Activated Protein C and Its Potential Applications in Prevention of Islet β-Cell Damage and Diabetes

Xue, Meilang

doi:10.1016/b978-0-12-800174-5.00013-2

Cited by 10 publications

(8 citation statements)

References 212 publications

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“…SERPINA5 inhibits activated protein c (aPc). aPc has a potential preventative role for islet β-cell damage and diabetes (79). a previous study observed that the plasma levels of APC were notably decreased in T2dM (80).…”

Section: Discussionmentioning

confidence: 92%

Identification of potential markers for type 2 diabetes mellitus via bioinformatics analysis

Lü

2020

Mol Med Rep

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Type 2 diabetes mellitus (T2dM) is a multifactorial and multigenetic disease, and its pathogenesis is complex and largely unknown. in the present study, microarray data (GSe201966) of β-cell enriched tissue obtained by laser capture microdissection were downloaded, including 10 control and 10 type 2 diabetic subjects. a comprehensive bioinformatics analysis of microarray data in the context of protein-protein interaction (PPi) networks was employed, combined with subcellular location information to mine the potential candidate genes for T2dM and provide further insight on the possible mechanisms involved. First, differential analysis screened 108 differentially expressed genes. Then, 83 candidate genes were identified in the layered network in the context of PPi via network analysis, which were either directly or indirectly linked to T2dM. of those genes obtained through literature retrieval analysis, 27 of 83 were involved with the development of T2dM; however, the rest of the 56 genes need to be verified by experiments. The functional analysis of candidate genes involved in a number of biological activities, demonstrated that 46 upregulated candidate genes were involved in 'inflammatory response' and 'lipid metabolic process', and 37 downregulated candidate genes were involved in 'positive regulation of cell death' and 'positive regulation of cell proliferation'. These candidate genes were also involved in different signaling pathways associated with 'Pi3K/akt signaling pathway', 'Rap1 signaling pathway', 'Ras signaling pathway' and 'MAPK signaling pathway', which are highly associated with the development of T2dM. Furthermore, a microrna (mir)-target gene regulatory network and a transcription factor-target gene regulatory network were constructed based on mirnet and networkanalyst databases, respectively. notably, hsa-mir-192-5p, hsa-mir-124-5p and hsa-mir-335-5p appeared to be involved in T2dM by potentially regulating the expression of various candidate genes, including procollagen c-endopeptidase enhancer 2, connective tissue growth factor and family with sequence similarity 105, member a, protein phosphatase 1 regulatory inhibitor subunit 1 a and cc motif chemokine receptor 4. Smad5 and Bcl6, as transcription factors, are regulated by ankyrin repeat domain 23 and transmembrane protein 37, respectively, which might also be used in the molecular diagnosis and targeted therapy of T2dM. Taken together, the results of the present study may offer insight for future genomic-based individualized treatment of T2dM and help determine the underlying molecular mechanisms that lead to T2dM.

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Section: Discussionmentioning

confidence: 92%

Identification of potential markers for type 2 diabetes mellitus via bioinformatics analysis

Lü

2020

Mol Med Rep

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“…PROC provides instructions for protein C, an important factor for controlling blood clotting and inflammation. Activated protein C, a derivative of protein C, functions in reducing inflammation and apoptosis and prevents pancreatic β-cell death [13].…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Markers of Type 2 Diabetes Mellitus Among Male Veterans With or Without Human Immunodeficiency Virus Infection

Mathur

Hui

Huang

et al. 2019

The Journal of Infectious Diseases

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Epigenetic modifications such as DNA methylation are associated with both human immunodeficiency virus (HIV) infection and type 2 diabetes mellitus (T2DM). We investigated epigenetic associations with T2DM according to HIV infection status and assessed interaction effects among 681 male participants of the Veterans Aging Cohort Study. Methylation at previously reported sites, cg1963031 (TXNIP), cg18181703 (SOCS3), and cg09152259 (PROC), was significantly associated with T2DM in HIV-infected individuals. We identified 3 novel associations with suggestive statistical significance: cg1231141 (ADAMTS2), cg19534769 (HGFAC), and cg13163919 (TLE3). Suggestive interaction with HIV infection status was found at cg17862404 (TSC22D1). The implicated genes are involved in inflammation, pancreatic β-cell function, and T2DM pathogenesis.

