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

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.

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Phenylalanine Impairs Insulin Signaling and Inhibits Glucose Uptake by Modifying IRβ

10.21203/rs.3.rs-483980/v1 ◽

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.

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Insulin Resistance Is Associated With Enhanced Brain Glucose Uptake During Euglycemic Hyperinsulinemia: A Large-Scale PET Cohort

10.2337/figshare.13342142.v1 ◽

2021 ◽

Author(s):

Eleni Rebelos ◽

Marco Bucci ◽

Tomi Karjalainen ◽

Vesa Oikonen ◽

Alessandra Bertoldo ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Fatty Acids ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

C Reactive Protein ◽

Brain Glucose ◽

Reactive Protein ◽

Wide Range

Objective Whereas insulin resistance is expressed as reduced glucose uptake in peripheral tissues, the relationship between insulin resistance and brain glucose metabolism remains controversial. Our aim was to examine the association of insulin resistance and brain glucose uptake (BGU) during a euglycemic hyperinsulinemic clamp in a large sample of subjects across a wide range of age and insulin sensitivity. Research Design and Methods [18F]-fluorodeoxyglucose positron emission tomography (PET) data from 194 subjects scanned under clamp conditions were compiled from a single-center cohort. BGU was quantified by the fractional uptake rate. We examined the association of age, sex, M value from the clamp, steady-state insulin and free fatty acids levels, C-reactive protein, HbA1c, and presence of type 2 diabetes with BGU using Bayesian hierarchical modeling. Results Insulin sensitivity, indexed by the M value, was associated negatively with BGU in all brain regions, confirming that in insulin resistant subjects BGU is enhanced during euglycemic hyperinsulinemia. In addition, the presence of type 2 diabetes was associated with a further increase in BGU. On the contrary, age was negatively related to BGU. Steady-state insulin levels, C-reactive protein, free fatty acids, sex, and HbA1c were not associated with BGU. Conclusions In this large cohort of subjects of either sex across a wide range of age and insulin sensitivity, insulin sensitivity is the best predictor of brain glucose uptake.

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Low Carb High Protein Diets as Management Tool of Insulin Resistance in Patients with Obesity and/or Type 2 Diabetes Mellitus

Obesity Open Access ◽

10.16966/2380-5528.131 ◽

2017 ◽

Vol 3 (2) ◽

Author(s):

Govers E

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

High Protein ◽

Management Tool ◽

High Protein Diets ◽

Protein Diets

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Phloridzin Acts as an Inhibitor of Protein-Tyrosine Phosphatase MEG2 Relevant to Insulin Resistance

Molecules ◽

10.3390/molecules26061612 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1612

Author(s):

Sun-Young Yoon ◽

Jae Sik Yu ◽

Ji Young Hwang ◽

Hae Min So ◽

Seung Oh Seo ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Muscle Cells ◽

Protein Tyrosine ◽

C2c12 Muscle Cells

Inhibition of the megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2, also named PTPN9) activity has been shown to be a potential therapeutic strategy for the treatment of type 2 diabetes. Previously, we reported that PTP-MEG2 knockdown enhances adenosine monophosphate activated protein kinase (AMPK) phosphorylation, suggesting that PTP-MEG2 may be a potential antidiabetic target. In this study, we found that phloridzin, isolated from Ulmus davidiana var. japonica, inhibits the catalytic activity of PTP-MEG2 (half-inhibitory concentration, IC50 = 32 ± 1.06 μM) in vitro, indicating that it could be a potential antidiabetic drug candidate. Importantly, phloridzin stimulated glucose uptake by differentiated 3T3-L1 adipocytes and C2C12 muscle cells compared to that by the control cells. Moreover, phloridzin led to the enhanced phosphorylation of AMPK and Akt relevant to increased insulin sensitivity. Importantly, phloridzin attenuated palmitate-induced insulin resistance in C2C12 muscle cells. We also found that phloridzin did not accelerate adipocyte differentiation, suggesting that phloridzin improves insulin sensitivity without significant lipid accumulation. Taken together, our results demonstrate that phloridzin, an inhibitor of PTP-MEG2, stimulates glucose uptake through the activation of both AMPK and Akt signaling pathways. These results strongly suggest that phloridzin could be used as a potential therapeutic candidate for the treatment of type 2 diabetes.

