Gene Could Help Explain Insulin Resistance
Health researchers have known for decades that Type 2 diabetes results from a phenomenon called insulin resistance, but what causes insulin resistance has remained a mystery. Now, researchers at the Stanford University School of Medicine and the University of Wisconsin-Madison have begun to untangle a web of connections that includes a gene; mitochondria, which produce energy for cells; insulin resistance; and how well the body’s metabolism functions. “We’ve identified a mechanism for insulin resistance that involves a gene that ties insulin resistance to mitochondrial function,” said Joshua Knowles, MD, PhD, an assistant professor of cardiovascular medicine at Stanford. A paper describing the work was published in the Oct. 4 issue of Cell Reports. Knowles is the senior author, and Indumathi Chennamsetty, PhD, a postdoctoral scholar at Stanford, is the lead author. Insulin is a hormone secreted by the pancreas that helps fat and muscle cells take glucose from the blood. When a person’s cells stop responding to insulin, the person has insulin resistance and glucose builds up in the blood, signaling the pancreas to produce ever more insulin. Insulin resistance severe enough to damage body tissues is common. One 2015 study estimated that nearly 35 percent of all U.S. adults are sufficiently insulin-resistant to be at greater risk of diabetes and cardiovascular disease. The environmental causes of the skyrocketing rate of insulin resistance in the United States include poor diet and sedentary habits, but the molecular mechanisms have been unknown, said Knowles. Suspect gene Previous work by Knowles and his team linked a variant of a human gene called NAT2 with insulin resistance in humans. In mice, suppressing a similar gene, called Nat1, caused metabolic dysfunct Continue reading >>
Seven Mutations In The Human Insulin Gene Linked To Permanent Neonatal/infancy-onset Diabetes Mellitus
Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic β cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM. Continue reading >>
Jbc : Journal Of Biological Chemistry
Abnormalities in lipid metabolism have been proposed as contributing factors to both defective insulin secretion from the pancreatic beta cell and peripheral insulin resistance in type 2 diabetes. Previously, we have shown that prolonged exposure of isolated rat islets of Langerhans to excessive fatty acid levels impairs insulin gene transcription. This study was designed to assess whether palmitate alters the expression and binding activity of the key regulatory factors pancreas-duodenum homeobox-1 (PDX-1), MafA, and Beta2, which respectively bind to the A3, C1, and E1 elements in the proximal region of the insulin promoter. Nuclear extracts of isolated rat islets cultured with 0.5 mm palmitate exhibited reduced binding activity to the A3 and C1 elements but not the E1 element. Palmitate did not affect the overall expression of PDX-1 but reduced its nuclear localization. In contrast, palmitate blocked the stimulation of MafA mRNA and protein expression by glucose. Combined adenovirus-mediated overexpression of PDX-1 and MafA in islets completely prevented the inhibition of insulin gene expression by palmitate. These results demonstrate that prolonged exposure of islets to palmitate inhibits insulin gene transcription by impairing nuclear localization of PDX-1 and cellular expression of MafA. The prevalence of diabetes mellitus is increasing dramatically in Western countries, in part because of the increase in obesity. Type 2 diabetes mellitus, the most frequent form of the disease, is characterized by defective insulin secretion from the pancreatic beta cells and peripheral insulin resistance. According to the lipotoxicity hypothesis, abnormalities in lipid metabolism contribute to both defects ( 1 ) and in particular to the inexorable decline of beta cell function ob Continue reading >>
Omim Entry - * 176730 - Insulin; Ins
Insulin, synthesized by the beta cells of the islets of Langerhans, consists of 2 dissimilar polypeptide chains, A and B, which are linked by 2 disulfide bonds. However, unlike many other proteins, e.g., hemoglobin, made up of structurally distinct subunits, insulin is under the control of a single genetic locus; chains A and B are derived from a 1-chain precursor, proinsulin, which was discovered by Steiner and Oyer (1967). Proinsulin is converted to insulin by the enzymatic removal of a segment that connects the amino end of the A chain to the carboxyl end of the B chain. This segment is called the C (for 'connecting') peptide. The human insulin gene contains 3 exons; exon 2 encodes the signal peptide, the B chain, and part of the C-peptide, while exon 3 