Glycotoxicity: The diabetes-dementia connection

The ‘Baby Boomer’ generation, defined as people born between the years of 1946 to 1964, is a demographic cohort that we are now observing that they’re entering the ages of 74 and older this year. The Alzheimer’s Association (2020) report shares that by 2030, over 20% of the population of the United States will comprise of seniors ages 65 and older, or 72 million. As the number of individuals in this population increase, so do the chances of the number of older adults with dementia, both current and newly diagnosed. In fact, the Alzheimer’s Association (2020) predicts that by 2025, 7.1 million older adults will be diagnosed with Alzheimer’s dementia, and by 2050 that number will reach 13.8 million.

Dementia is an overall or umbrella term encompassing a similar symptom picture. What is characteristic of the symptom picture of dementia is not just the classic memory problems, but also to do with language, problem-solving, executive functions, arithmetic and other cognitive and thinking capabilities performed as part of the activities of daily living.

Alzheimer’s Disease, or Alzheimer’s Dementia, is the most common cause of dementia, accounting for approximately 80% of cases (Alzheimer’s Association, 2020). The hallmark of the pathology of Alzheimer’s disease is the accumulation of beta-amyloid protein fragments that have aggregated outside neurons in the brain, as well as tau tangles that are twisted in neurons that eventually lead to the death of neurons and damage to brain tissue. This pathological development of impaired clearance of amyloid-beta peptides and thus accumulation occurs progressively over many years before symptoms emerge.

There is evidence in at least the early stages of dementia that cognitive decline is driven by metabolic processes (Bredesen, 2014). Diabetes is associated with the onset of dementia and Alzheimer’s Disease (Campbell, Stephenson, de Courten, Chapman, Bellman, & Aromataris, 2018). The authors observed that “people with diagnosed diabetes had a 73% increased risk of developing dementia and a 56% increased risk of developing Alzheimer’s Disease compared to the general population.” In fact, de la Monte & Wands (2008) had coined Alzheimer’s Disease “Type 3 Diabetes” as the evidence shows that Type 2 Diabetes Mellitus causes brain insulin resistance and cognitive impairment through disturbances in acetylcholine homeostasis and insulin-like growth factor signalling.

There are many mechanisms that are plausible with the association between diabetes and dementia. However, these factors may be, in fact, multifactorial and overlap with their associations. Like with any chronic disease, the underlying mechanisms are likely to be a combination of factors.

The mechanism behind the association between diabetes and dementia likely involves the involvement of chronic low-grade inflammation, oxidative stress, vascular damage, increased cerebral amyloid-beta peptides, hyperinsulinemia, brain insulin resistance and production of advanced glycation end-products.

One emerging mechanism of the development of dementia in patients with diabetes is how hyperinsulinemia can contribute to the production and formation of beta-amyloid plaque in the brain that leads to the onset of Alzheimer’s Disease (Campbell, Stephenson, de Courten, Chapman, Bellman & Aromataris, 2018). In diabetes, insulin resistance occurs as a result of repeated secretion of insulin over chronic fluctuations and rises in postprandial blood glucose levels. The sensitivity of insulin is reduced over time. As a result of insulin resistance, the body secretes more insulin to achieve the same level of storage it once had. This leads to hyperinsulinemia.

Hyperinsulinemia can contribute to a cascade of events over time, contributing to metabolic syndrome, with one common one being weight gain and increased adipose mass (Erion & Corkey, 2017). As homeostasis plays a role in keeping basal levels of insulin in the body, there is an enzyme that regulates the level of insulin called Insulin-degrading Enzyme.

Insulin-degrading enzyme (IDE) is a zinc metallopeptidase that degrades specific peptides, including insulin and amyloid beta-peptide (Song, Rodgers & Hersh, 2018). There is a growing number of studies reporting the secretion of IDE playing an important role in degrading insulin and amyloid beta-peptide (Song, Rodgers & Hersh, 2018) and thus implicated in Alzheimer’s Disease. This implication leads to future research regarding potential allosteric activation of IDE against beta-amyloid as a new strategy in Alzheimer’s Disease treatment (Kurochkin, Guarnera & Berezovsky, 2018).

