The Ultimate Guide to Restoring Glucose Metabolism

What if I told you a low carb diet is only a patch, not a cure.

Most people with insulin resistance, elevated cholesterol, triglycerides and other metabolic disorders have issues with glucose metabolism. They can’t metabolize glucose properly and then they think glucose is to blame. It’s even gotten to the point where people think glucose is toxic and it might even be harmful to eat more than 50g of carbs daily. Not even to mentioned fructose.

But it’s not glucose that’s the issue, it’s the body that’s struggling to metabolize it correctly.

Let’s start from the top. Carbs go into the mouth, are digested in the stomach and then absorbed in the small intestine. The remaining residue is excreted through pooping.

Absorption to storage of carbs

Dietary glucose goes into the general circulation after absorption first where it is stored in muscles as glycogen and oxidized to ATP and CO2. The remaining glucose, that’s not taken up by the muscles, goes to the liver to be stored as glycogen there. If liver glycogen is also full, then glucose oxidation is rapidly enhanced to burn off the remaining glucose. Only a very small amount, around 1-5% of ingested glucose, when eaten in large amounts (500g< daily), is converted to fat and stored in fat tissue. If you have not read my article on lipogenesis (the creation of fat from carbs), then I highly recommend you do so…after finishing this article first ofc.

Dietary fructose is partially converted to glucose in the intestine before absorption, and the remaining fructose goes directly to the liver for glycogen synthesis after absorption. This makes it a great tool for replenishing liver glycogen, more so than glucose. Fructose is also absorbed much slower than glucose and this also helps to prevent blood sugar dysregulation. If you haven’t read my articles on sugar and fructose, then be sure to check them out as well if you’d like to learn the truth/science about it.

Glucose enters a cell via the GLUT1 and GLUT4 transporters. GLUT4 is insulin-dependent, which means that GLUT4 doesn’t transport glucose into the cell in the absence of insulin. In a state of insulin resistance, GLUT4 doesn’t transport glucose into the cell even in the presence of insulin. This is thought to cause hyperglycemia. However, hyperglycemia is actually caused by an excess of lipolysis and gluconeogenesis (the creation of glucose from glycerol, lactate and amino acids) which is driven by cortisol, noradrenaline, adrenaline and glucagon.

Fructose enters cells via the GLUT2 and GLUT5 transporters in the liver and muscle, which is insulin-independent. Fructose actually has the ability to enhance glucose uptake into cells in the presence of insulin resistance, so fructose can actually lower high blood sugar. That’s why multiple studies have found that adding whole or dried fruit or even fruit juice to a meal rich in starches can dramatically lower the blood sugar response of the meal (R, R, R). In this study, eating an apple before a bowl of rice halved the glycemic response of the meal (R).

Glucose storage

Once glucose is inside the cell, it’s either stored as glycogen, or broken down by glycolysis to pyruvate.

Glucose is converted to glycogen by the enzyme glycogen synthase, which is inhibited by glycogen synthase kinase 3β (GSK-3β). So GSK-3β is a negative regulator of glycogen synthesis. If you can’t synthesize glycogen property, you might experience blood sugar rollercoasters, mood swings, low energy, etc.

Actually GSK-3β overactivation might be responsible for a whole lot of pathologies.

GSK-3β overactivation has been found in people with osteoporosis, atherosclerosis, cancer, cardiac hypertrophy, bipolar disorder, depression, acquired immunodeficiency syndrome (AIDS), malaria, inflammation and several neurodegenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD), and Huntington’s disease (HD) (R, R, R).

It not only inhibits glycogen synthesis, but also protein synthesis, which can reduce your ability to build muscle (R).

Elevated expression and over-activity of GSK-3β are associated with insulin resistance in type 2 diabetes. Therefore, GSK-3β inhibitors are under development for the treatment of type 2 diabetes and treatment with GSK-3β inhibitors improves glucose disposal and enhances liver glycogen synthesis by approximately two-fold (R, R).

So one of the key steps to fixing glucose metabolism is to inhibit GSK-3β.

Natural inhibitors of GSK-3β include (R, R, R, R, R):

• Ginger (10-gingerol)
• Zinc
• Insulin
• Lithium
• Beryllium
• Mercury
• Copper
• Qing dai
• DHEA
• BDNF
• Ketamine
• Dopamine receptor D1 and D2 activation (R)
• 5-HT2A antagonism and 5-HT1 (zinc, methylene blue, agmatine) and 7 agonism
• Noradrenaline (R)

With GSK-3β inhibited, we can expect better glycogen storage, lower blood sugar, better blood sugar control, less oxidative stress, better mood and a greater ability to build muscle.

Next on the list is glycolysis.

Glycolysis

Glycolysis is a pathway with 10 enzymes that converts glucose into pyruvate. Pyruvate can then be transported into the mitochondria or be converted to lactate. Under normal conditions with lots of oxygen present, most of the pyruvate enters the mitochondria and is used to create water, ATP and carbon dioxide.

