Submitted by derpderp3200 t3_zreetb in askscience
I'm newly diagnosed with fairly advanced prediabetes, and I've been reading some papers on its reversal, but one thing I'm struggling to find is- how and why do diet and exercise improve insulin sensitivity mechanistically?
Does the amount/strength of muscles also come into play, or is it mainly about their glucose turnover and participation or lack thereof in glucose utilization?
What about hepatic and brain insulin resistance?
Where does glucotoxicity come into all this? Does avoiding glucose spikes alone help alleviate insulin resistance, or do you need utilization specifically?
What happens to pancreatic beta cells when you change your lifestyle and/or take diabetes medication that limits glucose spikes?
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If you want to gain muscle you need to work your existing muscles to exhaustion/failure. This will stimulate repair and growth of new muscle cells. To facilitate this work you need to ensure you are getting protein as this is the main ingredient muscle cells. Cinnamon is not needed.
Blood sugar management while exercising is rarely a concern unless you have underlying blood sugar management issues or you are training for endurance.
If you are working out to lose weight high blood sugar is counter productive as your body will preferentially use glucose in your blood stream before it starts to use glycogen or stored fats for fuel. If you are working out to gain muscle, you are trying to exhaust the muscle, adding fuel doesn’t help you achieve that goal. The building of muscle takes place during the rest period, so it is at that point you might want to eat.
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If it's the repair/failure, then would muscle hypertrophy occur after intentional cellular stress like for example happens with fat when subjected to prolonged suction requiring angiogenesis?
Is protein necessary for exercise's benefits in improving glycemic control as well?
No, in order to gain muscle, engage in muscle-strengthing activities (i.e. resistance training) and consume adequate protein. Unless you have type I diabetes, you're not going to need to worry about your blood sugar during exercise.
I wanted to know about blood sugar effect on muscle growth directly, not fitness tips. Blood sugar is indirectly essential thing for working out
You asked about spiking blood sugar while training. A normal person with normal activity level can build muscle on a zero carb diet. Muscle protein synthesis drives muscle growth. Glycogen from carbs only serve as an energy source.
Yes, so it's indirectly linked since you need energy and fuel to have succesfull and beneficial workouts.
Fats, protein, and carbohydrates are all energy. There's no link requiring dietary carbohydrates to be THE energy source for a successful workout or building muscle. In the absence of dietary carbs your body will synthesize glucose as needed and convert fat to ketones. There are essential amino acids and essential fatty acids. There are no essential carbohydrates.
If you're the average person doing reps in a gym you'll build about the same amount of muscle regardless of carb intake assuming total calories, protein, and training routine are equal. There are freely available studies on this if you want greater detail.
We're talking of the same thing from such different point of views it feels like we're debating here. You speak of human digestion from factual medical standpoint and I speak of optimazing energy levels for working out.
It's true that fats and protein are sources of energy, but the process of protein and fats breaking down is so long you can't get this fast and easy energy needed for heavy lifting with them. Also sufficient amount of calories, healthy diet nutrient-wise and not feel like throwing up from practical point of view without carbs is pretty hard. I'm also considering what type of diet is easy to follow here because bulking and lifting requires so so much calories
I'm talking about requirements for the average person building muscle. It sounds like you're talking about workout intensity for a specific goal or sport. High intensity sports and higher rep weight lifting favor the fast glycolytic energy system. Low rep powerlifting and strength training favor the ATP-PC energy system, and endurance sports favor the oxidative system.
If you're playing a high intensity team sport or lifting in the higher rep ranges then supplying carbs for the glycolytic system is good for overall performance.
Yes, I was talking of more extreme cases, which I should've said from the get go.
Its not really. I fast for 20 hours a day and still work out for a couple hours.
For losing weight, sure makes sense, I have no idea. For seriously bulking up and getting stronger you have to time your meals and keep blood sugar up during workouts so you can lift more weights and feel energetic.
No, you don't, for the same reason that you don't need to be continuously refuelling your car during a mere 10 mile drive. Your body's fuel tank (glycogen) has more than enough storage to provide all the glucose needed to get through a workout.
