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Sempere, M. Diabetic Neuropathy. Encyclopedia. Available online: https://encyclopedia.pub/entry/8759 (accessed on 30 June 2024).
Sempere M. Diabetic Neuropathy. Encyclopedia. Available at: https://encyclopedia.pub/entry/8759. Accessed June 30, 2024.
Sempere, Mar. "Diabetic Neuropathy" Encyclopedia, https://encyclopedia.pub/entry/8759 (accessed June 30, 2024).
Sempere, M. (2021, April 17). Diabetic Neuropathy. In Encyclopedia. https://encyclopedia.pub/entry/8759
Sempere, Mar. "Diabetic Neuropathy." Encyclopedia. Web. 17 April, 2021.
Diabetic Neuropathy
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This entry is adapted from the peer-reviewed paper 10.3390/jpm11030230

Diabetic neuropathy is defined as the dysfunction of the peripheral nervous system in diabetic patients. It is considered a microvascular complication of diabetes mellitus. Its presence is associated with increased morbidity and mortality. Although several studies have found alterations at somatic motor, sensory levels and at the level of autonomic nervous system in diabetic patients, there is not a systematic approach regarding the differences in neuropathy between the major variants of diabetes, e.g., type 1 and 2 diabetes at both neurological and molecular level.

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1. Introduction

Diabetes is a chronic, metabolic disease characterized by elevated levels of blood glucose, which leads over time to serious damage to the heart, blood vessels, eyes, kidneys, and nerves. Its consequences are one of the most serious public health problems with a considerable impact on both human and health resources. Diabetes not only affects the individual’s functionality and quality of life, it is also associated with premature mortality as well as increased morbidity [1]. There are several forms of diabetes [2][3][4]. Type 1 diabetes is a chronic autoimmune disease characterized by the pancreas losing the ability to generate insulin, the hormone that regulates hyperglycemia. For this reason, people with type 1 diabetes will require daily insulin administration for life. Type 2 diabetes is characterized by the presence of high blood glucose levels due to the body’s resistance to insulin, which means that although this hormone is present in the circulation, the cells cannot use it properly to introduce the sugar into their interior.

The main causes of insulin resistance are lack of physical activity and the accumulation of adipose tissue, so excess weight and a sedentary lifestyle seem to be the main risk factors for the development of this disease. Maturity Onset Diabetes in the Young (MODY) is caused by genetic defects of the pancreatic beta cells due to different genetic alterations, presented as autosomal dominant inherited disorders leading to a defect in insulin secretion. Cystic fibrosis related diabetes is a genetic disease that affects multiple organs including the pancreas, which can lead to the development of diabetes. Diabetes can be secondary to the effects of some medications (for examples glucocorticoids and immunosuppressants drugs) that can alter the secretion or action of insulin. Pregnancy puts a great metabolic strain on the mother’s body, which can sometimes lead to some insulin resistance. As a result, the pancreas has to produce more insulin to get glucose into the cells and reduce its accumulation in the blood, and sometimes this organ is unable to secrete enough of the hormone, so blood glucose levels rise leading to gestational diabetes and glucose intolerance resembling type 2 diabetes.

The most prevalent types of diabetes are type 1 and 2, but type 2 diabetes is up to 10 times more frequent than type 1 diabetes. The incidence of type 1 diabetes increases with age until it reaches its peak at around 10 to 14 years of age, but the disease can debut at any age [5]. Meanwhile, the peak of the incidence of type 2 diabetes is later, at between 55 and 59 years old [6]. Type 1 and 2 diabetes show a slightly higher prevalence in men than in women. An estimated 462 million people worldwide, the equivalent to 6.28% of the world’s population, are affected by type 2 diabetes. The global incidence of type 1 diabetes began to rise in the 1950s with an average annual increase of 3–4% over the past three decades, and incidences of approximately 10–20 cases per 100,000 population in southern Europe and the United States of America [1][6]. Healthcare expenditure on diabetes care is at least 3.2 times higher than the calculated average per capita and increases to 9.4 times in the presence of complications. In terms of functionality, diabetes is among the top 10 disabling diseases [5], and among its diabetic complications, neuropathy affects quality of life and is associated with an increased risk of amputations [7][8], morbidity and mortality [9][10]. Diabetic peripheral neuropathy is the most common form of neuropathy worldwide. The most recent studies in Europe and the United States of America indicate a prevalence of diabetic peripheral neuropathy ranging from 6 to 51% of the population of people with diabetes. The prevalence of diabetic peripheral neuropathy in adults with type 1 diabetes is 6% at the onset of the disease, increasing to 30% after 13–14 years of progression [11][12]. This prevalence is somewhat higher among people with type 2 diabetes and is present in 26% of young people with type 2 diabetes. Among adults with diabetes, about 40% of patients at cardiovascular risk have peripheral neuropathy [11].

