Models of pancreatic regeneration in diabetes

Risbud, Makarand V.; Bhonde, Ramesh

doi:10.1016/s0168-8227(02)00103-1

Cited by 47 publications

(27 citation statements)

References 62 publications

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“…While we and others have made similar observations concerning the cystic transformation of islets both in vitro 7,8,10,11 and in vivo, 14 this is the first report of redifferentiation from the transformed cystic state back to endocrine cell clusters that resemble freshly isolated The plasticity of pancreatic tissues has perhaps best been demonstrated by the ability of acinar and ductal tissue to form new islets in vivo 63,64 and in vitro, 25,[65][66][67][68][69] but the mechanisms and exact cell types involved are not known. Moreover, islets produced in vitro do not display normal endocrine gene expression, insulin content or physiologic glucose-responsive insulin secretion.…”

Section: Discussionsupporting

confidence: 58%

Morphogenetic plasticity of adult human pancreatic islets of Langerhans

Lipsett

Sladek

et al. 2005

Cell Death Differ

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The aim of this study was to investigate the phenotypic plasticity of pancreatic islets of Langerhans. Quiescent adult human islets were induced to undergo a phenotypic switch to highly proliferative duct-like structures in a process characterized by a loss of expression of islet-specific hormones and transcription factors as well as a temporally related rise in the expression of markers of both duct epithelial and progenitor cells. Short-term treatment of these primitive duct-like structures with the neogenic factor islet neogenesisassociated protein ) induced their reconversion back to islet-like structures in a PI3-kinase-dependent manner. These neoislets resembled freshly isolated human islets with respect to the presence and topological arrangement of the four endocrine cell types, islet gene expression and hormone production, insulin content and glucoseresponsive insulin secretion. Our results suggest that adult human islets possess a remarkable degree of morphogenetic plasticity. This novel observation may have important implications for understanding pancreatic carcinogenesis and islet neogenesis.

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Section: Discussionsupporting

confidence: 58%

Morphogenetic plasticity of adult human pancreatic islets of Langerhans

Lipsett

Sladek

et al. 2005

Cell Death Differ

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“…The islet size analysis confirmed the distinct increase of neoislet population (o50 mm in diameter) during the restoration of normal blood glucose level (Figure 4c), which is also observed in other pancreas regeneration models. 23 …”

Section: Changes Of Pancreas Endocrine Cell Population In Ddc-stz-trementioning

confidence: 99%

Streptozotocin-induced diabetes can be reversed by hepatic oval cell activation through hepatic transdifferentiation and pancreatic islet regeneration

Kim

Shin

Kim

et al. 2007

Laboratory Investigation

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Hepatic oval cells have shown the potential to transdifferentiate into insulin-producing cells when cultured with high glucose concentrations. However, it remains unknown whether the oval cells can contribute to insulin production in diabetic mice. In this study, our aim was to investigate the response of activated hepatic oval cells to hyperglycemic conditions. C57BL/6 mice were fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 4 weeks to activate the hepatic oval cell population before inducing hyperglycemia with streptozotocin (STZ). Despite the initial hyperglycemia (341715 mg/dl), the blood glucose levels of DDC-STZ-treated mice were significantly improved within 6 weeks (185712 mg/dl). During the initial hyperglycemic stage, DDC-STZ-treated livers expressed pancreatic developmental, endocrine and exocrine genes. Hepatic insulin production was confirmed by immunohistochemistry and ELISA. These results suggested that transdifferentiated hepatic oval cell population contributed to the amelioration of hyperglycemia. We additionally determined that DDC-STZ-treated pancreata played a critical role in complete reversal of hyperglycemia as evidenced by extensive b-cell regeneration and increase of pancreatic insulin content after STZ treatment, which is rarely observed in other adult STZ models. Reversal of hyperglycemia in this model seems to be accomplished by biphasic insulin augmentation, first by hepatic transdifferentiation, and followed by endogenous b-cell regeneration in the pancreas. The DDC-STZ treatment provides a novel injury model for better understanding of the functional behavior of hepatic and pancreatic stem/progenitor cell population under hyperglycemic condition, which may yield critical information for developing b-cell-based therapies to treat diabetes. The pancreatic endocrine compartment is composed of the islets of Langerhans, which are clusters of four cell types that synthesize insulin (b-cells), glucagon (a-cells), somatostatin (d-cells) and pancreatic polypeptide (pp-cells). In mature rodent pancreatic islets, b-cells are located in the core, whereas a-, d-and pp-cells are in the rim. The pancreatic bcell possesses the ability to respond to minor increases in the plasma glucose levels, thereby keeping the blood glucose level within a very narrow range. 1 Progressive destruction of pancreatic b-cell leading to decreased insulin production and subsequent hyperglycemia is observed in all forms of diabetes mellitus. Therefore, the number of functional b-cells in the pancreas is of decisive importance in the development and progress of the disease. To date, the most effective long-term treatment of diabetes is islet transplantation, a procedure known as the Edmonton protocol. 2 However, there is currently a severe shortage of pancreas donors, creating a need for new strategies to generate pancreatic b-cells either in vitro or in vivo. Pancreatic stem/progenitor cells should be considered as the primary sources to generate insulin-producing cells. However, to dat...

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“…It is recognized that ␤-cell mass must be actively regulated throughout life (2)(3)(4)(5). The essential cellular and molecular bases for the regulation of ␤-cell mass in adults are incompletely understood, but they are currently thought to include three major processes: replication of differentiated ␤-cells, differentiation and neogenesis of ␤-cells from precursor cells, and the inhibition of ␤-cell apoptosis (6,7).…”

mentioning

confidence: 99%

Recovery of Islet β-Cell Function in Streptozotocin- Induced Diabetic Mice

et al. 2006

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Limitations in islet ␤-cell transplantation as a therapeutic option for type 1 diabetes have prompted renewed interest in islet regeneration as a source of new islets. In this study we tested whether severely diabetic adult C57BL/6 mice can regenerate ␤-cells. Diabetes was induced in C57BL/6 mice with high-dose streptozotocin (160؊170 mg/kg). In the absence of islet transplantation, all diabetic mice remained diabetic (blood glucose >400 mg/dl), and no spontaneous reversal of diabetes was observed. When syngeneic islets (200/mouse) were transplanted into these diabetic mice under a single kidney capsule, stable restoration of euglycemia for >120 days was achieved. Removal of the kidney bearing the transplanted islets at 120 days posttransplantation revealed significant restoration of endogenous ␤-cell function. This restoration of islet function was associated with increased ␤-cell mass, as well as ␤-cell hypertrophy and proliferation. The restoration of islet cell function was facilitated by the presence of a spleen; however, the facilitation was not due to the direct differentiation of spleen-derived cells into ␤-cells. This study supports the possibility of restoring ␤-cell function in diabetic individuals and points to a role for the spleen in facilitating this process.

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Models of pancreatic regeneration in diabetes

Cited by 47 publications

References 62 publications

Morphogenetic plasticity of adult human pancreatic islets of Langerhans

Morphogenetic plasticity of adult human pancreatic islets of Langerhans

Streptozotocin-induced diabetes can be reversed by hepatic oval cell activation through hepatic transdifferentiation and pancreatic islet regeneration

Recovery of Islet β-Cell Function in Streptozotocin- Induced Diabetic Mice

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