Almost all glucagon generated by endocrine pancreas (aka “islets”) is consumed by liver. And the only non-hepatic tissue which expresses glucagon to any significantly detectable extent is brain. Which is a rather “dark” (unmeasurable) region, but it is thought the brain may be the only other tissue that is much signaled by glucagon itself, in addition to liver.
For all tissues, including brain, peripheral to the portal axis (liver and islets and small intestine), the substitute for glucagon signaling is blood ketones (BHB, or beta-hydroxybutyrate). It is just astounding how few seem to have figured this out. Most of the tissues/organs/cells in body detect the fasting state in man via ketones, and only via ketones. The liver CONTROLS the fed-fasted state (on a continuum), and BK/BHB signals state of liver to other tissues. The BK signal is possibly the most vital signal for sustaining life in the entire body, and it is powerful.
There exists a negative feedback of BK acting upon beta cells to reduce islets-insulin secretion. This keeps ketone generation of liver, in response to portal glucagon, stable. Because islet insulin acts upon alpha cells to REDUCE glucagon secretion, and VERY powerfully. Once virtually all islets insulin production is lost this negative feedback is also eliminated. Thus, instability. This IS the medical/clinical state known as “insulin dependence”.
This has been known for a long time. By the islets/liver basic researchers. Like Unger.
It does not take much beta-cell function to maintain stabililty via adequate negative feedback. Maybe as little as 5% is still adequate, some estimates indicate. But 0% is too little. Hence, insulin dependence. A good thing to avoid I myself think.
For T2Ds, do NOT take sulfonylureas. These kill off the remaining beta cells rather quickly – usually within no more than 5 years at the dosage/titration for T2DM. After this, one becomes insulin dependent.
I have written elsewhere on the forum about the opportunity to avoid insulin dependence for T1DM, but it must be caught early enough (and first appearance of polydipsia and/or polyuria is quite adequately early enough, and before this (via HbA1c) is even better) and exactly the right intervention(s) for remainder of life must be applied.
If one is content to advance to insulin dependence then all of my advice does not apply. It is a manageable condition, nowadays, more than ever. With the advent of CGMs and insulin pumps especially, although the use of these requires expertise and is not foolproof.
I myself would not choose this path, were I either T2 or T1. But I am not. However, the standard clinical treatment, completely and overridingly and universally applied for diagnosed monogenic HNF-type diabetics like myself, IS sulfonylurea at 20% of the dose used/required for T2Ds. This can, and often does, bring the HNF diabetic to the state of insulin dependence within lifespan. I manage my own condition, and diagnosed my own condition with a glucose meter, watching BG response to meals. I use strictly insulin therapy, which does not destroy beta cells. Were I a T2D diagnosed clinically after loss of 80% of nondiabetic beta-cell function, I would most certainly do the same, and apply the same evolutionary diet as I do for myself as HNF type.
Susceptibility to ketoacidosis, and hence deaths within a few days without exogenous insulin, is like the prandial response to a meal of an insulin-deficient diabetic. There is inadequate negative feedback, or adequate positive feedback for instability. However, this will only last for as long as nutrients from the meal are being absorbed through gut and flowing in portal vein for a non-insulin-dependent diabetic. After this, in the interprandial (between meals/absorption) state, stability of BG is restored UNLESS the diabetic is fully insulin dependent.
Whereas without exogenous insulin, regardless of meals (which will make things worse admittedly, and cause death more rapidly), there is instability leading to DKA. No meals required, just lack of exogenous insulin supply. Then death due to both dehydration (which WILL tend to be largely owing to meals) and excessive ketones and pH of blood. The excessive pH alone is adequate to cause death, I believe. But survival by fasting in ketoacidosis would probably be extended quite a bit. Back before availability of porcine-source insulin for subcutaneous injection T1Ds would attempt to eat as low-carb as possible and as little as possible. Most would have also had some endogenous insulin production remaining as well – otherwise they would have been dead already. But they typically could survive for several years before death.
Onset of “overt” T1DM, after which the usual course of progression brings beta-cell function from 20% down to 0% over the course of many years (a few, at least – rarely if ever less than a year), is a much more acute event than for T2DM. There is more time for intervention – much more typically – with T2DM than with T1DM to avoid insulin dependence. But the same overstress of beta cells that brought beta-cell function from 100% to 20% will continue unless some intervention is applied. The correct/optimal intervention is exactly the same as for T1DM – insulin therapy and evolutionary (animal-sourced only) diet. There is just a bit more time usually. Sulfonylureas will further increase rate of apoptosis of beta cells a lot, and so everything is speeded up to almost the rate of progression of a typical case of T1DM.
That’s the biology. Very robustly established, for five decades mostly. But ignored, in general. Hope that makes sense.
I think that T2Ds have an easier path to take advantage than do T1Ds, in avoiding full insulin depedence. But the medical community (including medical insurance) will NOT assist with this, with precious few exceptions. So one is on one’s own.
