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Tuesday, 6 January 2015

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 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)


Passthecream said...

George, your site is a goldmine of information which I can only slowly digest. Here's a fairly delayed comment about this post!

I found this paper about glucagon and a-cells etc. - I can't imagine that you haven't already seen it - but it summarised things nicely for me and the figures are great:

In view of your more recent post about somatostatin it was interesting to read here that human ( and mice) alpha and beta cells share some subtypes of somatostatin receptors so it affects both ie suppresses glucagon and insulin production. Since the paper you discussed there was about the administration of S'stn to diabetic patients with little B-cell function then perhaps that was what did the trick, ie no B-cells to act on so it only acted to supress glucagon production, qed?

Thanks yet again!

Puddleg said...

Thanks -

I've also found evidence that B-OHB directly downregulates lipolysis in adpipocytes (niacin also lowers FFAs by acting on B-OHB receptor) and spares protein in muscle - an insulin-independent feedback loop - but I suspect one easily over-ridden by hyperglucagonaemia, hyperglycaemia, or both.
When the liver makes ketone bodies these are acetyl-CoA precursors, meaning that they are substitutes for both glucose and fatty acids in other cells. Thus both hepatic TGs and adipocyte FFAs need to be lowered because a substitute energy source replaces some of them.

Hey, there are also gamma cells in the pancreas - does anyone know WTF they do?

Immune cells maybe?

Puddleg said...

No, here we go - its function is basically glucagon-like rather than insulin-somatostatin.

Passthecream said...

One thing to decode from this - why does glucose seem to stimulate initial glucagon? The a-cells in the pancreas are inhibited by glucose so it seems contrary. Is that initial response to glucose in your graph too quick for pancreatic response?

What if the a-cells in the stomach and ileum respond to different signals than the pancreatic ones? That might also explain the protein response. There is that interesting result from bariatric surgery where as soon as portions of the stomach go off-line, the glucagon/insulin system normalises.

If course there might be yet another controlling hormone or signal (or two or three) missing from this simple picture eg insulin supposedly responds to full stomach signals before food moves along --- a nerve mediated response? You woudl expect glucagon to also respond like that.

It's amazing to see just how adaptable animal phsyiology is to different energy supplies. What you mention about B-OHb downregulating lipolysis is very nearly predictable similarly the path from +fat>+somatastatin>-glucagon>-glucose, and many similar scenarios. It's the best hybrid engine ever devised, just don't always be overfilling the fuel tanks or leaving the battery on charge for too long.


Puddleg said...

Yes, I have no idea why the early glucagon response to carbohydrate exists. Except that it is one of the signals that leads to the secretion of insulin.
Perhaps it is released first just to make sure there's no hypoglycaemia caused by the release of insulin; insulin may be released in large amounts before a great deal of the carbohydrate meal is absorbed, so a hit of glucagon precedes it?

Passthecream said...

I'm sure there is something very important to be teased out here but I'm damned if I know what it is: First if you look at Dr Kraft's work you might think you understand everything - it's the insulin stupid! Trying to reconcile that with Unger's ideas about glucagon just gives me a headache. I can see a little glimmer of understanding in that early phase glucagon response and the somatostatin and the leptin etc Meanwhile important medical decisions are being made by the followers of one camp or another.

There was a long and winding glucagon/diabetes post recently on M. Kendrick's blog where a bombastic specialist weighed in with some challengingly different opinions ... he had an axe to grind. He insisted that short time scale oscillations in blood sugar are very significant however many hormone subsytems behave like that and even simple models of insulin behaviour produce eg ultradian variations.

Point 4 in the abstract of this paper is interesting:

"The pulsatile administration of insulin (rather than continuous) results in reduced requirements for insulin."

Cart vs horse or dinosaur vs egg questions are usually what you end up with when you try to break a complex interacting system with multiple feedbacks into disconnected subunits. Complex oscillatory behaviours are what really happens when it's all hooked up; forced oscillations, critical damping, resonances, chaos, fractal patterns ...

