Introduction – The Vicious Cycle of Metabolic Dysregulation
Metabolism is the set of all chemical reactions in the body which sustain life. It is an incredibly complex network of reactions that regulate each other to maintain homeostasis, the ability of the organism to preserve internal stability. Unfortunately, the western lifestyle, especially the ultra-processed diet and lack of physical activity, can dysregulate homeostasis of many metabolic processes. As a result, an alarmingly high number of people need to fix their metabolism – 96 million people have prediabetes (38% of adult US population)1, and one third of US adults have metabolic syndrome2.
Here, we will explain why deltaG can be an immense help for anyone who decides to improve their lifestyle and restore the function of their metabolism. This blog is a story of a vicious cycle of metabolic dysregulation which can seriously affect your health. The main players of this cycle are elevated blood sugar levels, insulin resistance, excess body fat and inflammation. We will show you how deltaG can help you escape this vicious cycle. DeltaG won’t achieve this on its own, but it will significantly potentiate the health-promoting effects of a better diet or increased physical activity. So, let’s get to it.
The ability of metabolism to clear glucose out of the bloodstream is one of its most essential functions. The process depends on the hormone insulin. Our pancreas constantly checks the concertation of glucose in our blood. When blood glucose levels get high, the pancreas secretes insulin. Insulin travels through the bloodstream to the muscle or adipose tissue. It sends a signal to these tissues to absorb glucose from the bloodstream by increasing levels of glucose transporters on the muscle or fat cell membrane3.
Consumption of a western diet, which is high in sugar and fat, impairs the ability of our muscles and adipose tissue to sense insulin4. To maintain healthy blood glucose levels, our pancreas has to secrete more insulin into the bloodstream to provide a stronger signal to the muscle and adipose tissue. Eventually, the pancreas gets exhausted, and its capacity to secrete insulin diminishes. Progressively, the body loses the ability to clear glucose from the bloodstream because tissues are resistant to insulin (hence the name insulin resistance) and insulin production in the pancreas is low. As a result, glucose levels remain constantly elevated – a state called hyperglycaemia5.
Many parts of our body are susceptible to hyperglycaemia and get severely damaged by constant exposure to high blood sugar concentrations. High glucose can severely damage the retina, and untreated type 2 diabetes can lead to blindness6. Nerve endings in our toes get damaged and lead to very painful diabetic neuropathy7. The cells which form the lining of our blood vessels (endothelial cells) are constantly exposed to hyperglycemia. Therefore, these cells are also severely damaged by hyperglycemia, increasing the risk of the blood vessels getting blocked8. A 2019 study9 reported that insulin resistance is the most serious risk factor for coronary heart disease, the leading cause of death in the developed world.
As you can see, keeping your blood glucose in check is crucial for your health. Diet and exercise are the key lifestyle factors for keeping your blood glucose low. Avoiding foods high in sugar will prevent large blood glucose spikes. Exercise induces glucose uptake into the muscle, which is entirely independent of insulin and makes the job of the pancreas easier10. Fortunately, deltaG will help you to lower your blood glucose as well.
The ability of deltaG to lower blood glucose is one of the most well-documented effects of deltaG in humans. A study11 published in 2018 recruited twenty healthy volunteers who drank 25g of deltaG 30 minutes before an oral glucose tolerance test (OGTT). OGTT is a simple test consisting of consuming 75 grams of pure glucose. Blood samples are taken after OGTT to show how effectively your body clears glucose out of the bloodstream. While OGTT in the control group elevated blood glucose levels up to 6 mM on average, participants who drank deltaG never surpassed 5 mM. Furthermore, blood glucose levels stayed roughly 1 mM lower for 90 minutes after consumption of deltaG.
Indeed, drinking pure glucose during OGTT is different from eating a standard meal but deltaG lowers blood glucose after regular meals as well. In a 2017 study12, participants drank 25 – 35 grams of deltaG after they ate oats with banana, a high-carbohydrate meal. The meal elevated blood glucose to 5.5mM. One hour after drinking deltaG, blood glucose fell to 4 mM. These two studies show that deltaG significantly lowers acute glucose spikes after high-carbohydrate meals or OGTT.
The next step was to assess if deltaG could improve glucose control over the long term. One of the most rigorous studies ever done with deltaG was published in 202113. Twenty-one patients with type 2 diabetes drank 25g of deltaG thrice a day for 28 days. In total, participants consumed 1588 drinks during the study, and it was shown that deltaG is very safe to consume over a long period. Even more importantly, the study showed that deltaG significantly improves glycemic control.