Risk factors for the development of neuropathy include different variables such as age, duration of diabetes, glycemic control, and comorbidities such as hypercholesterolemia, hypertension, obesity, and smoking. With regard to diabetic neuropathy, studies reporting the prevalence of peripheral neuropathy in young people with diabetes have determined rates of 7% in patients with type 1 diabetes and 22% with type 2 diabetes [13].

These data suggest a difference in the pathophysiological mechanisms of diabetic neuropathy between patients with type 1 and type 2 diabetes. Given the characterization of the eventual differences between neuropathy in people with type 1 and type 2 diabetes, it is important to know the best tool to assess them, in order to treat and prevent their adverse effects, and to be able to plan specific care depending on the manifestations of neuropathy that may occur in the two most frequent types of diabetes.

2. Differences and Similarities in Neuropathy in Type 1 and 2 Diabetes

One of the modifiable factors that may be related to the development of diabetic neuropathy, especially in people with diabetes, is obesity, which is an entity that is often comorbid, especially in type 2 diabetic patients [14][15]. It is well-know that autonomic nervous system dysfunction has a bidirectional relationship with obesity [16]. On the one hand, there is good scientific evidence that alterations of the autonomic nervous system could be involved in the pathogenesis of obesity, and on the other hand, obesity (especially central, visceral obesity) induces autonomic nervous system dysfunction, which may be involved in hemodynamic and metabolic alterations that increase the cardiovascular risk of obese individuals such as the insulin resistance, among others, which increases the risk of type 2 diabetes [16][17]. According to this, the autonomic neuropathy in diabetics was more prevalent in obese patients. Regarding the incidence of cardiac autonomic neuropathy, it was higher in obese patients with type 2 diabetes which also adds higher odds to present comorbid arterial hypertension [18][15]. The incidence of erectile dysfunction and alterations in fasting gallbladder volume and less complete emptying increased with increasing body-mass index [19][20]. In contrast to autonomic neuropathy, BMI seems to not play a significant role on motor nerves alterations in diabetic patients [21], however much work should be done regarding sensorimotor neuropathy and obesity, taking into account that weight reduction significantly improved autonomous dysfunction in obesity and likely autonomic neuropathy in diabetes [16].

Regarding peripheral biomarkers associated to neuropathy, some of those are related to chronic inflammatory state such as the inflammatory cytokine IL-6 [22], and to the innate immune response receptor TLR4 [23] associated more frequently to the severity of neuropathy in type 2 diabetes patients. In type 1 diabetes, the most promising biomarker related to neuropathy appearance and severity is adiponectin, the richest adipokine in human plasma mainly secreted from white adipose tissue. Changes in the concentration of adiponectin isoforms in blood have also demonstrated in type 2 diabetes [24]. These differences in peripheral biomarkers might contribute to the pathophysiological progression of various diabetic neuropathy types and symptoms and it clearly deserves further studies.

The increase in life expectancy worldwide in recent decades, particularly among women, has meant that people with diabetes live longer with the disease and therefore suffer from its complications, with the most prevalent being diabetic neuropathy [25][26]. As a result, it is important to study age and gender as risk factors involved in the development of diabetic neuropathy. However, only six articles in this study have examined these issues. In their study, Grisold et al. [27] recently pinpointed that age and gender are possible risk factors for the development of diabetic peripheral neuropathy in type 1 and type 2 diabetes, although their exact contribution is unknown. After reviewing the articles, age was observed to be a risk factor in the development of autonomic cardiac neuropathy and motor neuropathy, with the latter measured in parameters of motor nervous excitability, and in both cases this relationship was only found in type 2 diabetics [21][28]. However, a relationship was detected between CAN and the “advanced age” factor in both type 1 and type 2 diabetic patients [29]. These results suggest that older age, which is a more typical characteristic in studies of type 2 diabetics, is a risk factor for diabetic neuropathy. With regard to the influence that gender could have in this aspect, little research has been done and no relationship has been found.