Puddleg said...

I don't see a conflict between Kraft and Unger. That glucagon has a dominant role in driving BG and therefore insulin higher doesn't change the problem or the solution, but instead makes the problem much clearer, warns us about what to expect and what to look for. Alpha cell resistance to insulin because of fat put in the alpha cell by hyperinsulinemia and glucotoxicity - that's a neatly ratcheting vicious cycle - it's the dinosaur and the egg alright!

I saw that Aoki paper the other day - George Cahill refered to it here.

Puddleg said...

Sorry your paper wasn't Aoki's

The limited success achieved in controlling diabetes and its complications with conventional insulin therapy suggests the need for reevaluation of the appropriateness of insulin administration protocols. Indeed, conventional subcutaneous insulin administration produces slowly changing blood insulin levels and suboptimal hepatocyte insulinization resulting in impaired hepatic capacity for processing incoming dietary glucose. The novel approach to insulin administration known as chronic intermittent intravenous insulin therapy (CIIIT) delivers insulin in a pulsatile fashion and achieves physiological insulin concentration in the portal vein. Done as a weekly outpatient procedure combined with daily intensive subcutaneous insulin therapy, this procedure has been shown to (1) significantly improve glycemic control while decreasing the incidence of hypoglycemic events, (2) improve hypertension control, (3) slow the progression of overt diabetic nephropathy, and (4) reverse some manifestations of diabetic autonomic neuropathy (e.g., abnormal circadian blood pressure pattern, severe postural hypotension, and hypoglycemia unawareness).

Passthecream said...

Thanks for the references George. I have some other links to modelling of insulin oscillation somewhere & will dig them out. This paper is old but they managed to model short and longer term pulses adequately just using insulin and glucose, portal vs peripheral:

I don't have the depth of understanding of cellular metabolism that you do. For me, the headache comes from trying to understand the dynamics of how these things interact; treating the different types of cells and their environments as black boxes, if you were to add in glucagon dynamics to that simple model you could get some very complex responses with modest parameter shifts - think of trying to reverse a car and trailer with very loose steering and bald tyres down a narrow driveway.


Passthecream said...

- and from what I can gather and simplifying it, insulin is widely anabolic in nature whereas glucagon is catabolic but not as widely. Which makes it much more interesting.


Puddleg said...

I think of glucagon in T2D as a small gear wheel turning the larger insulin wheel, which also provides varying amounts of resistance. A brake on the insulin wheel will slow the glucagon one (actually, low carb or fasting makes the glucagon action more appropriate to that state than it was to a carb overfeeding state - it's a relative slowing until the alpha cell glucotoxicity/lipotoxicity pathology resolves). But in T1D the insulin wheel breaks and the glucagon gear is freewheeling. Then you really need a specific brake for the glucagon wheel, but it's still best to have a diet for which the high glucagon rate is closer to appropriate.

Passthecream said...

It's the steam-punk model of diabetes! I like it and will probably have to build one.

Your gearwheel is a type of integrator; Babbage used them in his calculating engines. You might need a limited slip differential in there and a few levers & rack-and-pinion couplings with backlash and frontlash.


Passthecream said...

Here is a heavy duty Phd paper on the modelling of insulin and glucose dynamics from about 2004.


Puddleg said...

New thought on why there is a glucagon response to carbohydrate meals

- the increase in glucagon stimulates hepatic glycogenolysis
- glycogenolysis is a glycolytic reaction that supplies ATP to the glycogen-storing cell
(lactate is produced, then recycled to glucose by a subsequent hepatic cell; think of it as an assembly line spread out along the hepatic microcirculation)
- this primes the parenchymal cell with energy to store incoming glucose as glycogen quickly.
- meanwhile the post-prandial glucose can be used to fuel digestion and absorption.

But in diabetes, there is too much glycogenolysis and not enough glycogenesis. Hence elevated PPPG. Corrected by low carb.