scholarly journals Phenylalanine Impairs Insulin Signaling and Inhibits Glucose Uptake by Modifying IRβ

2021 ◽  
Author(s):  
Qian Zhou ◽  
Wan-Wan Sun ◽  
Jia-Cong Chen ◽  
Huilu Zhang ◽  
Jie Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Trna Synthetase ◽  
Blood Samples ◽  
Receptor Beta

Abstract Although elevated circulating amino acids are associated with the onset of type 2 diabetes (T2D), how amino acids act on cell insulin signaling and glucose uptake remains unclear. Herein, we report that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or overexpressing human phenylalanyl-tRNA synthetase (hFARS) developed insulin resistance and symptoms of T2D. Mechanistically, FARS phenylalanylated lysine 1057/1079 of IRβ (F-K1057/1079) inactivated IRβ and prevented insulin from generating insulin signaling to promote glucose uptake by cells. SIRT1 reversed F-K1057/1079 and counteracted the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels of white cells of T2D patients’ blood samples were positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitized insulin signaling and relieved T2D symptoms in hFARS-transgenic and db/db mice. We revealed mechanisms of how phenylalanylation inactivates insulin signaling that may be employed to control T2D.

Discordant effects of a chronic physiological increase in plasma FFA on insulin signaling in healthy subjects with or without a family history of type 2 diabetes

2004 ◽  
Vol 287 (3) ◽  
pp. E537-E546 ◽  
Author(s):  
Sangeeta R. Kashyap ◽  
Renata Belfort ◽  
Rachele Berria ◽  
Swangjit Suraamornkul ◽  
Thongchai Pratipranawatr ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Family History ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Low Dose ◽  
History Of ◽  
Plasma Ffa

Muscle insulin resistance develops when plasma free fatty acids (FFAs) are acutely increased to supraphysiological levels (∼1,500–4,000 μmol/l). However, plasma FFA levels >1,000 μmol/l are rarely observed in humans under usual living conditions, and it is unknown whether insulin action may be impaired during a sustained but physiological FFA increase to levels seen in obesity and type 2 diabetes mellitus (T2DM) (∼600–800 μmol/l). It is also unclear whether normal glucose-tolerant subjects with a strong family history of T2DM (FH+) would respond to a low-dose lipid infusion as individuals without any family history of T2DM (CON). To examine these questions, we studied 7 FH+ and 10 CON subjects in whom we infused saline (SAL) or low-dose Liposyn (LIP) for 4 days. On day 4, a euglycemic insulin clamp with [3-3H]glucose and indirect calorimetry was performed to assess glucose turnover, combined with vastus lateralis muscle biopsies to examine insulin signaling. LIP increased plasma FFA ∼1.5-fold, to levels seen in T2DM. Compared with CON, FH+ were markedly insulin resistant and had severely impaired insulin signaling in response to insulin stimulation. LIP in CON reduced insulin-stimulated glucose disposal (Rd) by 25%, insulin-stimulated insulin receptor tyrosine phosphorylation by 17%, phosphatidylinositol 3-kinase activity associated with insulin receptor substrate-1 by 20%, and insulin-stimulated glycogen synthase fractional velocity over baseline (44 vs. 15%; all P < 0.05). In contrast to CON, a physiological elevation in plasma FFA in FH+ led to no further deterioration in Rd or to any additional impairment of insulin signaling. In conclusion, a 4-day physiological increase in plasma FFA to levels seen in obesity and T2DM impairs insulin action/insulin signaling in CON but does not worsen insulin resistance in FH+. Whether this lack of additional deterioration in insulin signaling in FH+ is due to already well-established lipotoxicity, or to other molecular mechanisms related to insulin resistance that are nearly maximally expressed early in life, remains to be determined.

Does high dietary protein intake contribute to the increased risk of developing prediabetes and type 2 diabetes?

2021 ◽  
Vol 46 (1) ◽  
pp. 1-9
Author(s):  
Oana Ancu ◽  
Monika Mickute ◽  
Nicola D. Guess ◽  
Nicholas M. Hurren ◽  
Nicholas A. Burd ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Amino Acid ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Protein Intake ◽  
High Protein Diets ◽  
Protein Diets

Insulin resistance is a complex metabolic disorder implicated in the development of many chronic diseases. While it is generally accepted that body mass loss should be the primary approach for the management of insulin resistance-related disorders in overweight and obese individuals, there is no consensus among researchers regarding optimal protein intake during dietary restriction. Recently, it has been suggested that increased plasma branched-chain amino acids concentrations are associated with the development of insulin resistance and type 2 diabetes. The exact mechanism by which excessive amino acid availability may contribute to insulin resistance has not been fully investigated. However, it has been hypothesised that mammalian target of rapamycin (mTOR) complex 1 hyperactivation in the presence of amino acid overload contributes to reduced insulin-stimulated glucose uptake because of insulin receptor substrate (IRS) degradation and reduced Akt-AS160 activity. In addition, the long-term effects of high-protein diets on insulin sensitivity during both weight-stable and weight-loss conditions require more research. This review focusses on the effects of high-protein diets on insulin sensitivity and discusses the potential mechanisms by which dietary amino acids can affect insulin signalling. Novelty: Excess amino acids may over-activate mTOR, resulting in desensitisation of IRS-1 and reduced insulin-mediated glucose uptake.

