The Newfound Neurology of Type 1 Diabetes

For most of human history, type 1 diabetes mellitus was a terminal diagnosis. First documented in 1500 BCE in Egypt, diabetes was observed causing symptoms such as rapid weight loss, frequent urination, and shortly thereafter, death [1, 2]. In Ancient Rome, the way physicians diagnosed diabetes was by tasting the urine of people suffering from these symptoms, looking for a telltale “sweet” taste and smell (the word mellitus means “honey” in Latin) [1]. In the 1900’s, the only medical treatment for diabetes was an extremely low-calorie diet, which prolonged the patient’s lifespan but ultimately led to death by starvation [3]. 

In the last 50 years, significant advances in medicine have increased our understanding of diabetes and allowed the development of technology to facilitate management of the diagnosis. Diabetes is currently recognized as a chronic illness, a condition requiring ongoing treatment or monitoring, rather than the death sentence it once was [1,4]. Insulin, the hormone responsible for regulating the amount of glucose in the blood, was the first chemically synthesized human protein in 1963 [5]. In 1979, the first needle-free insulin delivery system was introduced [6]. The continuous glucose monitor was later released in 2006, allowing people with diabetes a real-time update of their blood glucose levels [7]. Because of these technological advancements, people with diabetes are able to more closely control their blood glucose levels, reducing the physical symptoms of hyperglycemia on their bodies [7].People with diabetes are now living longer than ever before as their physical symptoms improve, allowing researchers the opportunity to study the neurological effects of type 1 diabetes for the first time in history [7, 8].

The Cause of Diabetes

 Diabetes is caused by an autoimmune reaction that forces the body’s natural defense system to mistake its own insulin-making cells in the pancreas for foreign cells and attack them [6]. Insulin is released in response to rising glucose levels in your blood, lowering the amount of glucose in your blood when the insulin hormone detects high levels [6]. When your body stops producing insulin, this leads to high blood sugar, or hyperglycemia [2]. To manage hyperglycemia, people with diabetes inject synthesized insulin, which gets absorbed into the bloodstream via the fat layer under the skin [9]. However, injecting too much insulin can lead to hypoglycemia, or low blood sugar [7]. Both hypo- and hyperglycemia can have disastrous neurological effects, so the management of diabetes involves keeping your blood glucose levels within a certain range [10]. In current times, diabetic death is most often caused by cardiovascular disease, neuropathy, or retinopathy, as people with diabetes are much more susceptible to early disease onset than a healthy individual [11].

The Neurological Effects of Diabetes

There is a significant difference in ratings of quality of life between those with type 1 diabetes and the normal population [8]. People diagnosed with diabetes report a lower quality of life and less restful sleep than the normal population [8, 12]. While there exists hypotheses and theories about the cognitive effects of diabetes type 1, there is still a lot that scientists do not know and research is ongoing. The physical brain alterations, such as gray and white matter loss caused by diabetes, are only recently being explored. Neurological symptoms of diabetes are usually connected to the metabolic symptoms, such as hyper- and hypoglycemia [8]. A recent study demonstrated that cognitive impairments in those with treated diabetes are observed two years after diagnosis with type 1 diabetes [8]. Six years post diagnosis, attention, processing speed, long term memory, and executive function decreased, vital cognitive skills that are used in everyday functioning [8, 13]. The younger the child is when diagnosed with diabetes, the more drastic these differences are when compared to the normal population [8]. In children diagnosed before the age of 7, lower IQ scores and lower response times are reported following diagnosis [8].The most severely affected cognitive function studied is memory, and it is hypothesized that this is attributed to the combination of periods of high and low blood sugars [8, 13]. The study reports that the degradation of memory is “generally present but slow,” and it is important to emphasize that these effects become more severe as blood glucose levels worsen [8].  These observations were true across the entire sample of people with diabetes, treated or untreated [8].

Once diagnosed, the most important symptom to control is blood sugar level [6]. If blood sugar does not remain within a normal range, people with diabetes can experience organ damage, including kidney damage requiring dialysis treatment and eye damage which could result in blindness [9]. They are also at a higher risk of heart disease and stroke [9]. Neurologically, extended periods of hyperglycemia can also reduce gray matter volume, which is discussed in more detail below [2, 16]. Prior to diagnosis, children experience a long period of hyperglycemia so their bodies become adjusted to functioning with excess glucose in the blood [14]. Once they begin controlling their blood sugar again with insulin, it is common for children to experience severe periods of hypoglycemia, with symptoms including anxiety, fast heartbeat, confusion, dizziness, and seizures [8]. Unfortunately, these negative side effects of returning blood sugar to the normal range after diagnosis can induce anxiety around taking insulin, causing people with diabetes to fear the possibility of low blood sugar [8]. This can lead to noncompliance with medications and continued hyperglycemia [8].