Diabetic neuropathy is the most common complication of diabetes mellitus and the one that has the greatest impact on the life of the patient, with high rates of morbidity and mortality. Knowing how sensory, motor, and autonomic neuropathy affects each type of diabetes and their differences and similarities is essential for developing an adapted diagnostic and therapeutic plan in order to better address the disease and avoid irreversible damage.

This review has identified several aspects that require future research. One of the unknown factors identified is the different involvement of the nerve fibers responsible for each sensory function, and its possible relationship with its characteristic anatomy and physiology function or dysfunction in diabetes. Motor neuropathy and its peculiarities, typical of type 1 and type 2 diabetes, require a great deal of attention since it is the least investigated neuropathy domain investigated so far. As for autonomic neuropathy, it is important to clarify the mechanism of sympathetic and parasympathetic involvement in both types of diabetes, as well as the related disorders to alterations or autonomic nervous system. In this way, the characterization of the disease subtype will improve the diagnosis and treatment of neuropathy and it will consequently allow a more personalized and effective treatment besides glycemic index control.

References

  1. Norris, J.M.; Johnson, R.K.; Stene, L.C. Type 1 diabetes—Early life origins and changing epidemiology. Lancet Diabetes Endocrinol. 2020, 8, 226–238.
  2. Grulich-Henn, J.; Klose, D. Understanding childhood diabetes mellitus: New pathophysiological aspects. J. Inherit. Metab. Dis. 2018, 41, 19–27.
  3. Peixoto-Barbosa, R.; Reis, A.F.; Giuffrida, F.M.A. Update on clinical screening of maturity-onset diabetes of the young (MODY). Diabetol. Metab. Syndr. 2020, 12, 1–14.
  4. Zaccardi, F.; Webb, D.R.; Yates, T.; Davies, M.J. Pathophysiology of type 1 and type 2 diabetes mellitus: A 90-year perspective. Postgrad. Med. J. 2015, 92, 63–69.
  5. Xia, Y.; Xie, Z.; Huang, G.; Zhou, Z. Incidence and trend of type 1 diabetes and the underlying environmental determinants. Diabetes/Metabolism Res. Rev. 2019, 35, e3075.
  6. Khan, M.A.B.; Hashim, M.J.; King, J.K.; Govender, R.D.; Mustafa, H.; Al Kaabi, J. Epidemiology of Type 2 Diabetes–Global Burden of Disease and Forecasted Trends. J. Epidemiol. Glob. Health 2020, 10, 107–111.
  7. Gherman, D.; Dumitrescu, C.I.; Ciocan, A.; Melincovici, C.S. Histopathological changes in major amputations due to diabetic foot—A review. Romanian J. Morphol. Embryol. = Rev. Roum. de Morphol. et Embryol. 2018, 59, 699–702.
  8. Rorive, M.; Scheen, A.J. [News in the management of diabetic foot]. J. News Manag. Diabetic Foot. Rev. Med. Suisse 2019, 15, 1448–1452.
  9. Tesfaye, S.; Selvarajah, D. Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes/Metabolism Res. Rev. 2012, 28, 8–14.
  10. Azmi, S.; Petropoulos, I.N.; Ferdousi, M.; Ponirakis, G.; Alam, U.; Malik, R.A. An update on the diagnosis and treatment of diabetic somatic and autonomic neuropathy. F1000Research 2019, 8, 186.
  11. Hicks, C.W.; Selvin, E. Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in Diabetes. Curr. Diabetes Rep. 2019, 19, 1–8.
  12. Martin, C.L.; Albers, J.W.; Pop-Busui, R.; for the DCCT/EDIC Research Group. Neuropathy and Related Findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study. Diabetes Care 2014, 37, 31–38.
  13. Iqbal, Z.; Azmi, S.; Yadav, R.; Ferdousi, M.; Kumar, M.; Cuthbertson, D.J.; Lim, J.; Malik, R.A.; Alam, U. Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy. Clin. Ther. 2018, 40, 828–849.
