Effects of Diabetes Mellitus-Related Dysglycemia on the Functions of Blood–Brain Barrier and the Risk of Dementia

Abstract

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood–brain barrier (BBB), seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin-independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response, which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aβ aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.

Anti-Inflammatory Action of Resveratrol in the Central Nervous System in Relation to Glucose Concentration—An In Vitro Study on a Blood–Brain Barrier Model

“… Pro-inflammatory consequences of hyper- and hypoglycemia (marked in red and blue, respectively) in the central nervous system (CNS). Increased glucose inflow into pericytes and astrocytes in hyperglycemia leads to excess reduced nicotinamide adenine dinucleotide (NADH), which results in excessive reactive oxygen species (ROS) production and activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [ 3 , 11 , 17 ]. This damages the integrity of the blood–brain barrier (B-B-B) and increases its permeability [ 18 , 19 , 20 ].…”

“…Because nervous cells preferentially use glucose to obtain energy, and the influx of glucose to neurons is not insulin dependent [ 1 ], oscillations of glucose concentration can affect metabolic processes within the CNS. Both diabetes-related hyperglycemia and iatrogenic hypoglycemia (induced by anti-diabetic insulin treatment) may affect the functioning of the CNS [ 2 , 3 ]. Inflammation in the CNS can damage the neurons, as was documented with Alzheimer’s disease, Parkinson’s disease, encephalitis, meningitis, neurosarcoidosis, and hyperglycemia [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ].…”

“…Both diabetes-related hyperglycemia and iatrogenic hypoglycemia (induced by anti-diabetic insulin treatment) may affect the functioning of the CNS [ 2 , 3 ]. Inflammation in the CNS can damage the neurons, as was documented with Alzheimer’s disease, Parkinson’s disease, encephalitis, meningitis, neurosarcoidosis, and hyperglycemia [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Neuroinflammatory processes can be particularly difficult to predict in diabetes because the cytokine profile in the CNS depends on serum glucose concentration [ 10 ].…”

“…Hyperglycemia can result in an increased glucose influx to BBB-forming cells (both pericytes and astrocytes) [ 3 , 11 ]. Temporary, incidental high blood sugar levels are not harmful to neurons, because the passage of glucose into the cerebrospinal fluid is tightly regulated by a healthy BBB, but prolonged periods of hyperglycemia in diabetic patients can lead to the production of reactive oxygen species (ROS) in astrocytes and pericytes, primarily due to an accelerated process of aerobic oxidative glycolysis, followed by subsequent reactions in the tricarboxylic acid cycle that convert oxidized nicotinamide-adenine dinucleotide (NAD+) into its reduced form, NADH [ 12 , 13 , 14 ].…”

Chemokine CX3CL1 (Fractalkine) Signaling and Diabetic Encephalopathy

“…This may justify the introduction of DE, defined as the sum of the effects of insufficient insulin on the CNS. The pathomechanisms of cognitive deficits occurring in DE largely overlap with the pathomechanisms of other neurodegenerative diseases, resulting in neuronal loss [37]. The duration of diabetes increases the incidence of both diabetic neuropathy and DE, which do not immediately appear at the onset of the disease, especially when patients' blood glucose levels are well stabilized [38].…”