HbA1c score fell from 7.7% to 7.2% over the four weeks. Considering that HbA1c score represents mean glucose levels in the last 2-3 months and this study was only one month long, it could be expected that longer deltaG consumption would further improve glycaemic control. Fructosamine measurements are utilised by researchers to assess the effectiveness of shorter (less than 3 months) anti-diabetic treatments. DeltaG decreased fructosamine levels from 335 to 290 μM (45 μM decrease). To put this finding in perspective, an 8-week exercise program consisting of moderate-intensity exercise 3 times a week decreased fructosamine levels by 57 μM14. Considering that the exercise program was twice as long, the decrease of fructosamine by exercise is comparable to the one achieved by deltaG. This does not mean that we recommend using deltaG instead of exercise. Rather, it demonstrates the potency of combining both exercise and deltaG consumption. Participants also wore glucose monitors, and the mean daily glucose fell from 7.8 mM to 7.4 mM over the four weeks. These results clearly show that deltaG significantly improves the ability of our body to clear glucose from the bloodstream, and the estimated insulin resistance decreased by 10% after the daily deltaG consumption.
One of the reasons why deltaG can improve glycemia control might be due its effect on fatty acids. While it might sound counterintuitive, the level of circulating fatty acids is essential factor in glucose control15. A significant problem associated with obesity is that not all excess fat gets stored inside our fat cells. As a result, some fatty acids remain in circulation. High levels of fatty acids block insulin signalling in the muscle and prevent the entry of glucose into the muscle16. A study12 from 2017 showed that drinking deltaG decreases circulating free fatty acids after consuming a meal. Decreasing circulating fatty acids also lower your risk of non-alcoholic fatty liver disease17 and cardiovascular diseases18.
Losing weight is one of the most effective strategies for improving your metabolic health19. The popularity of the ketogenic diet exploded in the past decade, and it brought a lot of attention to ketones and ketosis. Unfortunately, many companies selling exogenous ketones took advantage of this and started making pseudoscientific claims like “ketones will make fat melt off your body”. At first, their argument sounds logical – a ketogenic diet induces ketosis and weight loss. Therefore, inducing ketosis with exogenous ketones causes weight loss as well. Well, not really. The truth is that ketones will help you to lose weight, but you still have to decrease your caloric intake and put in the effort. Ketones won’t make fat magically melt off your body.
The statistics for weight loss efforts are not very optimistic. Only about 20% of adults who try to lose weight by dieting manage to lose 10% of their weight and keep it off for a year20. Unsurprisingly, the biggest obstacle to successful weight loss is increased appetite21. Our appetite is controlled by multiple hormones secreted from various organs of the gastrointestinal tract. One of these hormones is ghrelin, termed the “hunger hormone”. Ghrelin is secreted in the stomach during low-calorie intake, travels via the bloodstream to the brain and signals that we need to eat22. The problem is that ghrelin affects dieting. It was reported that out of four hormones known to regulate appetite, only high levels of ghrelin were associated with a higher risk of weight regain in a group of 56 people who lost weight23. In other words, ghrelin can sabotage your weight loss efforts.
Therefore, decreasing ghrelin levels became a promising therapeutic strategy for weight loss and weight maintenance. A 2018 study24 recruited 15 healthy participants who came to the laboratory in the morning after an overnight fast. They drank deltaG and blood samples were taken for 4 hours after the drink. DeltaG significantly lowered circulating ghrelin compared to levels recorded after consuming a glucose drink with the same amount of calories as the deltaG drink. In agreement with ghrelin’s role in appetite control, participants also reported lower hunger and desire to eat after drinking deltaG. As increased appetite is the key factor which leads to poor adherence to weight loss strategies21, using deltaG to decrease appetite can significantly increase your chances of losing weight and maintaining your desired weight.
It became general knowledge that inflammation is bad for our health. While it is not uncommon to read headlines like “New Study Showed That Blueberries Are Anti-inflammatory” or “Hollywood Star Lost 20 Pounds Thanks to This Anti-inflammatory Diet”, not many of the articles explain why inflammation is harmful and what are the primary causes of inflammation.
The primary goal of our immune system is to react to pathogens, but the immune system also deals with non-pathogenic damage of tissues. We can use a simple cut on your finger as an example. When you cut your finger, you damage hundreds of cells in the area. Molecules typically residing inside the cell leak from the damaged cell into the circulation and can trigger an inflammatory response. Inflammation will stimulate the healing processes in the finger. Therefore, acute inflammation is an essential process required to deal with tissue damage. Inflammation becomes problematic when it is no longer an acute process which quickly resolves threats but rather a chronic condition. It is now well-established that metabolic dysfunction leads to chronic inflammation.
We are finally getting to the vicious cycle mentioned in the introduction. It is depicted in the picture below. As mentioned, hyperglycemia damages our cells. Similarly to a cut finger, tissues exposed to hyperglycemia leak molecules which can trigger inflammation. One such molecule is HMGB1 which normally resides in the cell nucleus, but hyperglycemia induces leakage of HMGB125, which triggers inflammation. Moreover, elevated circulating fatty acids also trigger inflammation26. The disability of cells to sense insulin also leads to inflammation as insulin regulates the expression of pro-inflammatory molecules27. The vicious cycle closes as the pro-inflammatory cytokine TNF-alpha blocks the transduction of signals from insulin to the muscle28. This further exacerbates hyperglycemia as muslce's ability to absorb glucose declines.
