I’ve talked about insulin resistance many instances beforehand (and in The Diabetes Code) and the way a basic mis-understanding of it utilizing the ‘lock and key’ paradigm has set the stage for our present failure to deal with sort 2 diabetes. Moderately than insulin resistance being a paradigm of ‘inner hunger’, it ought to actually be thought of a paradigm of overflow.
You probably have an extra of intra-cellular glucose, the liver will attempt to decompress itself by turning it into fats. It exports this fats as VLDL resulting in excessive triglycerides, low HDL and this fats will deposit in different visceral organs resulting in fatty liver, fatty pancreas, and belly weight problems. What’s the biochemical mechanism behind this? How does an overloaded cell block glucose entry into the cell? For this we have to talk about the citric acid cycle. (Warning: This dialogue assumes some fundamental data of biochemistry)
Once we eat, we devour a mix of three macronutrients – carbohydrates, proteins and fat. It doesn’t matter what macronutrients go in, we wish the identical output – mobile vitality within the type of ATP. Proteins, damaged down into their part amino acids, should not purely used for vitality, and are used as constructing blocks for brand spanking new proteins. There are some important fatty acids, too, however for essentially the most half, dietary fats and carbohydrates are primarily helpful as sources of vitality. So we have now three inputs (carbs, amino acids, and fat) and 1 output – mobile ATP. How does our physique metabolize meals into ATP? That’s the job of the citric acid cycle (additionally known as the tricarboxylic acid or TCA Cycle).
The TCA cycle, which takes place contained in the organelle referred to as the mitochondrion is pictured on the proper. Glucose is first became pyruvate via the method of glycolysis (actually – the breaking down of glucose). Below anaerobic situations, this can be utilized as a supply of vitality, with the tip end result being the manufacturing of lactic acid. However beneath regular cardio situations, it undergoes additional pyruvate oxidation into Acetyl CoA. This could then bear the TCA Cycle which generates the NADH and FADH2 crucial for the cell to bear oxidative phosphorylation.
Every cycle of the TCA cycle regenerates the unique substrate oxaloacetate in order that it might proceed working. Every Acetyl CoA supplies 2 carbons, which get changed into carbon dioxide, however within the course of generate three NADH and 1 FADH2, together with an ATP or GTP. So there’s not a complete lot of ATP generated with the TCA cycle instantly. However not directly, you’ll be able to proceed onto oxidative phosphorylation to generate 36 ATP per glucose, which requires the NADH and FADH2 for the electron transport chain.
Apart from glucose, there are different locations that amino acids and fatty acids might enter this cycle to in the end produce ATP. That is how all meals might in the end be changed into mobile ATP. Amino acids are typically not used for vitality, but when in extra, they’ll have their amino teams eliminated, making ammonia (NH3) as a waste product, which is then changed into NH4+ and excreted within the urine. Totally different amino acids enter at completely different factors within the cycle. For instance, glutamate enters the cycle as alpha ketoglutarate.
Fats (triglycerides) are damaged into glycerol and their fatty acid chains. Glycerol enters just like glucose. Fatty acids are damaged down by beta oxidation and mix with CoA to type acetyl CoA, permitting it to enter the TCA cycle easily.
However what occurs within the case that there’s an excessive amount of ATP? Take into account a similar scenario. Suppose that you simply usually purchase gasoline to energy your automotive. You drive to and from work on a regular basis and also you want about 50 liters or about 13 gallons every week. Abruptly, as a substitute of shopping for 50 L, you get 200 L per week. At first, you retailer a few of the extra in your gasoline tank. When that will get full, you purchase some jerry cans to retailer the additional. After that, it will get harmful. All that extra gasoline is now sloshing round and fairly quickly it’s going to blow up like in a Tom Cruise Hollywood motion film.
Contained in the cell, there may be solely a lot ATP that it will probably maintain. As soon as these shops are full, it can not maintain any extra. The logical motion is to cease placing extra gasoline within the tank. For the cell, which means it should cease the influx of vitamins into the cell.
The cell does this via a damaging suggestions loop. When there may be an excessive amount of ATP, the ATP itself, in addition to a few of the intermediates acts upon the complete course of to gradual it down. In your gasoline tank, when you’re pumping gasoline, when it will get full, the pump will robotically cease so that you simply don’t spill gasoline in all places. The cell does the identical factor.
When the cell notices an extra of ATP, it then places the brakes on the entire system. ATP will instantly inhibit glycolysis, pyruvate oxidation and the citric acid cycle in a determined effort to decelerate mobile manufacturing of ATP to keep away from the ‘automotive exploding’ situation.
Particularly, ATP and citrate (bear in mind this is among the key molecules produced by the citric acid cycle) will inhibit the enzyme phosphofructokinase (PFK), which blocks the conversion of glucose to pyruvate, step one within the chain. ATP additionally acts blocks the motion of pyruvate dehydrogenase (PDH) to dam the conversion of pyruvate to Acetyl CoA, the second step within the chain. ATP then acts at a number of websites inside the TCA cycle to cease its personal manufacturing.
This can be a fantastically elegant system that ensures that ATP is produced when wanted, however by no means to extra. When this course of grinds to a halt, glucose being on the very high of the chain, backs up. This slows down manufacturing of ATP and restores the system to regular. However what if we maintain feeding glucose into the system?
As glucose will increase inside the cells, there may be much less and fewer of a focus gradient for glucose to stream from exterior to contained in the cell. Keep in mind that insulin opens a gate for glucose to enter. Usually, the glucose focus exterior the cell is increased than that contained in the cell, and subsequently will stream inside following its focus gradient. If this gradient is minimized or eradicated, insulin has a more durable and more durable time pushing glucose contained in the cell, and therefore you see the glucose ranges within the blood exterior rise, resulting in the time period ‘insulin resistance’. However this isn’t a lock a key drawback. It’s an overflow scenario. The underlying drawback of ‘insulin resistance’ as generally used comes down to 2 easy issues – an excessive amount of glucose, which ends up in an excessive amount of insulin.
The answer, subsequently, is relatively easy and solely consists of two issues.
- Don’t put extra glucose into your physique
- Burn off the glucose
You’ll additionally word that ‘insulin resistance’ whereas carbohydrate dominated, may also be activated via, for instance, an excessive amount of fats (triglycerides). Any macronutrient might produce ATP, which is able to overload the system and trigger glucose to again up. Proteins and fat, nonetheless, are harder to overeat, as a result of they naturally activate satiety hormones that forestall this precise scenario. The logical answer? Fasting. Growth.