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.