Pancreatic Regeneration in the Face of Diabetes - Regenerative Medicine and Cell Therapy - page 171

regarding the changes in b cell mass during human pregnancy. Increase in insulin
resistance during human pregnancy is compensated by enhanced insulin secretion
to keep the blood glucose level at normal [ 16 , 17 ]. Analysis of pancreas from
pregnant women showed nearly 1.4-2.4-fold increase in b cell mass [ 18 , 19 ].
Unlike during rodent pregnancy, this increase is not achieved by hypertrophy or
replication. Instead, there is a possible neogenesis supported by the appearance of
new smaller islets and duct cells positive for insulin [ 19 ]. Regardless of the
mechanism involved, the regulated change in b cell mass is important to prevent
diabetes during pregnancy or other conditions of high metabolic demand, e.g.,
obesity, and a failure to meet this compensation is what finally leads to diabetes
[ 20 ].
9.3.2 Regeneration of b Cells Following Pancreatic Injury
Evidence of b cell regeneration also comes from mouse models of pancreatic
injury (chemically or surgically induced), and genetically manipulated mice (to
specifically destroy b cells) as well as human diabetic patients. It has been shown
in many different studies that b cells can proliferate in response to pancreatic
injury [ 21 ]. However, what is more controversial is the fact that whether or not
there is any b cell neogenesis, e.g., generation of insulin producing b cells from
pancreatic ductal cells. While pancreatic ductal cells do give rise to endocrine cells
during the embryonic phase of development [ 22 ], a similar process in adult life is
not clear. The initial evidence for such neogenesis comes from morphological
observation, showing the presence of insulin-expressing cells in or near to
pancreatic duct epithelium, following pancreatic injury in the form of partial
pancreatectomy or pancreatic duct ligation [ 23 , 24 ]. However, these studies were
not conclusive, as they did not involve any lineage tracing to specifically
demonstrate the origin of new b cells from ductal cells. Dor et al. [ 25 ] for the first
time used a genetic lineage tracing approach to prove that nearly all b cells in adult
life, during normal conditions or after 70 % pancreatectomy, are originated from
pre-existing b cells. It was further supported by a study from Teta et al. [ 26 ], where
they used two types of nucleotide analogs to sequentially label b cells and
concluded that no specialized progenitors are involved in b cell regeneration after
50 % pancreatectomy. However, because such lineage tracing is not 100 %
efficient, there still remains a possibility that some b cells might arise from sources
other than pre-existing b cells.
Another injury model to study pancreatic regeneration in rodents is pancreatic
duct ligation. A study by Inada et al. [ 27 ] supported the idea that pancreatic ductal
cells can give rise to b cells after duct ligation. To directly show the contribution
of ductal cells in b cell regeneration, the authors specifically labeled pancreatic
ductal cells by using carbonic anhydrase II-cre mouse line and a b-galactosidase
reporter mouse line. Following ductal ligation, indeed they found a significant
increase in the number of b-gal positive b cells showing the conversion of ductal