Roger Unger

I thought of Roger Unger, knowing his approximate age, this morning and decided to see if he was “still coming down for breakfast” (a Howie Carr favorite expression).

Anyway, not. Unger is one of the single most important researchers of human biology, endocrinology and modern degenerative conditions of the past century. He and colleagues first demonstrated, by extensive experiment back in the late 60s and early 70s onward (until he died last year) what the role of glucagon is, and that the role of insulin is mostly important ONLY in islets, as the intraislet primary regulator of the alpha cells (which secrete glucagon).

A previous generation of researchers had correctly hypothesized, at least as early as the 1950s, the paracrine endocrinology of the islets of Langerhans. But until Unger developed the first radioimmunoassay for glucagon, with the help of Sol Berson who (with his wife) had developed that for insulin in the mid-60s just before, the earlier hypotheses had been impossible to test via experiment. Rosalyn Yalow (Berson’s wife) won the Nobel Prize for the discovery years later in the '70s, after Berson himself had died (Nobel’s prize is/was not awarded posthumously, by rule). Hence, the famous “Yalow and Berson” discovery.

The field of research shortly thereafter went awry, emphasizing insulin over all else. Endogenous insulin would be of little importance at all in diabetes and prediabetes (aka MetS) but for its role strictly within islets (endocrine pancreas). Unger’s colleague at UT Southwestern (and there have been SO many of the most important diabetes researchers in the world at this one institution over the decades) Ralph Defronzo, despite doing his most important work very early in his career, developing the gold-standard of research-lab instrumentation for portal (and peripheral) blood glucose and insulin, etc. by means of insulin (and other hormonal/nutrient) clamping, is a prime example of a diabetes researcher ever since joined at hip to the institutional interests so much antithetical to accurate and helpful knowledge via research who has furthered the enormous misconceptions and falsehoods about insulin resistance (IR).

The concept of IR as the overriding cause of T2DM, prediabetes, CVD, and most other modern tissue-specific degenerative conditions is WRONG. IR is a DOWNSTREAM effect, and nothing much more. Not that it is of absolutely no consequence (in Alzheimer’s Disease, for example, and likely in CVD and ischemia/clotting of arteries, both via induced dysfunction of vascular endothelium which is the so-called BBB (blood brain barrier) in brain) – it is. But it is STRICTLY one of many, many downstream phenomena/sequelae. Including what Unger named “lipotoxicity” which, ironically, nearly obliterates fatty acid metabolism in insulin-regulated/expressing tissues (e.g. muscle) while having little negative impact upon glucose metabolism, thus making the prediabetic addicted to carb’s (and excessively frequent feeding) and chronically depriving the brain of fuel/energy due to the abnormal dependence of non-brain tissues upon glucose as fuel.

Of course, ALL attempts (which are still very much ongoing) to come up with a glucagon inhibitor (metreleptin being the latest and most powerful of all that I know of) have FAILED, because the cells will react and adapt to a loss of glucagon signal, pushing a diabetic animal model back into the diabetic condition (100%) after only temporary/transient normalization of BG via metreleptin (or any other mechanism of glucagon inhibition whatsoever, and there are countless such). This response is built into some of the most ancient parts of our genome, going back to primordial life/organisms on earth. Glucagon is THAT important to life and cellular viability/metabolism, and insulin is NOT. Not even close.

Instructively, it is the alpha cell function that is permanently degraded, via genomic destabilization and devolution (aka dedifferentiation in some instances), with the total loss of the intraislet insulin signal. Exogenous insulin can keep an “insulin dependent” (i.e. requiring exogenous insulin to avoid ketoacidosis and death within one to two days) diabetic alive and crudely compensate for the persistent portal hyperglucagonemia that is the defining characteristic of diabetes (with only MODY-2 being an exception, since this condition involves an enzyme deficiency and no insulin deficiency whatsoever, and is completely benign) by merely driving the inevitable and constant hyperglucagonemia and excessive hepatic glucose production into the tissues (e.g. muscle) peripherally to liver and portal vein.

Nearly the entire clinical and pharmaceutical field of medicine, respecting diabetes and prediabetes and all of the other modern degenerative conditions driven by prediabetes, is largely wrong-headed and with myriad adverse effects upon the “patient” or individual. Subcutaneous insulin is a useful and necessary tool for the diabetic, but medical/clinical insructions for how it is to be used are more incorrect than correct, at least in the interests of the individual diabetic.

