Thread by @ChrisMasterjohn

I’m listening to @PeterAttiaMD’s interview with @drjasonfung and I agree with Fung about 75% so far in his discussion on insulin resistance.

podcasts.apple.com/us/podcast/the…

He correctly lays out the flaws in the idea that cells are in a primarily energy-deprived state in common insulin resistance.

I agree with him common insulin resistance is a condition of energy overload. I argued that here: chrismasterjohnphd.com/blog/2016/08/2…

I disagree that selective hepatic insulin resistance is a house built on no foundation. He incorrectly argues it is based on insulin not getting into the cell, by which I think he means not activating its receptor.

Brown and Goldstein, who won the Nobe Prize in medicine in 1985 for the discovery of the LDL receptor, laid it out here nine years ago: ncbi.nlm.nih.gov/m/pubmed/20133…

Figure 1A shows it as a bifurcation in the resistant FoxO1 (glucose) pathway versus the non-resistant mTORC1 (lipids) pathway.

ncbi.nlm.nih.gov/core/lw/2.0/ht…

The insulin must rise to keep glucose normal as the FoxO1 pathway becomes resistant, and this causes additional lipogenesis in the liver since it stimulates the non-resistant mTORC1 pathway even more.

In the short term, extra insulin keeps glucose normal and elevates lipogenesis. In the long-term insulin cannot keep up and blood glucose rises.

I disagree again when he blames energy overload on too much insulin. Energy overload is shared across all energy sources. A hungry muscle will take in glucose without insulin. A full muscle will not. Energy overload is about ENERGY, not insulin.

At that point I stopped to write this. Back to my workout.

Overall I agree with him in his follow up discussion that the treatment of stuffing insulin into the system is wrong and the correct approach needs to be to eliminate the energy overload by creating an energy deficit.

I disagree with him even more strongly that the “whole body glucose” rather than blood glucose should be the center of the paradigm. The whole body *energy* status should be. This incorporates information from ATP/ADP/AMP, citrate, NADH/NAD+.

These signals are influenced by glucose and insulin but not determined by them. They are more holistically metrics of total energy status.

Also, we know very well that whole body glucose has a firm limit somewhere around 500 grams give or take, whereas we all have kilograms of fat and can gain more fat to an almost unlimited extent. A heavily obese person with insulin resistance is far more overfat than oversugared.

Around 55:30 he says that the liver has too much glucose as a result of too much insulin.

Insulin influences glucose uptake in muscle and fat via GLUT4.

Liver and pancreas are both distinguished by taking up any rise of glucose above basal levels without the help of insulin.

Liver and pancreas both express GLUT2, which is not insulin sensitive and instead mops up any and all extra glucose. They also express hexokinase-4, known as glucokinase which locks glucose into the cell according to the same properties: any and all extra, no insulin needed.

This is in contrast to muscle and fat, which express GLUT4 and hexokinase 2, both of which only take in glucose and lock it in the cell if insulin tells them to (or if energy status within the cell dictates demand).

The liver uniquely expresses glucose 6-phosphatase, which allows it to export glucose.

Anatomy dictates that when you eat glucose, the liver sees it first because it receives it via the portal vein. It takes up anything above basal requirements. However, if its glycogen storage capacity is exceeded it will release that glucose, and lock less of it in.

The excess not cleared by the liver is then taken up by the pancreas without the help of insulin and it then and there finally promotes insulin secretion (apart from a little preparatory insulin that began with taste receptors in your mouth).

That insulin then stimulates the glucose to go into muscle and fat.

It doesn’t make any sense that the liver has too much glucose because of insulin.

The liver taking up glucose is what prevents the pancreas from making insulin in the first place.

And the insulin it does make puts glucose into muscle and fat, not into the liver.

I disagree more strongly when he says rather than considering this insulin resistance we need to consider it hyperinsulinemia, because it is this insulin causing abdominal obesity and other aspects of metabolic syndrome.

First, there are other pathways of insulin signaling that become resistant. For example, glutathione synthesis becomes resistant, and GSH status can be normalized with a hyperinsulinemic clamp. So, for antioxidant defense and glycation defense you need MORE insulin signaling.

And there is a ton of mechanistic evidence that diabetes and it’s complications are partly if not largely driven by glycation, which, again, increases due to insulin resistance and more insulin signaling is protective of it.