Well yes of course, if you weigh 65kg and follow some main-gain program. It's possible to workout that way, but you will look like 90% of people who work out; normal. I'm talking of maximizing efficiency and strength here.
No. No one following any kind of strength training program needs to consume carbs mid-workout, unless they have type I diabetes (and therefore have no glucagon response and so their liver doesn't pump out glucose like it would in anyone else).
If you want to maximize efficiency and strength, spend your gym time lifting, rather than wasting time gulping down pure honey. (Not to mention that if you carry the belief that you need carbohydrates mid-workout, it's going to adversely affect your performance on workout where you forget to bring them, since you've created a psychological dependency on them that will give you a nocebo effect any time you don't have them. Whereas anyone else would be fine without them.)
Who or what are you arguing against? I never said any of that and you are just raging at nothing
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Muscle cells can take up glucose from the bloodstream through their own transporters without the need for insulin.
When you’re regularly active, your muscles pull the glucose out of the blood, effectively regulating your blood glucose without insulin needing to be involved. This allows all the cells in the body to readjust the number of insulin-receptors/glucose transporters needed, thereby making you more sensitive to insulin over time, and the pancreas won’t have to release as much insulin for any given amount of glucose in the blood.
Is this what "peripheral insulin sensitivity"(term I've come across in literature) refers to? How does it differ from pancreatic insulin sensitivity?
Do I understand you correctly that in this sense, above-basal levels of insulin are the body's second line mechanism against supraphysiological elevations of glucose?
I wonder if this is why Pioglitazone acts as an insulin sensitizer, being an agonist of PPAR-gamma, one of the receptors involved in mediating the benefits of physical activity.
There's a chance you're conflating two different concepts. Peripheral insulin insensitivity is often a function of peripheral insulin receptor expression and/or cytosolic signal impedance. Exercise may improve this in a couple ways, including the "insulin like effect" of contracting skeletal muscle as mentioned above: https://www.ncbi.nlm.nih.gov/books/NBK537322/ to be clear though, this mechanism is not sufficient to completely replace pancreatic secretion, otherwise exercising type 1 diabetics wouldn't need to take insulin.
Pancreatic signaling for the release of insulin, the ability to release insulin via beta cells, and the production of viable insulin would be separate mechanisms with their own pathologies.
What is "cytosolic signal impedance"? This is the first time I have come across this term.
Oh, I understand, so the impairments in beta cell function are a secondary, later, consequence of insulin insensitivity, which typically is at first driven by... what exactly?
Aside from uptake by muscle, what else plays a role here?
Two things need to happen for insulin receptors (or really any receptors) to work. 1) The receptors need to be expressed. This is the actual production (transcription/translation)of the protein. There are a lot of steps between transcription and getting the insulin receptors to the cell membrane. Any of them could be disrupted and then there's always post translational modifications such as glycosylation that can muck things up. 2) Binding of the insulin receptor has result in an intracellular signal cascade, leading to glucose receptors being transported to the cell membrane. I think what is meant by cytosolic signal impedence is that something gets interrupted between insulin receptor binding to glucose receptor translocation. Or even cell signaling to initiate insulin receptor expression.
It's hard to accurately describe the process of insulin resistance as being linear or having a single inciting event. It's more of a breakdown of the entire, circular(ish) system. But I suppose I think of insulin resistance "starting" in the cells that have the most insulin receptors like fat cells.
Glucose receptors, or transporters?
How does cytosolic signal impedance develop, here?
What is "cytosolic signal impedance"? This is the first time I have come across this term.
The cellular mechanism of action of insulin can generally be grouped under a "second messenger system". This means that the signal its self (initiated by the insulin molecule) does not actually enter into the cell, but is transduced from the outside to a signal cascade on the inside (cytosolic side).
As such, a receptor system will have an extracellular component, a transmembrane component, and a cytosolic component. Cytosolic impedance (of the insulin signal) can occur as a function of the expression of a particular factor (protein) which interferes with the signal transduction on the cytosolic side of the receptor.