Photo: © Piman Khrutmuang / Adobe Stock

There is current evidence to support that conventional glycemic control, such as the use of metformin to associate with a reduced risk of dementia (Campbell, Stephenson, de Courten, Chapman, Bellman & Aromataris, 2018). The use of metformin can be potential in preventing hyperinsulinemia, which contributes to the formation of amyloid-beta plaque and leading to the development of Alzheimer’s Disease (Campbell, Stephenson, de Courten, Chapman, Bellman & Aromataris, 2018). In addition to the reduction of hyperinsulinemia, metformin can also reduce the formation of advanced glycation end-products, inflammation and oxidative stress through it’s glucose-lowering effects (Campbell, Stephenson, de Courten, Chapman, Bellman & Aromataris, 2018).

Naturopathically, there are many options that focus on the therapeutic order, starting with establishing the foundations of optimal health. This is where physicians and practitioners assess for lifestyle habits and dietary counselling that can support increasing the sensitivity of insulin and regulating blood sugar levels.

Working with the diet and understanding the glycemic load can be an initial start in the patient’s care. Ensuring that patients reduce simple carbohydrates in their diet and opt to consume more complex, whole carbohydrates can prevent glucose spikes and dips, and eventual insulin resistance. Fasting has also been brought more to light by the works of Dr. Jason Fung, MD regarding hyperinsulinemia, insulin resistance and diabetes.

Sleep is also critical in insulin sensitivity. In fact, sleeping only four hours in one single night as opposed to eight induces insulin resistance (Donga, Dijk M, Dijk JG, Biermaz, Mammers, et al., 2010). Investigate if patients are having any difficulty with sleep onset and sleep maintenance, as sleep is something we do on a basis. Ensure patients are getting a minimum of 7-8 hours nightly and are feeling refreshed upon waking.

Physical activity is also just as important as diet, in that exercise not only sensitizes insulin but also contributes to weight loss, which also has an association with insulin sensitivity (Bird & Hawley, 2016). Muscle contraction stimulated improvements through resistance exercise promotes GLUT4 translocation to the cell membrane and increases glucose uptake allowing for improved glycemic control (Bird & Hawley, 2016).

Stress management is also a cornerstone of insulin sensitivity and weight management. Stress encourages the body to go into ‘fight-or-flight’ mode, which stimulates the production of cortisol, our stress hormone. Cortisol breaks down glycogen, which enters our bloodstream for our body to use as a quick source of energy. Ongoing chronic stress can keep cortisol levels high, which can continue to break down glycogen and lead to increasing levels of blood sugar. Stress can also make insulin more resistant (Adam, Hasson, Venture, Toledo-Coral, Le, Mahurkar et al., 2010).

There is now even evidence that the gut microbiome has a correlation to insulin sensitivity. As the Father of Modern Medicine, Hippocrates, states, “all disease begins in the gut.” Animal studies show that short-chain fatty acids, such as butyrate, play a role in glucose homeostasis through multiple mechanisms of action (Kim, Keogh & Clifton, 2018). In a clinical study observing 38 overweight or obese individuals, insulin sensitivity was associated with a higher abundance of Phascolarctobacterium and lower abundance of Dialister (Naderpoor, Mousa, Gomez-Arango, Barrett, Nitert & Courten, 2019). Those with higher insulin secretion had a lower abundance of Bifidobacterium compared to those with lower insulin secretion (Naderpoor, Mousa, Gomez-Arango, Barrett, Nitert & Courten, 2019). Gut health is potential in insulin sensitivity and could be indicated to conduct a comprehensive stool analysis.

Supplementation is helpful while working on the foundations mentioned above and by no means a replacement or alternative to our lifestyle as it states, these help ‘supplement’ our current diets and lifestyles. There are supplements that can assist in increasing insulin sensitivity, including cinnamon (Medagama, 2015), chromium (Anderson, Cheng, Bryden, Polansky, Cheng, Chi & Feng, 1997), magnesium (Mooren, Gruger, Volker, Golf, Wadepuhl, & Kraus, 2011), and berberine (Pang, Zhau, Zhou, Zhao, Wang, Gu & Tong, 2015).

Prevention is key as one approaches the middle and later ages. Recommend patients to act and get screened for their blood sugar levels. HbA1c is a better indicator of the blood sugar levels and potentially insulin tolerance tests as well. Even if medications are not indicated despite a borderline HbA1c, there are many things to start on that can prevent and optimize blood sugar levels and insulin sensitivity. By doing so, not only would it be supportive of your patient’s risk of cardiovascular disease, but also reduce the risk of developing Alzheimer’s dementia.

