Combined Expression of Pancreatic Duodenal Homeobox 1 and Islet Factor 1 Induces Immature Enterocytes to Produce Insulin

Kojima, Hideto; Nakamura, Takaaki; Fujita, Yukihiro; Kishi, Akio; Fujimiya, Mineko; Yamada, Syu; Kudo, Motoi; Nishio, Yoshihiko; Maegawa, Hiroshi; Haneda, Masakazu; Yasuda, Hitoshi; Kojima, Itaru; Seno, Masaharu; Wong, Norman C.W.; Kikkawa, Ryuichi; Kashiwagi, Atsunori

doi:10.2337/diabetes.51.5.1398

Cited by 133 publications

(94 citation statements)

References 53 publications

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“…We chose to use BTC, alone and in combination with PDX1 to attempt to regenerate b-cell mass. BTC is a mitogen and b-cell-stimulating hormone 16 that has been shown to induce insulin production in intestinal cells 17 and hepatocytes. 18 We used a 21 kDa membrane-anchored form of BTC that has been shown to induce insulin production in AR421 rat pancreatic cells.…”

Section: Discussionmentioning

confidence: 99%

Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1

Chen

Ding

et al. 2007

Gene Ther

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Ultrasound-targeted microbubble destruction (UTMD) was used to direct betacellulin (BTC) and pancreatic duodenal homeobox-1 (PDX1) to rat pancreas 48 h after islet destruction by streptozotocin (STZ). Sprague-Dawley rats were rendered diabetic by STZ injection. Controls included normal rats, STZ only without UTMD, and UTMD with DsRed reporter gene. Blood glucose increased dramatically in all rats 48 h after STZ, and continued to rise after UTMD with BTC alone. Blood glucose declined from day 3 to day 10 after UTMD with PDX1, but remained elevated (26178 mg/dl). However, in rats treated with both BTC and PDX1, blood glucose remained below 200 mg/dl throughout day 10. This was accompanied by normalization of blood insulin and C-peptide. Histology demonstrated islet-like clusters of glucagon-staining cells in the rats treated with BTC and PDX1, but these clusters disappeared by 30 days after UTMD treatment. Although regeneration of insulin-producing islets was not seen, diabetes was reversed for up to 15 days after a single UTMD treatment by ectopic insulin production by pancreatic acinar cells. These cells co-expressed amylase and insulin and demonstrated several b-cell markers by reverse transcription-PCR. Gene therapy by UTMD can reverse diabetes in vivo in adult rats by restoring pancreatic insulin production.

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Section: Discussionmentioning

confidence: 99%

Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1

Chen

Ding

et al. 2007

Gene Ther

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“…Appropriate controls included DNase pretreatment and omission of reverse transcriptase in the reaction. The sequences of individual PCR primers were as described (13,14).…”

Section: Methodsmentioning

confidence: 99%

“…Appropriate controls included DNase pretreatment and omission of reverse transcriptase in the reaction. The sequences of individual PCR primers were as described (13,14).Immunohistochemical Analysis. For the detection of insulin-or proinsulin-positive cells, we fixed 20-m-thick frozen sections or 5-m-thick paraffin sections and processed them for immunohistochemical staining by using the avidin-biotin peroxidase complex (ABC) method and diaminobenzidine (DAB)-nickel reactions as described (13,15).…”

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confidence: 99%

Extrapancreatic insulin-producing cells in multiple organs in diabetes

Kojima

Fujimiya

Matsumura

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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194

