Human diabetes associated with defects in nuclear regulatory proteins for the insulin receptor gene.

Brunetti, Antonio; Brunetti, Leonardo; Foti, Daniela; Accili, Domenico; Goldfine, Ira D.

doi:10.1172/jci118400

Cited by 36 publications

(29 citation statements)

References 45 publications

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“…The above observations were supported further by the evaluation of transcriptional regulation of the IR gene in EBV-transformed lymphoblasts from one patient with the usual features of type 2 diabetes, in which defects in nuclear proteins regulating the IR gene were previously reported (2). In EBV-transformed lymphoblasts from this patient, IR expression was decreased despite the fact that the IR gene was normal (2). As shown in Fig.…”

Section: Vol 23 2003 Regulation Of the Insulin Receptor Gene Promotsupporting

confidence: 81%

A Nucleoprotein Complex Containing Sp1, C/EBPβ, and HMGI-Y Controls Human Insulin Receptor Gene Transcription

Foti

Iuliano

Chiefari

et al. 2003

Molecular and Cellular Biology

127

156

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Section: Vol 23 2003 Regulation Of the Insulin Receptor Gene Promotsupporting

confidence: 81%

A Nucleoprotein Complex Containing Sp1, C/EBPβ, and HMGI-Y Controls Human Insulin Receptor Gene Transcription

Foti

Iuliano

Chiefari

et al. 2003

Molecular and Cellular Biology

127

156

View full text Add to dashboard Cite

“…Previous studies have reported similar findings concerning the effect of insulin on the expression of transcription factors (Hansen et al 2004;Rome et al 2003). Overall, these above transcription factors signaling pathways are essential for the energy metabolism and intracellular signaling pathways to adapt to environmental changes, such as insulin, and may also participate in the pathogenesis of the disease (Barroso et al 1999;Brunetti et al 1996).…”

Section: Gadd45bsupporting

confidence: 59%

Transcriptomic profiles of skeletal muscle tissue following an euglycemic-hyperinsulinemic clamp in insulin-resistant obese subjects

et al. 2012

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Insulin resistance in skeletal muscle is an early phenomenon in the pathogenesis of type 2 diabetes. Muscle is mainly responsible for insulin-stimulated glucose clearance from the bloodstream. Thus, regulation of gene expression in muscle tissue may be involved in the pathogenesis of insulin resistance. The objective was to investigate gene expression and metabolic pathways alterations in skeletal muscle tissue following an euglycemic-hyperinsulinemic clamp in obese insulin-resistant subjects. We carried out a transcriptome comparison of skeletal muscle tissue before and after a 3-h euglycemic-hyperinsulinemic clamp following 8-week supplementation with n-3 polyunsaturated fatty acid (PUFA) (1.8 g/day) with or without a supplement of fish gelatin (FG) (25 % of daily protein intake) in 16 obese insulin-resistant subjects. Results indicate that approximately 5 % (1932) of expressed transcripts were significantly changed after the clamp in both n-3 PUFA and n-3 PUFA ? FG supplementation periods. Of these differentially expressed transcripts, 1394 genes associated with enzymes, transcription and translation regulators, transporters, G protein-coupled receptors, cytokines, and ligand-dependent nuclear receptors were modified. Metabolic pathways that were significantly modified included liver X receptor/retinoid X receptors (RXR) activation, vitamin D receptor/RXR activation, interleukin (IL)-8, acute phase response, IL10, triggering receptor expressed on myeloid cells 1, peroxisome proliferatoractivated receptor, G-beta/gamma and hepatocyte growth factor and IL6 signaling. Taken together, results suggest that mainly inflammatory and transcription factors are modified following clamp in obese insulin-resistant subjects. Overall, understanding the changes in metabolic pathways due to insulin may be a potential target for the management of insulin resistance.

