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If a fully functional lab grown pancreas can exist, can it be used as a cure for type 2 diabetes?


Is it approximately equivalent to say that if a fully functional lab grown pancreas exists, then a way to cure Type 2 diabetes could soon exist?

Recently I've already checked out that only the remission exists with some gastric surgery.

reference: 1)http://care.diabetesjournals.org/content/34/Supplement_2/S361

2) http://www.medscape.com/viewarticle/733691(full access require membership)


Since the consensus is that the underlying initial problem in t2dm is the development of insulin insensitivity in the presence of a normally functioning pancreas, then replacing that pancreas at a more advanced stage of the disease will not cause normalisation of glucose levels.

http://journal.diabetes.org/clinicaldiabetes/v18n22000/pg80.htm


Modelling the endocrine pancreas in health and disease

Diabetes mellitus is a multifactorial disease affecting increasing numbers of patients worldwide. Progression to insulin-dependent diabetes mellitus is characterized by the loss or dysfunction of pancreatic β-cells, but the pathomechanisms underlying β-cell failure in type 1 diabetes mellitus and type 2 diabetes mellitus are still poorly defined. Regeneration of β-cell mass from residual islet cells or replacement by β-like cells derived from stem cells holds great promise to stop or reverse disease progression. However, the development of new treatment options is hampered by our limited understanding of human pancreas organogenesis due to the restricted access to primary tissues. Therefore, the challenge is to translate results obtained from preclinical model systems to humans, which requires comparative modelling of β-cell biology in health and disease. Here, we discuss diverse modelling systems across different species that provide spatial and temporal resolution of cellular and molecular mechanisms to understand the evolutionary conserved genotype–phenotype relationship and translate them to humans. In addition, we summarize the latest knowledge on organoids, stem cell differentiation platforms, primary micro-islets and pseudo-islets, bioengineering and microfluidic systems for studying human pancreas development and homeostasis ex vivo. These new modelling systems and platforms have opened novel avenues for exploring the developmental trajectory, physiology, biology and pathology of the human pancreas.


For diabetes, stem cell recipe offers new hope

Douglas Melton is as impatient as anyone for a cure for diabetes. His son developed the disease as an infant, and his daughter was diagnosed at age 14. For most of the past 2 decades, the developmental biologist at the Harvard Stem Cell Institute has focused his research on finding a cure. This week, he and his colleagues report a potentially significant step toward that goal: a recipe that can turn human stem cells into functional pancreatic β cells—the cells that are destroyed by the body’s own immune system in type 1 diabetes patients such as Melton’s son and daughter. The cells the researchers produced respond to glucose by producing insulin, just as normal β cells do. And when implanted into mice with a form of diabetes, the cells can cure the disorder.

“The diabetes research community has been waiting for ages for this type of breakthrough,” says Jorge Ferrer, who studies the genetics of β cells at Imperial College London. The lab-generated cells should be a valuable tool for studying diabetes and, Melton hopes, could eventually be used to treat patients.

Throughout the day, the pancreas regulates the body’s blood sugar levels, responding to an increase in glucose after a meal by secreting insulin, which helps cells take up the sugar. In type 1 diabetes, the body’s immune system mistakenly kills the β cells for still-unknown reasons, and the body is left without insulin. People control their diabetes by injecting carefully calibrated doses of insulin. But matching the precise insulin control achieved by the healthy pancreas is almost impossible, so researchers have hoped for decades to find a way to replace the missing cells.

When scientists isolated human embryonic stem (ES) cells in 1998, hopes soared. ES cells are pluripotent, which means that in theory they can turn into any of the body’s cell types—including β cells. Indeed, one of the first things researchers tried to make from ES cells was pancreatic β cells. Later they tried with so-called induced pluripotent stem (iPS) cells, made by reprogramming adult cells into an embryolike state. Either way, “it’s proved to be an extraordinarily complicated undertaking,” says Mark Magnuson of Vanderbilt University in Nashville, who studies pancreatic development.