encodes the remainder of the C-peptide and the A chain (Steiner and Oyer, 1967). The rat, mouse, and at least 3 fish species have 2 insulin genes (Lomedico et al., 1979). The single human insulin gene corresponds to rat gene II; each has 2 introns at corresponding positions. Deltour et al. (1993) showed that in the mouse embryo the 2 proinsulin genes are regulated independently, at least in part. The existence of a single insulin gene in man is supported by the findings in patients with mutations. The greatest variation among species is in the C-peptide. Receptor binding parts have been highly conserved. Some of these sites are involved with insulin-like activity, some with growth-factor activity, and some with both. INS-IGF2 Spliced Read-Through Transcripts By EST database analysis and RT-PCR, Monk et al. (2006) identified 2 read-through transcripts, which they called the INSIGF long and short isoforms, that contain exons from both the INS gene and the downstream IGF2 gene (147470). The INSIGF short isoform contains Continue reading >>
Global Haplotype Diversity In The Human Insulin Gene Region
Global Haplotype Diversity in the Human Insulin Gene Region 1 Department of Genetics, University of Leicester, Leicester LE1 7RH, UK 2 McDonald Institute for Archaeological Research, University of Cambridge, Cambridge CB2 3ER, UK The insulin minisatellite (INS VNTR) has been intensively analyzed due to its associations with diseases including diabetes. We have previously used patterns of variant repeat distribution in the minisatellite to demonstrate that genetic diversity is unusually great in Africans compared to non-Africans. Here we analyzed variation at 56 single nucleotide polymorphisms (SNPs) flanking the minisatellite in individuals from six populations, and we show that over 40% of the total genetic variance near the minisatellite is due to differences between Africans and non-Africans, far higher than seen in most genomic regions and consistent with differential selection acting on the insulin gene region, most likely in the non-African ancestral population. Linkage disequilibrium was lower in African populations, with evidence of clustering of historical recombination events. Analysis of haplotypes from the relatively nonrecombining region around the minisatellite revealed a star-shaped phylogeny with lineages radiating from an ancestral African-specific haplotype. These haplotypes confirmed that minisatellite lineages defined by variant repeat distributions are monophyletic in origin. These analyses provide a framework for a cladistic approach to future disease association studies of the insulin region within both African and non-African populations, and they identify SNPs which can be rapidly analyzed as surrogate markers for minisatellite lineage. The insulin minisatellite, located within the promoter of the human insulin gene, has been intensely investig Continue reading >>
Type 1 Diabetes Associates With The Insulin Gene.
Background The insulin gene (INS) on chromosome 11p 15 codes for the islet beta cell protein, pre-proinsulin, a peptide of 110 amino acids. Preproinsulin, a precursor, is processed by proteases to proinsulin by removal of the signal peptide and ultimately to biologically active insulin after the cleavage of C-peptide (figure 1). Autoimmunity to insulin in diabetes In type 1 diabetes insulin producing beta cells are the focus of autoimmune destruction, and their loss results in diabetes. Evidence from the NOD mouse model of autoimmune diabetes suggests that insulin is the primary autoantigen in this model   and autoantibodies to insulin can indeed be detected in humans in the first year of life. Further evidence that insulin itself plays a fundamental role in the pathogenesis of autoimmune diabetes emerged when genetic associations between INS and type 1 diabetes were reported by Bell and colleagues in 1984 in a relatively small study of 113 affected individuals compared with 83 healthy controls and 76 with type 2 diabetes. This association has been consistently replicated in every genetic analysis since: genome wide association studies (GWAS) have confirmed that the insulin gene locus is the second most important susceptibility locus after the HLA locus, contributing about 10% of genetic susceptibility. Molecular Biology of the insulin Gene The insulin gene comprises 3 exons and 2 introns interspersed with several polymorphisms in linkage disequilibrium. Type 1 diabetes is most closely associated with a variable number tandem repeat (VNTR) in the INS promoter  about 0.5Kb upstream of the transcription start site. Although highly polymorphic, three different classes of alleles exist at this locus, short class 1 variants (26-63 repeats), intermediate cla Continue reading >>