If you want to read the nitty gritty, here is a decent reference:
https://www.ncbi.nlm.nih.gov/books/NBK378978/
Oh, I understand, so the impairments in beta cell function are a secondary, later, consequence of insulin insensitivity, which typically is at first driven by... what exactly?
Beta cells are thought to be impaired by an autoimmune (or autoimmune like) attack on beta cells, though I think this is still up for debate. If they get taken out, you do not secret insulin, this is often a characteristic of a type 1 diabetic (vs. a type 2 in which you tend to see a decrease in the sensitivity down stream, in some cases as described above.)
Taking a step back, your body makes insulin to signal to cells to take in glucose from the blood. The cells will move a glucose transporter to their membrane allowing glucose to move into the cells from the blood. This is a great way to deliver energy to them and it is part of regulating blood glucose levels. From an evolutionary standpoint higher blood glucose is better than lower, if your sugar goes too low you cant outrun that lion chasing you and in extreme cases your heart can even stop. Meanwhile high blood sugar wont kill you (at least not for many years), even really high blood sugar wont instantly kill you (though it is very dangerous), so its better to go up than down. From this perspective insulin resistance makes some sense.
It has been theorized that insulin resistance historically was protective against low blood sugar during periods of fasting (between hunting meals/gathering food), the last thing you’d want is to eat a few berries after fasting for a few days and drop dead from low blood sugar as all your tissues try to take in more sugar than is available. However today that is not the problem and the insulin resistance we see now is beyond what is “normal”.
As insulin resistance develops your pancreas responds by producing more insulin, the result of this compensation is normal blood sugar. But as insulin resistance gets worse the additional insulin is no longer enough and so blood sugar rises. Foods that would not cause spikes in blood glucose for healthy people now cause spikes. And it doesn’t take much sugar, there are only a few grams of sugar circulating in your blood, going up by even 1 gram is very significant as its a tightly regulated system and over time it will lead to vascular problems which lead to other problems increasing the risk of mortality.
Diet and exercise (or lack of it) are the cause of many of these problems in the first place but they can reverse them too. Eating less simple carbs and more fiber (among other changes) exposes the body to less sugar spread out over more time which allows for the now impaired glucose delivery system to keep blood glucose levels normal.
Exercise increases the energy demand of muscles. When before they were told to take in sugar by another part of the body by insulin, now they do it themselves including through different mechanisms which improve their overall ability to take in sugar and lower blood sugar (even when not exercising). Aerobic exercise like running/walking will increase the amount of mitochondria in muscle cells which means they can use more energy (among other metabolic changes) allowing them to take in more sugar. Strength training exercises make muscle cells bigger, improve their ability to burn glucose anaerobically and increase their total energy needs (even at rest). More lean mass/muscle burns more calories and acts like a glucose sink.
In short you lower the amount of glucose your body has to deal with at any given time and you increase your body’s ability to move it out of the blood with diet and exercise. Not to mention there are health benefits to diet and exercise beyond type II diabetes management, pick a disease and odds are diet and exercise lower the risk of developing it and dying from it.
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Hi,
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Jason Fung has a lot of videos on this topic https://www.youtube.com/watch?v=r0d5lJzMXnM is one.
BAsically your cells are already full of enough sugar and so they start ignoring insulin signals . If you exercise you use up this store and they become more willing to accept sugar so they become more sensitive to insulin.
Diet has a similar effect if you use foods that do not convert to sugar or do so slowly ( LowCarb/Keto) since sugar availability becomes less , and cells start to tend to use up their stores they begin to become more sensitive to insulin to get more sugar.
Intermittent fasting, is an attempt to force the body to use up its stores and cause the same sort of reactions.
HHope this helps.
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I’m a nurse. This is an easy explanation I give to my patients.
Insulin lowers blood sugar. Carbs like sugars (bad carbs) increase blood sugar quickly, then fall quickly. Makes you want to eat more. Carbs like starches (good carbs) increase blood sugar, but keep at a steady range. Keeps you from eating more.