References

• Adam, T. C., Hasson, R. E., Ventura, E. E., Toledo-Corral, C., Le, K. A., Mahurkar, S., Lane, C. J., Weigensberg, M. J., & Goran, M. I. (2010). Cortisol is negatively associated with insulin sensitivity in overweight Latino youth. The Journal of clinical endocrinology and metabolism, 95(10), 4729–4735. https://doi.org/10.1210/jc.2010-0322
• Alzheimer’s Association. (2020). 2020 Alzheimer’s disease facts and figures. Retrieved from: https://doi.org/10.1002/alz.12068
• Anderson, R. A., Cheng, N., Bryden, N. A., Polansky, M. M., Cheng, N., Chi, J., & Feng, J. (1997). Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes, 46(11), 1786–1791. https://doi.org/10.2337/diab.46.11.1786
• Bird, S. R., & Hawley, J. A. (2017). Update on the effects of physical activity on insulin sensitivity in humans. BMJ open sport & exercise medicine, 2(1), e000143. https://doi.org/10.1136/bmjsem-2016-000143
• Bredesen D. E. (2014). Reversal of cognitive decline: a novel therapeutic program. Aging, 6(9), 707–717. https://doi.org/10.18632/aging.100690
• Campbell, J. M., Stephenson, M. D., de Courten, B., Chapman, I., Bellman, S. M., & Aromataris, E. (2018). Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis. Journal of Alzheimer’s disease : JAD, 65(4), 1225–1236. https://doi.org/10.3233/JAD-180263
• de la Monte, S. M., & Wands, J. R. (2008). Alzheimer’s disease is type 3 diabetes-evidence reviewed. Journal of diabetes science and technology, 2(6), 1101–1113. https://doi.org/10.1177/193229680800200619
• Donga E, van Dijk M, van Dijk JG, et al. A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects. J Clin Endocrinol Metab. 2010;95(6):2963-2968. doi:10.1210/jc.2009-2430
• Kim, Y. A., Keogh, J. B., & Clifton, P. M. (2018). Probiotics, prebiotics, synbiotics and insulin sensitivity. Nutrition research reviews, 31(1), 35–51. https://doi.org/10.1017/S095442241700018X
• Kurochkin, I. V., Guarnera, E., & Berezovsky, I. N. (2018). Insulin-Degrading Enzyme in the Fight against Alzheimer’s Disease. Trends in pharmacological sciences, 39(1), 49–58. https://doi.org/10.1016/j.tips.2017.10.008
• Medagama A. B. (2015). The glycaemic outcomes of cinnamon, a review of the experimental evidence and clinical trials. Nutrition journal, 14, 108. https://doi.org/10.1186/s12937-015-0098-9
• Mooren, F. C., Krüger, K., Völker, K., Golf, S. W., Wadepuhl, M., & Kraus, A. (2011). Oral magnesium supplementation reduces insulin resistance in non-diabetic subjects – a double-blind, placebo-controlled, randomized trial. Diabetes, obesity & metabolism, 13(3), 281–284. https://doi.org/10.1111/j.1463-1326.2010.01332.x
• Naderpoor, N., Mousa, A., Gomez-Arango, L. F., Barrett, H. L., Dekker Nitert, M., & de Courten, B. (2019). Faecal Microbiota Are Related to Insulin Sensitivity and Secretion in Overweight or Obese Adults. Journal of clinical medicine, 8(4), 452. https://doi.org/10.3390/jcm8040452
• Pang, B., Zhao, L. H., Zhou, Q., Zhao, T. Y., Wang, H., Gu, C. J., & Tong, X. L. (2015). Application of berberine on treating type 2 diabetes mellitus. International journal of endocrinology, 2015, 905749. https://doi.org/10.1155/2015/905749
• Song, E.S., Rodgers, D.W. & Hersh, L.B. (2018). Insulin-degrading enzyme is not secreted from cultured cells. Sci Rep, 8, 2335. https://doi.org/10.1038/s41598-018-20597-6

Dr. Romi Fung (B.Sc, M.Sc, ND, PhD Doctoral Student), is a Naturopathic Physician practicing in Richmond, British Columbia, Canada. A recent graduate from the Canadian College of Naturopathic Medicine, Romi helps patients living with dementia improve their quality of life by taking an integrative and functional approach. On top of his practice, Romi is currently pursuing doctoral studies in Aging and Health at Queen’s University and is an Adjunct Clinical Faculty at the Boucher Institute of Naturopathic Medicine. www.DrRomiFungND.com.

This article was originally published in Chiropractic + Naturopathic Doctor’s October 2020 edition.