First Successful Laboratory Production Of Human Insulin Announced
South San Francisco, Calif. -- September 6, 1978 -- Genentech, Inc. and City of Hope National Medical Center, a private research institution and hospital in Duarte, California today announced the successful laboratory production of human insulin using recombinant DNA technology. Insulin is a protein hormone produced in the pancreas and used in the metabolism of sugar and other carbohydrates. The synthesis of human insulin was done using a process similar to the fermentation process used to make antibiotics. The achievement may be the most significant advance in the treatment of diabetes since the development of animal insulin for human use in the 1920's. The insulin synthesis is the first laboratory production DNA technology. Recombinant DNA is the technique of combining the genes of different organisms to form a hybrid molecule. DNA (deoxyribonucleic acid), the substances genes are composed of, contains the chemical record in which genetic information is encoded. Scientists at Genentech and City of Hope inserted synthetic genes carrying the genetic code for human insulin, along with the necessary control mechanism, into an E. coli bacterial strain which is a laboratory derivative of a common bacteria found in the human intestine. Once inside the bacteria, the genes were "switched-on" by the bacteria to translate the code into either "A" or "B" protein chains found in insulin. The separate chains were then joined to construct complete insulin molecules. The development of genetically engineered human insulin was funded by Genentech. However, the work was a cooperative effort between Genentech and City of Hope. The synthesis of human insulin gene was accomplished by four scientists at City of Hope Medical Center led by Roberto Crea, Ph.D., and Keichi Itakura, Ph.D. Scien Continue reading >>
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Assigning The Polymorphic Human Insulin Gene To The Short Arm Of Chromosome 11 By Chromosome Sorting
, Volume 60, Issue1 , pp 1015 | Cite as Assigning the polymorphic human insulin gene to the short arm of chromosome 11 by chromosome sorting We have determined the subchromosomal location of the human insulin gene by analyzing DNA isolated from sorted human metaphase chromosomes. Metaphase chromosome suspensions were sorted into fractions according to relative Hoechst fluorescence intensity by the fluorescence activated chromosome sorter. The chromosomal DNA in each fraction was characterized by restriction endonuclease analysis. Initial sorts indicated that the insulin gene-containing fragment resided in a fraction containing chromosomes 9, 10, 11 and 12. Studies of cell lines that contained chromosome translocations permitted the assignment of the insulin gene to a derivative chromosome that contains portions of the short arm of chromosome 11. Simultaneous sorting of the normal homolog from this small derivative chromosome separated the two different sized insulin gene-containing restriction fragments in this individual. These data indicate that the two restriction fragments represent insulin gene polymorphism and not duplicate gene loci. Gene PolymorphismRestriction FragmentChromosome TranslocationMetaphase ChromosomeInsulin Gene These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves. This is a preview of subscription content, log in to check access. Unable to display preview. Download preview PDF. Balant L, Burr IM, Stauffacher W, Cameron DP, Buenzli HF, Humbel RE, Renold AE (1971) Insulin of spiny mice (Acomys cahirinus)-partial characterization and evidence for two insulins. Endocrinology 88:517521 Google Scholar Beckman G, Beckman L, Tarnvik A (1970) A rare subu Continue reading >>
Insulin (ipr004825) < Interpro < Embl-ebi
The insulin family of proteins groups together several evolutionarily related active peptides [ PMID: 6107857 ]: these include insulin [ PMID: 6243748 , PMID: 503234 ], relaxin [ PMID: 10601981 , PMID: 8735594 ], insect prothoracicotropic hormone (bombyxin) [ PMID: 8683595 ], insulin-like growth factors (IGF1 and IGF2) [ PMID: 2036417 , PMID: 1319992 ], mammalian Leydig cell-specific insulin-like peptide (gene INSL3), early placenta insulin-like peptide (ELIP) (gene INSL4), locust insulin-related peptide (LIRP), molluscan insulin-related peptides (MIP), and Caenorhabditis elegans insulin-like peptides. The 3D structures of a number of family members have been determined [ PMID: 2036417 , PMID: 1319992 , PMID: 9141131 ]. The fold comprises two polypeptide chains (A and B) linked by two disulphide bonds: all share a conserved arrangement of 4 cysteines in their A chain, the first of which is linked by a disulphide