Hyperlipid by Petro Dobromylskyj

20 January 2021

You need to get calories from somewhere, should it be from carbohydrate or fat?
  • ROS (01) Insulins are ubiquitous in eukaryotes
    I've had this paper lying around for years:

    Role of Insulin-Induced Reactive Oxygen Species in the Insulin Signaling Pathway

    Figure 4, shown below, sums up why it interests me

    Brief aside: The role of glucose in generating ROS from mitochondria is, to me, extremely dubious. It certainly can occur but it needs the activation of the glycerophosphate shuttle, which doesn't get a mention. But the GPS is how we convert cytoplasmic NADH in to mitochondrially inputted FADH2, with ROS generation resulting from the raised FADH2:NADH ratio intrinsic to this conversion acting on the CoQ couple. It will apply in the presence of insulin, not isolated hyperglycaemia. If you slog through the refs trail (not good) you need to realise FBS = insulin/IGF-1. Also few people even think of fatty acids in this respect, a serious omission. Enough of mitochondria, back to the cytoplasm. End aside.

    It's worth pointing out that the insulin receptor is thought to act as a G-protein coupled receptor which signals to an NADPH oxidase (probably NOX4) using a specific G protein. The NADPH oxidase generates H2O2 extracellularly (this becomes important in future posts) which re-enters the cell (some papers suggest there is a specific transporter) to oxidise cysteines on protein tyrosine phosphatases, disabling these enzymes. Without PTPases maintaining the suppression of insulin signalling both the insulin receptor and insulin receptor substrates autophosphorylate and so signalling takes off.

    That's all pretty straightforward and is verging on textbook.

    Nothing happens without ROS generation.

    This led me down a rabbit hole, thinking about how primordial insulin signalling might be and how primordial the ROS generation might be. Is insulin core, with ROS as a second messenger? People may have noticed that the most basic signalling is what interests me.

    How far back does insulin go? If we have a look at this review

    Insulin-like signaling within and beyond metazoans

    we can see that there is a recognisable insulin like receptor stemming from the common ancestor leading to both ourselves and sponges. That's pretty far back, marked by the blue lineage arrows in Figure 1 from the review:

    Insulin signalling is thought to be present in most, but not quite all, metazoans (blue circle).

    The review looks at the evidence for insulin signalling in yeasts, plants and a ciliated protozoan.

    Sacchromyces has no suggestion of an insulin receptor. However it responds to exogenous human insulin with a response remarkably recognisable as the response of human cells to insulin.

    Plants are more straightforward. They produce an insulin-like cysteine rich peptide which interacts with an insulin-like receptor to induce the effects typically seen in mammalian cells under insulin. In fact using this peptide on adipocytes produces exactly the same effects as human insulin.

    Neither the "plant insulin" nor its receptor have anything in common with metazoan insulin/receptor protein amino acid sequences.

    Except they have common "shape".  They are immuno-related. They look similar enough (shape/charge distribution) that they can be recognised by the same binding antibody.

    Exactly the same findings are duplicatable in the ciliate protozoan T pyriformis as for the Sacchromyces yeast.

    So. Different insulin-like hormones, different receptors. Genetically completely unrelated, but causing the cell to respond in the same way.

    The simplest answer is convergent evolution, as suggested in the review. I think this is correct. But there is a deeply insightful comment towards the end of the discussion. Almost insightful enough, but ever so slightly not quite there:

    "The convergent evolution of ligand-receptor pairs alone cannot explain however the biochemical similarities in the intracellular response to insulin observed outside metazoans, as illustrated above. One way to overcome this seeming inconsistency is by considering that independently evolved upstream components of pathways devoted to processing environmental information may have been tied to evolutionary conserved core metabolic and cellular growth signaling networks".

    The most obvious metabolic signalling molecules which adjust core metabolic function and cell growth are the ROS.

    Metazoans, plants, yeasts, protozoa; all will use ROS signals to control metabolism and growth. This is the evolutionary conserved process on to which various environmentally responsive ligands and receptors have been co-opted to respond. On at least four separate occasions. My opinion.

    A eukaryote is a derivative of a bacterium living inside an archaeon. Information about archaea is remarkably thin on the ground. I expect them to use ROS. Bacteria are more rewarding once you turn to Pubmed.

    Perhaps bacteria are where we should be looking to find the origin of the primordial ROS signal.

  • Where the UK is heading perhaps (or not)
    From January 13th 2021, early in Lockdown 3, UK.

    This is Dr Mary Ramsay, head of immunisation for PHE (Public Health England, UK government). She is reiterating exactly the manifesto of the Great Barrington Declaration. I think it was April 2020 that I heard Prof Sunetra Gupta first advocate this concept. Now, in the early days of Lockdown 3, suddenly there is a voice of reason from a government department. It's echoing Vallance/Whitty from March 2020, before they both had all of their immunology knowledge, presumably with most of the rest of their brain function (sarcasm warning again) removed, sometime during Lockdown 1.