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Insulin Resistance Is Associated With Enhanced Brain Glucose Uptake During Euglycemic Hyperinsulinemia: A Large-Scale PET Cohort

10.2337/figshare.13342142 ◽

2021 ◽

Author(s):

Eleni Rebelos ◽

Marco Bucci ◽

Tomi Karjalainen ◽

Vesa Oikonen ◽

Alessandra Bertoldo ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Fatty Acids ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

C Reactive Protein ◽

Brain Glucose ◽

Reactive Protein ◽

Wide Range

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Dietary protein paradox: decrease of amino acid availability induced by high-protein diets

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1993.264.6.g1057 ◽

1993 ◽

Vol 264 (6) ◽

pp. G1057-G1065 ◽

Cited By ~ 11

Author(s):

C. Moundras ◽

C. Remesy ◽

C. Demigne

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Dietary Protein ◽

High Protein ◽

Glutamine Metabolism ◽

Metabolic Adaptation ◽

Casein Diet ◽

Serine Dehydratase ◽

High Protein Diets ◽

Protein Diets

The aim of the present study was to evaluate the effect of changes in dietary protein level on overall availability of amino acids for tissues. For this purpose, rats were adapted to diets containing various concentrations of casein (7.5, 15, 30, and 60%) and were sampled either during the postprandial or postabsorptive period. In rats fed the protein-deficient diet, glucogenic amino acids (except threonine) tended to accumulate in plasma, liver, and muscles. In rats fed high-protein diets, the hepatic balance of glucogenic amino acids was markedly enhanced and their liver concentrations were consistently depressed. This response was the result of a marked induction of amino acid catabolism (a 45-fold increase of liver threonine-serine dehydratase activity was observed with the 60% casein diet). The muscle concentrations of threonine, serine, and glycine underwent changes parallel to plasma and liver concentrations, and a significant reduction of glutamine was observed. During the postabsorptive period, adaptation to high-protein diets resulted in a sustained catabolism of most glucogenic amino acids, which accentuated the drop in their concentrations (especially threonine) in all the compartments studied. The time course of metabolic adaptation from a 60 to a 15% casein diet has also been investigated. Adaptation of alanine and glutamine metabolism was rapid, whereas that of threonine, serine, and glycine was delayed and required 7-11 days. This was paralleled by a relatively slow decay of liver threonine-serine dehydratase (T-SDH) activity in contrast to the rapid adaptation of pyruvate kinase activity after refeeding a high-carbohydrate diet.(ABSTRACT TRUNCATED AT 250 WORDS)

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Common Risk Factors in Relatives and Spouses of Patients with Type 2 Diabetes in Developing Prediabetes

Healthcare ◽

10.3390/healthcare9081010 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1010

Author(s):

Wei-Hao Hsu ◽

Chin-Wei Tseng ◽

Yu-Ting Huang ◽

Ching-Chao Liang ◽

Mei-Yueh Lee ◽

...

Keyword(s):

Risk Factors ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Cell Function ◽

Diabetic Patients ◽

Β Cell ◽

Tyg Index ◽

Β Cell Function

Prediabetes should be viewed as an increased risk for diabetes and cardiovascular disease. In this study, we investigated its prevalence among the relatives and spouses of patients with type 2 diabetes or risk factors for prediabetes, insulin resistance, and β-cell function. A total of 175 individuals were included and stratified into three groups: controls, and relatives and spouses of type 2 diabetic patients. We compared clinical characteristics consisting of a homeostatic model assessment for insulin resistance (HOMA-IR) and beta cell function (HOMA-β), a quantitative insulin sensitivity check index (QUICKI), and triglyceride glucose (TyG) index. After a multivariable linear regression analysis, the relative group was independently correlated with high fasting glucose, a high TyG index, and low β-cell function; the relatives and spouses were independently associated with a low QUICKI. The relatives and spouses equally had a higher prevalence of prediabetes. These study also indicated that the relatives had multiple factors predicting the development of diabetes mellitus, and that the spouses may share a number of common environmental factors associated with low insulin sensitivity.