bond to the third, while the second and fourth are linked by interchain disulphide bonds to cysteines in the B chain. Insulin is found in many animals, and is involved in the regulation of normal glucose homeostasis. It also has other specific physiological effects, such as increasing the permeability of cells to monosaccharides, amino acids and fatty acids, and accelerating glycolysis and glycogen synthesis in the liver [ PMID: 6243748 ]. Insulin exerts its effects by interaction with a cell-surface receptor, which may also result in the promotion of cell growth [ PMID: 6243748 ]. Insulin is synthesised as a prepropeptide from which an endoplasmic reticulum-targeting sequence is cleaved to yield proinsulin. The sequence of prosinsulin contains 2 well-conserved regions (designated A and B), separated by an intervening connecting region (C), which is variable be Continue reading >>
Insulin Gene Expression Is Regulated By Dna Methylation
Abstract Insulin is a critical component of metabolic control, and as such, insulin gene expression has been the focus of extensive study. DNA sequences that regulate transcription of the insulin gene and the majority of regulatory factors have already been identified. However, only recently have other components of insulin gene expression been investigated, and in this study we examine the role of DNA methylation in the regulation of mouse and human insulin gene expression. Methodology/Principal Findings Genomic DNA samples from several tissues were bisulfite-treated and sequenced which revealed that cytosine-guanosine dinucleotide (CpG) sites in both the mouse Ins2 and human INS promoters are uniquely demethylated in insulin-producing pancreatic beta cells. Methylation of these CpG sites suppressed insulin promoter-driven reporter gene activity by almost 90% and specific methylation of the CpG site in the cAMP responsive element (CRE) in the promoter alone suppressed insulin promoter activity by 50%. Methylation did not directly inhibit factor binding to the CRE in vitro, but inhibited ATF2 and CREB binding in vivo and conversely increased the binding of methyl CpG binding protein 2 (MeCP2). Examination of the Ins2 gene in mouse embryonic stem cell cultures revealed that it is fully methylated and becomes demethylated as the cells differentiate into insulin-expressing cells in vitro. Figures Citation: Kuroda A, Rauch TA, Todorov I, Ku HT, Al-Abdullah IH, Kandeel F, et al. (2009) Insulin Gene Expression Is Regulated by DNA Methylation. PLoS ONE 4(9): e6953. Editor: Kathrin Maedler, University of Bremen, Germany Received: April 13, 2009; Accepted: August 5, 2009; Published: September 9, 2009 Copyright: © 2009 Kuroda et al. This is an open-access article distributed und Continue reading >>
Structure And Evolution Of The Insulin Gene
STRUCTURE AND EVOLUTION OF THE INSULIN GENE Joel C. Eissenberg, Iain L. Cartwright, Graham H. Thomas, and Sarah C. R. Elgin The rapid rate of current global climate change is having strong effects on many species and, at least in some cases, is driving evolution, particularly when changes in conditions alter patterns of selection. Climate change thus provides an opportunity ... Read More Figure 1: A framework for considering the direct evolutionary responses of organisms to climate change. Populations may be faced with (a) opportunities to take advantage of favorable climatic conditio... Figure 2: Genetic effects of climate change adaptation. (a) With evolution, the change in climate results in changes in allele frequencies. This can occur via natural selection: Suppose that the fitne... Figure 3: Summary of the flowering time genetic regulatory network. Shown are the four main genetic pathways influencing flowering time in Arabidopsis thaliana: photoperiod, autonomous, vernalization,... Figure 4: Associations between latitude and three interrelated variables measured across populations of Drosophila melanogaster from the eastern Australian coast. (a) Frequency of two indel alleles (2... Philip C. Bevilacqua, Laura E. Ritchey, Zhao Su, Sarah M. Assmann Single-stranded RNA molecules fold into extraordinarily complicated secondary and tertiary structures as a result of intramolecular base pairing. In vivo, these RNA structures are not static. Instead, they are remodeled in response to changes in the ... Read More Figure 1: Structural hierarchy and complexity of RNA illustrated by the GTPase center RNA from Escherichia coli. (a) Primary structure of GTPase center RNA, a 99-nucleotide (nt) region of large subuni... Figure 2: RNA folds differently in silico and in vivo. Mes Continue reading >>
Glucose-induced Transcription Of The Insulin Gene Is Mediated By Factors Required For Beta-cell-type-specific Expression.
