Regulation of insulin gene transcription

Department of Endocrinology and Metabolism, Hadassah University Hospital, Jerusalem, Israel.
Diabetologia (Impact Factor: 6.67). 04/2002; 45(3):309-26. DOI: 10.1007/s00125-001-0728-y
Source: PubMed


The mammalian insulin gene is exclusively expressed in the beta cells of the endocrine pancreas. Two decades of intensive physiological and biochemical studies have led to the identification of regulatory sequence motifs along the insulin promoter and to the isolation of transcription factors which interact to activate gene transcription. The majority of the islet-restricted (BETA2, PDX-1, RIP3b1-Act/C1) and ubiquitous (E2A, HEB) insulin-binding proteins have been characterized. Transcriptional regulation results not only from specific combinations of these activators through DNA-protein and protein-protein interactions, but also from their relative nuclear concentrations, generating a cooperativity and transcriptional synergism unique to the insulin gene. Their DNA binding activity and their transactivating potency can be modified in response to nutrients (glucose, NEFA) or hormonal stimuli (insulin, leptin, glucagon like peptide-1, growth hormone, prolactin) through kinase-dependent signalling pathways (PI3-K, p38MAPK, PKA, CaMK) modulating their affinities for DNA and/or for each other. From the overview of the research presented, it is clear that much more study is required to fully comprehend the mechanisms involved in the regulated-expression of the insulin gene in the beta cell to prevent its impairment in diabetes.

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Available from: Danielle Melloul, Jul 27, 2015
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    • "expression of the VGF precursor protein (Fig. 3A, inset), an effect blocked by pretreatment with cyclohexamide. This suggested that the effect was transcriptionally dependent, but we also cannot exclude the glucose-mediated translational regulation of mRNAs, which has been previously reported (Melloul et al. 2002). In a similar fashion, TLQP- 62 increased Ins1 and Vgf gene expression but not that of Ins2 at 2 h (Fig. 3B). "
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    ABSTRACT: Insulin secretion control is critical for glucose homeostasis. Paracrine and autocrine molecules secreted by cells of the islet of Langherans, as well as by intramural and autonomic neurons, control release of the different hormones that modulate insulin secretion. In pancreatic islets, the abundant presence of the granin protein VGF (nonacronymic; unrelated to VEGF) suggests that some of its proteolytically derived peptides could modulate hormone release. Thus, for the present study, we screened several VGF-derived peptides for their ability to induce insulin secretion, identifying the VGF C-terminal peptide TLQP-62 as the most effective fragment. TLQP-62 induced a potent increase in basal insulin secretion as well as in glucose-induced insulin release in several insulinoma cell lines. We found that this peptide stimulated insulin release via increased intracellular calcium mobilization and fast expression of the insulin 1 gene. Moreover, peripheral injection of TLQP-62 in mice improved glucose tolerance. Together, our findings suggest that TLQP-62, acting as an endocrine, paracrine, or autocrine factor, can be considered a new, strong insulinotropic peptide that can be targeted for innovative anti-diabetic drug discovery programs.
    Journal of Molecular Endocrinology 04/2015; 54(3). DOI:10.1530/JME-14-0313 · 3.08 Impact Factor
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    • "Hachimi-jio-gan is an eight-plant derived medical extract and its 1% dietary supplementation to rats for 4 weeks increased GLUT2 expression (Hirotani et al., 2007). Insulin is a hormone produced by the pancreatic b-cells and ensures the passage of glucose from blood to insulin-sensitive tissues such as liver, muscle and adipose tissues (Melloul et al., 2002). Insulin A expression in rat pancreas decreased upon STZ administration. "
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    International Journal of Food Sciences and Nutrition 02/2015; 66(3):1-7. DOI:10.3109/09637486.2014.1003534 · 1.21 Impact Factor
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    • "One of the direct targets of CREB is the neurogenic differentiation 1 transcription factor (NeuroD), which regulates the insulin expression and the sulfonylurea receptor 1 [22]. Among the other direct targets genes there are insulin itself and components of the exocytosis apparatus such as Rab3A and Rab27A, which are members of the Rab family, and two of their effectors, slp4 and Noc2 [23, 24]. The four genes contain a functional CRE able to bind ICER [25]. "
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    Journal of Diabetes Research 02/2014; 2014:768024. DOI:10.1155/2014/768024 · 2.16 Impact Factor
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