The overuse of prescription insulin is a major problem among type 2 diabetics. Why? Because type 2 diabetes is best defined at the cell level as “insulin resistance”. The function of the insulin receptor is in a state of compromise.
Among type 2 diabetics. the use of prescription insulin can have deleterious consequences. It is in effect making a bad problem worse, equivalent to throwing gasoline onto a house that is already burning.
Speaking from clinical experience, based largely upon empiricism of having witnessed the effects of insulin usage among type 2 diabetic clients, I have learned that it is very common to see glucose levels rise following insulin usage. The well intentioned physician wrongly believes that the problem is that not enough insulin is being used, and therefore the patient must increase the dosage.
Such a recommendation is ignorant of the fact that rising levels of circulating insulin will, over time further reduce the sensitization of insulin receptors on the surface of cells. The evidence of this exists among patients who do not experience a reduction in glucose levels following injecting insulin. In some instances, glucose levels can actually elevate in response to the injected insulin.
Modulate AMPK & GLUT Signaling Independent of Insulin
AMPK (AMP-activated protein kinase) is a master regulatory protein switch inside cells. It can be thought of in its dynamic balance with its counterpart mTOR (mammalian target of rapamycin). In simplified terms, AMPK is a protein responsible for mainly “breaking down”, “oxidizing” and “deconstructing” molecules in cells. mTOR is mainly responsible for processes that are “constructive”, “building”, “growth-promoting” and anabolic. The balance between these two protein systems modulates and influences dozens (or more) of cell processes.
In type two diabetes, there is an imbalance between AMPK and mTOR, favoring insufficient AMPK activity and excessive mTOR. This imbalance is now being studied as a key imbalance in type 2 diabetes (1, 2). One of the key functions of AMPK is to modulate the GLUT vesicle system in the cells. GLUT vesicle signaling enables glucose diffusion and entry from the blood into the cytoplasm (3). GLUT is a transporter. While insulin can activate the GLUT vesicle, in a state of insulin resistance (where insulin does not attach to receptors efficiently) this process is dysfunctional (4).
I have witnessed through the implementation of AMPK and GLUT-signaling therapies, glucose levels can be controlled more effectively. The requirement of insulin either reduces drastically, entirely, or is made unnecessary. Importantly, by modulating key cell-regulatory mechanisms, metabolic function can be improved, toxicity reduced (caused from high glucose & insulin), and a healthier state can be obtained.
Importantly, GLUT signaling can be activated independently of insulin signaling, via activation of AMPK (17, 18, 19). Exercise is a prime example of this. The drug metformin works in this manner (19), as does the plant alkaloid berberine (20). While it is known that AMPK can modulate insulin utilization and glucose diffusion, insulin can also function as an inhibitor of AMPK. The mechanism of this involves the phosphorylation of AMPK via the enzyme AKT (protein kinase B) and the protein kinase GSK3 (21). This is critical to understand, because it reveals the lack of necessity of insulin as a drug among type 2 diabetics, as well as insulin’s potential inhibitory effect on glucose diffusion into cells via AMPK inhibition.
The following is a list of potent AMPK-modulating compounds. I will discuss briefly those I believe yield the greatest effects.
- Intermittent caloric restriction – A process of restricting food and caloric intake inhibits mTOR (5) in a rodent model. In clinical and experimental work I have found that 15-18 hours of fasting seems to be efficacious for type 2 diabetics, done 1-2X weekly. The process seems to have a cumulative effect after 6-8 weeks, whereby fasting glucose readings begin to improve, sometimes significantly. There are arguments to make regarding intermittent fasting and caloric restriction during certain times of the year (winter versus summer) given the inherent biorhythms of AMPK and mTOR. These go beyond the scope of this article.