Several teams have turned stem cells into precursors of β cells, which mature when placed into experimental animals. But the cells take 6 weeks to become fully functional β cells, and they can’t be studied easily outside the body. Nevertheless, a clinical trial started last month to test their therapeutic use in patients.

In Cell this week, Melton and his colleagues report a complex recipe that can transform either human ES cells or iPS cells directly into functional β cells. The breakthrough is based on more than a decade of tenacious work in Melton’s lab. He and his colleagues have painstakingly studied the signals that guide pancreas development, applying what they and others have found to develop a method that turns stem cells into mature β cells. “There’s no magic to this,” Melton says. “It’s not a discovery so much as applied developmental biology.”

The protocol “is reproducible, but it is tedious,” Melton adds. The stem cells are grown in flasks and require five different growth media and 11 molecular factors, from proteins to sugars, added in precise combinations over 35 days to turn them into β cells. On the bright side, Melton says, the technique can produce 200 million β cells in a single 500 ml flask—enough, in theory, to treat a patient. Melton says the protocol seems to work equally well with ES and iPS cell lines.

Before the cells can be used to treat type 1 diabetes, researchers need to find a way to protect them from immunologic rejection. The same autoimmune response that triggered the disease would likely attack new β cells derived from the patient’s own iPS cells, and a normal immune response would destroy ES-derived β cells, which would appear foreign. (That has been a challenge for efforts to treat type 1 diabetes with received transplants of β cells from deceased organ donors.) Melton and colleagues are now exploring how to physically encapsulate their stem cell–derived β cells, as well as ways to modify the β cells to enable them to ward off immune attack.

In the meantime, the cells should help the study of the autoimmune disorder. The technique “potentially provides ways to create model systems for studying the genetic basis of diabetes, or to discover novel therapies to enhance existing β cells,” Ferrer says. Melton says his lab has iPS cell lines from people with diabetes—both type 1 and type 2, in which the β cells are not destroyed—and healthy controls. They are generating β cells from those cell lines to look for differences that might explain how the different forms of the disease develop. They will also screen for chemicals that can stop or even reverse the damage diabetes does to β cells.

Melton says his son and daughter—now 23 and 27 years old—were pleased but unsurprised by his group’s progress. Reversing the parent-child role, they gently nagged him to “get going and solve the [immune-rejection] problem.”


The anatomy of pancreas development

The pancreas is often described as two organs in one, due to the distinct function and organization of its endocrine and exocrine components. In higher vertebrates, it might more properly be thought of as four organs, as it comprises anatomically distinct dorsal and ventral lobes. Referred to in humans as the tail and head, respectively, these two pancreatic lobes arise as thickenings along the dorsal and ventral surfaces of the posterior foregut,near the prospective hepatic endoderm (Fig. 1A). These thickenings are histologically recognizable by approximately 9 days of development (E9.0-E9.5) in the mouse(Wessells and Cohen, 1967). Retaining luminal continuity with the gut tube, these structures evaginate into the surrounding mesenchyme as dense epithelial buds, which subsequently expand, branch and differentiate to yield a fully functional organ system prior to birth (Fig. 1A, Fig. 2). Gut rotation brings the two lobes into close apposition in humans, their ductal systems undergo partial fusion, although this process is less obvious in rodents.

The bulk of the mature pancreas is comprised of acinar cells, connected to the intestine via a highly branched ductal tree, while islets are primarily scattered through the central regions of the organ. Several separate endocrine cell types comprise the islet: β-cells are the most prominent (50-80% of the total, depending on species) (Brissova et al., 2005 Cabrera et al.,2006), and tend to segregate to the islet core, with other cell types arranged closer to the mantle (see Fig. 3R). Glucagon-producingα-cells are the next most-common cell type the remaining islet cells,each comprising a small minority of the total, include δ-cells, which produce somatostatin, PP cells, which produce pancreatic polypeptide, and the recently-described ϵ-cells, which produce ghrelin(Prado et al., 2004 Wierup et al., 2002).

