Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling

2003 ◽  
Vol 31 (6) ◽  
pp. 1152-1156 ◽  
Author(s):  
Y. Le Marchand-Brustel ◽  
P. Gual ◽  
T. Grémeaux ◽  
T. Gonzalez ◽  
R. Barrès ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Glucose Transport ◽  
Insulin Signalling ◽  
Serine Phosphorylation ◽  
Insulin Receptor Substrate

Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterized by a decrease in the insulin effect on glucose transport in muscle and adipose tissue. Tyrosine phosphorylation of IRS-1 (insulin receptor substrate 1) and its binding to PI 3-kinase (phosphoinositide 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Various studies have implicated lipids as a cause of insulin resistance in muscle. Elevated plasma fatty acid concentrations are associated with reduced insulin-stimulated glucose transport activity as a consequence of altered insulin signalling through PI 3-kinase. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that non-esterified fatty acids, as well as other factors such as tumour necrosis factor α, hyperinsulinaemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser307 as one of the phosphorylated sites. Moreover, several kinases able to phosphorylate this serine residue have been identified. These exciting results suggest that Ser307 phosphorylation is a possible hallmark of insulin resistance in biologically insulin-responsive cells or tissues. Identification of IRS-1 kinases could enable rational drug design in order to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes.

scholarly journals The role of inflammation and macrophage accumulation in the development of obesity-induced type 2 diabetes mellitus and the possible therapeutic effects of long-chainn-3 PUFA

2010 ◽  
Vol 69 (2) ◽  
pp. 232-243 ◽  
Author(s):  
Elizabeth Oliver ◽  
Fiona McGillicuddy ◽  
Catherine Phillips ◽  
Sinead Toomey ◽  
Helen M. Roche
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Receptor ◽  
Insulin Signalling ◽  
Serine Phosphorylation ◽  
Therapeutic Effects ◽  
Low Grade

The WHO estimate that >1×106deaths in Europe annually can be attributed to diseases related to excess body weight, and with the rising global obesity levels this death rate is set to drastically increase. Obesity plays a central role in the metabolic syndrome, a state of insulin resistance that predisposes patients to the development of CVD and type 2 diabetes mellitus. Obesity is associated with low-grade chronic inflammation characterised by inflamed adipose tissue with increased macrophage infiltration. This inflammation is now widely believed to be the key link between obesity and development of insulin resistance. In recent years it has been established that activation of pro-inflammatory pathways can cross talk with insulin signalling pathways via a number of mechanisms including (a) down-regulation of insulin signalling pathway proteins (e.g. GLUT4 and insulin receptor substrate (IRS)-1), (b) serine phosphorylation of IRS-1 blocking its tyrosine phosphorylation in response to insulin and (c) induction of cytokine signalling molecules that sterically hinder insulin signalling by blocking coupling of the insulin receptor to IRS-1. Long-chain (LC)n-3 PUFA regulate gene expression (a) through transcription factors such as PPAR and NF-κB and (b) via eicosanoid production, reducing pro-inflammatory cytokine production from many different cells including the macrophage. LCn-3 PUFA may therefore offer a useful anti-inflammatory strategy to decrease obesity-induced insulin resistance, which will be examined in the present review.

Echinops Spp. Polysaccharide B Ameliorates Metabolic Abnormalities in a Rat Model of Type 2 Diabetes Mellitus

2020 ◽  
Vol 19 (1) ◽  
pp. 106-114
Author(s):  
Guang Hao ◽  
Xiaoyu Ma ◽  
Mengru Jiang ◽  
Zhenzhen Gao ◽  
Ying Yang
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Insulin Receptor ◽  
Skeletal Muscles ◽  
Insulin Receptor Substrate ◽  
Sprague Dawley

