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Gene Expression Modifications in Type 2 Diabetes

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Abstract

We know that the mammalian genome is extensively transcribed, and the study of the gene expression would be a better tool to understand the molecular mechanisms that underlie the phenotype of the disease. Changes in gene expression are considered an important component of the pathogenesis of diabetes, and they may be the result of the direct effects of decreased insulin action via receptor-mediated signaling, as well as indirect effects secondary to the metabolic and humoral changes associated with the disease.

In this chapter, we will review some data regarding gene expression changes in four tissues that participate in the pathophysiology of obesity and T2D. The pancreas is an organ that is responsible of insulin production and secretion. This hormone is the key player in glucose and energy homeostasis in cells of almost every tissue. The liver is another organ that plays a role in energy metabolism by regulating glycogen storage and lipid metabolism. The adipose tissue has been implicated in the T2D development mainly because its function is not concealed to lipid storage but because it has important endocrine functions. Finally, we will discuss gene expression changes in muscle which is the tissue that consumes a large amount of circulating glucose and become insulin resistant after exposure to negative environments and genetic stimulus.

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Suggested/Further Reading

  • Bugliani M, Liechti R, Cheon H, Suleiman M, Marselli L, Kirkpatrick C, et al. Microarray analysis of isolated human islet transcriptome in type 2 diabetes and the role of the ubiquitin-proteasome system in pancreatic beta cell dysfunction. Mol Cell Endocrinol. 2013;367(1–2):1–10. (This paper highlights the importance of the ubiquitin-proteasome system in beta cell dysfunction in human T2D).

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  • Danielsson A, Ponten F, Fagerberg L, Hallstrom BM, Schwenk JM, Uhlen M, et al. The human pancreas proteome defined by transcriptomics and antibody-based profiling. PLoS One. 2014;9(12):e115421. (They employed genome-wide RNA sequencing to identify genes with elevated expression in pancreas).

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Authors and Affiliations

  1. Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI IMSS, Mexico City, Mexico

    Fernando Suarez-Sanchez & Jaime Gomez-Zamudio

Authors
  1. Fernando Suarez-Sanchez
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  2. Jaime Gomez-Zamudio
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Editor information

Editors and Affiliations

  1. Multidisciplinary Diabetes Center, Mexico City, Mexico

    Joel Rodriguez-Saldana

Glossary

3′-UTR region

Untranslated regions (UTRs) at the 3′end of mRNA contain important sequences that are related to the regulation of gene translation. The 3′-UTR plays a critical role in the stability of mRNA and in posttranscriptional regulation.

Apoptosis

Is a process of programmed cell death, which is considered to be important in several processes including normal cell turnover, development and function of immune system, hormone-dependent atrophy, embryonic development, and chemical-induced cell death. Human conditions such as neurodegenerative diseases, ischemic damage, autoimmune disorders, and many types of cancer are related to inappropriate apoptosis.

Bariatric surgery

Is a surgical process employed to reduce weight in obese patients, by restricting the amount of food the stomach can hold, causing malabsorption of nutrients. The most common bariatric surgery procedures are gastric bypass, sleeve gastrectomy, adjustable gastric band, and biliopancreatic diversion with duodenal switch.

Damage-associated molecular patterns (DAMPs)

Are cell-derived molecules that can initiate and perpetuate immunity in response to trauma, ischemia, and other setting of tissue damage in the absence of overt pathogenic infection. DAMPs can be found into the nucleus and cytoplasm (HMGB1), cytoplasm alone (S100 proteins), exosomes (HSP), extracellular matrix (hyaluronic acid), and in plasma such as complement (C3a, C4a, and C5a). Examples of nonprotein DAMPs include ATP, uric acid, heparin sulfate, RNA, and DNA. Increased levels of DAMPs are associated with inflammatory diseases such as sepsis, arthritis, atherosclerosis, systemic lupus erythematosus, Crohn’s disease, and cancer.

Deacetylation

Histones acetylation has been linked to transcriptional activation. The enzymes regulating the histone acetylation are the histone acetyltransferases (HATs). On the contrary, the deacetylation by histone deacetylases (HDACs) is related to transcriptional repression.