Glucose-induced transcription of the insulin gene is mediated by factors required for beta-cell-type-specific expression. Department of Molecular Physiology and Biophysics, Vanderbilt Medical Center, Nashville, Tennessee 37232. The insulin gene is expressed exclusively in pancreatic islet beta cells. The principal regulator of insulin gene transcription in the islet is the concentration of circulating glucose. Previous studies have demonstrated that transcription is regulated by the binding of trans-acting factors to specific cis-acting sequences within the 5'-flanking region of the insulin gene. To identify the cis-acting control elements within the rat insulin II gene that are responsible for regulating glucose-stimulated expression in the beta cell, we analyzed the effect of glucose on the in vivo expression of a series of transfected 5'-flanking deletion mutant constructs. We demonstrate that glucose-induced transcription of the rat insulin II gene is mediated by sequences located between -126 and -91 bp relative to the transcription start site. This region contains two cis-acting elements that are essential for directing pancreatic beta-cell-type-specific expression of the rat insulin II gene, the insulin control element (ICE; -100 to -91 bp) and RIPE3b1 (-115 to -107 bp). The gel mobility shift assay was used to determine whether the formation of the ICE- and RIPE3b1-specific factor-DNA element complexes were affected in glucose-treated beta-cell extracts. We found that RIPE3b1 binding activity was selectively induced by about eightfold. In contrast, binding to other insulin cis-acting element sequences like the ICE and RIPE3a2 (-108 to -99 bp) were unaffected by these conditions. The RIPE3b1 binding complex was shown to be distinct from the glucose-inducible fac Continue reading >>
The Insulin Gene And Diabetes Mellitus : A New Approach
JavaScrip is disabled for your browser. Some features of this site may not work without it. The Insulin gene and Diabetes Mellitus : a new approach Diabetes mellitus comprises a heterogeneous group of disorders characterized by chronic hypergly- caemia, and a propensity to develop microangiopathy, neuropathy, nephropathy and atherosclerosis. It is a common condition and is seen in all ethnic groups. The causes of diabetes are poorly understood, but appear to involve some form of interaction between hereditary and environmental factors. The genetics of diabetes is still unclear, but a picture is slowly emerging. Recently, associations with two HLA-DR antigens 3 and 4 (coded for by genes on chromosome 6) have been demonstrated with insulin- dependent diabetes, but are not sufficient to explain the entire genetic component of this disease. It has been postulated that a second gene locus might be involved. One such gene may be the human insulin gene which is located on the short arm of chromosome 11. Continue reading >>
The polypeptide hormone insulin is required for normal glucose homeostasis. Lack of insulin or insulin insufficiency leads to diabetes that affects up to 5% of the human population. Gene location Insulin is formed as a precursor protein preproinsulin. This is coded by the INS gene. In some animals there are two insulin genes or two genes that code for insulin. In most animals, including humans, a single gene is present. The hypothesis of a single gene is enhanced by the genetic studies of inheritance of defects in the insulin gene. In addition, there seems to be no sex-predilection while inheriting defects in the insulin gene. This means that the gene coding for insulin does not lie in the sex chromosomes (XX for females and XY for males) but in the autosomes (the 20 pairs of chromosomes barring the one pair of sex chromosomes). The insulin gene has been recently uncoded in its complete form in genomic studies. Human and rat insulin genes have been cloned and the DNA has been sequenced. It was seen that mouse and rat insulins are identical and they have similar gene sequences and organization. Similarities in genetic sequences in human have been found as well. Studies reveal that the 14-kilobase fragment that codes for insulin lies on the chromosome 11 in humans. Gene stimulation and inhibition The insulin gene is expressed almost exclusively in pancreatic β-cells. Glucose in blood is the major stimulant that regulates the insulin gene expression and enables the beta cells to produce insulin and maintain an adequate store of intracellular insulin to sustain the secretory demand. Glucose in blood acts via transcription factors like pancreatic/duodenal homeobox-1 (PDX-1, mammalian homologue of avian MafA/L-Maf (MafA), Beta2/Neuro D (B2)), and controls the rate of transcr Continue reading >>
This article is about the insulin protein. For uses of insulin in treating diabetes, see insulin (medication). Not to be confused with Inulin. Insulin (from Latin insula, island) is a peptide hormone produced by beta cells of the pancreatic islets, and it is considered to be the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of, especially, glucose from the blood into fat, liver and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat. Beta cells are sensitive to glucose concentrations, also known as blood sugar levels. When the glucose level is high, the beta cells secrete insulin into the blood; when glucose levels are low, secretion of insulin is inhibited. Their neighboring alpha cells, by taking their cues from the beta cells, secrete glucagon into the blood in the opposite manner: increased secretion when blood glucose is low, and decreased secretion when glucose concentrations are high. Glucagon, through stimulating the liver to release glucose by glycogenolysis and gluconeogenesis, has the opposite effect of insulin. The secretion of insulin and glucagon into the Continue reading >>