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“…At the protein level, there was only an increase in activated protein C in T2D after insulin infusion and euglycaemia. Activated protein C is a natural anticoagulant with anti‐inflammatory and anti‐apoptotic properties, recognized as beneficial in preventing β‐cell destruction in T1D . Thus, elevated activated protein C levels, observed after insulin infusion, might suggest activation of protective mechanisms in people with T2D; however, under insulin‐induced hypoglycaemia, 13 proteins showed significant alterations and > 200 proteins showed nominally significant changes; the majority of those proteins were significantly relevant only in T2D.…”

Section: Discussionmentioning

confidence: 99%

“…Activated protein C is a natural anticoagulant with anti-inflammatory and anti-apoptotic properties, recognized as beneficial in preventing β-cell destruction in T1D. 40 Thus, elevated activated protein C levels, observed after insulin infusion, might suggest activation of protective mechanisms in people with T2D; however, under insulin-induced hypoglycaemia, 13 proteins showed significant alterations and > 200 proteins showed nominally significant changes; the majority of those proteins were significantly relevant only in T2D. Overall, the analysis showed that the proteins altered at nominally significant levels are linked predominantly with inflammation and inflammatory diseases such as rheumatoid arthritis or psoriasis.…”

Section: Discussionmentioning

confidence: 99%

Metabolic and proteomic signatures of hypoglycaemia in type 2 diabetes

Halama

Kahal

Bhagwat

et al. 2018

Diabetes Obesity Metabolism

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Aims: To determine the biochemical changes that underlie hypoglycaemia in a healthy control group and in people with type 2 diabetes (T2D). Materials and methods:We report a hypoglycaemic clamp study in seven healthy controls and 10 people with T2D. Blood was withdrawn at four time points: at baseline after an overnight fast; after clamping to euglycaemia at 5 mmol/L; after clamping to hypoglycaemia at 2.8 mmol/ L; and 24 hours later, after overnight fast. Deep molecular phenotyping using non-targeted metabolomics and the SomaLogic aptamer-based proteomics platform was performed on collected samples.Results: A total of 955 metabolites and 1125 proteins were identified, with significant alterations in >90 molecules. A number of metabolites significantly increased during hypoglycaemia, but only cortisol, adenosine-3 0 ,5 0 -cyclic monophosphate (cyclic AMP), and pregnenolone sulphate, were independent of insulin. By contrast, identified protein changes were triggered by hypoglycaemia rather than insulin. The T2D group had significantly higher levels of fatty acids including 10-nonadecenoate, linolenate and dihomo-linoleate during hypoglycaemia compared with the control group. Molecules contributing to cardiovascular complications such as fattyacid-binding protein-3 and pregnenolone sulphate were altered in the participants with T2D during hypoglycaemia. Almost all molecules returned to baseline at 24 hours. Conclusions:The present study provides a comprehensive description of molecular events that are triggered by insulin-induced hypoglycaemia. We identified deregulated pathways in T2D that may play a role in the pathophysiology of hypoglycaemia-induced cardiovascular complications. K E Y W O R D S hypoglycaemia, type 2 diabetes, clinical physiology, glucose metabolism 1 | INTRODUCTION In healthy individuals, blood glucose levels are maintained within a narrow range by mechanisms that dynamically respond to starvation, food intake, physical exercise and physiological stresses. After a meal, insulin secretion restores normoglycaemia by simultaneously decreasing hepatic glucose production and stimulating glucose uptake by skeletal muscle and adipose tissue. 1 Conversely, during fasting, regulatory hormonal responses are activated to prevent hypoglycaemia (defined as blood glucose <3.9 mmol/L [70 mg/dL]). 2 Decreasing glucose levels to between 3.6 and 3.9 mmol/L (65 and 70 mg/dL) stimulates epinephrine secretion, hepatic glucose release (glycogenolysis) and glucose formation (gluconeogenesis). 3 Epinephrine inhibits insulin secretion and decreases utilization of glucose by peripheral tissues, and increases the release of gluconeogenic substrates. Hypoglycaemia results in cortisol secretion that limits glucose utilization whilst simultaneously enhancing hepatic glucose production. 3 *Anna Halama and Hassan Kahal and contributed equally to this work.

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Activated Protein C and Its Potential Applications in Prevention of Islet β-Cell Damage and Diabetes

Cited by 10 publications

References 212 publications

Identification of potential markers for type 2 diabetes mellitus via bioinformatics analysis

Identification of potential markers for type 2 diabetes mellitus via bioinformatics analysis

DNA Methylation Markers of Type 2 Diabetes Mellitus Among Male Veterans With or Without Human Immunodeficiency Virus Infection

Metabolic and proteomic signatures of hypoglycaemia in type 2 diabetes

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