1. Diabetes Mellitus and Brain Function
Every year, there is a growing incidence of both type 1 and type 2 diabetes. Despite different causes of the disease (failure in insulin production or insulin resistance), the effect of the disease remains the same: hyperglycaemia [1
]. It has been observed that people with diabetes caused by autoimmune reactions can also have or develop insulin resistance, typically linked to type 2 diabetes. Decreased insulin sensitivity impairs management of the disease and increases the risk of chronic complications. As a consequence, it worsens the prognosis of people with diabetes. Despite increasingly better tools for the control and regulation of the glucose level in blood, the percentage of good metabolic management of the disease is poor. Within years, diabetes may lead to decreased quality of life due to the development of numerous complications, such as eye, kidney, nerve and heart damage [1
]. Finally, it involves premature death.
Diabetes also significantly influences the function of the central nervous system (CNS). It is a well-known fact that diabetes increases the risk of neurologic and psychiatric diseases. In Latinos over 60 years old, diabetes causes a higher risk of depression symptoms [2
]. It was also proved that women in Australia who had diabetes experienced anxiety disorders more often than healthy women [3
]. Moreover, children with type 1 diabetes were found to very often also suffer from psychiatric diseases, which in their case correlated with higher concentrations of HbA1c (glycated hemoglobin) [4
]. Type 2 diabetes is also related to increased risk of Alzheimer’s disease and vascular dementia [5
]. Higher glucose concentration in brain tissues and higher insulin resistance correlated with the severity of Alzheimer’s disease and the expression of its symptoms [6
]. Moreover, there is a hypothesis that Alzheimer’s disease is a diabetes type 3. Insulin resistance is related to the production of beta-amyloid deposits in the CNS [7
]. It was also proven that in patients with Parkinson’s disease, insulin resistance occurred more often in a group of patients with dementia than in patients suffering from Parkinson’s disease but without coexisting dementia [5
]. There are also data about the role of neurotrophins and metabolic effects in the course of anorexia nervosa [8
], which occurs more often in the diabetic population.
Factors that could contribute to improving the prognosis and metabolic control of diabetic patients are still being searched for. It is known, however, that one such factor is systematic physical activity. The exact mechanisms of its influence on glycemia remain unexplored. There are numerous premises that increased secretion of neurotrophins might be one such mechanism. Apart from this, physical activity has a positive impact on CNS function, as it improves cognitive functions, improves memory, and decreases the risk of dementia.
The purpose of this review article is to explore the connection between brain-derived neurotrophic factor (BDNF) and diabetes. In particular, we explore the hypothesis that increased levels of neurotrophins in target tissues of people with diabetes, induced by physical activity, will improve the course of the disease.
Neurotrophins are a family of proteins that consist of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins NT-3 and NT-4/5. Neurotrophins are responsible for increasing the survival of neurons and their damage resistance [9
BDNF via its receptors, p75 NT receptor (p75NTR) and tyrosine kinase receptor B (TrkB), affects neurons in multiple ways. Mature BDNF acts on neurons mainly via the Trk receptor [10
]. BDNF can stimulate nerve regeneration and is responsible for the development, plasticity and support of the nervous system [9
Neurotrophins are produced mainly by the CNS, but also by peripheral tissues [11
]. BDNF and also its mRNA as well as TrkB are largely found in the hypothalamus, limbic system and other areas of the brain, such as hippocampus nuclei [10
]. What is more, BDNF is also expressed in the skeletal muscle, endothelial cells, liver, adipose tissues, and activated immune cells [10
]. Blood serum and plasma also contain BDNF. Studies have shown that peripheral BDNF is stored in platelets [10
In addition to its central effects on brain tissue, BDNF has a role in energy homeostasis in humans [9
]. Thus, the amount of data about the role of BDNF in metabolic control, especially glucose metabolism and insulin resistance, is still increasing [14
]. BDNF is also named “metabokine” because of its effects on glycemia, lipid profile and energy homeostasis. BDNF levels are impaired in atherosclerosis, acute coronary syndrome and metabolic syndrome [16
]. Moreover, altered BDNF level is related to increased appetite, obesity, type 2 diabetes, depression, as well as Alzheimer’s and Parkinson’s diseases [17
]. BDNF has become an interesting target as a treatment option. The functions of BDNF in diabetes are presented in Figure 1
The factors influencing BDNF concentration in target tissues are still being researched. Komori et al. investigated the effect of intravenous leptin injection in mice. Their results suggest that leptin induces BDNF expression in the dorsomedial part of the ventromedial hypothalamic nucleus [13
]. There are ongoing studies on the relationship between BDNF and adipocytokines, such as leptin, resistin, and adiponectin.
4. BDNF and Chronic Complications of Diabetes
Despite huge progress in the diagnosis and treatment of diabetes, its chronic complications still remain an important clinical problem. Diabetes is a leading cause of blindness and non-traumatic foot amputations. It is also responsible for kidney failure and the need for renal replacement therapy as the most common reason. Finally, diabetes is an independent risk factor of cardiovascular diseases, which are the main cause of death in this group of patients.
