1197Identification of insulin signaling pathway-related circulating circRNAs as novel biomarkers of type 2 diabetes

Abstract Background The underlying molecular mechanism of type 2 diabetes (T2D) and insulin resistance is that abnormalities occur in the complex insulin signaling pathway. Circular RNAs (circRNAs) are involved in the development of diseases by regulating gene expression and become promising novel biomarkers for diseases. This study screened and validated the insulin signaling pathway-related circulating circRNAs, which are associated with T2D. Methods Based on circRNA microarray, candidate circRNAs involved in the insulin PI3K/Akt signaling pathway were selected and validated by RT-qPCR. The association between circRNAs and T2D and their clinical significance were further assessed by logistic regression model, correlation analysis and ROC curve in a large cohort. The miRNA targets of validated circRNAs was verified by dual-luciferase reporter assay. Results A total of 370 upregulated circRNAs and 180 downregulated circRNAs were differentially expressed between new T2D cases and controls. hsa_circ_0063425, hsa_circ_0056891 and hsa_circ_0104123 were selected as candidate circRNAs for validation. Low expressed circ_0063425 and hsa_circ_0056891 were independent predictors of T2D, impaired fasting glucose (IFG) and insulin resistance. The two-circRNA panel had a high diagnostic accuracy for discriminating T2D and IFG from healthy controls. miR-19a-3p and miR-1-3p were identified as the miRNA targets of hsa_circ_0063425 and hsa_circ_0056891, respectively. Significantly positive correlations were found between the expression levels of AKT and hsa_circ_0063425, PI3K and hsa_circ_0056891, in the total sample and subgroups stratified by glucose levels. Conclusion hsa_circ_0063425 and hsa_circ_0056891 are valuable circulating biomarkers for early detection of T2D, which may be involved in regulation of PI3K/AKT signaling. Key messages Insulin signaling pathway-related circulating circRNAs was identification as novel biomarkers of type 2 diabetes. Keywords circRNA; type 2 diabetes; insulin signaling; biomarker.

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Identification of Circulating hsa_circ_0063425 and hsa_circ_0056891 as Novel Biomarkers for Detection of Type 2 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab101 ◽

2021 ◽

Author(s):

Ya-Ke Lu ◽

Xi Chu ◽

Shuo Wang ◽

Yue Sun ◽

Jie Zhang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Early Detection ◽

Expression Profiles ◽

Akt Signaling ◽

Luciferase Reporter ◽

Circular Rnas ◽

Healthy Controls ◽

Mirna Targets ◽

Novel Biomarkers

Abstract Context Circular RNAs (circRNAs), which are involved in the development of diseases by regulating gene expression, have become promising novel biomarkers for diseases. Objective The aim of the present study was to identify the circulating circRNA biomarkers for early detection of type 2 diabetes (T2D). Methods The circRNA expression profiles were screened by microarray and compared between 5 new T2D cases and 5 healthy controls. The expression of candidate circRNAs that may be involved in the insulin phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway were validated by RT-qPCR in a second sample with 30 T2D cases and 30 controls. The association between circRNAs and T2D and their clinical significances were further assessed by logistic regression model, correlation analysis, and ROC curve in a large cohort comprising 313 subjects. The microRNA (miRNA) targets of circRNAs were verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. Results Low expressed circ_0063425 and hsa_circ_0056891 were independent predictors of T2D, impaired fasting glucose (IFG), and insulin resistance. The 2-circRNA panel had a high diagnostic accuracy for discriminating T2D and IFG from healthy controls, especially when body mass index was integrated. miR-19a-3p and miR-1-3p were identified as the miRNA targets of hsa_circ_0063425 and hsa_circ_0056891, respectively. Significant positive correlations were found between the expression levels of AKT and hsa_circ_0063425, PI3K and hsa_circ_0056891, in the total sample and subgroups stratified by glucose levels. Conclusion Downregulated hsa_circ_0063425 and hsa_circ_0056891 might contribute to the pathogenesis of T2D. They are valuable circulating biomarkers for early detection of T2D, which may be involved in regulation of PI3K/AKT signaling.

