Palmitate induced Fetuin-A secretion from pancreatic β-cells adversely affects its function and elicits inflammation

Mukhuty, Alpana; Fouzder, Chandrani; Mukherjee, Sandip; Malick, Chandan; Mukhopadhyay, Satinath; Bhattacharya, Samir; Kundu, Rakesh

doi:10.1016/j.bbrc.2017.08.022

Cited by 41 publications

(28 citation statements)

References 21 publications

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“…48,49 Pro-inflammatory cytokines upregulate NMU at the mRNA and peptide levels. 48,49 Pro-inflammatory cytokines upregulate NMU at the mRNA and peptide levels.…”

Section: Discussionmentioning

confidence: 99%

Neuromedin U suppresses insulin secretion by triggering mitochondrial dysfunction and endoplasmic reticulum stress in pancreatic β‐cells

2019

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Neuromedin U (NMU), a highly conserved peptide in mammals, is involved in a wide variety of physiological processes. NMU, which is synthesized in β‐cells and co‐localizes with insulin, directly acts on β‐cells via NMU receptor 1 (NMUR1) to suppress glucose‐stimulated insulin secretion (GSIS). The mechanism underlying this insulinostatic effect has yet to be elucidated. We observed that NMU caused mitochondrial dysfunction by impairing mitochondrial biogenesis, respiration, and mitochondrial Ca2+ uptake in β‐cell‐derived MIN6‐K8 cells. NMU administration induced the endoplasmic reticulum (ER) stress, as reflected by the activation of ER stress signaling pathways involving ATF6, XBP‐1s, and PERK‐ATF4‐CHOP. Nmu knockdown in MIN6‐K8 cells increased the number of insulin granules and improved mitochondrial biogenesis and function. NMU was upregulated in both the islets of db/db mice and palmitate‐treated MIN6‐K8 cells. Our results highlight the crucial role of NMU in the maintenance of β‐cell function and glucose metabolism through regulation of mitochondria dysfunction and ER stress. In pathological stages that develop into diabetes, upregulation of NMU could suppress the insulin secretion by inducing mitochondrial dysfunction and ER stress, which may contribute to subsequent β‐cell dysfunction.

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“…48,49 Pro-inflammatory cytokines upregulate NMU at the mRNA and peptide levels. 48,49 Pro-inflammatory cytokines upregulate NMU at the mRNA and peptide levels.…”

Section: Discussionmentioning

confidence: 99%

Neuromedin U suppresses insulin secretion by triggering mitochondrial dysfunction and endoplasmic reticulum stress in pancreatic β‐cells

2019

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“…The pattern-recognition proteins (Toll-like receptors, TLRs) interact with a myriad of protein ligands, including fetuin-A, which was recently reported to be a ligand for TLR4, with implications in the etiology of lipid metabolism and diabetes [78,79]. Because of TLR4’s involvement in cancer cell signaling, it is likely that fetuin-A is one of the ligands that signals through TLR4 to drive tumor progression.…”

Section: Fetuin-a and Toll-like Receptormentioning

confidence: 99%

“…Recent studies have indicated a robust cross-talk between fatty pancreas and fatty liver affecting the local inflammation and insulin secretion by the islets cells. In these studies, differentiated adipocytes were detected in the vicinity of pancreatic islet cells [19,79]. Expression levels of cytokines such as IL6 and CXCL8 were elevated by fetuin-A and free fatty acids such as palmitate in a TLR4-dependent manner [19,79,89].…”

Section: Action Of Fetuin-a On β-Islets Cells Of the Pancreasmentioning

confidence: 99%

“…In these studies, differentiated adipocytes were detected in the vicinity of pancreatic islet cells [19,79]. Expression levels of cytokines such as IL6 and CXCL8 were elevated by fetuin-A and free fatty acids such as palmitate in a TLR4-dependent manner [19,79,89]. Interestingly, it has been demonstrated that free fatty acids such as palmitate do not bind directly to TLR4 but rather via fetuin-A [78].…”