Hyperglycemia

Long periods of hyperglycemia can lead to decreased gray matter volume, which is the part of the brain that houses the cell bodies of the neurons and is vital to our daily function [15]. Hyperglycemia specifically reduces gray matter in the occipital lobe of the brain [8, 16]. The occipital lobe is responsible for visual processing, and reduced gray matter in this lobe suggests a reason for the vision problems many people with diabetes experience from hyperglycemia [13, 17]. Hyperglycemia can also cause loss of white matter in the frontal and parietal lobes of the brain. [8, 15]. White matter is responsible for information transfer; when there is less white matter in the brain, information is transferred slower and less effectively [18]. A combination of these factors, particularly the decrease in white matter in the frontal lobe, causes decreased executive function [8]. Executive function is the cognitive domain that allows humans to engage in “higher-order” thinking, including making rational decisions, organizational skills, and breaking down a complex problem into parts, and is usually associated with the frontal lobe [17]. In adolescence, when the onset of type 1 diabetes usually occurs, executive function is particularly important because of the higher rate of risk-taking behaviors that occur at this time in one's life [8]. Drinking alcohol and smoking, some examples of risk-taking behavior, have more severe effects in diabetic bodies than in healthy individuals, especially at younger ages [8]. Although the physical effects of long term hyperglycemia, like heart disease, kidney problems, and stroke,  are well known and warned against, the neurological effects are not [8, 19].

Hypoglycemia

Hypoglycemia, on the other hand, has effects that are still being explored. Hypoglycemia can cause seizures, which can result in impaired memory and slower processing speed (the speed in which it takes someone to make decisions and solve problems) [20, 13]. Seizures caused by hypoglycemia also decrease white matter volume in the amygdala and hippocampus, the areas of the brain that control emotion and memory, respectively [19]. 

Another impact that these brain changes can have is on working memory [8]. Working memory is what allows important information to be readily available, which is a skill that we need frequently, and impairment could contribute to slower processing speed. [13] The cognitive deficits that diabetes can cause may influence a person’s ability to effectively manage their blood sugar levels, as this requires attention to detail and memory, which can lead to poorer control of blood sugar levels and perpetuate the cycle between poorly controlled blood sugar and cognitive impairment [13]. 

Other Effects

Unfortunately, even if blood glucose levels are within healthy boundaries, diabetes still has some measurable consequences on the brain. Due to the attention to diet that diabetes treatment requires, females with type 1 diabetes are twice as likely to develop an eating disorder as those without diabetes [21]. Eating disorders can lead to more hypoglycemic and hyperglycemic events, worsening the aforementioned effects [8, 21].

Personal Reflection on Diabetes

Based on these studies and other emerging research, a diabetes diagnosis can be very scary. What remains promising, though, is our ever increasing advancements in medicine that give people with diabetes more tools and resources to manage this diagnosis and to learn to live with it. 

Anecdotally, my interest in type 1 diabetes stems from my own diagnosis eight years ago! As I have learned in the last near-decade, hope should never be lost. Diabetics have more resources than ever before to manage our chronic illness, and experts are working every day to develop a cure. Until then, the best treatment for diabetes is a healthy balance between carbohydrate counting and living a fulfilling life, while taking a few moments after every snack or meal to calculate carbs and inject insulin. 

The most important treatment for diabetes is perseverance. Every day is a new battle, and considering the neurological effects of low and high blood sugar, simple tasks can be made much more difficult after years of dealing with diabetes. The best way to combat these effects is by managing one’s blood sugar to the best of their ability. Striving for perfection in treatment can become exhausting, but “good enough” is just that! Keeping good enough control of one’s blood sugar is the key to minimizing the neurological effects of diabetes and living a healthy, happy life.

One should always keep in mind, too, that the research addressing diabetes’ neurological effects is brand new, emerging in only the last five years! There is more to be learned and explored in the brains of people with diabetes, and new technological advances are being made every year. Perhaps we will soon learn of the benefits of a slight excess of glucose in the brain, or a new link will be found between insulin and neurons. So, until a cure for type 1 diabetes exists, let’s keep the insulin pumping and those neurons firing!

References:

1. Lakhtakia, R. (2013). The history of diabetes mellitus = نظرة تاريخية عن مرض السكري. Sultan Qaboos University Medical Journal, 13(3), 368–370. https://doi.org/10.12816/0003257 

2. Ramachandran, A. (2014). Know the signs and symptoms of diabetes. The Indian journal of medical research. Retrieved February 7, 2022, from https://pubmed.ncbi.nlm.nih.gov/25579136/. 