When someone is exercising vigorously, there isn’t enough oxygen in the muscle and normal oxidative phosphorylation isn’t creating enough ATP, thus glycolysis is significantly increased. Glycolysis itself generates only 2 ATP molecules for each glucose molecule compared to oxidative phosphorylation, which generates 36 molecules of ATP per glucose molecule. Glycolysis is clearly ineffective at generating enough energy, but it can speed up significantly in order to ramp up ATP production. However, this process wastes glucose very rapidly.

So after exercise or during rest, oxygen concentrations return to normal and the ATP demand drops, do glycolysis slows down and oxidative metabolism takes over again.

However, some people, due to mitochondrial defects, can’t produce enough ATP through oxidative phosphorylation, so their glycolysis has to step in and create the ATP.

An interesting study found that inhibiting glycolysis switches cells back towards oxidative phosphorylation (R).

Glycolysis is inhibited by:

• NADH
• Pyruvate
• ATP
• Shikonin found in gromwell plant (R)
• Lapachol inhibits pyruvate kinase M2 (R). Lapachol was unable to cause apoptosis of tumor cells, but it was able to sensitize it to apoptosis through chemicals, such as DNP.
• Serotonin antagonists, as serotonin speeds up glycolysis and increases lactate and vasoconstriction (R, R, R)
• Citric acid (R)
• Cannabinoids (R, R)
• Olive leaf extract (R, R)
• Anti-inflammatory compounds, such as curcumin (R)
• Cardamoms (R)
• Oxygen-rich tissue. Hypoxia activates hypoxia-inducible factor -1 (HIF-1), which upregulates the glucose transporters (GLUT) and induces the expression of glycolytic enzymes, such as hexokinase, pyruvate kinase, and lactate dehydrogenase. Hypoxia is also a potent inducer of mTOR, which is known to be involved in cancer growth. Glycolysis creates no CO2 compared to oxidative phosphorylation, so forcing oxidative phosphorylation will increase CO2, which in turn will help to re-oxygenate tissue. Curcumin also effectively inhibits hypoxia and reduces glucose import and oxidation through glycolysis (R).

After pyruvate has been created, it can either be shuttled into the mitochondria and converted to acetyl-CoA for oxidative phosphorylation via the enzymes pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) or be converted to lactate by the enzyme lactate dehydrogenase (LDH). The latter is present in cancer (Warburg effect), together with elevated glycolysis, even in the presence of oxygen.

We want to inhibit LDH and boost PDH and PC.

Inhibiting lactate production

Pyruvate is converted to lactate by the enzyme lactate dehydrogenase (LDH), which uses NADH as a cofactor. As mentioned above, pyruvate and NADH inhibits glycolysis, so if LDH is overactive, it’s converting too much pyruvate and NADH to lactate and NAD and this speeds up glycolysis, which wastes glucose in a feedforward loop.

There are a few forms of LDH and for this article, I want to focus on LDH5. I quote from this paper (R):

“hLDH5 was found to be overexpressed in a wide range of tumors, where it is now considered as a useful prognostic factor, such as oral squamous cell carcinoma [11], gastric cancer [12], non-small-cell lung cancer [13,14], colorectal cancer [15], endometrial cancer tissues [16], non-Hodgkin B-cell lymphomas [17], melanoma [18], squamous head and neck cancer [19] and esophageal squamous cell carcinoma [20]. Upregulation of hLDH5 confers a growth advantage, ensuring energy supply to highly glycolytic cancer cells, whereas this enzyme is not fundamental for healthy cells that normally rely on OXPHOS.”

Quite good summary don’t you think.

A few natural inhibitors of LDH include (R, R, R, R):

• Cardamonin (found in cardamoms)
• Spatholobus suberectus
• Chinese Gallnut
• Bladderwrack
• Kelp
• Babul
• Arjun
• Pipsissewa
• Cinnamon
• Pink Rose Buds/Petals
• Wintergreen
• Cat’s Claw
• Witch Hazel Root
• Rhodiola Root
• Curcumin

Now that we know how to inhibit LDH, we want to get the pyruvate into the mitochondria and convert it to acetyl-CoA for proper oxidation in the TCA cycle.

Pyruvate dehydrogenase

A few promoters of the pyruvate dehydrogenase enzyme include:

• Magnesium (R)
• Calcium (R)
• Vitamin B1 (R) – a B1 deficiency can cause lactic acidosis, because if pyruvate cannot be converted to acetyl-CoA, it’s wasted to lactate instead. That’s why big doses of vitamin B1 are very effective at lowering lactate.
• Vitamin B2 (R)
• r-lipoic acid (R)
• Vitamin B5 (R)
• Melatonin (R)

Pyruvate carboxylase’s cofactor is biotin, so make sure you’re consuming enough biotin for this enzyme.

Before we can move on, I have to mention the Randle cycle.