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63Identification of insulin signaling pathway-related circulating circRNAs as biomarkers of type 2 diabetes

International Journal of Epidemiology ◽

10.1093/ije/dyab168.731 ◽

2021 ◽

Vol 50 (Supplement_1) ◽

Author(s):

Yu-xiang Yan ◽

Jia-Jiang-Hui Li ◽

Huan-Bo Xiao ◽

Jing Dong ◽

Xi Chu

Keyword(s):

Type 2 Diabetes ◽

Signaling Pathway ◽

Insulin Signaling ◽

Expression Profiles ◽

Insulin Signaling Pathway ◽

Circular Rnas ◽

Circulating Biomarkers ◽

Real Time Quantitative Pcr ◽

Novel Biomarkers

Abstract Background The underlying molecular mechanism of type 2 diabetes (T2D) is that abnormalities occur in the insulin signaling pathway. Circular RNAs (circRNAs) are involved in the development of diseases by regulating gene expression and become promising novel biomarkers for diseases. This study systematically screened and validated the insulin signaling pathway-related circulating circRNAs in T2D. Methods circRNA expression profiles were screened by microarray between five T2D patients and five healthy controls. The candidate circRNAs were then selected from those differently expressed circRNAs whose potential target miRNAs are involved in regulating key genes in the isulin signaling pathway. The expression of candidate circRNAs were validated in a second sample with 20 T2D cases and 20 controls by real-time quantitative PCR. Eventually, the association between circRNAs and T2D and their clinical significance were further confirmed in a large independent sample, including 103 T2D cases, 93 controls and 80 individuals with impaired fasting glucose (IFG) as prediabetes cases. Results Four circRNAs including hsa_circ_0063425, hsa_circ_0056891, hsa_circ_0078166 and hsa_circ_0071336 were validated by RT-qPCR. Low expressed circ_0063425, hsa_circ_0056891 and hsa_circ_0071336 were independent predictor of T2D, IFG and insulin resistance. The three-circRNA panel had a high accuracy for diagnosing T2D and IFG, especially when BMI was integrated. Bioinformatics Gene Ontology and pathway analysis confirmed that these circRNAs involve in the regulation of insulin signaling pathway. Conclusion circ_0063425, hsa_circ_0056891 and hsa_circ_0071336 are valuable circulating biomarkers for T2D, and may involve in regulating insulin signaling pathway. Key messages Insulin signaling pathway-related circulating circRNAs were identification as biomarkers of T2D.

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Sphingolipids as a Culprit of Mitochondrial Dysfunction in Insulin Resistance and Type 2 Diabetes

Frontiers in Endocrinology ◽

10.3389/fendo.2021.635175 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kamila Roszczyc-Owsiejczuk ◽