DNA hypermethylation

DNA methylation is a heritable epigenetic mark that involves the covalent transfer of a methyl group to a cytosine ring of DNA. The methylation reaction is catalyzed by a family of DNA methyltransferases (DNMTs). DNA methylation is associated with decreased transcriptional activity.

Enhancer

Is a DNA sequence that activators or transcriptional factors bind and increase gene transcription. Its location is variable in the gene; it can be present in the 5′-UTR, 3′-UTR, or into the coding region of the gene.

Epigenetics

Epigenetics is the study of biological mechanisms that switch genes on and off. There are three major levels of epigenetic changes: (1) chemical modification at nucleotide level (DNA methylation and RNA interference), (2) modifications at histone level, and (3) nucleosome remodeling.

Glycosylated hemoglobin (HbA1c)

Is also known as glycated hemoglobin. The glycation of hemoglobin consists in a nonenzymatic interaction between glucose and the amino groups of the valine and lysine residues in hemoglobin. This interaction is irreversible and is a test that indicates the exposition of the proteins to glucose for the last 3 months.

Genome-wide association studies (GWAS)

Are studies that identify DNA markers (SNPs) in the whole genome that are common to the human genome and to determine how these SNPs are distributed across different populations. GWAS are used to determine genetic risk markers associated with a disorder, for example, diabetes, obesity, hypertension, or cancer.

Knockout mice

Is a model used in the laboratory in which a mouse has inactivated or “knocked out” an existing gene by replacing it or disrupting it with an artificial piece of DNA.

Maturity-onset diabetes of the young (MODY)

Is a rare form of diabetes different from both type 1 and type 2 diabetes and runs strongly in families. It is caused by a mutation in a single gene.

OLEFT rats

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model of spontaneous T2D. This rat model of T2D is characterized by mild obesity with visceral fat accumulation and late-onset insulin resistance. It resembles human obese patients with T2D.

Pathogen-associated molecular patterns (PAMPs)

Are derived from microorganisms and recognized by pattern recognition receptor (PPR)-bearing cells of the innate immune system as well as many epithelial cells. Major PAMPs are microbial nucleic acids, including DNA, double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), and 5′-triphosphate RNA, as well as lipoproteins, surface glycoproteins, and membrane components (peptidoglycans, lipoteichoic acid, lipopolysaccharide, and glycosylphosphatidylinositol).

Promoter

The promoters are sequences in the DNA that define the start point in the transcription of a gene.

Reactive oxygen species (ROS)

Are radical and non-radical oxygen species formed by the partial reduction of oxygen, for example, superoxide anion (O2−), hydrogen peroxide (H2O2), and hydroxyl radical (HO•). They are generated endogenously by the oxidative phosphorylation process in the mitochondria or are produced from interactions with exogenous sources such as xenobiotic compounds.

Roux-en-Y gastric bypass (RYGB)

Is often called gastric bypass and is considered the “gold standard” of weight loss surgery. This surgery consists to create a new stomach pouch, using a small portion of the stomach. The smallest stomach is connected directly to the middle portion of the small intestine (jejunum), bypassing the rest of the stomach and the upper portion of the small intestine (duodenum).

Single nucleotide polymorphisms (SNPs)

Are a variation in a single position in a DNA sequence among individuals. This variation has to be present in almost 1% of a population to be considered as a SNP.

Streptozotocin (STZ)-induced diabetes

Streptozotocin is a glucosamine-nitrosourea compound derived from Streptomyces achromogenes. STZ is employed to induce cellular damage specifically in β-cells, resulting in hypoinsulinemia and hyperglycemia.

Transcriptomic

The transcriptome is the complete set of expression products transcribed from the genome in a specified tissue or populations of cells. Transcriptomic has emerged as a powerful technic that analyzes 1000 of genes in one sample using RNA microarrays. This technic has allowed the study of gene expression patterns on several tissues involved in the pathogenesis of the T2D and to identify genetic markers for the early diagnosis of T2D.

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Suarez-Sanchez, F., Gomez-Zamudio, J. (2019). Gene Expression Modifications in Type 2 Diabetes. In: Rodriguez-Saldana, J. (eds) The Diabetes Textbook. Springer, Cham. https://doi.org/10.1007/978-3-030-11815-0_10

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  • DOI: https://doi.org/10.1007/978-3-030-11815-0_10

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