Blood sugar optimization is all the rage these days.

Most people believe that insulin resistance is caused by dietary carbohydrates. But it’s not.

As I described in my previous article on how insulin works, high blood sugar is caused by elevated lipolysis and gluconeogenesis. If you haven’t read that article yet, do so by clicking on this link. It will take you to that article in a new tab where you can leisurely read through it, catch up on everything and come back here.

To improve fasting glucose, fasting insulin and insulin sensitivity, we need to focus on lowering elevated gluconeogenesis and lipolysis.

Gluconeogenesis & lipolysis

Gluconeogenesis is the process of converting amino acids (and to a lesser extent lactate and glycerol) into glucose. This process is upregulated during fasted periods or when eating a low carb diet to ensure that blood sugar remains stable. It can also help to prevent blood sugar crashes between meals, regardless of your carb intake.

The more glycogen you have, the less active liver gluconeogenesis will be. As liver glycogen starts to fall, gluconeogenesis increases to make up for the drop in available glucose.

Lipolysis is the process where fatty acids are released from fat stores. This happens normally after a meal when most of the glucose from a meal has been taken up by the muscles, brain, liver, adipose tissue, etc., and insulin starts to drop. There is no on or off switch for lipolysis. For a very oversimplified example, a massive carb meal might shut lipolysis down by 90% for about 10-20 minutes and then its activity increases again. A low carb meal might shut lipolysis down only 20% or less, when a low carb meal is eaten. This difference between foods with different GIs, such as white rice (100% glucose) and agave syrup (90% fructose); white rice will shut lipolysis down to a much greater extent than agave syrup.

A few promoters of gluconeogenesis and lipolysis include:

1. Cortisol
2. Estrogen
3. Inflammation
4. Glucose oxidation inhibitors
5. Serotonin
6. Glucagon
7. Growth hormone
8. Lipolysis (stimulates gluconeogenesis)
9. Hypoxia
10. Noradrenaline & Adrenaline

If any of them are in excess, they can contribute to hyperglycemia and insulin resistance. Insulin can suppress all of them, but the issue is when the liver or adipose tissue becomes insulin resistant and these hormones and processes aren’t downregulated by insulin.

Thus, lipolysis and gluconeogenesis remain highly active even when carbs are eaten. So we want to lower these hormones and processes to ensure optimal insulin sensitvity.

Why not just stick with anti-diabetic drugs such as metformin, you might ask? Because anti-diabetic agents like metformin, sulfonylureas, and GLP1 agonists lose their effectiveness over time (R).

Let’s start with cortisol.

#1 Cortisol

Cortisol promotes lipolysis and gluconeogenesis and contributes to the pathology of insulin resistance and diabetes. Prolonged elevated cortisol will lead to the destruction of many organs, including the pancreas.

“Glucocorticoids enhance gluconeogenesis in the liver. It inhibits insulin secretion and peripheral glucose uptake. Glucocorticoids also increase insulin resistance, and induce inflammatory cytokines by activating the glucocorticoid receptor in adiposities. Thus, excess cortisol related to diabetes mellitus.⁷² Thus inhibiting glucocorticoid activity by using glucocorticoid receptor antagonists is one of the most promising treatment approaches.”

Reference

Aspirin, progesterone, magnesium, zinc, vitamin D, niacinamide, Tribulus Terrestris, Rhodiola Rosea, phosphatidylserine, etc., are great inhibitors of excess cortisol.

If you want to learn more on lowering cortisol, check out my full article on it.

Due to this reason, the current approach directed to tissue-specific glucocorticoid metabolism, by inhibiting 11b-hydroxysteroid dehydrogenase (11b-HSD), which catalyzes the conversion of cortisone, to the active form cortisol without affecting the pituitary-adrenal axis. Overexpression of 11b-HSD related to metabolic syndromes like T2DM and obesity. Thus, inhibition of 11b-HSD improves insulin sensitivity, hyperglycemia, and lipid profile

Reference

A few good inhibitors of 11beta-HSD include niacinamide, vitamin A, vitamin D, aspirin and emodin.

#2 Estrogen

Excess estrogen is clearly harmful, however, fraudulent research shows that estrogen therapy is beneficial.

