Carrageenan Inhibits Insulin Signaling through GRB10-mediated Decrease in Tyr(P)-IRS1 and through Inflammation-induced Increase in Ser(P)307-IRS1

Bhattacharyya, Sumit; Feferman, Leo; Tobacman, Joanne K.

doi:10.1074/jbc.m114.630053

Cited by 39 publications

(25 citation statements)

References 44 publications

(39 reference statements)

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“…It has been confirmed that an imbalance of insulin signaling pathway is one of the principal cause of insulin resistance, e. g. the IRS1/AKT signaling pathway. Phosphorylation of IRS1 Ser307 accounts for insulin resistance, whereas insulin sensitivity is promoted with elevated hepatic AKT activity [39,40]. In our study, knockdown of leap2 in HFD-fed mice attenuated glucose tolerance and insulin sensitivity, while the insulin-related IRS1/AKT signaling was activated.…”

Section: Discussionsupporting

confidence: 48%

Liver Expressed Antimicrobial Peptide 2 is Associated with Steatosis in Mice and Humans

Xue

Zhang

et al. 2020

Exp Clin Endocrinol Diabetes.

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Background and Aims Liver expressed antimicrobial peptide 2 (LEAP2) is recently identified as a regulator in energy metabolism. This study aims to 1) investigate the role of leap2 in hepatic steatosis in C57BL/6 mice; 2) evaluate the association between circulating LEAP2 levels and liver fat contents in a hospital based case-control study. Methods The rodent experiment: western blotting and qPCR were performed to evaluate leap2 levels, lipid metabolism pathways and insulin signaling. shRNA was used to knockdown leap2. The clinical study: commercial ELISA kits were used to measure circulating LEAP2 levels (validated by western blotting). Liver fat content was estimated using MRI-derived proton density fat fraction and FibroScan-derived controlled attenuation parameter. Results The rodent experiment found the hepatic expression and secreted levels of leap2 were increased in mice with diet-induced steatosis. Leap2 knockdown ameliorated steatosis via lipolytic/lipogenic pathway and improved insulin sensitivity via IRS/AKT signaling. The clinical study reported increased circulating levels of LEAP2 in the subjects with steatosis. Moreover, LEAP2 correlated positively with age, body mass index, waist-to-hip ratio, liver fat content, fasting insulin and HOMA-IR, whereas inversely with acyl-ghrelin. Furthermore, the circulating levels of LEAP2 are dependent on liver fat content, acyl-ghrelin and fasting glucose. Lastly, circulating LEAP2 is an independent predictor of NAFLD. Conclusions The study suggests LEAP2 is associated with hepatic steatosis, which may involve lipolytic/lipogenic pathway and insulin signaling.

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Section: Discussionsupporting

confidence: 48%

Liver Expressed Antimicrobial Peptide 2 is Associated with Steatosis in Mice and Humans

Xue

Zhang

et al. 2020

Exp Clin Endocrinol Diabetes.

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“…Based on findings in previous mechanistic studies, additional outcome measures of interest were the inflammatory measures: serum IL-8, cellular phospho-(Ser307)-IRS1, and phospho-(Ser473)-AKT1. These had been shown to be modified in previous studies of carrageenan exposure [13][14][15].…”

Section: Methodsmentioning

confidence: 87%

“…Oral carrageenan caused systemic inflammation, leading to impaired insulin signaling in the mouse liver. Carrageenan exposure inhibited insulin signaling by effects on both hepatic phospho-insulin receptor substrate 1 (IRS1) and growth-factor receptor bound protein 10 (GRB10) [13][14][15]. Carrageenan increased phospho-(Ser307/312)-IRS1, a negative regulator of insulin signaling, and reduced phospho-Tyr-IRS1, a positive regulator of insulin signaling.…”

Section: Introductionmentioning

confidence: 99%

Carrageenan-Free Diet Shows Improved Glucose Tolerance and Insulin Signaling in Prediabetes: A Randomized, Pilot Clinical Trial

Feferman

Bhattacharyya

Oates

et al. 2020

Journal of Diabetes Research

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Objectives. Carrageenan is well known to cause inflammation and is used in laboratory experiments to study mediators and treatments of inflammation. However, carrageenan is added to hundreds of processed foods to improve texture. Previous work indicated that low concentrations of carrageenan in drinking water caused marked glucose intolerance and insulin resistance in a mouse model. This exploratory, clinical study tested the impact of the no-carrageenan diet in prediabetes. Research Design and Methods. Participants with prediabetes (n=13), defined as HbA1c of 5.7%-6.4%, enrolled in a 12-week, randomized, parallel-arm, feeding trial. One group (n=8) was provided all meals and snacks with no carrageenan. A second group (n=5) received a similar diet with equivalent content of protein, fat, and carbohydrate, but with carrageenan. Blood samples were collected at baseline and during oral glucose tolerance tests at 6 and 12 weeks. The primary outcome measure was changed in %HbA1c between baseline and 12 weeks. Statistical analysis included paired and unpaired t-tests, correlations, and 2×2 ANOVAs. Results. Subjects on no carrageenan had declines in HbA1c and HOMA-IR (p=0.006, p=0.026; paired t-test, two tailed). They had increases in C-peptide (p=0.029) and Matsuda Index (2.1±0.7 to 4.8±2.3; p=0.052) and declines in serum IL-8, serum galectin-3, and neutrophil phospho-(Ser307/312)-IRS1 (p=0.049, p=0.003, and p=0.006; paired t-tests, two tailed). Subjects on the diet with carrageenan had no significant changes in these parameters. Significant differences between no-carrageenan and carrageenan-containing diet groups for changes from baseline to 12 weeks occurred in C-peptide, phospho-Ser-IRS1, phospho-AKT1, and mononuclear cell arylsulfatase B (p=0.007, p=0.038, p=0.0012, and p=0.0008; 2×2 ANOVA). Significant correlations were evident between several of the variables. Conclusions. Findings indicate improvement in HbA1c and HOMA-IR in participants on no-carrageenan diets, but not in participants on carrageenan-containing diets. Significant differences between groups suggest that removing carrageenan may improve insulin signaling and glucose tolerance. Larger studies are needed to further consider the impact of carrageenan on development of diabetes.