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Vascular dysfunction and insulin stimulated blood flow : impact of physical inactivity and type 2 diabetes

10.32469/10355/48201 ◽

2014 ◽

Author(s):

◽

Leryn J. Boyle

Keyword(s):

Physical Activity ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Blood Flow ◽

Insulin Sensitivity ◽

Endothelial Function ◽

Physical Inactivity ◽

Vascular Dysfunction ◽

Insulin Stimulation

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Individuals with type 2 diabetes (T2D) have blunted femoral artery insulin mediated blood flow which is critical for the delivery and uptake of glucose into skeletal muscle. However, it is unclear in humans the precise mechanisms by which insulin resistance impairs insulin stimulated blood flow. Further, chronic physical inactivity is a powerful stimulus for reduced insulin sensitivity and vascular dysfunction; however, the effects of short term, modest reductions in physical activity are limited. Thus, we examined 1) if inactivity for 5 days would impair endothelial function in healthy individuals (study one) 2) if reducing whole body insulin sensitivity, via 5 days of inactivity, would impair the blood flow response to insulin stimulation in parallel with glycemic control (study two) and 3) phosphorylation of endothelial nitric oxide (eNOS) and endothelin-1 (ET-1) production to insulin stimulation would be decreased and increased, respectively, in insulin resistant individuals (study three). We demonstrated significant reductions in endothelial function with only 5 days of reduced daily steps while blood flow to glucose ingestion was unaltered. Further, in obese humans with type 2 diabetes it does not appear that that the reduction in blood flow to 1 hr of insulin stimulation is due to altered peNOS or ET-1. Collectively, these data suggest that reduced daily physical activity and chronic insulin resistance mediate negative impacts on vascular function and insulin stimulated blood flow and signaling.

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Increasing endogenous PPARγ ligands improves insulin sensitivity and protects against diet-induced obesity without side effects of thiazolidinediones

10.21203/rs.3.rs-490889/v1 ◽

2021 ◽

Author(s):

Yu-Hua Tseng ◽

Lee-Ming Chuang ◽

Yi-Cheng Chang ◽

Meng-Lun Hsieh ◽

Lun Tsou ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Side Effects ◽

Knockout Mice ◽

Fasting Glucose ◽

Binding Mode ◽

Fluid Retention ◽

Diet Induced Obesity

Abstract Insulin resistance and obesity are pivotal features of type 2 diabetes mellitus. Peroxisome proliferator-activated receptor γ (PPARγ) is a master transcriptional regulator of systemic insulin sensitivity and energy balance. The anti-diabetic drug thiazolidinediones are potent synthetic PPARγ ligands and insulin sensitizers with undesirable side effects including increased adiposity, fluid retention, and osteoporosis, which limit their clinical use. We and others have proved that 15-keto-PGE2 is an endogenous natural PPARγ ligand. 15-keto-PGE2 is catalyzed by prostaglandin reductase 2 (PTGR2) to become inactive metabolites. We found that 15-keto-PGE2 level is increased in Ptgr2 knockout mice. Ptgr2 knockout mice were protected from diet-induced obesity, insulin resistance, and hepatic steatosis without fluid retention nor reduced bone mineral density. Diet-induced obese mice have drastically reduced 15-keto-PGE2 levels compared to lean mice. Administration of 15-keto-PGE2 markedly improved insulin sensitivity and prevented diet-induced obesity in mice. We demonstrated that 15-keto-PGE2 activates PPARγ through covalent binding to its cysteine 285 residue at helix 3, which restrained its binding pocket between helix 3 and β-sheets of the PPARγ ligand binding domain. This binding mode differs from the helix12-dependent binding mode of thiazolidinediones. We further identified a small-molecule PTGR2 inhibitor BPRPT245, which interferes the interaction between the substrate-binding sites of PTGR2 and 15-keto-PGE2. BPRPT245 increased 15-keto-PGE2 concentration, activated PPARγ, and promoted glucose uptake in adipocytes. BPRPT245 also prevented diet-induced obesity, improved insulin sensitivity and glucose tolerance, lowers fasting glucose without fluid retention and osteoporosis. In humans, reduced serum 15-keto-PGE2 levels were observed in patients with type 2 diabetes compared with controls. Furthermore, serum 15-keto-PGE2 levels correlate inversely with insulin resistance and fasting glucose in non-diabetic humans. In conclusion, we identified a new therapeutic approach to improve insulin sensitivity and protect diet-induced obesity through increasing endogenous natural PPARγ ligands without side effects of thiazolidinediones.

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Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice

Scientific Reports ◽

10.1038/s41598-019-51196-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Denise E. Lackey ◽

Felipe C. G. Reis ◽

Roi Isaac ◽

Rizaldy C. Zapata ◽

Dalila El Ouarrat ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Target Genes ◽

Obese Mice ◽

Tissue Macrophage

Abstract Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity.

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