scholarly journals Differential Insulin Receptor Substrate-1 (IRS1)-Related Modulation of Neuropeptide Y and Proopiomelanocortin Expression in Nondiabetic and Diabetic IRS2−/− Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1129-1140 ◽  
Author(s):  
Emma Burgos-Ramos ◽  
Águeda González-Rodríguez ◽  
Sandra Canelles ◽  
Eva Baquedano ◽  
Laura M. Frago ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Food Intake ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Janus Kinase ◽  
Insulin Receptor Substrate ◽  
Mrna Levels ◽  
Hypothalamic Inflammation

Insulin resistance and type 2 diabetes correlate with impaired leptin and insulin signaling. Insulin receptor substrate-2 deficient (IRS2−/−) mice are an accepted model for the exploration of alterations in these signaling pathways and their relationship with diabetes; however, disturbances in hypothalamic signaling and the effect on neuropeptides controlling food intake remain unclear. Our aim was to analyze how leptin and insulin signaling may differentially affect the expression of hypothalamic neuropeptides regulating food intake and hypothalamic inflammation in diabetic (D) and nondiabetic (ND) IRS2−/− mice. We analyzed the activation of leptin and insulin targets by Western blotting and their association by immunoprecipitation, as well as the mRNA levels of neuropeptide Y (NPY), proopiomelanocortin, and inflammatory markers by real-time PCR and colocalization of forkhead box protein O1 (FOXO1) and NPY by double immunohistochemistry in the hypothalamus. Serum leptin and insulin levels and hypothalamic Janus kinase 2 and signal transducer and activator of transcription factor 3 activation were increased in ND IRS2−/− mice. IRS1 levels and its association with Janus kinase 2 and p85 and protein kinase B activation were increased in ND IRS2−/−. Increased FOXO1 positively correlated with NPY mRNA levels in D IRS2−/− mice, with FOXO1 showing mainly nuclear localization in D IRS2−/− and cytoplasmic in ND IRS2−/− mice. D IRS2−/− mice exhibited higher hypothalamic inflammation markers than ND IRS2−/− mice. In conclusion, differential activation of these pathways and changes in the expression of NPY and inflammation may exert a protective effect against hypothalamic deregulation of appetite, suggesting that manipulation of these targets could be of interest in the treatment of insulin resistance and type 2 diabetes.

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 Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1236
Author(s):  
Jesús Burillo ◽  
Patricia Marqués ◽  
Beatriz Jiménez ◽  
Carlos González-Blanco ◽  
Manuel Benito ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Progressive Disease

Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer’s disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction.

Genistein and Momordica charantia L. prevents oxidative stress and upregulate proglucagon and insulin receptor mRNA in diabetic rats.

2021 ◽  
Author(s):  
Wusa Makena ◽  
Abdullahi Ibrahim Iliya ◽  
Joseph Olajide Hambolu ◽  
James Abrak Timbuak ◽  
Uduak Emmanuel Umana ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Insulin Receptor ◽  
Mrna Expression ◽  
Insulin Signaling ◽  
Diabetic Rats ◽  
Momordica Charantia ◽  
Receptor Mrna ◽  
Group I

Type 2 diabetes (T2D) occur as a result of insulin resistance and malfunction in insulin signaling. Controlling hyperglycemia and activation of insulin signaling are important in the management of T2D. The study aimed to evaluate the effect of Genistein and Momordica charantia L. fruit on oxidative stress, markers of inflammation, and their role on proglucagon and insulin receptor mRNA expression by RT-PCR in diabetic rats. Thirty-five albino rats were divided into seven groups (n=5). Group I (non-diabetic) and group II (diabetic control) were treated with distilled water, groups III and IV received 250mg/kg and 500mg/kg lyophilized MCF respectively. Groups V and VI received 10mg/kg and 20mg/kg Genistein respectively while group VII received 500mg/kg Metformin. The administration lasted for 28 days. MCF and Genistein significantly reduced IL-1β and TNFα levels that was elevated in serum of diabetic rats. Treatment with MCF and Genistein significant increased the expression of proglucagon mRNA in the small intestine and insulin receptor mRNA in the liver of diabetic rats. In conclusion, MCF and Genistein ameliorate type 2 diabetes complications by preventing the loss of insulin-positive cells, inhibiting IL-1β and TNFα and up-regulating proglucagon and insulin receptor mRNA expression. Novelty: • MCF and Genistein has an inhibitory effect on diabetic induced IL-1β and TNFα production. • MCF and Genistein up-regulates proglucagon and insulin receptor mRNA expression.

Insulin Signaling and Action in Fat Cells: Associations with Insulin Resistance and Type 2 Diabetes

1999 ◽  
Vol 892 (1 THE METABOLIC) ◽  
pp. 119-126 ◽  
Author(s):  
ULF SMITH ◽  
METTE AXELSEN ◽  
EUGENIA CARVALHO ◽  
BJORN ELIASSON ◽  
PER-ANDERS JANSSON ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Signaling ◽  
Fat Cells
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