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“…For instance, as a negative mediators of insulin signaling, ser (P) 307 -IRS−1 blocks the interaction between the IRS−1 and IR, which may lead to the insulin resistance [27]. On the contrary, insulin-initiated the increase in tyrosine phosphorylation of IRS−1 exhibited a positive effects on insulin sensitivity in C57BL/6J mice [28]. In our previous study, the level of ser (P) 307 -IRS−1 was increased in the hippocampus of diabetic rats with depression [15].…”

Section: Discussionmentioning

confidence: 99%

Zuogui Jiangtang Jieyu Decoction Ameliorates Depression-Like Behavior in Diabetic Rats via Activation of Neuronal and Astrocytic IR/IRS-1 Signaling Pathway

Yang

Jia

Meng

et al. 2020

Preprint

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Background: Zuogui Jiangtang Jieyu decoction(ZJJ) is a Chinese herbal formulation on the strength of Zuogui Wan which recorded in the “Jing Yue Quan Shu” in the Ming dynasty. It is mainly used for treatment of diabetes-related depression in current clinical applications and researches. This study aims to investigate whether brain IR/IRS-1 signaling pathway involved in the therapeutic effect of ZJJ on depression-like behavior in diabetic rats.Methods: Sprague Dawley rats were fed with high fat diet, and subjected to streptozotocin injection to establish the diabetes animal model. After treatment with different doses of ZJJ (20.530 g/kg or 10.265 g/kg) for 4 weeks, blood glucose level and peripheral insulin resistance were measured. Forced-swimming test (FST) and Morris water maze test (MWMT) were applied for mood and cognitive function assessment. Then western blot was used to analyze the protein levels of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphatidylonositol-3-kinase (PI3K), and protein kinase B (AKT) in the hippocampus of diabetic rats. Meanwhile, immunofluorescence and double-labeling immunofluorescence were performed to analyze the above proteins expression in the neuron and astrocyte, respectively. At last, energy metabolism and glycogen metabolism were tested by using ELISA. Additionally, the insulin-sensitive glucose transporter 4 (GLUT4) and the lactate transporter monocarboxylate transporter 4 (MCT4) were analyzed by using western blot.Results: ZJJ administration significantly decreased blood glucose and improved peripheral insulin resistance of diabetic rats. Besides, ZJJ improved the depression-like behavior and cognitive dysfunction caused by diabetes. Furthermore, result of the western blot analysis showed that ZJJ treatment increased the expression of phospho-IR, phospho-IRS-1, phospho-PI3K, and phospho-AKT in the hippocampus of diabetic rat. Moreover, result of immunofluorescence showed that the above proteins were increased not only in the neuron but also in the astrocyte after ZJJ administration. In addition, ZJJ increased the content of ATP, glycogen and lactate, as well as the expression of GLUT4 and MCT4 in the hippocampus of diabetic rats.Conclusions: These findings suggested that ZJJ improves the depression-like behavior of diabetic rats by activating both neuronal and astrocytic IR/IRS-1 signaling pathway. And the brain IR/IRS-1 signaling pathway plays an important role in astrocyte-neuron metabolic coupling, providing a potential mechanism by which IR/IRS-1 signaling pathway may contribute to the treatment of ZJJ on diabetes related depression.

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Carrageenan Inhibits Insulin Signaling through GRB10-mediated Decrease in Tyr(P)-IRS1 and through Inflammation-induced Increase in Ser(P)307-IRS1

Cited by 39 publications

References 44 publications

Liver Expressed Antimicrobial Peptide 2 is Associated with Steatosis in Mice and Humans

Liver Expressed Antimicrobial Peptide 2 is Associated with Steatosis in Mice and Humans

Carrageenan-Free Diet Shows Improved Glucose Tolerance and Insulin Signaling in Prediabetes: A Randomized, Pilot Clinical Trial

Zuogui Jiangtang Jieyu Decoction Ameliorates Depression-Like Behavior in Diabetic Rats via Activation of Neuronal and Astrocytic IR/IRS-1 Signaling Pathway

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Carrageenan Inhibits Insulin Signaling through GRB10-mediated Decrease in Tyr(P)-IRS1 and through Inflammation-induced Increase in Ser(P)307-IRS1

Cited by 39 publications

References 44 publications

Liver Expressed Antimicrobial Peptide 2 is Associated with Steatosis in Mice and Humans

Liver Expressed Antimicrobial Peptide 2 is Associated with Steatosis in Mice and Humans

Carrageenan-Free Diet Shows Improved Glucose Tolerance and Insulin Signaling in Prediabetes: A Randomized, Pilot Clinical Trial

Zuogui Jiangtang Jieyu Decoction&nbsp;Ameliorates Depression-Like Behavior in Diabetic Rats via Activation of Neuronal and Astrocytic IR/IRS-1 Signaling Pathway

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Zuogui Jiangtang Jieyu Decoction Ameliorates Depression-Like Behavior in Diabetic Rats via Activation of Neuronal and Astrocytic IR/IRS-1 Signaling Pathway