3. Mazur, A. (2011, March 11). Why were "starvation diets" promoted for diabetes in the pre-insulin period? Nutrition journal. Retrieved February 7, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062586/ 

4. Raghupathi, W., & Raghupathi, V. (2018). An Empirical Study of Chronic Diseases in the United States: A Visual Analytics Approach. International journal of environmental research and public health, 15(3), 431. https://doi.org/10.3390/ijerph15030431

5. Karas JA, Wade JD, Hossain MA. The Chemical Synthesis of Insulin: An Enduring Challenge. Chem Rev. 2021 Apr 28;121(8):4531-4560. doi: 10.1021/acs.chemrev.0c01251. Epub 2021 Mar 9. PMID: 33689304.

6. Diagnosis and classification of diabetes mellitus. (2011). Diabetes Care, 34(Supplement_1). https://doi.org/10.2337/dc11-s062 

7. Akil AA, Yassin E, Al-Maraghi A, Aliyev E, Al-Malki K, Fakhro KA. Diagnosis and treatment of type 1 diabetes at the dawn of the personalized medicine era. J Transl Med. 2021 Apr 1;19(1):137. doi: 10.1186/s12967-021-02778-6. PMID: 33794915; PMCID: PMC8017850.

8. Litmanovitch, E., Geva, R., & Rachmiel, M. (2015). Short and long term neuro-behavioral alterations in type 1 diabetes mellitus pediatric population. World journal of diabetes, 6(2), 259–270. https://doi.org/10.4239/wjd.v6.i2.259

9. Miller, R. G., Secrest, A. M., Sharma, R. K., Songer, T. J., & Orchard, T. J. (2012). Improvements in the life expectancy of type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complications study cohort. Diabetes, 61(11), 2987–2992. https://doi.org/10.2337/db11-1625

10. U.S. Department of Health and Human Services. (n.d.). What is diabetes? National Institute of Diabetes and Digestive and Kidney Diseases. Retrieved February 25, 2022, from https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes 

11. Distiller, L. A. (2014, June 15). Why do some patients with type 1 diabetes live so long? World journal of diabetes. Retrieved February 7, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058732/

12. Livingstone, S. J., Levin, D., Looker, H. C., Lindsay, R. S., Wild, S. H., Joss, N., Leese, G., Leslie, P., McCrimmon, R. J., Metcalfe, W., McKnight, J. A., Morris, A. D., Pearson, D. W., Petrie, J. R., Philip, S., Sattar, N. A., Traynor, J. P., & Colhoun, H. M. (2015).

13. Cowan N. (2014). Working Memory Underpins Cognitive Development, Learning, and Education. Educational psychology review, 26(2), 197–223. https://doi.org/10.1007/s10648-013-9246-y

14. Karamanou, M., Protogerou, A., Tsoucalas, G., Androutsos, G., & Poulakou-Rebelakou, E. (2016). Milestones in the history of diabetes mellitus: The main contributors. World journal of diabetes, 7(1), 1–7. https://doi.org/10.4239/wjd.v7.i1.1

15. Mercadante AA, Tadi P. Neuroanatomy, Gray Matter. [Updated 2021 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK553239/

16. Yu KKK, Cheing GLY, Cheung C, Kranz GS, Cheung AK. Gray Matter Abnormalities in Type 1 and Type 2 Diabetes: A Dual Disorder ALE Quantification. Front Neurosci. 2021 Jun 7;15:638861. doi: 10.3389/fnins.2021.638861. PMID: 34163319; PMCID: PMC8215122.

17. Backeström, A., Papadopoulos, K., Eriksson, S., Olsson, T., Andersson, M., Blennow, K., Zetterberg, H., Nyberg, L., & Rolandsson, O. (2021, March 19). Acute hyperglycaemia leads to altered frontal lobe brain activity and reduced working memory in type 2 diabetes. PLOS ONE. Retrieved April 14, 2022, from 

18. Filley CM, Fields RD. White matter and cognition: making the connection. J Neurophysiol. 2016 Nov 1;116(5):2093-2104. doi: 10.1152/jn.00221.2016. Epub 2016 Aug 10. PMID: 27512019; PMCID: PMC5102321.

19. Yang, Y., & Wang, J.-Z. (2017). From structure to behavior in basolateral amygdala-hippocampus circuits. Frontiers in Neural Circuits, 11. https://doi.org/10.3389/fncir.2017.00086

20. Dingledine, R., Varvel, N. H., & Dudek, F. E. (2014). When and how do seizures kill neurons, and is cell death relevant to epileptogenesis?. Advances in experimental medicine and biology, 813, 109–122. https://doi.org/10.1007/978-94-017-8914-1_9

21. Murphy R, Pigott A. Eating disorders and type 1 diabetes. Clin Child Psychol Psychiatry. 2021 Jul;26(3):589-594. doi: 10.1177/13591045211028165. Epub 2021 Jun 21. PMID: 34154458.