Anyway, here and there you might find an unbiased study that found the following:

Men with higher E(2) levels had an increased risk of later diabetes independent of obesity, while men with lower total testosterone and SHBG had an increased risk of diabetes that appeared to be dependent on obesity.

Reference

Also:

Estrogens are significantly elevated in diabetic men. Amelioration of the hyperglycemia and diminished estrogen production appear responsible for the reversibility of the abnormalities seen in adult-onset diabetics

Reference

A few good aromatase inhibitors include androsterone, aspirin, vitamin E, Tongkat Ali, vitamin D, vitamin A, etc. Check out my article on how to inhibit the aromatase and lower estrogen.

#3 Inflammation

Insulin resistance almost always comes back to inflammation.

In T2DM patient adiposities are in a state of inflammation and release proinflammatory mediators like Tumor necrosis factor-alpha (TNF-α), and interleukin-1b (IL-1b). Studies showed that inflammation has a significant effect on the pathogenesis of T2DM, insulin resistance, impaired insulin secretion, and its complications. Several studies showed that drugs that reduce inflammation increase insulin sensitivity and improve glucose control in insulin-resistant patients with T2DM (R).

Reference

A few major sources of inflammation include:

• Gut irritation
• Aldosterone – due to low sodium intake or excess sodium excretion during hypoinsulinemia or insulin resistance.
• Parathyroid hormone – due to low calcium intake and vitamin D levels.
• Excess estrogen (R) – “Estrogens influence immune and inflammatory processes, as revealed by increased inflammatory responses to infection and sepsis and higher rate of autoimmune diseases in women when compared to men as well as by the variation of chronic inflammatory disease activity” (R)
• Polyunsaturated fat – which is easily damaged by toxins and free radicals and which is also used by the COX and LOX enzymes to create inflammatory by-products.
• Excess heavy metals, such as iron. Check my article on which tests you should get for iron and how to interpret them.

A few ways to lower inflammation is to:

• Eat enough calcium (relative to phosphate) and salt
• Use vitamin E (TocoVit is my preference)
• Support the electron transport chain (ETC) with CoQ10 (avoid statins as they lower CoQ10), vitamin C, vitamin K2 (MK-4), succinic acid and methylene blue. A faulty ETC can leak a significant amount of free radicals that create oxidative damage.
• Consume enough zinc, copper, selenium and manganese are they are important for anti-oxidant enzymes.
• Use small amounts of aspirin daily as it inhibits the COX enzymes as well as other markers of inflammation, such as the NF-κB pathway.
  • “Salsalate, a prodrug of salicylate, has shown beneficial effects on glycemia, and insulin sensitivity, through inhibition of the NF-κB pathway, which has a key role in the pathogenesis of T2DM and becomes promising therapeutic targets” (R). Aspirin is just as effective so you can save a lot of money and just get aspirin.
• Reduce gut inflammation by eliminating gut-irritating foods, speeding up transit time and binding and eliminating gut endotoxin and serotonin. Activated charcoal is ideal for this. I like to take 1 tsp activated charcoal 2-3x week.
• Consume herbs, such as ginger, turmeric, cardamons, olive leaf extract, bitter melon, etc.
• Eat lots of whole fruit. Fruits contain lots of healthy compounds that are anti-inflammatory.

#4 Glucose oxidation promoters

Gluconeogenesis uses lactate as a precursor, so lowering lactate can help to reduce the activity of gluconeogenesis. Pyruvate dehydrogenase (PDH) is the rate limited enzyme in glucose oxidation and it’s inhibited by pyruvate dehydrogenase kinase (PDHK).

PDHK inhibitors or PDH promoters increases pyruvate oxidation and decreases the level of compounds (e.g. lactate) for gluconeogenesis in the liver. Several PDHK inhibitors are in a clinical trial including, JTT-251, AZD 2545, and leelamine which have proven effective in lowering blood glucose levels in diabetic rodent models.

Natural promoters of PDH include vitamin B1 and Pyrucet (combination of ethyl acetoacetate and ethyl pyruvate). Substances that inhibit lipolysis such as niacin and aspirin are also able to increase PDH, as fatty acids activate PDHK and inhibit PDH.