The visible anatomy of the developing pancreas is prefigured by the molecular anatomy of differential gene expression, and few genes are better studied in this regard than the homeodomain transcription factor Pdx1. The initial expression of Pdx1 (E8.5-E9.0) marks the pre-pancreatic endoderm before it has visibly thickened(Ahlgren et al., 1996 Guz et al., 1995 Offield et al., 1996)(Fig. 2), and corresponds to the classically defined period of pancreatic specification(Wessells and Cohen, 1967). Early Pdx1 expression is therefore a useful marker of pancreatic identity, although it expands over the next several days of development to encompass the posterior stomach, duodenum and bile duct. Another transcription factor, Ptf1a, is also expressed in the early pancreas, and its endodermal expression remains pancreas-specific throughout development(Kawaguchi et al., 2002).

Pancreatic anatomy, lineages and genes. (A) The dorsal and ventral pancreata (dp and vp, respectively) arise at approximately E8.5 in the mouse (top), from two strips of gut endoderm (marked dp, vp) that are located adjacent to the forming liver (li) within the developing gut endoderm. At E10.5 (middle), the pancreatic primordia bud out into the surrounding mesenchyme and occupy a position between the stomach (st) and intestine (in). Subsequent gut rotation, from E12.5 onward (bottom), brings the two lobes into closer apposition, although each maintains its original ductal connection to the intestine and/or common bile duct (cbd). (B) Lineage tracing indicates that all mature pancreatic cell types derive from progenitors that express Pdx1 and/or Ptf1a (purple), and that a subset of these progenitors go on to express Ngn3 and differentiate into islet cells. Genes listed in red are required for various aspects of the indicated steps, as described in the text.

Pancreatic anatomy, lineages and genes. (A) The dorsal and ventral pancreata (dp and vp, respectively) arise at approximately E8.5 in the mouse (top), from two strips of gut endoderm (marked dp, vp) that are located adjacent to the forming liver (li) within the developing gut endoderm. At E10.5 (middle), the pancreatic primordia bud out into the surrounding mesenchyme and occupy a position between the stomach (st) and intestine (in). Subsequent gut rotation, from E12.5 onward (bottom), brings the two lobes into closer apposition, although each maintains its original ductal connection to the intestine and/or common bile duct (cbd). (B) Lineage tracing indicates that all mature pancreatic cell types derive from progenitors that express Pdx1 and/or Ptf1a (purple), and that a subset of these progenitors go on to express Ngn3 and differentiate into islet cells. Genes listed in red are required for various aspects of the indicated steps, as described in the text.

Genetic-lineage tracing (Box 1) shows that Pdx1 + cells represent progenitors of all the mature pancreatic cell types, including duct, islet and acinar cells (Gu et al., 2002)(Fig. 1B). Pdx1 is expressed broadly in the pancreas during the first several days of pancreas development, as the organ grows and branches (Figs 2, 3). Ptf1a expression is similarly broad at the early stages, and Kawaguchi et al.(Kawaguchi et al., 2002) have found, through lineage tracing with a Ptf1a Cre knock-in allele, that Ptf1a + cells contribute to all three mature lineages. These authors also observed that a minor population of duct and islet cells was not labeled by Ptf1a Cre , possibly due to the fact that Ptf1a expression becomes restricted to acinar precursor cells by approximately E13.5 (Fig. 2).

