1. Do I have to "adapt" to ketones in order to use them?
No. Ketones are a quick energy source and are created to primarily replace glucose so people who are the most glucose dependent will be the easiest to get into ketosis. This is why it is not difficult for diabetics to go into ketosis. It is quite easy for them to produce ketones. It is the people who can use free fatty acids directly that tend to have lower ketosis.
2. Is insulin resistance always the cause of too much glucagon expression or can other things be implicated as well?
Glucagon overproduction is the outcome of low or insufficient leptin which is the direct result of abnormal insulin release/expression (hyperinsulinemia/insulin resistance). Leptin helps regulate glucagon. Abnormal insulin release/expression always results in a starvation adaptation which destroys leptin expression in tissues like the liver as well as the brain.
This is why, on this blog, we describe the timeline of obesity/diabetes as blood glucose dysregulation first, insulin degradation second and finally leptin resistance as the end result.
3. Does glucagon only release glycogen from the liver or does it also convert protein into glucose?
Glucagon releases stored glycogen into glucose which is then released into the blood stream. It also breaks down protein into glucose energy. Leptin resistance always ensures that protein is wasted into glucose due to hyperglucagonemia. So basically glucagon is responsible for glycogenolysis and gluconeogenesis.
Now, I often make the statement on this blog that glucagon will "break down everything you eat into glucose" simply because this is the easiest and most simplified way of describing the process above, to someone who has zero understanding of metabolism and how it works. But, we know that there are a lot of pedantic people out there that get caught up in the minutia of semantics, as though I am giving a dissertation at a medical conference, rather than just simplifying metabolic processes for the layman on a blog.
So for the sake of these people's sanity, and prevent any comments "correcting" me, I will be more precise and mention on this post that glucagon itself does not have the ability to directly convert protein into glucose. It simply regulates the breakdown of glycogen and the synthesis of new glucose molecules, in order to maintain blood glucose levels. Protein is not a direct substrate for glucose production. Amino acids can be used as substrates for gluconeogenesis, but this process is indirect and occurs through the action of other enzymes and metabolic pathways, not directly mediated by glucagon.
But at the end of the day, on this blog, the only thing that matters to YOU is that glucagon will break down everything you eat into glucose, due to insulin resistance. Period. The details do not matter. Glucagon does this irrespective of the nuance. This is not a blog for medical students or biochemists. This is a blog for the average obese person, who is struggling with their symptoms, to try and gain some understanding of what's happening to them so they can have a better chance of correcting it. For this reason, it makes zero difference for them to know the exact, complicated pathways of glycogenolysis and gluconeogenesis. All they need to know is that glucagon is the cause and it is regulated through insulin and leptin, both of which are malfunctioning in them. This gives them something they can target to better address their condition. So it doesn't matter how it happens, it just matters that it happens and it's happening to you.
4. I read on a weight loss group that ghrelin is responsible for over eating and so it causes weight gain. Does lowering ghrelin truly cause weight loss and should that be the target to achieve my goals?
Ghrelin is often referred to as the "hunger hormone" but the research on this has not been straightforward. There has been contradictory findings in studies. Studies show that ghrelin is actually low in the obese and in binge eaters compared to healthy individuals. Yet, ghrelin is released by the stomach to stimulate appetite so it would make sense that its reduction would result in lower appetite. How can one hormone do two different things?
This is actually very common in the many systems of the body. Hormones can have the opposite effects depending on their concentrations and cross talk with other chemicals and systems in the body. This is why I am so leery of blaming any one hormone for any one process as the body uses redundancies for many of its functions. Why make multiple hormones to do many things, when the same one can do all these things depending on the information it receives from the individual's overall neuroendocrine state? You can think of hormones as traffic cops. They can either stop, speed up or redirect traffic flow depending on the road/driving conditions.
So the only thing you need to concentrate on is your blood glucose regulation. None of this other flim-flam will help. It might be fascinating. It might be interesting. But it is not useful. The diet industry always has a new culprit for overweight/obesity every single day and this can be seen on tabloid magazines everywhere. At the end of the day, the only true mitigator of overweight/obesity/diabetes is blood glucose regulation. In that context, ghrelin has been shown to stimulate both cortisol and growth hormone, both of which cause hyperglycemia so at least we know that over production of ghrelin will disrupt blood glucose.
Don't target anything except your blood glucose regulation.
5. How is leptin a "slave to insulin"? You have mentioned this many times before but I am curious to know the mechanism behind it.
If insulin is low, leptin will also be low. Usually, when leptin is high, it means insulin is also high or the fat cells are highly insulin sensitive. For the overweight/obese, the former is the case.
This is why sometimes insulin levels do not correlate with the level of obesity. Some obese do not display hyperinsulinemia through serum insulin levels but their insulin expression is always high at the fat cells. Some thin people have hyperinsulinemia but their insulin expression is not very high at the fat cells. This is the case with certain ethnicities who develop diabetes at much lower body fat percentages.
So leptin always tracks closely with insulin and it is affected by insulin release/expression. Normalizing insulin is enough to normalize leptin and weight.
6. Does calorie restriction really cause a longer life span?
Sort of.
When calories and protein are chronically restricted, it down regulates the sympathetic nervous system (SNS). This leads to lower blood pressure, heart rate, glucose release and thyroid hormone conversion. Basically everything slows down. These effects have been shown to increase life span in test animals.
We don't know what the implications of this are for humans. When humans are starved, their health is significantly impaired regardless of any increase in life span. This most likely has to do with our large brains which require a significant amount of nutrients and calories. It is easy to starve a mouse and increase its lifespan, without any health consequences, since mice do not live long anyway. Humans on the other hand have a median life expectancy of about 72 years. That's a lot of time for things to go wrong. Increasing that time through starvation only makes more things go wrong.