Doing TRUE research into biology and cellular metabolism (i.e. biochemistry) is HARD, HARD work. Unger was one of precious few driven to do this. He is an example of what has become more and more rare for the last century, and this deleterious trend is still well in place. The paucity of such strivers in the field of research is absolutely appalling and dangerous for societies all across the world. The amount of depletion of such work within only my own lifespan is stunning.

This post is certainly relevant to both T1DM and T2DM as well as MODY or monogenic diabetes. But it is for T2DM that IR has, by far, most corrupted the clinical and pharmaceutical industries with enormously damaging adverse impact upon “patients”. I put the last word in quotes because I really do not consider a T2D to be a patient (nor a T1D). The acquired forms of diabetes are just that, and result from continuous anti-evolutionary diet and metabolic/cellular biochemical insult. BOTH of them. These, and other tissue-specific degenerative modern conditions, are NOT pathogenic in nature.

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P.S. I should add, as addendum, that more than half of the population in countries such as USA will retain the condition of prediabetes (MetS) for life, and are NOT susceptible to overt T2DM. Why? I will answer below. But this is clearcut from the research in the field of islets study in autopsied pancreas/organs (e.g. Peter Butler and his lab at UCLA).
Guenther Boden (another no longer coming down for breakfast, unfortunately) elucidated the rough percentages in population of those susceptible, and those not, to the so-called “decompensation” phase of progression of the T2DM degeneration due to modern urban industrialized diet.
Those susceptible (due virtually exclusively to genome strictly within the beta cells of the individual – this is clearcut from yet another focused field of cellular/molecular research) WILL develop clinically overt and diagnosed T2DM, unless diet is corrected before degeneration progresses adequately far. For ALL forms of diabetes (excepting MODY-2 which is not an insulin-deficient form, and is benign) the clinical symptoms of polyuria and polydipsia first present when 80% of aggregate beta-cell population function has been lost. At this point the remaining beta-cell (aggregate function) can no longer generate and store insulin intracellularly in granule form. Hence, the acute insulin response (to meals, and absorption via gut into portal vein of glucose and amino acids (monomer forms of most dietary carb’s and protein)) goes haywire/missing, and there is sudden extreme/acute dysregulation of BG as a consequence. Leading to symptoms and diagnosis. It is rare that diabetes is ever diagnosed before beta-cell function declines to 20%, by HbA1c for example. I am a diabetic with completely stable insulin deficiency of 60% (i.e. ~40% beta-cell function) who uses highly disciplined insulin subcutaneous therapy to control the whole-body hyperglycemia otherwise intrinsic to my monogenic condition. Self-diagnosed, of course. I will never come close to losing another 20% of beta-cell function, because I maintain a strictly evolutionary (or pre-agriculture modern hominid emulating) diet, much less become insulin dependent.
My paternal grandfather, from whom I inherited the mutations in the homeobox gene, giving me one more of my three rare genetic conditions (in kidneys), DID lose the additional 20% via modern diet and MetS/prediabetes prior to decompensation and clinical diagnosis (incorrectly, mostly, of T2DM). For the usual reason(s).
Now for the answer to “why?”. Some remain prediabetic for life and some decline into overt T2DM. Because some of us (likely those with longer familial exposure to agriculture) can “compensate” by increase of the beta-cell population in islets (these will remain prediabetic) and some cannot. Both prediabetes and T2DM are metabolically damaging to tissues all over the body – possibly the sustained form of prediabetes is worse, since a higher level of hyperinsulinemia can be sustained for much, much longer, wreaking more havoc.

Very interesting posts @Mac2 the issue of dietary changes throughout our evolution and what is health-promoting versus illness-inducing may be even more complex than you state.

Eating a strictly animal diet can work but that does require eating the entire animal, and many would have difficulties with some organ meats for example. High protein/high fat diets have other consequences that can shorten lifespans, clearly in the individual but also in the population as a whole.

The glucagon vs insulin discussion is another interesting topic which for the present doesn’t lend itself to clear therapeutic interventions.

Overly processed, sugared, and preserved foods that are relatively nutrient deficient are certainly a bigger problem leading to many of modern societies’ ill health outcome including heart disease, obesity, etc. But I’m sure you know that.

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Obviously this is your view on things. However people seem to be able to control blood sugars by cutting out processed foods, not carbs alone. Several programs exist because of that.