As shown, deltaG has the potential to manipulate important nodes of the vicious cycle which triggers inflammation. DeltaG lowers your blood glucose levels which can prevent pro-inflammatory cellular damage. DeltaG decreases levels of circulating fatty acids, which trigger inflammation themselves and contribute to insulin resistance. These effects alone will significantly improve metabolic function. However, the benefits of deltaG do not end here.
One of the key molecules which regulate chronic inflammation is called NLRP3. NLRP3 is sensitive to the aforementioned damage-associated molecules like HMGB129. Moreover, an increase in circulating fatty acids also activates NLRP330. Activation of NLRP3 is considered to be a key factor in chronic inflammation associated with metabolic dyfunction31. The good news is that β-hydroxybutyrate, the ketone body elevated by deltaG, blocks the activity of NLRP3. BHB was shown to block NLRP3 in mice32 and cultured human immune cells33. Recently, preliminary evidence showed that increasing circulating BHB blocks NLRP3 in people with type 2 diabetes34. Moreover, BHB also blocks NF-kB, another key activator of chronic inflammation35.
To sum up, deltaG alleviates both the signals that promote inflammation (hyperglycemia and elevated fatty acids) and also blocks NLRP3, the receiver of these signals, which executes the inflammatory response. The combination of these effects makes deltaG a potent anti-inflammatory agent. Lowering inflammation is crucial for our health. Chronic inflammation not only worsens insulin resistance28 but is now recognised as one of the most significant risk factors for cancer36, cardiovascular diseases37 or Alzheimer's disease38, the most dreaded diseases of the modern world.
- National Diabetes Statistics Report - https://www.cdc.gov/diabetes/data/statistics-report/index.html
- Moore, J.X., Chaudhary, N. and Akinyemiju, T., 2017. Peer reviewed: Metabolic syndrome prevalence by race/ethnicity and sex in the United States, National Health and Nutrition Examination Survey, 1988–2012. Preventing chronic disease, 14.
- Watson, R.T. and Pessin, J.E., 2001. Intracellular organization of insulin signaling and GLUT4 translocation. Recent progress in hormone research, 56(1), pp.175-194.
- Esmaillzadeh, A., Kimiagar, M., Mehrabi, Y., Azadbakht, L., Hu, F.B. and Willett, W.C., 2007. Dietary patterns, insulin resistance, and prevalence of the metabolic syndrome in women. The American journal of clinical nutrition, 85(3), pp.910-918.
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- Boulton, A.J. and Malik, R.A., 1998. Diabetic neuropathy. Medical Clinics of North America, 82(4), pp.909-929.
- Laakso, M., 1999. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes, 48(5), pp.937-942.
- Adeva-Andany, M.M., Martínez-Rodríguez, J., González-Lucán, M., Fernández-Fernández, C. and Castro-Quintela, E., 2019. Insulin resistance is a cardiovascular risk factor in humans. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 13(2), pp.1449-1455.
- Sampson, M., Clark, A., Bachmann, M., Garner, N., Irvine, L., Howe, A., Greaves, C., Auckland, S., Smith, J., Turner, J. and Rea, D., 2021. Lifestyle intervention with or without lay volunteers to prevent type 2 diabetes in people with impaired fasting glucose and/or nondiabetic hyperglycemia: a randomized clinical trial. JAMA internal medicine, 181(2), pp.168-178.
- Myette‐Côté, É., Neudorf, H., Rafiei, H., Clarke, K. and Little, J.P., 2018. Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals. The Journal of physiology, 596(8), pp.1385-1395.
- Stubbs, B.J., Cox, P.J., Evans, R.D., Santer, P., Miller, J.J., Faull, O.K., Magor-Elliott, S., Hiyama, S., Stirling, M. and Clarke, K., 2017. On the metabolism of exogenous ketones in humans. Frontiers in physiology, 8, p.848.
- Soto‐Mota, A., Norwitz, N.G., Evans, R., Clarke, K. and Barber, T.M., 2021. Exogenous ketosis in patients with type 2 diabetes: Safety, tolerability and effect on glycaemic control. Endocrinology, Diabetes & Metabolism, 4(3), p.e00264.
- Moura BP, Amorim PR, Silva BP, Franceschini SC, Reis JS, Marins JC. Effect of a short-term exercise program on glycemic control measured by fructosamine test in type 2 diabetes patients. Diabetol Metab Syndr. 2014;6(1):16.
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- Vanni, E., Bugianesi, E., Kotronen, A., De Minicis, S., Yki-Järvinen, H. and Svegliati-Baroni, G., 2010. From the metabolic syndrome to NAFLD or vice versa?. Digestive and liver Disease, 42(5), pp.320-330.
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- Gibson, A.A. and Sainsbury, A., 2017. Strategies to improve adherence to dietary weight loss interventions in research and real-world settings. Behavioral Sciences, 7(3), p.44.
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