This study examined the in vivo effects of Echinops spp. polysaccharide B on type 2 diabetes mellitus in Sprague-Dawley rats. We constructed a type 2 diabetes mellitus Sprague-Dawley rat models by feeding a high-fat and high-sugar diet plus intraperitoneal injection of a small dose of streptozotocin. Using this diabetic rat model, different doses of Echinops polysaccharide B were administered orally for seven weeks. Groups receiving Xiaoke pill and metformin served as positive controls. The results showed that Echinops polysaccharide B treatment normalized the weight and blood sugar levels in the type 2 diabetes mellitus rats, increased muscle and liver glycogen content, improved glucose tolerance, increased insulin secretion, and reduced glucagon and insulin resistance indices. More importantly, Echinops polysaccharide B treatment upregulated the expression of insulin receptor in the liver, skeletal muscles, and pancreas, and significantly improved the expression levels of insulin receptor substrate-2 protein in the liver and pancreas, as well as it increased insulin receptor substrate-1 expression in skeletal muscles. These two proteins play crucial roles in increasing insulin secretion and in controlling type 2 diabetes mellitus. The findings of the present study suggest that Echinops polysaccharide B could improve the status of diabetes in type 2 diabetes mellitus rats, which may be achieved by improving insulin resistance. Our study provides a new insight into the development of a natural drug for the control of type 2 diabetes mellitus.

scholarly journals Increased Interaction With Insulin Receptor Substrate 1, a Novel Abnormality in Insulin Resistance and Type 2 Diabetes

Diabetes ◽  
2014 ◽  
Vol 63 (6) ◽  
pp. 1933-1947 ◽  
Author(s):  
Michael Caruso ◽  
Danjun Ma ◽  
Zaher Msallaty ◽  
Monique Lewis ◽  
Berhane Seyoum ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Receptor ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1

Lipid metabolism, exercise and insulin action

2006 ◽  
Vol 42 ◽  
pp. 47-59 ◽  
Author(s):  
Arend Bonen ◽  
G. Lynis Dohm ◽  
Luc J.C. van Loon
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Insulin Signalling ◽  
Acid Oxidation ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Severely Obese

Skeletal muscle constitutes 40% of body mass and takes up 80% of a glucose load. Therefore, impaired glucose removal from the circulation, such as that which occurs in obesity and type 2 diabetes, is attributable in large part to the insulin resistance in muscle. Recent research has shown that fatty acids, derived from adipose tissue, can interfere with insulin signalling in muscle. Hence, insulin-stimulated GLUT4 translocation to the cell surface is impaired, and therefore, the rate of glucose removal from the circulation into muscle is delayed. The mechanisms provoking lipid-mediated insulin resistance are not completely understood. In sedentary individuals, excess intramyocellular accumulation of triacylglycerols is only modestly associated with insulin resistance. In contrast, endurance athletes, despite accumulating large amounts of intramyocellular triacylglycerols, are highly insulin sensitive. Thus it appears that lipid metabolites, other than triacylglycerols, interfere with insulin signalling. These metabolites, however, are not expected to accumulate in athletic muscles, as endurance training increases the capacity for fatty acid oxidation by muscle. These observations, and others in severely obese individuals and type 2 diabetes patients, suggest that impaired rates of fatty acid oxidation are associated with insulin resistance. In addition, in obesity and type 2 diabetes, the rates of fatty acid transport into muscle are also increased. Thus, excess intracellular lipid metabolite accumulation, which interferes with insulin signalling, can occur as a result of impaired rates of fatty acid oxidation and/or increased rates of fatty acid transport into muscle. Accumulation of excess intramyocellular lipid can be avoided by exercise, which improves the capacity for fatty acid oxidation.

Targeting type 2 diabetes: lessons from a knockout model of insulin receptor substrate 2

2014 ◽  
Vol 92 (8) ◽  
pp. 613-620 ◽  
Author(s):  
Joana Moitinho Oliveira ◽  
Sandra A. Rebuffat ◽  
Rosa Gasa ◽  
Ramon Gomis
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Beta Cell ◽  
Insulin Receptor ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Mitogen Activated Protein Kinase ◽  
Insulin Receptor Substrate ◽  
Beta Cell Failure