And saying

How is that even abnormal since that is what our bodies are programed to do? Abnormality of processing might have started because our eating pattern warped so much with the availability of so much processed food and an abundance of food in general. Glucose being used as fuel is a basic trait of how our bodies function. You can use other ways to help fuel but glucose is one of the easiest for a reason. That would not be abnormal.

And then saying

I would beg to differ with you here too. I would die without insulin. That is sort of like saying red blood cells are so much more important than the iron that helps makes them.You would die without iron too.

Things might play a more key part in how our bodies function, but our bodies have a tendency to have some checks and balances to try to function right.

I think you are trying to turn things to prove your theory. If you so disagree with the research being done because it goes against what you believe then I suggest you go into research and research what you are interested in. Or specifically help fund, raise funds for the research you want.

Time and time again plant based diets have proven in research to bring health benefits. That would be mostly glucose based fuel. Two recent studies just even came out about preventing heart disease.

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Yes, any insulin-dependent diabetic WILL die without exogenous insulin. I am well aware. But the relative importance of glucagon vs. insulin IS clearcut based upon some of what I discussed and hence implied.
Namely, that the genome of alpha cells WILL BE destabilized and permanently degraded/deranged by total lack of islets insulin signal.
And MOST importantly, ALL attempts to compensate by inhibiting glucagon, which have been ongoing now for five decades, WILL (in my opinion) always and forevermore be, and certainly have been so far, unsuccessful. THIS is what indicates the relative importance of glucagon over insulin for sustaining life. The genome treats loss of glucagon signal as UNACCEPTABLE and overrides any pharmaceutical attempt to eliminate it with time and epigenetic response/transformation, and so restores a diabetic animal model to the state of full-blown diabetes after only temporary efficacy of ANY pharmaceutical intervention to restore glucose regulation. In the short term the interventions work, but NEVER in the long term. NEVER, so far across five decades.
Insulin is thought to be (and I believe correctly) a more ancient hormone than glucagon. Its fundamental primordial importance derives, in all forms of cellular life, from the lack of ability to store and save protein in cells, unlike forms of fuel (e.g. carb’s for plants and FAs for animals). And protein is the fundamental molecule of all life on earth.
Glucagon is, arguably, a later/newer evolutionary derivative/transformation of insulin. Its hormonal action is directly inverse to that of insulin. But for advanced animals such as modern hominids it IS the MOST powerful hormone. Gram for gram, acting upon liver, I believe the ratio is several orders of magnitude, going admittedly from recall.
What one needs to understand is that insulin is STRICTLY an ANABOLIC hormone. And glucagon is STRICTLY a CATABOLIC hormone. The relative importance of catabolism vs. anabolism is starkly different.
We DO need some anabolism, in the long run, to survive as species (plural). So as to live and grow long enough to reproduce. But we don’t need MUCH, and we don’t need it most of the time. Just a minority of the time, periodically.
We need catabolism ALL of the time – in the short term (to keep the brain supplied with fuel, second to second), and in the medium term (to respond epigenetically to changes in enviroment, such as the seasons), and in the long-term (to maintain and repair the cells). But anabolism ALWAYS OVERRIDES catabolism in cellular life, because food/nutrition (especially protein) is the scarce resource normally. Whereas catabolism is the default state while not absorbing nutrients, for cellular organisms.
There are ONLY two fuels that (human) brain is differentiated to utilize. Unlike many/most other non-brain tissues, this does NOT include FAs (fatty acids). So it is only glucose and ketones. Glucagon controls supply of both, via liver. Nothing else, including insulin, has any significantly powerful/competing effect directly upon liver. So it is portal glucagon, and glucagon alone essentially.
One must read the research literature and the QUANTITATIVE measurements on this. Since the early 1970s, and continuing right up until today.
I hope the above justifies my admittedly brief and inadequately explained/underpinned statement. But my statement IS/WAS correct. Understanding of the biology is necessary to understand the statement. Very few do, or would. This is why I am attempting to teach.
You would die without glucagon too, and quicker. Within seconds. Glucagon is entirely responsible for keeping your brain supplied with fuel (either, or both, glucose and/or ketones). Your argument that insulin is more important than glucagon does not bear close scrutiny. I hope you understand.