183

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Insulin-producing cells normally occur only in the pancreas and thymus. Surprisingly, we found widespread insulin mRNA and protein expression in different diabetic mouse and rat models, including streptozotocin-treated mice and rats, ob͞ob mice, and mice fed high-fat diets. We detected in diabetic mice proinsulinand insulin-positive cells in the liver, adipose tissue, spleen, bone marrow, and thymus; many cells also produced glucagon, somatostatin, and pancreatic polypeptide. By in situ nucleic acid hybridization, diabetic, but not nondiabetic, mouse liver exhibited insulin transcript-positive cells, indicating that insulin was synthesized by these cells. In transgenic mice that express GFP driven by the mouse insulin promoter, streptozotocin-induced diabetes led to the appearance of GFP-positive cells in liver, adipose tissue, and bone marrow; the fluorescent signals showed complete concordance with the presence of immunoreactive proinsulin. Hyperglycemia produced by glucose injections in nondiabetic mice led to the appearance of proinsulin-and insulin-positive cells within 3 days. Bone marrow transplantation experiments showed that most of the extrapancreatic proinsulin-producing cells originated from the bone marrow. Immunoreactive proinsulin-and insulin-positive cells were also detected in the liver, adipose tissue, and bone marrow of diabetic rats, indicating that extrapancreatic, extrathymic insulin production occurs in more than one species. These observations have implications for the regulation of insulin gene expression, modulation of selftolerance by insulin gene expression, and strategies for the generation of insulin-producing cells for the treatment of diabetes.pancreatic islets ͉ hyperglycemia ͉ ob͞ob ͉ obesity ͉ bone marrow transplantation I nsulin is normally produced in highly specialized cells of the endocrine pancreas. The tissue-specific expression of insulin is tightly regulated at the transcriptional level, and the major regulatory elements are located in the 5Ј flanking region of the insulin gene (1). Insulin expression is specific to ␤ cells in the pancreatic islets, although proinsulin has also been detected in the fetal and postnatal thymus and spleen͞lymphoid tissues (2, 3), a pattern of promiscuous expression of normally tissuerestricted ''peripheral'' proteins in these tissues (4, 5). Immunoreactivity to insulin plays a key role in autoimmune diabetes in NOD mice (6, 7) and in type 1 diabetes in humans (7); expression of minute amounts of insulin in the thymus is believed to be important in the induction of tolerance to insulin and other ''self-antigens '' (8-11). In this study, we found insulin gene transcription and protein expression in multiple tissues outside the pancreas and thymus in mice and rats with diabetes. The widespread occurrence of extrapancreatic, extrathymic insulin gene products in diabetic animals is surprising; it suggests that we should revise our thinking on the regulation of insulin gene expression, the mechanism of immune tolerance to insulin, the pathophysi...

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“…We investigated the changes in the islets of Langerhans morphology and pancreatic insulin mRNA and protein levels following ghrelin administration in this animal model. Further, we studied the resulting alterations in the expression levels of pancreatic and duodenal homeobox 1 (Pdx1), one of the major pancreatic transcriptional factors thought to play a key role in the development and regeneration of the pancreas [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Ghrelin prevents development of diabetes at adult age in streptozotocin-treated newborn rats

et al. 2006

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Aims/hypothesis: Ghrelin, a stomach-derived hormone, functions in multiple biological processes, including glucose metabolism and cellular differentiation and proliferation. In this study, we examined whether early treatment with ghrelin can regenerate beta cells of the pancreas in an animal model of diabetes mellitus, the n0-STZ model, in which neonatal rats are injected with streptozotocin (STZ) at birth.Methods: Following administration of ghrelin to n0-STZ rats from postnatal days 2 to 8, we examined beta cell mass, mRNA expression levels of insulin and of pancreatic and duodenal homeobox 1 (Pdx1) gene, and pancreatic morphology on days 21 and 70. In addition, we investigated the effects of ghrelin on beta cell replication. Results: By day 21, ghrelin treatment increased pancreatic expression of insulin and Pdx1 mRNA in n0-STZ rats. The number of replicating cells was also significantly increased in the ghrelin-treated n0-STZ model. At day 70, n0-STZ rats exhibited hyperglycaemia, despite slight increases in plasma insulin levels. Ghrelin treatment resulted in the improvement of plasma glucose levels, which were associated with normal plasma insulin levels. Pancreatic insulin mRNA and protein levels were significantly increased in ghrelin-treated n0-STZ model animals. Conclusions/interpretation: These findings suggest that ghrelin promotes regeneration of beta cells in STZ-treated newborn rats. Thus, early administration of ghrelin may help prevent the development of diabetes in disease-prone subjects after beta cell destruction.

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Combined Expression of Pancreatic Duodenal Homeobox 1 and Islet Factor 1 Induces Immature Enterocytes to Produce Insulin

Cited by 133 publications

References 53 publications

Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1

Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1

Extrapancreatic insulin-producing cells in multiple organs in diabetes

Ghrelin prevents development of diabetes at adult age in streptozotocin-treated newborn rats

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