Insulin receptor substrate 2 (IRS2) is a widely expressed protein that regulates crucial biological processes including glucose metabolism, protein synthesis, and cell survival. IRS2 is part of the insulin – insulin-like growth factor (IGF) signaling pathway and mediates the activation of the phosphotidylinositol 3-kinase (PI3K)–Akt and the Ras–mitogen-activated protein kinase (MAPK) cascades in insulin target tissues and in the pancreas. The best evidence of this is that systemic elimination of the Irs2 in mice (Irs2−/−) recapitulates the pathogenesis of type 2 diabetes (T2D), in that diabetes arises as a consequence of combined insulin resistance and beta-cell failure. Indeed, work using this knockout mouse has confirmed the importance of IRS2 in the control of glucose homeostasis and especially in the survival and function of pancreatic beta-cells. These studies have shown that IRS2 is critically required for beta-cell compensation in conditions of increased insulin demand. Importantly, islets isolated from T2D patients exhibit reduced IRS2 expression, which supports the likely contribution of altered IRS2-dependent signaling to beta-cell failure in human T2D. For all these reasons, the Irs2−/− mouse has been and will be essential for elucidating the inter-relationship between beta-cell function and insulin resistance, as well as to delineate therapeutic strategies to protect beta-cells during T2D progression.

scholarly journals Interleukin-1α Inhibits Insulin Signaling with Phosphorylating Insulin Receptor Substrate-1 on Serine Residues in 3T3-L1 Adipocytes

2006 ◽  
Vol 20 (1) ◽  
pp. 114-124 ◽  
Author(s):  
Jianying He ◽  
Isao Usui ◽  
Ken Ishizuka ◽  
Yukiko Kanatani ◽  
Kazuyuki Hiratani ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Proinflammatory Cytokines ◽  
Insulin Signaling ◽  
Serine Phosphorylation ◽  
Insulin Receptor Substrate ◽  
Akt Phosphorylation ◽  
Iκb Kinase ◽  
Serine Kinases

Abstract Proinflammatory cytokines are recently reported to inhibit insulin signaling causing insulin resistance. IL-1α is also one of the proinflammatory cytokines; however, it has not been clarified whether IL-1α may also cause insulin resistance. Here, we investigated the effects of IL-1α treatment on insulin signaling in 3T3-L1 adipocytes. IL-1α treatment up to 4 h did not alter insulin-stimulated insulin receptor tyrosine phosphorylation, whereas tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and the association with phosphatidylinositol 3-kinase were partially inhibited with the maximal inhibition in around 15 min. IRS-1 was transiently phosphorylated on some serine residues around 15 min after IL-1α stimulation, when several serine kinases, IκB kinase, c-Jun-N-terminal kinase, ERK, and p70S6K were activated. Chemical inhibitors for these kinases inhibited IL-1α-induced serine phosphorylation of IRS-1. Tyrosine phosphorylation of IRS-1 was recovered only by the IKK inhibitor or JNK inhibitor, suggesting specific involvement of these two kinases. Insulin-stimulated Akt phosphorylation and 2-deoxyglucose uptake were not inhibited only by IL-1α. Interestingly, Akt phosphorylation was synergistically inhibited by IL-1α in the presence of IL-6. Taken together, short-term IL-1α treatment transiently causes insulin resistance at IRS-1 level with its serine phosphorylation. IL-1α may suppress insulin signaling downstream of IRS-1 in the presence of other cytokines, such as IL-6.

scholarly journals Chronic Tumor Necrosis Factor-α Treatment Causes Insulin Resistance via Insulin Receptor Substrate-1 Serine Phosphorylation and Suppressor of Cytokine Signaling-3 Induction in 3T3-L1 Adipocytes

Endocrinology ◽  
2007 ◽  
Vol 148 (6) ◽  
pp. 2994-3003 ◽  
Author(s):  
Ken Ishizuka ◽  
Isao Usui ◽  
Yukiko Kanatani ◽  
Agussalim Bukhari ◽  
Jianying He ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Serine Phosphorylation ◽  
Cytokine Signaling ◽  
Insulin Receptor Substrate ◽  
Signal Transducer ◽  
Suppressor Of Cytokine Signaling ◽  
Transcription 3