  14. Aulich, J.; Cho, Y.H.; Januszewski, A.S.; Craig, M.E.; Selvadurai, H.; Wiegand, S.; Jenkins, A.J.; Donaghue, K.C. Associations between circulating inflammatory markers, diabetes type and complications in youth. Pediatr. Diabetes 2019, 20, 1118–1127.
  15. Ayad, F.; Belhadj, M.; Pariès, J.; Attali, J.R.; Valensi, P. Association between cardiac autonomic neuropathy and hypertension and its potential influence on diabetic complications. Diabet. Med. 2010, 27, 804–811.
  16. Guarino, D.; Nannipieri, M.; Iervasi, G.; Taddei, S.; Bruno, R.M. The Role of the Autonomic Nervous System in the Pathophysiology of Obesity. Front. Physiol. 2017, 8, 665.
  17. Fidan-Yaylali, G.; Yaylali, Y.T.; Erdogan, Ç.; Can, B.; Senol, H.; Gedik-Topçu, B.; Topsakal, S. The Association between Central Adiposity and Autonomic Dysfunction in Obesity. Med Princ. Pr. 2016, 25, 442–448.
  18. Gulichsen, E.; Fleischer, J.; Ejskjaer, N.; Eldrup, E.; Tarnow, L. Screening for Diabetic Cardiac Autonomic Neuropathy Using a New Handheld Device. J. Diabetes Sci. Technol. 2012, 6, 965–972.
  19. Fedele, D.; Coscelli, C.; Cucinotta, D.; Forti, G.; Santeusanio, F.; Viaggi, S.; Fiori, G.; Velonà, T.; Lavezzari, M.; the Members of the Diade Study Group†. Incidence of Erectile Dysfunction in Italian Men with Diabetes. J. Urol. 2001, 166, 1368–1371.
  20. Palasciano, G.; Portincasa, P.; Belfiore, A.; Baldassarre, G.; Cignarelli, M.; Paternostro, A.; Albano, O.; Giorgino, R. Gallbladder volume and emptying in diabetics: The role of neuropathy and obesity. J. Intern. Med. 1992, 231, 123–127.
  21. Arnold, R.; Kwai, N.; Lin, C.S.-Y.; Poynten, A.M.; Kiernan, M.C.; Krishnan, A.V. Axonal dysfunction prior to neuropathy onset in type 1 diabetes. Diabetes/Metabolism Res. Rev. 2013, 29, 53–59.
  22. Jin, H.Y.; Park, T.S. Role of inflammatory biomarkers in diabetic peripheral neuropathy. J. Diabetes Investig. 2017, 9, 1016–1018.
  23. Rudofsky, G.; Reismann, P.; Witte, S.; Humpert, P.M.; Isermann, B.; Chavakis, T.; Tafel, J.; Nosikov, V.V.; Hamann, A.; Nawroth, P.; et al. Asp299Gly and Thr399Ile genotypes of the TLR4 gene are associated with a reduced prevalence of diabetic neuropathy in patients with type 2 diabetes. Diabetes Care 2003, 27, 179–183.
  24. Swarbrick, M.M.; Havel, P.J. Physiological, Pharmacological, and Nutritional Regulation of Circulating Adiponectin Concentrations in Humans. Metab. Syndr. Relat. Disord. 2008, 6, 87–102.
  25. Boulton, A.J.; Vileikyte, L.; Ragnarson-Tennvall, G.; Apelqvist, J. The global burden of diabetic foot disease. Lancet 2005, 366, 1719–1724.
  26. Williams, R.; Colagiuri, S.; Almutairi, R.; Aschner Montoya, P.; Basit, A.; Beran, D. IDF Diabetes Atlas, 9th ed.; Suvi, K., Belma, M., Pouya, S., Paraskevi, S., Eds.; International Diabetes Federation: Brussels, Belgium, 2019.
  27. Grisold, A.; Callaghan, B.C.; Feldman, E.L. Mediators of diabetic neuropathy. Curr. Opin. Endocrinol. Diabetes Obes. 2017, 24, 103–111.
  28. Pan, Q.; Li, Q.; Deng, W.; Zhao, D.; Qi, L.; Huang, W.; Ma, L.; Li, H.; Li, Y.; Lyu, X.; et al. Prevalence and Diagnosis of Diabetic Cardiovascular Autonomic Neuropathy in Beijing, China: A Retrospective Multicenter Clinical Study. Front. Neurosci. 2019, 13, 1144.
  29. Pappachan, J.M.; Sebastian, J.; Bino, B.C.; Jayaprakash, K.; Vijayakumar, K.; Sujathan, P.; A Adinegara, L. Cardiac autonomic neuropathy in diabetes mellitus: Prevalence, risk factors and utility of corrected QT interval in the ECG for its diagnosis. Postgrad. Med J. 2008, 84, 205–210.
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Mar Sempere
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