Type 2 Diabetes, Obesity, and Cancer Share Some Common and Critical Pathways

Rahman, Ishrat Tasnim; Athar, Tanwir; Islam, Mohammad Mahmudul

doi:10.3389/fonc.2020.600824

Cited by 30 publications

(15 citation statements)

References 100 publications

(133 reference statements)

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“…According to the World Health Organization, approximately 38.2 million children less than 5 years old were obese in 2019. Global statistics show obesity is a risk component contributing to the development of severe metabolic disorders such as nonalcoholic fatty liver disorder (NAFLD) [ 1 ], cancer [ 2 ], type 2 diabetes mellitus (T2M) [ 3 ], and cardiovascular disorders (CVDs) [ 4 ]. Obesity alters preexisting adipocyte hypertrophy, preadipocyte differentiation, macrophages, T-cell infiltration at the adipose site, the release of inflammatory cytokines, and increases insulin resistance (IR) [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Adipocyte, Immune Cells, and miRNA Crosstalk: A Novel Regulator of Metabolic Dysfunction and Obesity

Kiran

Kumar

et al. 2021

Cells

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Obesity is characterized as a complex and multifactorial excess accretion of adipose tissue (AT) accompanied with alterations in the immune response that affects virtually all age and socioeconomic groups around the globe. The abnormal accumulation of AT leads to several metabolic diseases, including nonalcoholic fatty liver disorder (NAFLD), low-grade inflammation, type 2 diabetes mellitus (T2DM), cardiovascular disorders (CVDs), and cancer. AT is an endocrine organ composed of adipocytes and immune cells, including B-Cells, T-cells and macrophages. These immune cells secrete various cytokines and chemokines and crosstalk with adipokines to maintain metabolic homeostasis and low-grade chronic inflammation. A novel form of adipokines, microRNA (miRs), is expressed in many developing peripheral tissues, including ATs, T-cells, and macrophages, and modulates the immune response. miRs are essential for insulin resistance, maintaining the tumor microenvironment, and obesity-associated inflammation (OAI). The abnormal regulation of AT, T-cells, and macrophage miRs may change the function of different organs including the pancreas, heart, liver, and skeletal muscle. Since obesity and inflammation are closely associated, the dysregulated expression of miRs in inflammatory adipocytes, T-cells, and macrophages suggest the importance of miRs in OAI. Therefore, in this review article, we have elaborated the role of miRs as epigenetic regulators affecting adipocyte differentiation, immune response, AT browning, adipogenesis, lipid metabolism, insulin resistance (IR), glucose homeostasis, obesity, and metabolic disorders. Further, we will discuss a set of altered miRs as novel biomarkers for metabolic disease progression and therapeutic targets for obesity.

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Section: Introductionmentioning

confidence: 99%

Adipocyte, Immune Cells, and miRNA Crosstalk: A Novel Regulator of Metabolic Dysfunction and Obesity

Kiran

Kumar

et al. 2021

Cells

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“…Diabetic chronic hyperglycemia is associated with long-term damage, dysfunction, and failure of various organs such as the kidneys, eyes, nerves, blood vessels, and heart (1,17,19,24,(32)(33)(34). T2D is most often found to be frequent in the case of obesity, and it is characterized by abnormal insulin secretion and/or a decreased sensitivity to insulin, which is also known as insulin resistance, and it results in increased blood glucose levels; T2D is known to be strongly associated with obesity (29). There are a number of biological processes and mechanisms that are considered to be the source of association between these conditions via mediating inflammation in adipose tissue and systemic insulin resistance, such as oxidative stress, endoplasmic reticulum stress, hypoxia, amyloid and lipid deposition, lipotoxicity, and glucotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Some of the factors that promote inflammation are altered functions of specific T lymphocyte cells, B lymphocytes, Th1, and Th17 (24)(25)(26)(27)(28). As mentioned above, T2D is also linked with obesity (29), and these diseases are also the case of metabolic disorder; there thus exists strong evidence for an immune-metabolic connection (10,30,31).…”