Then second there is lots of work on metabolic consequences occurring in obesity after the personal fat threshold is reached. Storing fat in adipose tissue is protective (which insulin does) and exceeding the capacity to do so causes metabolic dysfunction.

Notably, WHY is abdominal obesity a specific problem? It’s the one fat pad that empties free fatty acids directly into the liver instead of the general circulation. The problem is *losing* the capacity to store fat there, not storing fat there.

So seeing insulin as the problem because it promotes fat storage is backwards. Fat storage is protective and exceeding the capacity to store fat causes metabolic dysfunction. Insulin has a positive role here.

I outlined this here, with references: chrismasterjohnphd.com/podcast/2016/1…

At the 1h mark, he points out that ATP inhibits glycolysis, which is how the “overflow paradigm” works.

I 100% agree. High ATP will decrease glucose intake partly through that mechanism.

But why is he so focused on glucose when you can make ATP from fat too?

They then discuss how fasting is the most effective way to lower insulin.

True, but even in Fung’s explanation this should be focused on lowering ATP (and, I would add, other signals of energy status like citrate, ATP/ADP ATP/AMP and NADH/NAD+ ratios).

Fasting does that too.

The iron here is the conclusion is to lower all sources of energy, which is the strongest way to address total energy overload, but his explanation is very glucose-centric, even when his explanation of how glucose causes harm is via ATP.

At 1:12:30 he says that obesity is a mechanism of protection, which aligns with what I said above.

He explains this by saying that not taking in glucose protects cells, which I also agree with.

However these cells also stop holding fat.

And his previous explanation was that ATP shuts down glucose uptake, and ATP can be derived from fat.

And it is fatty acids that aren’t stored in adipose tissue that contribute most to metabolic dysfunction.

I agree the cell is protecting itself but it isn’t all about glucose.

In support of obesity as protection against too much glucose & insulin, he cites the fatty liver & metabolic dysfunction that occurs in lipodystrophies, defects in fat storage.

But these are defects in storing fat. Fat, not glucose, winds up in the liver and causes dysfunction.

I agree with him that peeing out glucose is protective against too much glucose.

However, this is not about total-body glucose but blood glucose. Too much glucose in the blood can kill you just by osmotic effects, apart from stuffing too much into your brain.

The normal way you lower blood glucose is with first liver storage without insulin, then insulin (protective)-dependent storage in first muscle and then when that’s full fat. When fat is full (or storage is defective) you are forced into things like glycosuria.

That’s not a protection against insulin. It’s downstream from insulin not being sufficient and is a protection against extreme hyperglycemia itself.

But what caused it? Not specifically glucose or insulin. Energy overload, including fat.

I don’t know if we would agree on the details, but I agree with Fung that inflammation is “messy” to think about and has to many living parts to act on itself.

On the one hand, inflammatory activity initiated by overstuffed adipose tissue does play a role in metabolic dysfunction. On the other hand, inflammation starting in the gut and finished in adipose tissue is important to restructuring adipose tissue to store more fat.

I covered that here: chrismasterjohnphd.com/podcast/2016/1…

It’s more complicated than inflammation being good or bad.

At 1:37, he says that insulin resistance is caused by too much insulin in the exact same way that antibiotic resistance is caused by too much antibiotics.

Antibiotic resistance is caused by selective pressure causing non-resistant bacteria to die.

Insulin resistance is not caused by selective pressure exerted by insulin to kill all of the non-resistant muscle cells, allowing the resistant muscle cells to take over the population.

They really are not even slightly analogous.

Now, you could say that “too much insulin” downregulates insulin sensitivity, but he already said ATP is a major factor in shutting down response to insulin, and you can make ATP from fat.

And there are other cell signals involved, including energy signals but also including ROS. None of it is specific to glucose or insulin. It’s energy overload and poor support for clean energy burning.

I addressed that here: chrismasterjohnphd.com/blog/2016/08/2…

He goes on to make a very good point, that it is difficult to target nutrient sensors because they are multiple and overlapping.

However, I don’t think he goes far enough in pointing out the full multitude or the degree of overlap.

He says there are three: MTOR responds to protein, insulin to carbs, and AMPK to all energy. He points out each have different time cycles.

However, MTOR does not just respond to protein. It in fact is inhibited by AMPK, so it responds to total energy status.