#5 Serotonin

Serotonin promotes gluconeogenesis in the liver and inhibiting serotonin synthesis normalizes hyperglycemia in mice (R). Furthermore, serotonin enhances the synthesis of fat in adipose tissue and reduces brown adipose tissue activity, thus reducing the metabolic rate (R).

A few other actions of serotonin in the body are to cause diarrhea, cooling the body in cold weather, heating the body in hot weather, causing vasoconstriction, increasing blood pressure, contributing to asthma, causing carcinoid syndrome, inflammation (of the pancreas, gut, heart, prostate, etc.), insulin resistance, fat gain, etc. (R)

Serotonin is created from the amino acid tryptophan and this is what this study found in relation to tryptophan and diabetes:

First, serum tryptophan level was found significantly higher in future T2D and was positively and independently associated with diabetes onset risk. Patients with higher tryptophan level tended to present higher degree of insulin resistance and secretion, triglyceride and blood pressure.

Reference

Pharmacologic inhibition or genetic deletion of a rate-limiting enzyme in peripheral serotonin synthesis (tryptophan hydroxylase type 1 (TPH1)) protects mice from high-fat diet–induced obesity and insulin resistance (R).

In fact, several pharmaceutical TPH1 inhibitors are in the pipeline for treating type II diabetes (R).

A few best ways to lower serotonin is to:

• Reduce gut serotonin by:
  • Avoiding gut-irritating foods
  • Speeding up transit time
  • Using activated charcoal (1 tsp 2-3x week) to bind and excrete gut serotonin
  • Improve thyroid function as hypothyroid leads to slow transit time
  • Consume choline, which helps to speed up transit time
• Inhibit 5-HT2A (which’s activation promotes adipogenesis) with:
  • Bacopa (iHerb, NeuroActive (10% off code)),
  • Ginkgo Biloba (iHerb, NeuroActive (10% off code)),
  • Feverfew (iHerb)
  • Cat’s claw
• Inhibit 5-HT2B (which stimulate gluconeogenesis and organ fibrosis) with (as a side note, these drugs also antagonize 5-HT2A and other serotonin receptors):
  • Cyproheptadine
  • Metergoline
  • Lisuride 
  • Mianserin
  • Yohimbine
  • Cat’s claw
• Inhibit 5-HT3 (which’s activation inhibits brown adipose tissue activity) with:
  • Ginger
  • Cat’s claw

Anti-serotonin drugs in general have insulin sensitizing effects:

Cyproheptadine and metergoline improve glucose metabolism in chemical diabetes probably by reducing insulin resistance. This may depend either on decreased secretion of counter-regulatory hormones or on a direct pharmacological action of the drugs on glucose utilization, possibly mediated by their common antiserotoninergic properties.

Reference

I’m not trying to encourage the use of drugs, but merely to point out the potent involvement of serotonin.

#6 Glucagon

Glucagon facilitates hepatic glucose production by glycogenolysis and gluconeogenesis by activating glucagon receptor. Glucagon also inhibits glycogen synthesis but facilitates lipolysis. It also antagonizes insulin effect to inhibit these processes.³⁷ The enhanced glucagon activity and the decreased insulin-mediated suppression of glucagon activity contribute to hyperglycemia and ketoacidosis in T2DM patients. 

Reference

Glucagon like peptide-1 (GLP-1) suppresses glucagon and gluconeogenesis and GLP-1 is usually reduced due to:

• Excess catecholamines
• Gut dysbiosis (R)
• H. pylori (R)
• Insufficient bile acids, such as TDCA (tauro-deoxycholate; bile acid) (R)

A few things that can increase GLP-1 include:

• Sardine protein (R)
• Orange juice (R)
• Cinnamon (R)

#7 Growth hormone

Growth hormone is also involved in insulin resistance:

GH is one of the glucose counter-regulatory hormones, rising in response to hypoglycaemia, it has both intrinsic hyperglycaemic actions and causes insulin resistance. 

Reference

Estrogen, serotonin, and hypothyroid are promoters of growth hormone (GH) secretion, whereas dopamine and insulin are the main GH inhibitors.

Check out this article of mine on how to increase dopamine and what foods can increase dopamine.