Piotr Zabielski

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Protein Kinase ◽

Mitochondrial Dysfunction ◽

Signaling Pathway ◽

Mitochondrial Function ◽

Insulin Signaling ◽

Skeletal Muscles ◽

Insulin Signaling Pathway

Insulin resistance is defined as a complex pathological condition of abnormal cellular and metabolic response to insulin. Obesity and consumption of high-fat diet lead to ectopic accumulation of bioactive lipids in insulin-sensitive tissues. Intracellular lipid accumulation is regarded as one of the major factors in the induction of insulin resistance and type 2 diabetes (T2D). A significant number of studies have described the involvement of ceramides and other sphingolipids in the inhibition of insulin-signaling pathway in both skeletal muscles and the liver. Adverse effects of sphingolipid accumulation have recently been linked to the activation of protein kinase Cζ (PKCζ) and protein phosphatase 2A (PP2A), which, in turn, negatively affect phosphorylation of serine/threonine kinase Akt [also known as protein kinase B (PKB)], leading to decreased glucose uptake in skeletal muscles as well as increased gluconeogenesis and glycogenolysis in the liver. Sphingolipids, in addition to their direct impact on the insulin signaling pathway, may be responsible for other negative aspects of diabetes, namely mitochondrial dysfunction and deficiency. Mitochondrial health, which is characterized by appropriate mitochondrial quantity, oxidative capacity, controlled oxidative stress, undisturbed respiratory chain function, adenosine triphosphate (ATP) production and mitochondrial proliferation through fission and fusion, is impaired in the skeletal muscles and liver of T2D subjects. Recent findings suggest that impaired mitochondrial function may play a key role in the development of insulin resistance. Mitochondria stay in contact with the endoplasmic reticulum (ER), Golgi membranes and mitochondria-associated membranes (MAM) that are the main places of sphingolipid synthesis. Moreover, mitochondria are capable of synthesizing ceramide though ceramide synthase (CerS) activity. Recently, ceramides have been demonstrated to negatively affect mitochondrial respiratory chain function and fission/fusion activity, which is also a hallmark of T2D. Despite a significant correlation between sphingolipids, mitochondrial dysfunction, insulin resistance and T2D, this subject has not received much attention compared to the direct effect of sphingolipids on the insulin signaling pathway. In this review, we focus on the current state of scientific knowledge regarding the involvement of sphingolipids in the induction of insulin resistance by inhibiting mitochondrial function.

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Influence of miRNA in insulin signaling pathway and insulin resistance: micro-molecules with a major role in type-2 diabetes

Wiley Interdisciplinary Reviews - RNA ◽

10.1002/wrna.1240 ◽

2014 ◽

Vol 5 (5) ◽

pp. 697-712 ◽

Cited By ~ 97

Author(s):

Chiranjib Chakraborty ◽

C. George Priya Doss ◽

Sanghamitra Bandyopadhyay ◽

Govindasamy Agoramoorthy

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Signaling Pathway ◽

Insulin Signaling ◽

Insulin Signaling Pathway

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Duodenal-jejunal exclusion improves insulin resistance in type 2 diabetic rats by upregulating the hepatic insulin signaling pathway

Nutrition ◽

10.1016/j.nut.2014.10.012 ◽

2015 ◽

Vol 31 (5) ◽

pp. 733-739 ◽

Cited By ~ 13

Author(s):

Ze-Qiang Ren ◽

Peng-Bo Zhang ◽

Xiu-Zhong Zhang ◽

Shou-Kun Chen ◽

Hong Zhang ◽

...

Keyword(s):

Insulin Resistance ◽

Signaling Pathway ◽

Insulin Signaling ◽

Diabetic Rats ◽

Insulin Signaling Pathway ◽

Hepatic Insulin Signaling ◽

Type 2 Diabetic

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Akt/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes

Diabetes Metabolic Syndrome and Obesity Targets and Therapy ◽

10.2147/dmso.s48260 ◽

2014 ◽

pp. 55 ◽

Cited By ~ 132

Author(s):

Richard Mackenzie ◽

Bradley Elliott

Keyword(s):

Type 2 Diabetes ◽

Signaling Pathway ◽

Insulin Signaling ◽

Insulin Signaling Pathway

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Potential Roles of Adipocyte Extracellular Vesicle–Derived miRNAs in Obesity-Mediated Insulin Resistance

Advances in Nutrition ◽

10.1093/advances/nmaa105 ◽

2020 ◽

Cited By ~ 1

Author(s):

Yujeong Kim ◽

Ok-Kyung Kim

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Signaling Pathway ◽

Insulin Signaling ◽

Metabolic Disorders ◽

Extracellular Vesicle ◽

Extracellular Mirnas

ABSTRACT Recently, extracellular microRNAs (miRNAs) from adipose tissue have been shown to be involved in the development of insulin resistance. Here, we summarize several mechanisms explaining the pathogenesis of obesity-induced insulin resistance and associated changes in the expression of obesity-associated extracellular miRNAs. We discuss how miRNAs, particularly miR-27a, miR-34a, miR-141-3p, miR-155, miR210, and miR-222, in extracellular vesicles secreted from the adipose tissue can affect the insulin signaling pathway in metabolic tissue. Understanding the role of these miRNAs will further support the development of therapeutics for obesity and metabolic disorders such as type 2 diabetes.

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