Box 1. Lineage tracing and pancreas development.Genetic-lineage-tracing techniques have produced considerable insight into the development of the pancreas and other tissues. The most common lineage-tracing approach uses Cre recombinase, which can delete DNA segments that are flanked by loxP (so-called floxed) sites(Branda and Dymecki, 2004). Mouse strains have been developed in which the ubiquitous expression of a reporter gene, such as LacZ, is prevented by a floxed sequence being placed between the promoter and the reporter(Soriano, 1999) Cre-mediated deletion of this sequence results in heritable marking of the Cre-expressing cell. When Cre expression is driven by a promoter that is active in progenitor cells, the descent of those cells in various classes of differentiated offspring can be traced (Gu et al.,2002 Kawaguchi et al.,2002) (see Fig. 1). Conversely, if Cre is co-expressed with a differentiation marker, such as insulin, one can determine whether differentiated cells change their phenotype in the course of embryogenesis or adulthood. Such an approach was used to refute the hypothesis that mature α- and β-cells are derived from progenitors that co-express glucagon and insulin(Herrera, 2000). Lineage tracing can therefore offer valuable insights that are not obvious from histological studies. A major limitation to the technique, however, is its relatively low resolution: if a particular Cre driver labels multiple differentiated cell types, it is impossible to distinguish whether that driver was active in multipotent progenitors or in separate classes of tissue-restricted precursor cells. A further limitation is that recombination converts an analog input (i.e. the level of Cre expression per cell), into a digital output (either the reporter gene is activated or not). A given Cre transgene can therefore fail to label a tissue of interest either because its promoter is completely silent in the progenitors of that tissue, or because the level of its expression falls below a crucial threshhold for recombination. Cre transgenes often give incomplete labeling of specific tissues or cell types, possibly due to this sensitivity threshhold.

Ptf1a and Pdx1 each play crucial roles in pancreas specification, as discussed below, yet were identified for their roles in adult cell type-specific gene expression. Consistent with its later phase of expression, Ptf1a was identified as an acinar gene activator(Krapp et al., 1996), and Ptf1a-deficient pancreata entirely lack acinar cells(Krapp et al., 1998). Pdx1, meanwhile, was identified as a regulator of the rat insulin 1(Ins1) gene (Ohlsson et al.,1993), and from E15.5 onwards its expression becomes mainly restricted to β-cells. (Note that rodents have two insulin genes, whereas primates have only one as the regulation and pancreatic expression of these genes are nearly identical, I refer to them collectively as insulin.)The transitions of Pdx1 and Ptf1a expression coincide with the overall conversion of progenitors to mature endocrine and exocrine cells(Figs 2, 3). This conversion is also reflected in the dynamic expression of the bHLH transcription factor neurogenin 3 (Neurog3, also known as Ngn3), which specifically marks precursors of islet cells(Gu et al., 2002)(Fig. 1). Ngn3 + cells appear in small numbers in the early organ,dramatically increase during mid-embryogenesis, and finally decline towards birth (Figs 2, 3)(Gradwohl et al., 2000 Schwitzgebel et al., 2000). Similar to neurons, therefore, islet cells are ordinarily generated during a restricted developmental window this process is termed neogenesis, in order to distinguish it from the proliferation of pre-existing islet cells.

Stages of pancreas development. Schematic cross-sections of developing embryos and organs, representing the progression of pancreas development. (A) Concomittant with specification of the organ, Pdx1 and Ptf1a initiate expression in two restricted domains of the gut endoderm (en). Nearby tissues, including notochord (nt) and aorta(ao), may promote this specification process(Kim et al., 1997 Lammert et al., 2001 Yoshitomi and Zaret, 2004).(B) Mesenchyme (mes) surrounds the thickening buds as the first Ngn3 + pro-endocrine cells appear. (C) Subsequent outgrowth produces a dense epithelial bud, in which early α-cells begin to differentiate. (D) Further growth and branching precedes the secondary transition, which is marked by a massive differentiation ofβ-cell and acinar cells, as well as by the progressive restriction of Pdx1 and Ptf1a expression to these respective cell types.(E) The organ has assumed its mature form by birth, with distinct islets of Langerhans scattered among exocrine acini and ducts.