Serine phosphorylation of insulin receptor substrate (IRS)-1 and the induction of suppressor of cytokine signaling 3 (SOCS3) is recently well documented as the mechanisms for the insulin resistance. However, the relationship between these two mechanisms is not fully understood. In this study, we investigated the involvement of SOCS3 and IRS-1 serine phosphorylation in TNFα-induced insulin resistance in 3T3-L1 adipocytes. TNFα transiently stimulated serine phosphorylation of IRS-1 from 10 min to 1 h, whereas insulin-stimulated IRS-1 tyrosine phosphorylation was inhibited only after TNFα treatment longer than 4 h. These results suggest that serine phosphorylation of IRS-1 alone is not the major mechanism for the inhibited insulin signaling by TNFα. TNFα stimulation longer than 4 h enhanced the expression of SOCS3 and signal transducer and activator of transcription-3 phosphorylation, concomitantly with the production of IL-6. Anti-IL-6 neutralizing antibody ameliorated suppressed insulin signaling by 24 h TNFα treatment, when it partially decreased SOCS3 induction and signal transducer and activator of transcription-3 phosphorylation. These results suggest that SOCS3 induction is involved in inhibited insulin signaling by TNFα. However, low-level expression of SOCS3 by IL-6 or adenovirus vector did not affect insulin-stimulated IRS-1 tyrosine phosphorylation. Interestingly, when IRS-1 serine phosphorylation was enhanced by TNFα or anisomycin in the presence of low-level SOCS3, IRS-1 degradation was remarkably enhanced. Taken together, both IRS-1 serine phosphorylation and SOCS3 induction are necessary, but one of the pair is not sufficient for the inhibited insulin signaling. Chronic TNFα may inhibit insulin signaling effectively because it causes both IRS-1 serine phosphorylation and the following SOCS3 induction in 3T3-L1 adipocytes.

Protein Tyrosine Phosphatase 1B Inhibitors: A Novel Therapeutic Strategy for the Management of type 2 Diabetes Mellitus

2019 ◽  
Vol 25 (23) ◽  
pp. 2526-2539 ◽  
Author(s):  
Pranav K. Prabhakar ◽  
Ponnurengam M. Sivakumar
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Receptor ◽  
Therapeutic Strategy ◽  
Insulin Signalling ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatase 1B

Diabetes is one of the most common endocrine non-communicable metabolic disorders which is mainly caused either due to insufficient insulin or inefficient insulin or both together and is characterized by hyperglycemia. Diabetes emerged as a serious health issue in the industrialized and developing country especially in the Asian pacific region. Out of the two major categories of diabetes mellitus, type 2 diabetes is more prevalent, almost 90 to 95% cases, and the main cause of this is insulin resistance. The main cause of the progression of type 2 diabetes mellitus has been found to be insulin resistance. The type 2 diabetes mellitus may be managed by the change in lifestyle, physical activities, dietary modifications and medications. The major currently available management strategies are sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors, dipeptidyl peptidase-IV inhibitors, and glucagon-like peptide-1 (GLP-1) agonist. Binding of insulin on the extracellular unit of insulin receptor sparks tyrosine kinase of the insulin receptor which induces autophosphorylation. The phosphorylation of the tyrosine is regulated by insulin and leptin molecules. Protein tyrosine phosphatase-1B (PTP1B) works as a negative governor for the insulin signalling pathways, as it dephosphorylates the tyrosine of the insulin receptor and suppresses the insulin signalling cascade. The compounds or molecules which inhibit the negative regulation of PTP1B can have an inductive effect on the insulin pathway and finally help in the management of diabetes mellitus. PTP1B could be an emerging therapeutic strategy for diabetes management. There are a number of clinical and basic research results which suggest that induced expression of PTP1B reduces insulin resistance. In this review, we briefly elaborate and explain the place of PTP1B and its significance in diabetes as well as a recent development in the PTP1B inhibitors as an antidiabetic therapy.

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