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“…This attractive hypothesis is supported by the recent identification of mutated transcription factors in subtypes of maturity-onset diabetes of the young (39,40) and in other particular forms of type 2 diabetes (13,14). If this also occurs in the common form of type 2 diabetes, one can predict that the impaired regulation of gene expression may play a primary role in the pathogenesis of the disease.…”

Section: Discussionmentioning

confidence: 98%

“…It is well known that environmental factors play a major role in type 2 diabetes, in addition to genetic predisposition. Alterations in the transcriptional mechanisms involved in the adaptation of the cells to environmental changes may thus participate in the pathogenesis of the disease (13,14). In keeping with this hypothesis, the expression of some important genes involved in insulin action and glucose metabolism has been found to be altered in peripheral tissues of type 2 diabetic patients.…”

mentioning

confidence: 78%

Regulation by Insulin of Gene Expression in Human Skeletal Muscle and Adipose Tissue

et al. 2001

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Defective regulation of gene expression may be involved in the pathogenesis of type 2 diabetes. We have characterized the concerted regulation by insulin (3-h hyperinsulinemic clamp) of the expression of 10 genes related to insulin action in skeletal muscle and in subcutaneous adipose tissue, and we have verified whether a defective regulation of some of them could be specifically encountered in tissues of type 2 diabetic patients. Basal mRNA levels (determined by reverse transcriptase-competitive polymerase chain reaction) of insulin receptor, insulin receptor substrate-1, p85␣ phosphatidylinositol 3-kinase (PI3K), p110␣PI3K, p110␤PI3K, GLUT4, glycogen synthase, and sterol regulatory-element-binding protein-1c (SREBP-1c) were similar in muscle of control (n ‫؍‬ 17), type 2 diabetic (n ‫؍‬ 9), type 1 diabetic (n ‫؍‬ 9), and nondiabetic obese (n ‫؍‬ 9) subjects. In muscle, the expression of hexokinase II was decreased in type 2 diabetic patients (P < 0.01). In adipose tissue, SREBP-1c (P < 0.01) mRNA expression was reduced in obese (nondiabetic and type 2 diabetic) subjects and was negatively correlated with the BMI of the subjects (r ‫؍‬ ؊0.63, P ‫؍‬ 0.02). Insulin (؎1,000 pmol/l) induced a two-to threefold increase (P < 0.05) in hexokinase II, p85␣PI3K, and SREBP-1c mRNA levels in muscle and in adipose tissue in control subjects, in insulin-resistant nondiabetic obese patients, and in hyperglycemic type 1 diabetic subjects. Upregulation of these genes was completely blunted in type 2 diabetic patients. This study thus provides evidence for a specific defect in the regulation of a group of important genes in response to insulin in peripheral tissues of type 2 diabetic patients. Diabetes 50: 1134 -1142, 2001 I nsulin resistance is the main metabolic feature of type 2 diabetes (1,2), and several studies indicate that it generally precedes the onset of the disease (2,3). In vivo, skeletal muscle is the major site for insulin-dependent glucose disposal, and type 2 diabetic patients are characterized by a marked decrease in insulinstimulated glucose utilization in muscle mainly due to reduced glucose uptake and storage (1,2). Insulin stimulates glucose uptake by increasing the translocation of GLUT4-containing vesicles to the plasma membrane and by modifying the activity of enzymes involved in glucose metabolism (4). Insulin action is initiated by binding of the hormone to cell membranes and activation of the insulin receptor tyrosine kinase that results in the stimulation of intracellular signaling cascades (4). Among these cascades, the phosphatidylinositol 3-kinase (PI3K) pathway is thought to play a crucial role in the effects of insulin on glucose metabolism (5). Several defects in the insulin signaling pathways have been identified in skeletal muscle of type 2 diabetic patients. Impaired phosphorylation of insulin receptor and insulin receptor substrate (IRS)-1 in response to insulin has been reported (6 -8), and the induction of PI3K and Akt kinase activities have been found to be reduced (8 -10). The stimulat...

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Human diabetes associated with defects in nuclear regulatory proteins for the insulin receptor gene.

Cited by 36 publications

References 45 publications

A Nucleoprotein Complex Containing Sp1, C/EBPβ, and HMGI-Y Controls Human Insulin Receptor Gene Transcription

A Nucleoprotein Complex Containing Sp1, C/EBPβ, and HMGI-Y Controls Human Insulin Receptor Gene Transcription

Transcriptomic profiles of skeletal muscle tissue following an euglycemic-hyperinsulinemic clamp in insulin-resistant obese subjects

Regulation by Insulin of Gene Expression in Human Skeletal Muscle and Adipose Tissue

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