Section: Introductionmentioning

confidence: 97%

In-Silico Study of Immune System Associated Genes in Case of Type-2 Diabetes With Insulin Action and Resistance, and/or Obesity

et al. 2021

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Type-2 diabetes and obesity are among the leading human diseases and highly complex in terms of diagnostic and therapeutic approaches and are among the most frequent and highly complex and heterogeneous in nature. Based on epidemiological evidence, it is known that the patients suffering from obesity are considered to be at a significantly higher risk of type-2 diabetes. There are several pieces of evidence that support the hypothesis that these diseases interlinked and obesity may aggravate the risk(s) of type-2 diabetes. Multi-level unwanted alterations such as (epi-) genetic alterations, changes at the transcriptional level, and altered signaling pathways (receptor, cytoplasmic, and nuclear level) are the major sources that promote several complex diseases, and such a heterogeneous level of complexity is considered as a major barrier in the development of therapeutics. With so many known challenges, it is critical to understand the relationships and the shared causes between type-2 diabetes and obesity, and these are difficult to unravel and understand. For this purpose, we have selected publicly available datasets of gene expression for obesity and type-2 diabetes, have unraveled the genes and the pathways associated with the immune system, and have also focused on the T-cell signaling pathway and its components. We have applied a simplified computational approach to understanding differential gene expression and patterns and the enriched pathways for obesity and type-2 diabetes. Furthermore, we have also analyzed genes by using network-level understanding. In the analysis, we observe that there are fewer genes that are commonly differentially expressed while a comparatively higher number of pathways are shared between them. There are only 4 pathways that are associated with the immune system in case of obesity and 10 immune-associated pathways in case of type-2 diabetes, and, among them, only 2 pathways are commonly altered. Furthermore, we have presented SPNS1, PTPN6, CD247, FOS, and PIK3R5 as the overexpressed genes, which are the direct components of TCR signaling.

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“…Biased activation of the insulin receptor was envisioned by Brown and Goldstein as a mechanism to mitigate selective hepatic insulin resistance in the pathogenesis of hepatic steatosis [ [221] , [222] , [223] ]. A hallmark of T2D is the impairment of insulin signaling mediating glycemic control while excess signaling continues to drive lipid biosynthesis [ 224 ] and mitogenicity [ 225 ]. A liver-targeted biased agonist of the insulin receptor could therefore be transformational.…”

Section: Next-generation Insulin Analogsmentioning

confidence: 99%

Structural principles of insulin formulation and analog design: A century of innovation

Jarosinski

Dhayalan

Chen

et al. 2021

Molecular Metabolism

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Background The discovery of insulin in 1921 and its near-immediate clinical use initiated a century of innovation. Advances extended across a broad front, from the stabilization of animal insulin formulations to the frontiers of synthetic peptide chemistry, and in turn, from the advent of recombinant DNA manufacturing to structure-based protein analog design. In each case, a creative interplay was observed between pharmaceutical applications and then-emerging principles of protein science; indeed, translational objectives contributed to a growing molecular understanding of protein structure, aggregation and misfolding. Scope of review Pioneering crystallographic analyses—beginning with Hodgkin's solving of the 2-Zn insulin hexamer—elucidated general features of protein self-assembly, including zinc coordination and the allosteric transmission of conformational change. Crystallization of insulin was exploited both as a step in manufacturing and as a means of obtaining protracted action. Forty years ago, the confluence of recombinant human insulin with techniques for site-directed mutagenesis initiated the present era of insulin analogs. Variant or modified insulins were developed that exhibit improved prandial or basal pharmacokinetic (PK) properties. Encouraged by clinical trials demonstrating the long-term importance of glycemic control, regimens based on such analogs sought to resemble daily patterns of endogenous β-cell secretion more closely, ideally with reduced risk of hypoglycemia. Major conclusions Next-generation insulin analog design seeks to explore new frontiers, including glucose-responsive insulins, organ-selective analogs and biased agonists tailored to address yet-unmet clinical needs. In the coming decade, we envision ever more powerful scientific synergies at the interface of structural biology, molecular physiology and therapeutics.

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Type 2 Diabetes, Obesity, and Cancer Share Some Common and Critical Pathways

Cited by 30 publications

References 100 publications

Adipocyte, Immune Cells, and miRNA Crosstalk: A Novel Regulator of Metabolic Dysfunction and Obesity

Adipocyte, Immune Cells, and miRNA Crosstalk: A Novel Regulator of Metabolic Dysfunction and Obesity

In-Silico Study of Immune System Associated Genes in Case of Type-2 Diabetes With Insulin Action and Resistance, and/or Obesity

Structural principles of insulin formulation and analog design: A century of innovation

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