- Berberine: a bitter plant alkaloid with many diverse functions. Berberine has shown to be equally or more effective than the diabetic drug metformin at modulating GLUT signaling (6). Berberine also possesses actions featuring triglyceride lipolysis (breakdown), reduction in hemoglobin A1C, and reduction of postprandial glucose (7). Berberine enables glucose entry into cells independently of insulin (20). I am a big fan of berberine extract. I typically see its benefit in combination with other botanicals and nutrients at a dose of 700-1,000mg daily, taken with food. If used in excess, it could in some instances cause a rise in serum potassium, likely due to effects on insulin signaling and associated potassium ion channels in cells. This has only been observed (by me) in excess of 1,200mg daily in a small number of case studies. Berberine also possesses numerous anti-microbial actions, and is often used as an anti-fungal. Type 2 diabetics often have yeast and fungal imbalances (likely due to high glucose and pseudo-hypoxic states), so berberine could be of additional benefit here.
- Bitter melon: Is a bitter type of fruit derived from southeast Asia, Malaysia, India and Sri Lanka. Similar to berberine, Bitter melon has been historically used for numerous anti-microbial actions, including anti-viral and anti-parasitic effects. Some evidence indicates bitter melon triterpenoids reduce a protein known as adiponectin, which is correlated with obesity and in the development of insulin resistance (9), making it of use in adipose fat loss. I believe this is true based upon clinical observations. Bitter melon is a good modulator of AMPK and glucose disposal (8). I would use it in combination with other botanicals and nutrients, usually at a dosage of 250-1,000mg daily, taken with food.
- Lipoic Acid: Is an important disulfide, water-soluble B-vitamin-like antioxidant with diverse functions. Lipoic acid participates in the activation of NrF2 (10), a response element signaling pathway that modulates antioxidant switching, such as glutathione and thioredoxin. Intracellular sulfur signaling is a crucial, yet overlooked process of cell biology. Lipoic acid modulates GLUT, as well as enhances insulin sensitization (11), and plays important roles in intracellular processes, including those related to nerve conduction (useful in neuropathy and retinopathy) (12). The R-lipoic acid form is better than alpha, as R-lipoic acid will be better absorbed. Some liposomal forms now exist, which will likely greatly enhance uptake of either form. I would use 600mg of alpha lipoic acid daily with food, or 200-300mg of the R-lipoic form daily with food, for best effects. It is best combined with other nutrients and botanicals.
- Chromium: Is a trace mineral that sensitizes insulin receptor function and modulates GLUT and AMPK (13). By itself, chromium has disappointed in its overall effects. Special forms now exist, which seem to enhance its utilization. These include a form named dinicocysteinate. I would use chromium in some form but not by itself, and ideally with the bigger guns (berberine, bitter melon, lipoic acid) at a dose of 300-400mcg daily with food.
- TUDCA: Who has heard of this? Few people. This is a taurine-based bile acid. It gained popularity in the bodybuilding world, but few appreciate what it has really been shown to do. One study found a 30% improvement in insulin sensitivity in muscle and liver cells in 20 obese subjects (14). Some of its mechanisms are related to the ability to relieve endoplasmic reticulum stress, which led to its study as potentially beneficial in neurodegenerative diseases, such as Alzheimer’s, Huntington’s, ALS and Parkinson’s as well as in retinal degeneration. TUDCA also appears to be a choice recommendation in cholestasis conditions (15). My experience with TUDCA is that its quite effective at improving insulin sensitivity at a dose of at least 1,000mg daily (as much as 1,750mg daily). It has shown to cause nausea in some people (reason not known). TUDCA may slightly decrease HDL cholesterol levels, in some subjects. If tolerated, it could be a good choice that addresses hepatic and insulin-signaling-related needs.
In addition to the benefits of a carbohydrate-restrictive diet (16), an overwhelming amount of published literature exists on the effects of nutrients and botanicals for the modulation of the cellular mechanisms of type 2 diabetes. These include the abilities to improve insulin sensitization through the use of GLUT and AMPK modulating supplementation, as well as to operate independently of insulin signaling.
One of the most powerful tools a diabetic can use to monitor their health, track their progress, and make adjustments to their diet, lifestyle and supplemental protocol is through the use of an accurate and easy to use glucose/ketone meter. The one that I recommend and use is THIS.
With the correct food plan, exercise and lifestyle modifications, as well as targeted supplementation, it is entirely possible to improve the health and cell biological mechanisms in type 2 diabetes mellitus.