Stages of pancreas development. Schematic cross-sections of developing embryos and organs, representing the progression of pancreas development. (A) Concomittant with specification of the organ, Pdx1 and Ptf1a initiate expression in two restricted domains of the gut endoderm (en). Nearby tissues, including notochord (nt) and aorta(ao), may promote this specification process(Kim et al., 1997 Lammert et al., 2001 Yoshitomi and Zaret, 2004).(B) Mesenchyme (mes) surrounds the thickening buds as the first Ngn3 + pro-endocrine cells appear. (C) Subsequent outgrowth produces a dense epithelial bud, in which early α-cells begin to differentiate. (D) Further growth and branching precedes the secondary transition, which is marked by a massive differentiation ofβ-cell and acinar cells, as well as by the progressive restriction of Pdx1 and Ptf1a expression to these respective cell types.(E) The organ has assumed its mature form by birth, with distinct islets of Langerhans scattered among exocrine acini and ducts.

Dynamics of endocrine specification and differentiation.(A-F) Brightfield photomicrographs of Pdx1 immunostaining at various stages of mouse dorsal pancreas (dp) development. From E11.5-E15.5, Pdx1 is expressed throughout the pancreatic epithelium (as well as in the posterior stomach, st), and is subsequently downregulated in acini (ac) and ducts (du)while being maintained in islet β-cells (is). (G-L) Confocal immunofluorescence photomicrographs at equivalent stages, for the pan-epithelial marker E-cadherin (green) and the islet precursor marker Ngn3(red). Ngn3 expression is rare at E11.5, dramatically peaks during the secondary transition (E13.5-E15.5) and declines again at E17.5, becoming undetectable in neonatal and adult pancreas. Arrowheads indicate proto-acinar clusters at the periphery of the branched epithelium, from which Ngn3expression is consistently excluded. (M-R) Confocal detection of glucagon (green) and insulin (red). Glucagon + α-cells are relatively common at E11.5 and E13.5, wheras large numbers of insulin + β-cells are not detected until after E13.5. From E17.5 onwards, endocrine cells aggregate into recognizable islets, withβ-cells at their cores and α-cells distributed peripherally. Scale bar in all images, 50 μm.

Dynamics of endocrine specification and differentiation.(A-F) Brightfield photomicrographs of Pdx1 immunostaining at various stages of mouse dorsal pancreas (dp) development. From E11.5-E15.5, Pdx1 is expressed throughout the pancreatic epithelium (as well as in the posterior stomach, st), and is subsequently downregulated in acini (ac) and ducts (du)while being maintained in islet β-cells (is). (G-L) Confocal immunofluorescence photomicrographs at equivalent stages, for the pan-epithelial marker E-cadherin (green) and the islet precursor marker Ngn3(red). Ngn3 expression is rare at E11.5, dramatically peaks during the secondary transition (E13.5-E15.5) and declines again at E17.5, becoming undetectable in neonatal and adult pancreas. Arrowheads indicate proto-acinar clusters at the periphery of the branched epithelium, from which Ngn3expression is consistently excluded. (M-R) Confocal detection of glucagon (green) and insulin (red). Glucagon + α-cells are relatively common at E11.5 and E13.5, wheras large numbers of insulin + β-cells are not detected until after E13.5. From E17.5 onwards, endocrine cells aggregate into recognizable islets, withβ-cells at their cores and α-cells distributed peripherally. Scale bar in all images, 50 μm.

Ngn3 is expressed in duct-like epithelial cells that are centrally located within the developing pancreas as these cells differentiate, they downregulate Ngn3, exit the epithelium and aggregate into proto-islet structures (Pictet and Rutter,1972 Schwitzgebel et al.,2000). Importantly, the spectrum of endocrine differentiation changes through embryogenesis, with α-cells being born quite early (see Box 2) and other cell types,including β-cells, not being generated in significant numbers until E13.5 or later (Herrera et al.,1991 Pictet and Rutter,1972) (Figs 2, 3). Interestingly, β-cell differentiation occurs simultaneously with that of acinar cells, albeit in a different region of the organ (Fig. 2), during a period termed the `secondary transition'(Pictet and Rutter, 1972). Newly differentiated islet cells are non-dividing, although they resume low levels of proliferation towards birth(Sander et al., 2000).

