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The Role of Pi, Glutamine and the Essential Amino Acids in Modulating the Metabolism in Diabetes and Cancer

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Abstract

Purpose

Re-examine the current metabolic models.

Methods

Review of literature and gene networks.

Results

Insulin activates Pi uptake, glutamine metabolism to stabilise lipid membranes. Tissue turnover maintains the metabolic health. Current model of intermediary metabolism (IM) suggests glucose is the source of energy, and anaplerotic entry of fatty acids and amino acids into mitochondria increases the oxidative capacity of the TCA cycle to produce the energy (ATP). The reduced cofactors, NADH and FADH2, have different roles in regulating the oxidation of nutrients, membrane potentials and biosynthesis. Trans-hydrogenation of NADH to NADPH activates the biosynthesis. FADH2 sustains the membrane potential during the cell transformations. Glycolytic enzymes assume the non-canonical moonlighting functions, enter the nucleus to remodel the genetic programmes to affect the tissue turnover for efficient use of nutrients. Glycosylation of the CD98 (4F2HC) stabilises the nutrient transporters and regulates the entry of cysteine, glutamine and BCAA into the cells. A reciprocal relationship between the leucine and glutamine entry into cells regulates the cholesterol and fatty acid synthesis and homeostasis in cells. Insulin promotes the Pi transport from the blood to tissues, activates the mitochondrial respiratory activity, and glutamine metabolism, which activates the synthesis of cholesterol and the de novo fatty acids for reorganising and stabilising the lipid membranes for nutrient transport and signal transduction in response to fluctuations in the microenvironmental cues. Fatty acids provide the lipid metabolites, activate the second messengers and protein kinases. Insulin resistance suppresses the lipid raft formation and the mitotic slippage activates the fibrosis and slow death pathways.

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Acknowledgments

LV acknowledges umpteen number of authors and former students (both cited and not cited in the article), who shared their research articles on request, which helped in shaping the hypothesis and development of the article to its final shape. MI would like to acknowledge all staff of the Institute of Biotechnology, University of Gondar, Gondar, Ethiopia, for their constant encouragement and support extended. The University of Hyderabad partly supported ABMR laboratory through institutional funding from DST-FIST (DBT-RNAi, DST-SERB), Government of India. GBM acknowledges UGC-CSIR for student fellowship.

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  1. Lakshmipathi Vadlakonda

    Present address: , Hyderabad, India

Authors and Affiliations

  1. Institute of Biotechnology, University of Gondar, Gondar, Ethiopia

    Meera Indracanti

  2. Amity Stem Cell Institute, Amity University Haryana, Amity Education Valley Pachgaon, Manesar, Gurugram, HR, 122413, India

    Suresh K. Kalangi

  3. Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India

    B. Meher Gayatri, Navya G Naidu & Aramati B. M. Reddy

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  1. Lakshmipathi Vadlakonda
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Contributions

The corresponding author (LV) formulated the hypothesis and developed the scheme and the write-up. MI participated in the discussion and development of gene networks by using the geneMANIA and the String databases.SK contributed to literature collection and compilation of literature. GBM, NN, and ABMR participated in the day to day discussions and supported in literature collection, during the write-up, which helped in shaping the article in its’ final form.

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Correspondence to Lakshmipathi Vadlakonda.

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Vadlakonda, L., Indracanti, M., Kalangi, S.K. et al. The Role of Pi, Glutamine and the Essential Amino Acids in Modulating the Metabolism in Diabetes and Cancer. J Diabetes Metab Disord 19, 1731–1775 (2020). https://doi.org/10.1007/s40200-020-00566-5

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