It responds to a handful of amino acids. For methionine, it specifically responds to SAMe, which is methionine activated by ATP.

SAMe is a fed state signal that is highest when both animal protein intake (providing methionine) and ATP (total energy level) are highest.

Excess SAMe is buffered by glycine, which is most abundant in skin and bones.

So MTOR is responding to total energy status at multiple points (SAMe and AMPK), is responding to protein in general, and is responding to the degree to which muscle protein eggs and dairy (methionine) exceed skin and bones (glycine).

I agree with him that AMPK reflects total energy. I suspect it is disproportionately activated by exercise though because I think AMP levels will be higher during active energy depletion than simple energy deprivation.

I agree that insulin is first and foremost reflecting carbs. However, at the cellular level insulin secretion is initiated by ATP. This only reflects carbs because the pancreas is wired to take in carb as its main energy source.

Insulin secretion is then amplified by multiple signals from anaplerosis (overfilling the TCA cycle, which only protein and carbs can do) cycling of fatty acids (to which anything supplying energy can contribute) so even insulin is reflecting a complex symphony of energy inputs.

But these aren’t the only 3!

Acetyl groups.

During the fed state, citrate rises and this supplies cystosolic acetyl CoA, which becomes the source of nuclear acetyl groups.

Acetylation of the nuclear genome turns off autophagy genes and turns on antioxidant and repair genes.

NADH/NAD+ ratio and ATP/ADP ATP/AMP ratios act directly on enzymes to control their rates of activity. These ratios are high in the fed state and low in the fasting state.

ROS generated in the ETC corresponds largely to energy flux. It can increase from both a supply push (overfed) and demand pull (exercise). For energy uptake, it will be contradicted by low-nrg signals during exercise but will exacerbate high-nrg signals in the overfed state.

Then the rate of respiration itself exerts powerful control over these pathways simply by controlling substrate availability. If you use an ATP molecule, you have a new ADP to phosphorylate. That sets off a domino effect through the whole system.

So you can’t isolate one, two, or three big control points. Rather, you have many nodes of control in a highly webbed network, where the overall force of mutilple signals acting in concert will push the system in one or another direction.

Fung has correctly identified fasting as a prime mover. Exercise is another. Eating is another. You can’t mimic the network effects of the signaling symphony that these states initiate with a small molecule that targets a specific control point even if it’s a key node.

I just finished it, so conclusions:

Overall, what I hear Fung saying is that fasting is a safe and highly practical intervention that can reduce metabolic dysfunction quickly in people who are very ill, and that this is superior to standard treatment.

That makes complete sense to me.

I disagree with the carb and insulin centricity of his explanatory model. In a defense of fasting over carbohydrate restriction, it’s a moot point.

Ultimately what one clinician finds practical versus another probably depends on the patient population, but I comment him for pushing forward with fasting against the backdrop of paranoia or the assumption that because it’s hard patients won’t do it.

Medicine tends to be paranoid about compliance, and that feeds into never having patients do tough things even when the payoff is high. I like that Fung is moving the needle there.

Fung seemed skeptical that fasting is of benefit for healthy people to promote longevity. He said the data’s not there. I agree.

He said that it’s probably not harmful either.

I agree with some limited qualifiers.

Almost no one is going to black out or have seizures. As he acknowledged, healthy lean people might lose muscle mass. I think some people fast too much and wind up in a higher stress, lower recovery state unnecessarily.

My suspicion leans in that direction, that people who are lean and healthy should be wary of fasting too much because they are likely to tend toward too much stress and too little recovery on that end.

Fung was clear that he’s targeting obese sick people with metabolic dysfunction.

I think some lean healthy people use Fung’s work to use fasting themselves but I don’t hear him calling out for healthy lean people to do so.

My quibbles are really with his theoretical model.

Where does that become practical?

In the recognition that insulin, acetylation, and other fed-state signals promote defense against ROS and glycation, and repair of damaged tissues.

By missing that these processes are reciprocally regulated with fasting state autophagy, he places no emphasis on the need to restore a robust fed state.

By not acknowledging these pathways as resistant in the overfed state, the need to return to a healthy fed state gets lost.

Fasting may be an excellent way to quickly and forcefully correct an overfed state, but the healthy fed state has to be honored and given an equal place at the table for people to find the right carbohydrate intake and the right balance of fasting and feeding once they are lean.

This concludes my thoughts.