In this study, 4mg of metergoline was able to significantly suppress growth hormone and prolactin:

Both GH and PRL levels remained suppressed during a 6 day course of treatment with metergoline. These results are consistent with the hypothesis that the inhibitory effect of metergoline on GH and PRL release is determined by inactivation of serotonin receptors in the hypothalamus or at the pituitary.

Reference

#8 Lipolysis

In an insulin resistant state, insulin is unable to shut lipolysis down to the required degree. Thus, there are elevated fatty acids in the blood that further interfere with the action of insulin and inhibit proper glucose oxidation.

A few things that drive excess lipolysis include:

• Excess cortisol
• Adrenaline and noradrenaline
• Serotonin (R)
• Estrogen
• Inflammation
• Hypoxia

Lipolysis can be inhibited by aspirin and niacin. However, niacin causes an overshoot in lipolysis a few hours later, which can worsen insulin resistance. For this reason, it would be best to take it with your last meal of the day. As a bonus, niacin helps with sleep.

I’ve already touched on all of the bullet points above, except the hypoxia, so let’s discuss that next.

#9 Hypoxia

This one is huge. If your cells are not getting enough oxygen, then lipolysis and gluconeogenesis are enhanced, inflammation increased, stress hormones become elevated (and this leads to mood disorders such as anxiety, depression, anger, irritability, etc.), glycogen storage is reduced and glucose is wasted to lactate. This is really one of the major reasons why some people can’t tolerate carbs or create energy in general.

So how do you fix the hypoxia? First off, carbon dioxide (CO2) is essential for proper tissue oxygenation, because carbon dioxide “pushes” oxygen into cells and optimizes oxygenation and energy production. Without sufficient CO2, proper energy production cannot take place.

This this article of mine on how to increase CO2 and thus one on how to maximize CO2 production from exercise.

A few causes of hypoxia include:

• Hypertension
• Lung disorders
• Low hemoglobin
• Excess NO
• Obstructive sleep apnea
• Hyperventilation
• Inflammation
• Estrogen (R)
• Endotoxin (R)
• Vitamin B1 deficiency (R)

Things to help resolve hypoxia

• Methylene blue
• Red light
• Bag breathing
• Adenosine (R) – niacin increases adenosine
• Vitamin B3 (niacinamide & niacin (R))
• Vitamin B1 (R)
• Vitamin B2 (R)
• Vitamin B6, B12, folate and choline are protective (R)

#10 Noradrenaline & adrenaline

Noradrenaline and adrenaline are catecholamines that are created in the brain and in the adrenal gland. Noradrenaline works synergistically with thyroid hormone to boost the metabolism, but if it is in excess, it can contribute to mental disorders such as depression, anxiety, panic, anhedonia, etc, as well as overstimulation of gluconeogenesis and lipolysis.

However, it’s adrenaline that’s actually the main culprit here. Adrenaline is the main stimulator of lipolysis (at least during exercise (R)) and type 1 diabetics rely on adrenaline for survival since it potently stimulates gluconeogenesis and lipolysis.

Adrenaline is created from noradrenaline and the enzyme that creates it (phenylethanolamine-N-methyl transferase (PEMT)) uses SAMe, a methyl donor, as a cofactor.

PEMT is under the control of stress and ACTH and cortisol are potent stimulators of this enzyme (R).

A few things that can help to lower adrenaline include:

• Things that resolve hypoxia
• Things that lower cortisol
• Salt (R)
• Inosine (R)
• Taurine (R)
• Magnesium (R)
• Progesterone (R) (Progestene & CortiNon)

Conclusion

Although all of this might seem overwhelming, the most important things to do would be:

• Improve digestion and avoid gut irritation
• Manage stress
• Sleep enough
• Get lots of sunlight
• Eat nutritious food such as dairy, organ meat, shellfish, fruits, certain tubers and leafy greens.
• Optimize glucose oxidation

Dr Ray Peat’s recommendations for diabetics:

• Lots of sugar (preferably from fruit for the potassium)
• Milk (for the protein and calcium as well as the other nutrients)
• Vitamin D
• Vitamin K2
• Vitamin B1
• Vitamin B3 (niacinamide)
• Magnesium
• Pregnenolone & progesterone
• Thyroid
• Coffee
• Cocoa
• Gelatin
• Salt
• Aspirin

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