The observation that islets arise from duct-like progenitors has led to the longstanding hope that the duct of the mature pancreas could be coaxed into renewed β-cell neogenesis. As we shall see, it remains unclear whether this occurs in the normal pancreas, or whether it can be induced in vitro. The same uncertainty applies to essentially all potential sources of transplantable β-cells. The only tissue that unambiguously exhibitsβ-cell neogenesis is the embryonic pancreas, and reproducing this feat elsewhere will probably require that we understand how it happens in situ.


Research carrired out at DanStem

The image was made by Assistent Professor Jacqueline Ameri from the Semb group

By recapitulating key developmental stages that occur during normal pancreas development, human pluripotent stem cells (hPSCs) can be ultimately guided into mature insulin producing beta cells. Lower panel depicts a bright field image of undifferentited hPSCs (left image) that have been directed to an intermediate stage consisting of the pancreatic progenitors (PPs, middle fluorescence image) that have the capacity to form all the cells that are found in the pancreas including the beta cells (right fluorescence image). Professor Henrik Semb and his group are currently planning a phase 1/2 trial to test the safety and efficacy of the hPSC-derived insulin expressing cells derived in our lab. Furthermore, they are working with developing methods for expanding the PPs with the purpose of using them as the starting cell population for producing beta cells.

The group headed by Professor Anne Grapin-Botton focuses on understanding the impact of cellular and organ architecture on the cells’ fate choices in the pancreas and how this information is integrated with cell signalling to control cell differentiation into more specialized cell types. The overall aim is to gain new insight into human syndromes impairing pancreas development and further guide the generation of functional, insulin producing beta cells for future cell-based Diabetes therapy. Three-dimensional (3D) architecture is important for cell differentiation in the pancreas. However, current protocols aimed at directing differentiation of embryonic stem cells into beta cells are usually applied to cells grown at the bottom of a dish in 2 dimensions. The group has been successful in developing an in vitro culture system that leads to the 3D self-organization of mini-pancreas from dispersed progenitors. Progenitor cells are early descendants of stems cells, which can expand tremendously but not indefinitely. These cells can form many pancreatic cell types.

The Serup group focuses their research on developmental biology of the pancreas with the overall aim of understanding the signalling events that regulate growth and differentiation of pancreatic cell types with special emphasis on the insulin producing beta cell. The group has a special interest in the Notch signalling pathway. Recent work from Professor Palle Serup and his group suggest that understanding the direction of signalling as well as the temporal window(s) through which Notch acts will be informative for establishing protocols for the generation of fully functional beta cells from human embryonic stem cells.


Key Points

A definitive cure for type 1 diabetes mellitus (T1DM) will address both the β-cell deficit and the autoimmune response to cells that express insulin

Cells that express insulin have been obtained through differentiation of stem cells of either embryonic or adult origin, as well as genetically reprogrammed and transdifferentiated cells

The most effective differentiation protocols for the derivation of cells that express insulin recapitulate normal embryonic development

Knowledge of the transcription factors that regulate development of the embryonic pancreas has aided the evaluation of different strategies used to obtain β cells

Clinical trials have used bone marrow-derived mesenchymal stromal cells and umbilical cord blood cells to suppress the immune response in patients with T1DM

Even though challenges remain, the possibility of an effective stem-cell therapy for T1DM is a realistic goal for the foreseeable future


Abstract

Cases of type 2 diabetes mellitus have significantly increased in recent years. Researchers worldwide are combining their knowledge of biology, medicine, tissue engineering, and microtechnology to develop new effective treatments. An important aspect of current research is to develop of a complete model of three-dimensional pancreatic islets to test various factors that affect disease development and evaluate new therapies and drugs. Several methods have allowed the development of three-dimensional research models. The use of Lab-on-a-chip systems with appropriate microstructure geometry is a promising solution to macroscale problems. Such a device allows the development of a complete platform reflecting conditions that prevail in the body. Organ-on-a-chip platforms are successfully used mainly in studies of lung, heart, and liver diseases. This review presents the current state of knowledge on the creation of three-dimensional pancreatic islet structures in both microscale and microfluidic systems. We highlight the most important aspects of developing the geometry of such devices. We also discuss analytical detection methods that are suitable for detecting hormones that are secreted from pancreatic islets and, in combination with appropriate Lab-on-a-chip systems, can be used as a Micro Total Analysis System (μTAS).


