Dataset Information

Forkhead Box Protein 1 (FoxO1) Inhibits Accelerated ? Cell Aging in Pancreas-specific SMAD7 Mutant Mice.

ABSTRACT: The mechanisms underlying the effects of exocrine dysfunction on the development of diabetes remain largely unknown. Here we show that pancreatic depletion of SMAD7 resulted in age-dependent increases in ? cell dysfunction with accelerated glucose intolerance, followed by overt diabetes. The accelerated ? cell dysfunction and loss of proliferation capacity, two features of ? cell aging, appeared to be non-cell-autonomous, secondary to the adjacent exocrine failure as a "bystander effect." Increased Forkhead box protein 1 (FoxO1) acetylation and nuclear retention was followed by progressive FoxO1 loss in ? cells that marked the onset of diabetes. Moreover, forced FoxO1 expression in ? cells prevented ? cell dysfunction and loss in this model. Thus, we present a model of accelerated ? cell aging that may be useful for studying the mechanisms underlying ? cell failure in diabetes. Moreover, we provide evidence highlighting a critical role of FoxO1 in maintaining ? cell identity in the context of SMAD7 failure.

SUBMITTER: Xiao X

PROVIDER: S-EPMC5336177 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

Forkhead Box Protein 1 (FoxO1) Inhibits Accelerated β Cell Aging in Pancreas-specific SMAD7 Mutant Mice.

Xiao Xiangwei X Chen Congde C Guo Ping P Zhang Ting T Fischbach Shane S Fusco Joseph J Shiota Chiyo C Prasadan Krishna K Dong Henry H Gittes George K GK

The Journal of biological chemistry 20170105 8

The mechanisms underlying the effects of exocrine dysfunction on the development of diabetes remain largely unknown. Here we show that pancreatic depletion of SMAD7 resulted in age-dependent increases in β cell dysfunction with accelerated glucose intolerance, followed by overt diabetes. The accelerated β cell dysfunction and loss of proliferation capacity, two features of β cell aging, appeared to be non-cell-autonomous, secondary to the adjacent exocrine failure as a "bystander effect." Increa ...[more]

PMID: 28057752

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Project description:Aims/hypothesisCarbohydrate-free diet prevents hyperglycaemia and beta cell destruction in the New Zealand Obese (NZO) mouse model. Here we have used a sequential dietary regimen to dissociate the effects of obesity and hyperglycaemia on beta cell function and integrity, and to study glucose-induced alterations of key transcription factors over 16 days.MethodsMice were rendered obese by feeding a carbohydrate-free diet for 18 weeks. Thereafter, a carbohydrate-containing diet was given. Plasma glucose, plasma insulin and total pancreatic insulin were determined, and forkhead box O1 protein (FOXO1) phosphorylation and the transcription factors pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 protein (NKX6.1) and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (MAFA) were monitored by immunohistochemistry for 16 days.ResultsDietary carbohydrates produced a rapid and continuous increase in plasma glucose in NZO mice between day 2 and 16 after the dietary challenge. Hyperglycaemia caused a dramatic dephosphorylation of FOXO1 at day 2, followed by a progressive depletion of insulin stores. The loss of beta cells was triggered by apoptosis (detectable at day 8), associated with reduction of crucial transcription factors (PDX1, NKX6.1 and MAFA). Incubation of isolated islets from carbohydrate-restricted NZO mice or MIN6 cells with palmitate and glucose for 48 h resulted in a dephosphorylation of FOXO1 and thymoma viral proto-oncogene 1 (AKT) without changing the protein levels of both proteins.Conclusions/interpretationThe dietary regimen dissociates the effects of obesity (lipotoxicity) from those of hyperglycaemia (glucotoxicity) in NZO mice. Obese NZO mice are unable to compensate for the carbohydrate challenge by increasing insulin secretion or synthesising adequate amounts of insulin. In response to the hyperglycaemia, FOXO1 is dephosphorylated, leading to reduced levels of beta cell-specific transcription factors and to apoptosis of the cells.

Dataset Information

Forkhead Box Protein 1 (FoxO1) Inhibits Accelerated ? Cell Aging in Pancreas-specific SMAD7 Mutant Mice.

Publications

Forkhead Box Protein 1 (FoxO1) Inhibits Accelerated β Cell Aging in Pancreas-specific SMAD7 Mutant Mice.

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