Once you abuse sugars/carbs too much over time, insulin stops being able to work. So then your blood sugars go back up, causing Diabetes type 2.
In type 2 diabetes, your liver is producing an overload of sugar and your pancreas insulin cannot lower it anymore since it’s been abused so much.
Type 1 occurs when you are young and your pancreas stops producing insulin.
This is why diet and exercise are super important to stop Diabetes type 2. So that your body can resist the sugar/carbs. Smoking can cause damage to the walls of arteries and veins. This puts you at risk for a whole slue of Heart and Blood pressure issues. The high blood sugar also does damage to these, including you nerves. This can make you permanently lose feeling in feet and legs. Can also cause permanent nerve pain. This leads to diabetic wounds that heal very, very slowly.
Basically, having diabetes sucks.
Hi, thanks for your answer, but I've already done some reading of related literature, and was looking for a more technical explanation of what happens on a cellular level. Pathways, etc.
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There is no consensus on insulin resistance, but this is what I think is going on...
The best measurement for insulin resistance is known as a "hyperinsulinemic euglycemic clamp". It's a fairly invasive procedure and is therefore only used sometimes in research settings.
Therefore much of the research uses measures that correlate well with the euglycemic clamp technique. A commonly-used one is known as HOMA-IR, and it is calculated using fasting insulin and fasting glucose. Because of the way the formula works, it is more of a measurement of insulin, and therefore high values are an indication of hyperinsulinemia, or constant elevated insulin.
This makes it a far better measure of metabolic health than HbA1c, which is what is commonly used to diagnose prediabetes and type II diabetes, but it's not often used.
The hyperinsulinemia is responsible for a lot of issues that come from prediabetes or type II - it makes is harder to metabolize fat and that leads to elevated weight gain and high triglycerides.
As for what causes the hyperinsulinemia, that's where there's a lack of consensus.
My opinion is that excess fructose leads to fat accumulation in the liver, which leads to NAFLD, which leads to the liver making too much glucose (disregulated gluconeogenesis), and that is what leads to the hyperinsulinemia - the constant supply of glucose means insulin levels cannot go back to normal.
To fix insulin resistance, you need to get rid of the hyperinsulinemia. From a mechanistic standpoint, that would mean somehow dealing with the disregulated gluconeogenesis. You could either fix the fat accumulation in the liver - somehow - or you could make the glucose wanted rather than unwanted.
In other words, you need to be in ketosis - a state where gluconeogenesis is normal. Which means either a very-low-carb diet, a very-low-calorie diet, or a fasting diet.
If you look at the clinical evidence for treating type II diabetes, the only real effective treatments are gastric bypass (forced low calorie diet), low-calorie diets (<800 cal/day), or keto diets. There is also some evidence for fasting, though that is less studied.
The other common diets significantly underperform these options.
I've only had it checked twice, but curiously enough I don't have hyperinsulinemia, but still have elevated fasting glucose and huge spikes after food(on OGTT had a drop below fasting values instead). I'm also on the verge of being underweight, what I struggle with is persistent lack of appetite rather than weight gain.
I'm also a young person with "treated" sleep apnea. Quotes because my impression is CPAP et al largely just convert apneas into subtler microarousals that have milder physiological consequences but comparable effects on sleep quality.
About T2DM, my impression from reading literature has been that while full blown diabetes are fairly similar to each other, earlier dysglycemia has a number of phenotypes that only start to converge after beta cells begin failing.
What do you get from HOMA-IR?
Note that OGTT is *not* a measure of insulin resistance, it's a measure of carbohydrate tolerance, and there are a number of things that affect carbohydrate intolerance.
If you are carb intolerant, eating a lot of carbs is not a great idea in my opinion. What does your diet look like?
WRT sleep apnea, it is associated with insulin resistance but there's not agreement on which way the association goes.
Oh, sorry. I'm trying to build a working model of this whole thing, but have been struggling with substantial brain fog that in retrospect has roughly correlated with my fasting insulin and postprandial fatigue getting worse over the past few years...