P.S. The pugilist’s liver shot/blow is demonstrative of what I have described, in terms of the need for glucagon virtually every second to sustain brain.
When well placed (difficult but possible to do) the recipient of the blow will be put into temporary coma – i.e. knockout for more than the full count. Immediately.
Look up how Mickey Ward of Lowell, Mass. won his boxing title of champion. Just one of many examples of the liver shot. By the way, I live in Lowell. But I knew about the endocrinology of islets/liver long before I had heard the story of Ward.
The blow, when effective, prevents liver from supplying glucose to brain for just a few seconds. Which is all it takes for the brain to sense catastrophic fuel crisis and shut down the rest of the body to preserve as much energy for itself as possible. The boxer will reawaken soon enough, since the acute insult to liver is only temporary from a single blow. But he will have lost by knockout.
Without the constant glucagon signal GUARANTEEING adequacy of some combination of glucose and ketones (the latter being the preferred fuel of brain – this can also be simply explained but I will not herein), the brain will die. And so will we thereby.
There is a buffer/reservoir of glycogen stored in liver. Glucagon can release, via glycogenolysis, glucose from this reservoir almost instantly, for delivery via hepatic artery to the body tissues, but most importantly to brain. THAT is what glucagon is necessary for, second to second. It is NOT an exaggeration to state this. There is NO comparable short-term requirement for insulin. Especially not so for normal evolutionary status, which does NOT include insulin-dependent diabetes which can ONLY be ACQUIRED via modern industrial diet. I have a homeobox-mutations induced deficiency, but am NOT even close to being insulin dependent. Otherwise my ancestral line preceding me could not have survived, and I would not be here.
As well, death in the FULLY insulin-dependent diabetic requires at least a day or more. Which is more than a few seconds.
And prior to availability of any form of exogenous insulin, T1Ds survived for years with proper intervention. Not many, but years. Largely as a result of the fact that they still had SOME endogenous insulin left (maybe a few percent of nondiabetic beta-cell function by time of death, still, I might guess). But nevertheless, years. The clinical history prior to porcine insulin is rich with such cases.

P.S. Marie, and back to Unger, he had pretty much fully understood all of what I have written (above) for most of his long life. Others have as well. He had many colleagues. Alan Cherrington is an example of a next generation still active (Vanderbilt Univ), and he (unsurprisingly) worked and published some with Unger later in Unger’s career. And Unger was even an MD! But never practiced as a clinician, I believe. During his residency, sure, by necessity. I think that he went almost immediately into basic research thereafter. He started in NYC (maybe with a very brief period of clinical practice if any – would have to review his bio) and had already begun career as researcher there, before going to UTSW quite early in his career. Within a few years, I believe, of getting his MD.
I have read the research of others, like Unger, very thoroughly. I do my own research and development professionally, and I am not in biology or medicine or pharma. What is lacking is not the basic research, oftentimes, as in this case. What is lacking is the understanding and recognition of its results by most of society. And of course these results are suppressed, quite actively, by powerful institutional interests very often or usually. Because these interests and the biology itself are so often antithetical.
It requires a high degree of skill and effort to fully vet the research literature as I have. Most of it – the VAST majority – is pure junk and advocacy/propaganda. One must know how to vet and understand the experimental methods (if any at all, as there are not in observational studies). There ARE hugely powerful competing interests to legitimate scientific discovery and investigation. Nearly ALL of the money is behind these interests. The true scientific researchers are starved of support (or, one might say “fuel”). It is not a financially rewarding course of career choice. One must be driven by zealous intellectual pursuit, as with Unger and many others. But such people are in the very limited minority in modern societies – believe me.
I have an advanced education, I suppose, having graduated from one of the most famous technological/scientific/engineering colleges in the world. And I have spent my entire life since in technology pursuits professionally. I am still at it. Probably will be until I die. That is my retirement plan. Work until death, that is. At least, as long as I am having a bit of enjoyment and satisfaction from it.
But despite my college education, the vast majority of my knowledge has come since. By constant effort and reading and investigation, still ongoing. This knowledge does not come cheap. It requires a massive personal effort and dedication.
I am merely trying to pass on some benefit in short form in this forum to others, by very occasional contributions. I find most unreceptive. But maybe a small number not completely so, by which I justify any continued participation.
Your suggestions for major revision of my personal life and efforts are not meritorious from my point of view. And I would suggest that you consider your own counsel for yourself first and foremost, with respect to your last few paragraphs especially.