Researchers identify a previously unknown developmental cause of diabetes.


It is known that diabetes is a disease that commonly inflicts the pancreas, the organ responsible for insulin production. More specifically, it inflicts the cells that produce insulin, which are found in the endocrine tissue of the pancreas.  However, the mature pancreas is composed of two functional components, namely exocrine and endocrine tissue. Both tissue types originate during embryonic organogenesis from a common pool of multipotent pancreatic progenitors located within the pancreatic buds.

Although recent studies have demonstrated that genes function in the specification/differentiation of particular cell types during pancreatogenesis, there remains limited understanding about the degree of interplay between endocrine and exocrine development.  Now, a study from researchers at Kyoto University shows that exocrine tissue regulates proper formation of endocrine precursors and the expansion and function of endocrine tissues during embryonic and postnatal stages.  The team state that the exocrine tissues of the pancreas, which are not involved in insulin production, instead could make a promising target for iPS cell-based diabetes treatment.  The opensource study is published in the journal Scientific Reports.

Earlier studies from the lab showed that in a Ptf1a mutant mouse model, the timing of endocrine cell differentiation was normal, however, the total number of insulin-producing β cells was substantially reduced and the structure of islets disturbed, resulting in impaired glucose homeostasis.  These findings supported the hypothesis that exocrine pancreatic tissue functions as a matrix necessary for proper endocrine pancreas formation.  Previous studies from other groups have also shown that the gene Pdx1 is indispensable for the formation of both pancreatic exocrine and endocrine cells during development.  Therefore, the current study investigates whether diseased exocrine tissue could cause deficiencies in the production of endocrine cells, using Pdx1 as a starting point.

The current study utilised a mouse model that depleted the Pdx1 gene, which in the pancreas is exclusively found in exocrine tissue.  Results show that this caused an underdeveloped pancreas with the mice exhibiting a diabetes phenotype, such as low insulin levels, suggesting endocrine development was also affected. Data findings show that endocrine progenitor cells that did not have the mutation in the mutant mice also showed poor survival.

Results show that the mutant mice showed exocrine defects and also fewer endocrine precursors and endocrine cells with less proliferation and delayed maturation, resulting in impaired glucose homeostasis. The researchers state that these findings are the first to support the hypothesis that the exocrine pancreas is required for proper endocrine development and function, and that normal development of the pancreas occurs in an interactive, coordinated manner between the two tissues.

The team surmise that their findings suggest non-cell autonomous effects, which describes the phenomenon where cells with genetic defects may cause malfunction in neighbouring, genetically healthy cells, and could have important implications for diabetes treatment.  For the future, the researchers state that it means the exocrine cells secrete something that promotes the differentiation and survival of endocrine cells during development, and could lead to promising treatments for diabetes.

Source: Center for iPS Cell Research and Application (CiRA), Kyoto University

In normal mice (top), the pancreas forms with normal spatial organization as seen by the distinct patterning of different colored cell types. In Pdx1 mutant mice (bottom), however, the pancreas is much smaller and loses its spatial organization. Scale bars = 50 micro meter.  Credit: Kawaguchi Laboratory, CiRA, Kyoto University.

In normal mice (top), the pancreas forms with normal spatial organization as seen by the distinct patterning of different colored cell types. In Pdx1 mutant mice (bottom), however, the pancreas is much smaller and loses its spatial organization. Scale bars = 50 micro meter. Credit: Kawaguchi Laboratory, CiRA, Kyoto University.

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