Further Notes on Glucagon Dominant Hepatic Metabolism

The idea of the various forms of diabetes and pre-diabetes as a too ready susceptibility to glucagon dominance of hepatic metabolism, as described in the previous post, is not intended to diagnose or treat any disease (which I am not qualified to do, but I could not afford to buy the iamnotadoctor.com web address). It's a heuristic, a rule of thumb which puts what I've been reading into context, and which hopefully encapsulates a useful way of thinking about these diseases.
It produces many other thoughts, questions, and findings that seem consistent with the facts.

Firstly, a question; if the liver is producing higher than normal blood glucose levels, even between meals, why is there any need for glucose in the diet at all?
Secondly, a fact and a question; not all glucose usage depends on insulin. The brain uptake doesn't, and the liver uptake doesn't either, but in the case of the liver important pathways of glucose usage (glycogenisis and lipogenesis) do require insulin. So what happens to glucose taken up by the liver when these pathways are blocked? I am guessing that glycolysis generates excess NADH - the reductive stress that high glucose concentrations generate in cell cultures - which slows down fatty acid oxidation, which requires NAD+. This may be why feeding a little glucose decreased ketonemia even in pre-insulin diabetes. However, then we have to explain Petren's 1924 finding that a high fat, restricted protein diet suppressed ketonaemia. I wish I had a translation of the original paper, which was in German - all I have is this tantalizing hint. Was he talking about the patients in his practice (Karl Petren was a famous diabetes clinician), or some one-off short-term experiment?Edit: Ketogenesis consumes NADH and relieves reductive stress. This is more in line with the Petren finding.

If you had no, or low, insulin production from beta cells, or severe insulin resistance, it seems likely to me that carbohydrate itself would contribute to elevated glucagon. This seems wrong, but in fact a rise in glucagon is the first step in the insulin production cascade. Glucagon stimulates its counter-hormone insulin, which then suppresses glucagon.





 So, imagine what happens in column one without insulin to bring down the glucagon, or if the phase 1 insulin response is delayed (as in pre-diabetes) or if the alpha cells of the pancreas have become insulin resistant. Glucose in this context is contributing to an elevation of glucagon, yet it's not a substrate that glucagon-dominated metabolism can act on. Instead, the rise in glucagon is going to result in even more glucose being produced from hepatic metabolism.

What is the requirement for carbohydrate? I see it as a requirement for those useful and essential nutrients that are highly associated with carbohydrate. Magnesium, ascorbate, folate, potassium (which meat also supplies), carotenoids, fibre, and a different variety of trace elements to supplement those found in meat.
From this perspective it makes sense to include non-starchy vegetables and fruit in the diet if possible. Fruits and sweet root veges, in a low carb diabetic diet, may have advantages over starches (and are certainly not inferior to them, unless sweetness is an appetite trigger). Pre-insulin diets for diabetics were woefully lacking in micronutrients and this may well have produced inferior results to those seen today.
There are other reasons why we see better results today than was generally the case historically. The general diet is higher in carbohydrate and sugar and lower in fat, so there is more room for improvement. Diabetes is usually diagnosed sooner, pre-diabetes is diagnosed more often, there are multiple noninvasive biofeedback devices to check sugar and ketones with, and there is the safety net of insulin. It is hard to avoid the conclusion that insulin, if needed, is the ideal drug treatment for diabetes. Drugs which stimulate beta cell insulin secretion give inferior results and seem liable to exacerbate the loss of beta cell function, especially if they simultaneously upregulate amylin secretion; whereas insulin, like a ketogenic diet, is giving the beta cells a rest.
And what effect does this have? Hat tip to the astute Melchior Meijer for pointing out the relevance of this study on the Hyperlipid blog.

Long-term ketogenic diet causes glucose intolerance and reduced β and α-cell mass but no weight loss in mice.
(Sounds bad! What happened????) Long-term KD resulted in glucose intolerance that was associated with insufficient insulin secretion from β-cells. After 22 wk, insulin-stimulated glucose uptake was reduced. A reduction in β-cell mass was observed in KD-fed mice together with an increased number of smaller islets. Also α-cell mass was markedly decreased, resulting in a lower α- to β-cell ratio.
That sounds like an effect that might rein in glucagon a little, if it translates to humans.

And here we have Calorie's Proper's 2012 take on this; Gluca-Gone Wild!

And Peter D.'s post on insulin that got me started on this road.

Also, a video lecture by Robert Unger - "A New Biology for Diabetes".

And an AHSC2012 presentation by Maelán Fontes about antinutrients which, among other things, dysregulate glucagon.


These antinutrients are opioids, and, curiously, opiates and other psychoactive drugs were once used in attempts to control diabetes.

(excerpt from Fatal Thirst - Diabetes in Britain until Insulin, 2010 by Elizabeth Lane Furdell)