Randle cycle and glucose oxidation

The Randle cycle is the direct competition of glucose and fat for oxidation into the mitochondria. The original biochemical mechanism explained the inhibition of glucose oxidation by fatty acids. Long chain fatty acids also inhibit glucose uptake into the liver, which interferes with proper glycogen storage.

Fatty acids are transported into the mitochondria and converted to acetyl-CoA through beta-oxidation. Pyruvate is converted to acetyl-CoA by PDH. The excess acetyl-CoA produced by beta-oxidation inhibits PDH, thus inhibiting glucose oxidation.

To prevent this, we need to be insulin sensitivity as insulin inhibits lipolysis and promotes the formation of triglycerides, and this lowers free fatty acids (FFAs). FFAs are the guilty party and not triglycerides.

So there are two ways we can go about this. First is to inhibit CPT-1 which would inhibit the transport of fat into the mitochondria, and secondly, is to inhibit beta-oxidation itself. Both techniques would inhibit fatty acid oxidation inhibition of PDH.

Mildronate is a drug that inhibits the synthesis of carnitine, so that would lower CPT activity and beta-oxidation activity. This increases glucose oxidation significantly. It’s also used as a performance enhancing drug exactly for this purpose. The fats that cannot enter the mitochondria are broken down to medium chain fatty acids by peroxisomal β-oxidation. The medium chain fats can then freely enter the mitochondria and oxidized as fuel. Medium chain fats, such as the fats found in MCT oil and coconut oil, don’t interfere with glucose oxidation.

Alternatively to mildronate, we can directly inhibit fatty acid oxidation by inhibiting mitochondrial β-oxidation. A good product that can do this, and boost PDH at the same time, is Pyrucet (sold by IdealabsDC), which contains ethyl acetoacetate and ethyl pyruvate. Keep in mind these ingredients don’t inhibit β-oxidation 100%, but around 50% if you stick to the doses recommended. This should inhibit excess (and incomplete) β-oxidation and allow PDH and glucose oxidation to resume maximally.

Last up on the list we have the electron transport chain.

Fixing the electron transport chain for proper glucose oxidation

The TCA cycle (aka ctric acid cycle) creates NADH and FADH2 from glucose, fat and protein. The NADH and FADH2 donate their hydrogens to complex 1 and 2 respectively. Complex 1 and 2 then donate their electrons to complex 3, and from complex 3 to cytochrome c oxidase and lastly to complex 4.

If one of the complexes isn’t working properly, then the NADH and/or FADH2 builds up and the electrons react with oxygen, fats, proteins, DNA, etc., and creates oxidative stress, inflammation, protein damage, etc. It can then also increase lactate dehydrogenase.

So we want to make sure that the complexes are working properly. Eating a nutritious diet with ample vitamins and minerals (especially vitamin B1, B2, B3, vitamin E, copper and choline) will ensure that the complexes have the proper “building blocks” for running as they should.

A few important compounds that can alternatively accept the electrons from NADH and FADH2 and give it to cytochrome C oxidase are:

• Methylene blue (R)
• Vitamin K2 (R)
• Vitamin C (R)
• Lapachol (R)
• CoQ10 (R)
• PQQ (R)

Using these electron acceptors can help to increase ATP and CO2 production and lower oxidative stress, inflammation, excess glycolysis and lactate production and help to ensure that glucose oxidation is working optimally.

Conclusion

To sum it all up, to optimize glucose oxidation, this is what’s important.

• Lower inflammation and free fatty acids to improve insulin sensitivity
• Improve glycogen synthesis
• Slow down glycolysis
• Inhibit lactate formation and increase PDH
• Optimize the ETC

The stack I would use to accomplish this is:

• Glycogen synthesis
  • Zinc – eat lots of red meat, oysters, organ meat, which are also balanced with other minerals such as copper.
  • DHEA if DHEA levels are low. DHEA promotes glycogen storage and inhibits excess glycolysis.
  • Lithium if depressed and/or have bipolar
  • Coffee
  • Inhibit excess lipolysis with aspirin if fasted and post-prandial free fatty acids are elevated
• Inhibiting excess glycolysis
  • Turmeric and olive leaf extract if I have high inflammation
  • Lapachol from Pau d Arco tea/supplement.
• Inhibiting lactate production
  • Turmeric, cinnamon and cardamoms
  • Kelp
  • Rhodiola Rosea – also great against stress
  • Vitamin B1 – doses of 600mg
• Optimizing PDH
  • 600mg vitamin B1 (with Pyrucet if a little more oomph is needed)
  • Magnesium – cocoa is a great source, alternatively, use 200-400mg supplemental magnesium daily
• Supporting the ETC
  • 5mg methylene blue
  • 5mg vitamin K2 (up to 40mg vitamin K3 have been used in research for energy metabolism)
  • 200mg succinic acid
  • 1g vitamin C

There you have it all. I hope this is helpful to your journey of recovery or your quest on maximizing exercise performance. If you have any questions, feel free to ask by leaving it in the comments below.

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