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Differential and complementary effects of glucose and prolactin on islet DNA synthesis and gene expression.

ABSTRACT: The mechanisms by which lactogenic hormones promote ?-cell expansion remain poorly understood. Because prolactin (PRL) up-regulates ?-cell glucose transporter 2, glucokinase, and pyruvate dehydrogenase activities, we reasoned that glucose availability might mediate or modulate the effects of PRL on ?-cell mass. Here, we used male rat islets to show that PRL and glucose have differential but complementary effects on the expression of cell cyclins, cell cycle inhibitors, and various other genes known to regulate ?-cell replication, including insulin receptor substrate 2, IGF-II, menin, forkhead box protein M1, tryptophan hydroxylase 1, and the PRL receptor. Differential effects on gene expression are associated with synergistic effects of glucose and PRL on islet DNA synthesis. The effects of PRL on gene expression are mirrored by ?-cell overexpression of signal transducer and activator of transcription 5b and are opposed by dexamethasone. An ad-small interfering RNA specific for cyclin D2 attenuates markedly the effects of PRL on islet DNA synthesis. Our studies suggest a new paradigm for the control of ?-cell mass and insulin production by hormones and nutrients. PRL up-regulates ?-cell glucose uptake and utilization, whereas glucose increases islet PRL receptor expression and potentiates the effects of PRL on cell cycle gene expression and DNA synthesis. These findings suggest novel targets for prevention of neonatal glucose intolerance and gestational diabetes and may provide new insight into the pathogenesis of ?-cell hyperplasia in obese subjects with insulin resistance.

SUBMITTER: Arumugam R

PROVIDER: S-EPMC3198965 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Differential and complementary effects of glucose and prolactin on islet DNA synthesis and gene expression.

Arumugam Ramamani R Fleenor Donald D Lu Danhong D Freemark Michael M

Endocrinology 20110114 3

The mechanisms by which lactogenic hormones promote β-cell expansion remain poorly understood. Because prolactin (PRL) up-regulates β-cell glucose transporter 2, glucokinase, and pyruvate dehydrogenase activities, we reasoned that glucose availability might mediate or modulate the effects of PRL on β-cell mass. Here, we used male rat islets to show that PRL and glucose have differential but complementary effects on the expression of cell cyclins, cell cycle inhibitors, and various other genes kn ...[more]

PMID: 21239441

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Project description:ObjectivesTo investigate genetic differences in middle ear mucosa (MEM) with nontypeable Haemophilus influenzae (NTHi) infection. Genetic upregulation and downregulation occurs in MEM during otitis media (OM) pathogenesis. A comprehensive assessment of these genetic differences using the techniques of complementary DNA (cDNA) library creation has not been performed.DesignThe cDNA libraries were constructed from NTHi-infected and noninfected chinchilla MEM. Random clones were picked, sequenced bidirectionally, and submitted to the National Center for Biotechnology Information (NCBI) Expressed Sequence Tags database, where they were assigned accession numbers. These numbers were used with the basic local alignment search tool (BLAST) to align clones against the nonredundant nucleotide database at NCBI.ResultsAnalysis with the Web-based statistical program FatiGO identified several biological processes with significant differences in numbers of represented genes. Processes involved in immune, stress, and wound responses were more prevalent in the NTHi-infected library. S100 calcium-binding protein A9 (S100A9); secretory leukoprotease inhibitor (SLPI); beta(2)-microglobulin (B2M); ferritin, heavy-chain polypeptide 1 (FTH1); and S100 calcium-binding protein A8 (S100A8) were expressed at significantly higher levels in the NTHi-infected library. Calcium-binding proteins S100A9 and S100A8 serve as markers for inflammation and have antibacterial effects. Secretory leukoprotease inhibitor is an antibacterial protein that inhibits stimuli-induced MUC1, MUC2, and MUC5AC production.ConclusionsA number of genes demonstrate changes during the pathogenesis of OM, including SLPI, which has an impact on mucin gene expression; this expression is known to be an important regulator in OM. The techniques described herein provide a framework for future investigations to more thoroughly understand molecular changes in the middle ear, which will likely be important in developing new therapeutic and intervention strategies.

Dataset Information

Differential and complementary effects of glucose and prolactin on islet DNA synthesis and gene expression.

Publications

Differential and complementary effects of glucose and prolactin on islet DNA synthesis and gene expression.

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