIII, and Artemin, all belonging to the TGFβ superfamily. Of those, only BMP9 had previously been identified as having an active role in glucose homeostasis (Chen et al., 2003). The gene encoding TGFβ receptor III has been shown to be up regulated in pancreata from obese human patients compared to lean subjects (Muharram et al., 2005), while Artemin and its receptor GFRα3 have, to the best of our knowledge, not been described in pancreatic islet function.

Tests on small molecule mediators of BMP/TGFβ and Artemin signaling identified Alk5 inhibitor II as a potent compound able to restore mature β cell identity even in islets from severely diabetic mice. This inhibitor also blocked the loss of specific β cell gene expression under cytokine-induced stress. Alk5 inhibitor II, identified using mouse β cells, can induce the expression of key β cell transcription factors in human islets. While human UCN3 is a marker of the functional maturation for both β and α cells (van der Meulen et al., 2012; Benner et al., 2014), and despite evidence that UCN3 is not a faithful marker for functional β cell maturation in human islets during human pancreas development (Hrvatin et al., 2014), the signals that reverse β cell de-differentiation (i.e., inhibition of Alk5 signaling) may be conserved between mouse and human.

Alk5 inhibitor II has been previously identified by Rezania et al. in an independent screen aimed at inducing functionally mature endocrine cells from human embryonic stem cells (Rezania et al., 2011). Ichida et al. showed that this inhibitor can replace Sox2 in cell reprogramming (Ichida et al., 2009). Interestingly, it was recently reported that β cells of mice carrying a conditional deletion of both Alk5 (referred to as TGFβ receptor I) and TGFβ receptor II do not proliferate in response to inflammatory cytokines (Xiao et al., 2013). In our results, Alk5 inhibitor II restored specific β cell gene expression in de-differentiated β cells, blocked cytokine-induced β cell stress, and stimulated over-expression of these genes in β cells from healthy, non-diabetic mice, and humans. It is noteworthy that the up regulation of SMAD7, a downstream mediator of TGFβ signaling, promotes β cell proliferation (Xiao et al., 2014). Inhibition of Alk5 would inhibit SMAD7-induced proliferation. This may hint on the intriguing idea that β cell proliferation, at least under inflammatory stress, may require a phase of de-differentiation. Taken together, these results suggest that Alk5 signaling may be constitutively active in β cells, that sustaining mature β cell phenotype depends on constant inhibition of this signal, and that the inhibition of Alk5 signaling may confer its effect by inducing expression of β cell transcription factors including MafA, Nkx6.1, and Pdx1. This postulated inhibition of Alk5 signaling in mature β cells develops during the first postnatal weeks, when the cells reach their fully mature state (Blum et al., 2012; Szabat et al., 2010; Szabat et al., 2011), and is reduced under diabetic stress or when the cells are taken out of their proper niche and grown in vitro. If inhibition of Alk5 signaling is not restored, the β cells will evidently de-differentiate and disappear. Alk5 is a broadly expressed protein and its activity is required in many other tissues besides β cells. Indeed, our preliminary attempts to inject high dosage of Alk5 inhibitor II to diabetic mice resulted in overall poor health without significant reduction of blood glucose. We therefore suggest that screening for compounds that inhibit Alk5 signaling specifically in β cells may yield compounds that in combination with traditional blood-glucose lowering medicines will delay, prevent, or perhaps restore the loss of healthy, mature β cell function in T2D patients.

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Author details

1. Barak Blum

   Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States

   Contribution

   BB, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   blum@fas.harvard.edu

   Competing interests

   The authors declare that no competing interests exist.

2. Adam N Roose

   Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States

   Contribution

   ANR, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

3. Ornella Barrandon

   Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States

   Contribution

   OB, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

4. René Maehr

   Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States

   Present address

   Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States

   Contribution

   RM, Acquisition of data, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

5. Anthony C Arvanites

   Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States

   Contribution

   ACA, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

6. Lance S Davidow

   Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States

   Contribution

   LSD, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

7. Jeffrey C Davis

   Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States

   Contribution

   JCD, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

8. Quinn P Peterson

   Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States

   Contribution

   QPP, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

9. Lee L Rubin

   Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States

   Contribution

   LLR, Conception and design, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

10. Douglas A Melton

    1. Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States
    2. Howard Hughes Medical Institute, Harvard University, Cambridge, United States

    Contribution

    DAM, Conception and design, Analysis and interpretation of data, Drafting or revising the article

    For correspondence

    dmelton@harvard.edu

    Competing interests

    The authors declare that no competing interests exist.

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