LIM-homeodomain Transcription Factor Isl-1 Mediates the Effect of Leptin on Insulin Secretion in Mice

Chen, Juan; Fu, Rui; Cui, Yan; Li, Yushan; Pan, Jirong; Liu, Jiali; Luo, Hanpeng; Yin, Jingdong; Li, Defa; Cui, Sheng

doi:10.1074/jbc.m113.450536

Cited by 16 publications

(19 citation statements)

References 53 publications

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“…In the pancreas, STAT3 signaling is required for the correct development and maintenance of endocrine pancreas (11). In addition, leptin-induced activation of STAT3 plays a crucial role in inhibiting insulin secretion in mice (12).…”

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confidence: 99%

An Activating Mutation in STAT3 Results in Neonatal Diabetes Through Reduced Insulin Synthesis

et al. 2017

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Neonatal diabetes mellitus (NDM) is a rare form of diabetes diagnosed within the first 6 months of life. Genetic studies have allowed the identification of several genes linked to the development of NDM; however, genetic causes for ∼20% of the cases remain to be clarified. Most cases of NDM involve isolated diabetes, but sometimes NDM appears in association with other pathological conditions, including autoimmune diseases. Recent reports have linked activating mutations in with early-onset autoimmune disorders that include diabetes of autoimmune origin, but the functional impact of-activating mutations have not been characterized at the pancreatic β-cell level. By using whole-exome sequencing, we identified a novel missense mutation in the binding domain of the STAT3 protein in a patient with NDM. The functional analyses showed that the mutation results in an aberrant activation of STAT3, leading to deleterious downstream effects in pancreatic β-cells. The identified mutation leads to hyperinhibition of the transcription factor Isl-1 and, consequently, to a decrease in insulin expression. These findings represent the first functional indication of a direct link between an NDM-linked activating mutation in and pancreatic β-cell dysfunction.

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confidence: 99%

An Activating Mutation in STAT3 Results in Neonatal Diabetes Through Reduced Insulin Synthesis

et al. 2017

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“…Complex cell signalling pathways intimately regulate insulin expression in the pancreatic cells. Our recent studies suggest that Isl1 regulates the effect of leptin and kisspeptin on insulin secretion in mice2223, so we speculate that the interaction between PIASy and Isl1 may be involved in mediating insulin gene expression and secretion. Coinciding with the above thought, both PIASy and Isl1 are expressed in human and mouse pancreas and NIT beta cells.…”

Section: Discussionmentioning

confidence: 84%

“…In our recent studies, Isl1 was suggested to regulate the effect of leptin and kisspeptin on insulin secretion in mice2223. To identify whether the interaction between Isl1 and PIASy is involved in regulating insulin synthesis and secretion, first we detected the expressions of PIASy and Isl1 in mouse pancreatic islet and NIT beta cells using standard PCR and immunofluorescence.…”

Section: Resultsmentioning

confidence: 99%

“…Pancreatic islets were isolated and cultured as described previously2246. The NIT pancreatic β cell line and human embryonic kidney 293FT cells were maintained in Dulbecco’s Modified Eagle Medium (DMEM) with 10% foetal bovine serum and 1% penicillin-streptomycin at 37 °C with 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Radioimmunoassays were performed as described previously using the insulin radioimmunoassay reagents provided by the Beijing North Institute Biological Technology (Beijing, China)2223. For each radioimmunoassay the intra-assay and inter-assay coefficients of variation were less than 10% and 15%.…”

Section: Methodsmentioning

confidence: 99%

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Protein Inhibitor of Activated STAT Y (PIASy) Regulates Insulin Secretion by Interacting with LIM Homeodomain Transcription Factor Isl1

Yan

Zhang

et al. 2016

Sci Rep

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It is known that the LIM homeodomain transcription factor Isl1 is highly expressed in all pancreatic endocrine cells and functions in regulating pancreatic development and insulin secretion. The Isl1 mutation has been found to be associated with type 2 diabetes, but the mechanism responsible for Isl1 regulation of insulin synthesis and secretion still needs to be elucidated. In the present study, the protein inhibitor of activated STAT Y (PIASy) was identified as a novel Isl1-interacting protein with a yeast two-hybrid system, and its interaction with Isl1 was further confirmed by a co-immunoprecipitation experiment. PIASy and Isl1 colocalize in human and mouse pancreas and NIT beta cells. Furthermore, PIASy and Isl1 upregulate insulin gene expression and insulin secretion in a dose-dependent manner by activating the insulin promoter. PIASy and Isl1 mRNA expression levels were also increased in type 2 diabetic db/db mice. In addition, our results demonstrate that PIASy and Isl1 cooperate to activate the insulin promoter through the Isl1 homeodomain and PIASy ring domain. These data suggest that that PIASy regulates insulin synthesis and secretion by interacting with Isl1 and provide new insight into insulin regulation, although the detailed molecular mechanism needs to be clarified in future studies.

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An Insight into Vital Genes Responsible for β-cell Formation

Narayan

Agrawal

et al. 2023

Advances in Experimental Medicine and Biology

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LIM-homeodomain Transcription Factor Isl-1 Mediates the Effect of Leptin on Insulin Secretion in Mice

Cited by 16 publications

References 53 publications

An Activating Mutation in STAT3 Results in Neonatal Diabetes Through Reduced Insulin Synthesis

An Activating Mutation in STAT3 Results in Neonatal Diabetes Through Reduced Insulin Synthesis

Protein Inhibitor of Activated STAT Y (PIASy) Regulates Insulin Secretion by Interacting with LIM Homeodomain Transcription Factor Isl1

An Insight into Vital Genes Responsible for β-cell Formation

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