Section: Action Of Fetuin-a On β-Islets Cells Of the Pancreasmentioning

confidence: 99%

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Impact of Fetuin-A (AHSG) on Tumor Progression and Type 2 Diabetes

Ochieng

Nangami

Sakwe

et al. 2018

IJMS

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Fetuin-A is the protein product of the AHSG gene in humans. It is mainly synthesized by the liver in adult humans and is secreted into the blood where its concentration can vary from a low of ~0.2 mg/mL to a high of ~0.8 mg/mL. Presently, it is considered to be a multifunctional protein that plays important roles in diabetes, kidney disease, and cancer, as well as in inhibition of ectopic calcification. In this review we have focused on work that has been done regarding its potential role(s) in tumor progression and sequelae of diabetes. Recently a number of laboratories have demonstrated that a subset of tumor cells such as pancreatic, prostate and glioblastoma multiform synthesize ectopic fetuin-A, which drives their progression. Fetuin-A that is synthesized, modified, and secreted by tumor cells may be more relevant in understanding the pathophysiological role of this enigmatic protein in tumors, as opposed to the relatively high serum concentrations of the liver derived protein. Lastly, auto-antibodies to fetuin-A frequently appear in the sera of tumor patients that could be useful as biomarkers for early diagnosis. In diabetes, solid experimental evidence shows that fetuin-A binds the β-subunit of the insulin receptor to attenuate insulin signaling, thereby contributing to insulin resistance in type 2 diabetes mellitus (T2DM). Fetuin-A also may, together with free fatty acids, induce apoptotic signals in the beta islets cells of the pancreas, reducing the secretion of insulin and further exacerbating T2DM.

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“…Fetuin-A, a secreted glycoprotein, can promote lipotoxicity in β-cells through the TLR4-JNK-NF-κB signaling pathway [153]. Later it was also discovered that pancreatic β-cells are capable of secreting fetuin-A under free fatty acid stimulation which ultimately leads to inflammation [154].…”

Section: Tlr4mentioning

confidence: 99%

Emerging Role of Pancreatic β-Cells during Insulin Resistance

Mukhuty¹,

Fouzder²,

Das³

et al. 2019

Type 2 Diabetes [Working Title]

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In today's world, type 2 diabetes has become a part of every household and leads to various complications including high blood sugar level, diabetic retinopathy, diabetic foot, diabetic nephropathy and diabetic neuropathy. Yet people lack awareness about this disease and its detrimental effects. For a better understanding of this disease we must know about the causes and preventive measures since the medications used in treating type 2 diabetes have moderate to severe side effects. Type 2 diabetes is characterized by loss of insulin receptor activity in skeletal muscle and adipocytes, compensatory insulin secretion from pancreatic β-cells, β-cell dysfunction and death. The proper functioning of β-cells is a major criterion for preventing advent of type 2 diabetes. The different natural or physiological insulin secretagogues include glucose, amino acids and fatty acids, which stimulate insulin secretion under the influence of various hormones like incretins, leptin, growth hormone, melatonin and estrogen. However, excess of nutrients lead to β-cell dysfunction and dearth of insulin involving various signal molecules like SIRT1, PPARγ, TLR4, NF-ΚB, Wnt, mTOR, inflammasomes, MCP1, EGFR, and Nrf2. A deeper insight into the functioning of these signaling molecules will also create new avenues for therapeutic interventions of curing β-cell dysfunction and death.

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Palmitate induced Fetuin-A secretion from pancreatic β-cells adversely affects its function and elicits inflammation

Cited by 41 publications

References 21 publications

Neuromedin U suppresses insulin secretion by triggering mitochondrial dysfunction and endoplasmic reticulum stress in pancreatic β‐cells

Neuromedin U suppresses insulin secretion by triggering mitochondrial dysfunction and endoplasmic reticulum stress in pancreatic β‐cells

Impact of Fetuin-A (AHSG) on Tumor Progression and Type 2 Diabetes

Emerging Role of Pancreatic β-Cells during Insulin Resistance

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