Is hyperglucagonemia part of metabolic syndrome / prediabetes?

Well, in answer to myself, that is a good question. Which I have investigated. It would be hard to come up with a more unpopular question, to which almost noone (with money or large institutional interests) wants an answer, fearing what it might be. So there are not (or were not, last I looked quite a few years ago) many studies that have been generated and designed to investigate.
From the few that I found, the answer appears to be YES. And it probably depends (in magnitude, at least) upon whether the study cohort member is, or is not, ultimately susceptible to T2DM via descent and progression well into the so-called “decompensation” stage of prediabetes. Which more than half of the population are NOT, it appears.
For those who evade, or never enter, the decompensation phase, but instead are genetically capable of upregulating beta-cell population in islets (a “permanent” form of extension of the “compensation” phase), the question is more tricky to answer. To design a study, one would have to attempt to ID those who have long been prediabetic and have upregulated beta-cell population. And the latter is determined at autopsy, in general, so for a study cohort this would be hard to do to say the least.
It is interesting, at least, to attempt a thought experiment.
The permanent prediabetic exists in a state of chronic hyperinsulinemia, by definition essentially. This is extremely common. I have an uncle in this state, and he has been for most of life as would also generally be the case. Only years of life not in this state would have been his youngest.
There is a positive feedback for the T2DM-susceptible prediabetic that will result in overt diabetes ultimately, unless diet is corrected early enough to arrest (and slowly reverse) loss of beta cells and to abruptly correct/normalize the morphological state of the beta cells extant in islets. Hence, the beta-cell population/number is NOT stable. It will decline. What the MDs call “progression”. Hah! Love these medical terms, which so obscure what is going on, at best. And generally, I think, to obfuscate and make medical practice appear as hocus pocus (mysterious and opaque) to the general public. When one does not understand what one is doing, but nevertheless makes money from it, best to do so for one’s “job security” and industry/institutional best interests.
It is entirely different for the stable unsusceptible permanent prediabetic. Key word being “stable”. What is the equilibrium status, in terms of the endocrinology (of islet hormones, especially) of this type of individual?
Well, I think the results of the thought experiment would be thus:

  1. The constant state of extreme whole-body hyperinsulinemia suggests (to say the least) constant excess of HGP/HGO (hepatic glucose production or output – these are terms of art that one should well recognize if one wants to read any basic literature), requiring the permanent “compensation”.
  2. Where does this excess HGP derive from? From hyperglucagonemia. Chronic hyperglucagonemia. Glucagon regulates HGP – nothing else. Insulin does NOT compensate at the level of liver. Its potency is trivial at the level of liver, in comparison to that of glucagon.
  3. Why the hyperinsulinemia, then? Well, because of the whole-body moderate hyperglycemia and instability of glucose regulation. This gives most middle-aged men who will never become T2Ds a higher HbA1c than mine, and even many higher than I had, or would have, without insulin therapy but with the same diet. I went quite a few years in this condition. So I know the numbers.
  4. To elaborate on (3) above, the chronic whole-body hyperglycemia is recharged with every meal. Supercharged. But it is the basal (interprandial) equilibrium that is relatively destabilized (dysregulated), with substantial BG elevation on average, in prediabetes (or MetS). So in between meals the increased beta-cell population (for one class of prediabetic – the permanent ones) are constantly working to lower BG but can never “catch up”. Whole-body IR (and there is really no such thing – IR (or IS, the inverse) is tissue/organ-specific and independent, always) may further reduce potential potency, but this is a tertiary issue at most. And it is the FA metabolism that is all but destroyed in muscle and other high-mass insulin-regulated tissues. Glucose metabolism is slightly degraded, but not much, in MetS / prediabetes / hyperinsulinemia. This is basic textbook stuff – known for many decades now. Cellular metabolism (albeit pathological for MetS) 101.
  5. Is there IR (insulin resistance) in the alpha cells themselves? I have delved into, as much as possible, investigating this as well. Even harder to verify than the hyperglucagonemia of the prediabetic state (both stable and unstable, in aggregate). Answer appears to be yes, but difficult to be confident. Could be better studied – would be informative. Will it be? Unlikely – another answer noone wants to know.
    But to the degree that IR exists in alpha cells, this would aggravate hyperglycemia still more of course. Alpha cells, if not insulin-resistant in MetS, would be uniquely so in NOT responding to highly chronically abnormally high levels of human/animal hormone. At least at the levels of the membrane receptors, but also at the level of cytoplasmic transporters.
    Maybe I should ask my endo what he thinks. Oh, that’s right, I don’t have one! Because my form of diabetes is not even recognized in clinical practice nor by medical insurance. Gee golly whiz. Sorry for the sarcasm, those of you who think that MDs and medicine know a lot about biology. According to my observations, the basic research teams of the pharma companies know more than anyone else in medical fields, far more. But still, they necessarily have professional interests at stake. They do NOT endeavor purely on behalf of the interests of patients, but maybe just the most so of any in medical fields.
    I sure do have a lot of complications of diabetes, anyway, from five decades of completely unrecognized monogenic diabetes. It will probably take me another decade (based upon the limited case history) to regenerate most of the vagus nerve still not yet regenerated. Complications in feet and lower leg, including a highly unusual form of neuropathy (nothing like that reported for T2DM) have been notably reduced (indicating significant regeneration of neural tissues) but not eliminated – just reduced so far. Maybe another decades for those. There are some tissues that can never be regenerated, according to the case history, but most can and will be.
    Anyway, there may be not a single other forum participant with monogenic diabetes. Dunno. Matters not – if one understands the biology one can understand how to apply it to any form of diabetes. For self-management of one’s own condition. This I recommend. Use the MDs for what they are useful for. And not more.
    And for metabolic conditions (and T2DM certainly is this, but even T1DM though certainly immunological in nature, results from modern diet – the immunological, generally permanent, insult to the lymphocytes is induced by chronically highly excessive acute insulin response from islets) drugs are not the answer, and are often not even helpful in general. I distinguish human hormones as med’s, but not drugs. Vit D (a misnomer in two fundamental respects) would be another highly used human hormone that all in modern society should be supplementing orally I think.