Early in the year had a HOMA-IR(glucose, insulin) of 0.51(94mg/dl, 2.2 uIU/ml), more recently 1.2(105mg/dl, 4.6uIU/ml). OGTT at both timepoints showed a glucose drop below fasting, with reasonable insulin numbers, which I suspect is rapid gastric emptying that sometimes occurs in prediabetes/T2DM, and is often associated with largely the same set of postprandial fatigue/brainfog symptoms I get(going by Sigstad’s score criteria). Glucose peak likely occurred before 1h mark. On a glucose meter, my fasting glucose is consistently ~105, which very easily jumps to 150-170 even with a single sandwich or some lowish-glycemic-index buckwheat, and to 180-220 with what I'd consider "a normal meal".
I thought that impaired glucose tolerance was a consequence of impaired first-phase insulin secretion, which in turn strongly correlates with fasting insulin levels, which I thought was a function of insulin resistance... I don't know, I just hope so badly that treating this stuff will fix the brain fog that's been getting worse and worse for years now :(
About apnea, it's likely apnea->dysglycemia- glucose metabolism follows a diurnal cycle susceptible to disruption even by sleep restriction, and sleep disordered breathing as a spectrum causes abnormal autonomic tone, while much less of a case can be made for dysglycemia->apnea. Maybe damage to upper airway dilator muscle innervation, airway edema, or tongue base fat deposition... though most likely each of these would require anatomically compromised airway just like most cases do.
Interesting.
Your HOMA-IR would suggest that you are mildly insulin resistant, though opinions differ on what a good threshold is.
I believe the symptoms you are getting and the low blood glucose is a sign of reactive hypoglycemia. I don't have enough knowledge about dumping syndrome to have any opinion on it.
I can tell you that I had pretty significant reactive (or postprandial) hypoglycemia - I'd get back from lunch and 90 minute later I'd really want to go to sleep.
For me, the fix was to switch from the sandwiches and burritos I was eating to something that was much, much lower in refined carbs - salads and burrito bowls without the carbs. I ended up full keto and these days I'm what I would call "keto adjacent".
Given that you are having issues with carbohydrate intake, going low-carb for a while would be an interesting experiment.
I never really had hypoglycemia after an actual meal(I know you can get the adrenergic subset of hypoglycemia symptoms without objective hypoglycemia, but it doesn't seem to fit the bill), and my fatigue seems independent of glucose levels- sometimes it hits while they're still high, sometimes after they go back down, sometimes minimal symptoms start before it reaches the peak. I get hours of horrid brain fog, restlessness, anxiety, overwhelming desire to lie down, spend 45-90min in a food coma, and be groggy for several hours afterwards. It gets lighter in the evening, and it's bad enough that I'm afraid of eating during the day. But I'll have to force myself since science suggests that skipping breakfast and one meal a day worsen glucose tolerance, which tracks with my symptoms getting worse after I switched to this.
I'm trying to limit my carb intake, but it's very difficult. For one I'm vegetarian, for two, between ADHD, Sleep Disordered Breathing, and the part of fatigue I now presume to by dysglycemia related, I'm an extremely low functioning person and taking care of myself stretches my capacity very thin.
A lot of the time it's a choice between having some bread and going hungry, and I've been going hungry for a longer time now, which is also bad for my energy levels.
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JCS3 t1_j13pq31 wrote
If a muscle cell is not doing any work and is already full of glucose/glycogen it begins to down regulate the number of insulin receptors on its surface. Exercise causes muscle cells to use their glucose, creating a need for more glucose to find its way into those cells.
If your blood sugar is regularly high, all of your non-lipid cells begin to down regulate their insulin receptors, as again they don’t need the energy and apparently sugars are abundant. Lipid cells take excess glucose and convert it to fat to be released when glucose levels are low. By eating well, your blood sugar levels drop, and non-lipid cells start to up-regulate insulin receptors to ensure they have the energy they need to function.