Hepatic stem cells

Adult stem/progenitor cells from liver tissue are good source for making insulin-producing cells, as liver and pancreas share common bipotential precursor cells within the embryonic endoderm. Many studies have demonstrated that adult hepatocytes, human fetal liver cells, and hepatic stem cells can be differentiated into insulin-producing cells by forced expression of beta cell transcription factors and/or manipulating the external microenvironment.

Jin et al. recently reported that when immortalized liver epithelial progenitor cells, derived from regenerative liver, were stably transduced with Pdx-1, followed by treatment with various growth factors they differentiated into insulin-expressing cells. These cells secreted insulin in response to glucose, and transplantation of these cells ameliorated diabetes in STZ-induced diabetic scid mice (24). Ectopic expression of Pdx-1 in the liver of mice induced insulin expression and ameliorated STZ-induced diabetes (25). Expression of Pdx1-VP16, a constitutive active form of Pdx-1, in the liver together with NeuroD or Ngn-3, more efficiently induced the differentiation of hepatocytes into insulin-expressing cells (26).

Rat hepatic oval stem cells, which can differentiate into hepatocytes and bile duct epithelium, differentiate into pancreatic endocrine cells when cultured in a high glucose environment, secrete insulin in response to glucose, and have the ability to reverse hyperglycemia in STZ-induced diabetic NOD/scid mice (27). Human fetal liver progenitor cells expressing Pdx-1 can convert to insulin-expressing cells (28).


REVIEW article

/>Nazia Parveen and />Sangeeta Dhawan *
  • Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, United States

Pancreatic beta cells play a central role in regulating glucose homeostasis by secreting the hormone insulin. Failure of beta cells due to reduced function and mass and the resulting insulin insufficiency can drive the dysregulation of glycemic control, causing diabetes. Epigenetic regulation by DNA methylation is central to shaping the gene expression patterns that define the fully functional beta cell phenotype and regulate beta cell growth. Establishment of stage-specific DNA methylation guides beta cell differentiation during fetal development, while faithful restoration of these signatures during DNA replication ensures the maintenance of beta cell identity and function in postnatal life. Lineage-specific transcription factor networks interact with methylated DNA at specific genomic regions to enhance the regulatory specificity and ensure the stability of gene expression patterns. Recent genome-wide DNA methylation profiling studies comparing islets from diabetic and non-diabetic human subjects demonstrate the perturbation of beta cell DNA methylation patterns, corresponding to the dysregulation of gene expression associated with mature beta cell state in diabetes. This article will discuss the molecular underpinnings of shaping the islet DNA methylation landscape, its mechanistic role in the specification and maintenance of the functional beta cell phenotype, and its dysregulation in diabetes. We will also review recent advances in utilizing beta cell specific DNA methylation patterns for the development of biomarkers for diabetes, and targeting DNA methylation to develop translational approaches for supplementing the functional beta cell mass deficit in diabetes.


Concluding remarks

It is becoming increasingly apparent that mitochondrial dysfunction is associated with many different clinical defects. As there is currently no reliable therapeutic that can rescue mitochondrial function, we should welcome all advances that are grounded in thorough research. Numerous reports indicate that defects can apparently be ameliorated by either endogenous or exogenous mitochondrial transplantation. We should consider these approaches with an open mind, providing the supporting data have been thoroughly validated. For patients with a poor prognosis, such as those children with Pearson's syndrome, it is argued that any treatment that shows any potential of success could be considered even if we may not understand exactly how the procedure works. The key to progress is that we must be convinced that the treatment is indeed working. It will certainly be interesting to follow the outcome of this trial.