The traditional risk factors for diabetic angiopathy are hyperglycemia, duration of the disease, dyslipidemia, smoking, and insulin resistance. New, non-traditional risk factors and markers are still sought after. Among those new factors, neurotrophins have a place.
In the research described below, the authors mainly focused on the serum level of BDNF as a risk factor for diabetes complications. The authors also noticed the potential therapeutic role of BDNF.
Ola et al. in their research investigated the serum level of BDNF in blood samples from 88 individuals (47 patients suffering from proliterative diabetic retinopathy, 22 diabetic patients with no retinopathy, 19 healthy participants). Patients suffering from proliferative diabetic retinopathy had a decreased level of BDNF in the serum compared to a healthy control group and diabetic patients with no retinopathy.
Ola et al. also conducted tests on rats. They used adult male Sprague–Dawley rats, 9–10 weeks of age. Streptozocin was injected intraperitoneally and citrate buffer was administered to non-diabetic animals in order to induce the development of diabetes. After 3/10 weeks, the rats were killed and their retinas were examined. Then, their blood was collected from the heart (control/diabetic animals). A significant difference in the serum level of BDNF was evident in the 10-week group with diabetes (there was no significant difference in the three-week group). The serum level of BDNF was higher in the control group than in the 10-week diabetes rat group. Moreover, the level of BDNF in the retinal homogenate of both the three-week and 10-week diabetes rat groups was lower than in the control group [36
Kaviarasan et al. were searching for risk factors of diabetic retinopathy. They conducted a study on a group of 114 participants. The majority of participants were people suffering from type 2 diabetes (27 individuals had no complications, 30 patients had non-proliferative diabetic retinopathy, and 30 patients had proliferative diabetic retinopathy), but they also examined 27 healthy participants as a control group. They revealed that BDNF levels were lower in patients suffering from proliferative diabetic retinopathy and non-proliferative diabetic retinopathy compared to the control group. What is more, this research proved that BDNF has a positive correlation with interleukin-10. This study shows that a low serum level of BDNF is a risk factor for diabetic retinopathy [37
Seki et al. investigated the effects of intraocular administration of BDNF to streptozotocin-induced diabetic rats. In their research, they used adult male Wistar rats, nine weeks of age. Streptozocin was injected intraperitoneally, and non-diabetic animals were administered with a citrate buffer. Diabetes was confirmed by determining the level of glucose in the blood. The rats also had BDNF injected into their vitreous cavities. Rats were killed four weeks after the streptozicin injection, and their retinas were examined. Seki et al. suggested that dopaminergic amacrine cells degenerate in the retinas of diabetic rats. They proved that non-diabetic rats had a higher tyrosine hydroxylase density (marker for retinal dopaminergic amacrine cells) in their retinas than diabetic animals. It was shown that the protein and mRNA levels of BDNF in the retinas of diabetic animals were lower than those of normal control rats. Injection of BDNF into the vitreus cavities of diabetic rats prevented dopaminergic amacrine cells from degeneration. This study suggests that BDNF may have a role in the treatment of early retinal neuropathy [38
Sun et al. in their experiment investigated blood samples from 110 healthy individuals, 83 patients suffering from diabetes mellitus type 2, and 65 patients with diabetic peripheral neuropathy. They tried to find correlations between serum BDNF levels and clinical parameters in diabetic peripheral neuropathy. Serum levels of BDNF in the diabetes type 2 group and the control group were higher compared to the diabetic peripheral neuropathy group. Serum levels of BDNF in the control group were higher compared to the patients with diabetes mellitus type 2. Qin Sun et al. revealed that BDNF levels were correlated with the course of disease for patients, fasting C-peptide, 2-hour postprandial C-peptide level, glycosylated hemoglobin level, and 24-hour urinary microalbumin excretion [39
Li et al. conducted a study on a group of rats. The study explained the properties of exogenous BDNF in animals with streptozotocin-induced diabetic neuropathic pain. The research proved that continued intrathecal administration of BDNF to diabetic animals relieved mechanical and thermal hyperalgesia. What is more, administration of BDNF reduced the hyperexcitability of dorsal root ganglion neurons. This study suggests that BDNF may have a role in the treatment of painful diabetic neuropathy [40
In summary, in the course of diabetes, the most important issue is the development of neurovascular complications. It was proved that a low serum level of BDNF was a risk factor for diabetic retinopathy. Moreover, in people with diabetic peripheral neuropathy, BDNF serum levels were lower in comparison with a group with diabetes without complications and a healthy control group [36
]. There is also evidence for the therapeutic possibilities of BDNF. The injection of BDNF into the vitreous cavities of diabetic rats prevented dopaminergic amacrine cells from degeneration [38
]. Moreover, the study showed that continued intrathecal administration of BDNF to diabetic rats relieved hyperalgesia [40
The studies above suggest that a low level of BDNF may be a risk factor of diabetic neurovascular complications and that the administration of exogenous BDNF may have a role in the treatment of diabetes complications.