Effects of glucose on the brain

Though there is a great amount of attention given to the effects of diabetes on the peripheral nervous system, it is important not to overlook the disease’s effects on our brains. While other organs in the body may rely on alternative sources of energy, such as fatty acids, the brain relies almost solely on glucose, using ketones as a last resort. For this reason, the blood brain barrier is rich in Glut1 active glucose transporters, and over 99% of the glucose that passes it is used by neurons and glia. Thus, the metabolic efficiency and continuous demands of the brain render it uniquely susceptible to fluctuations in glucose concentration in the body.

As we discuss in this chapter, hyperglycemia and hypoglycemia both can have detrimental effects on cognition as well as mood. These effects are evident in people with Type 1 and Type 2 diabetes. The most common manifestations of cognitive deficit are neural slowing, attention deficit, and executive functioning. Patients with type 2 diabetes in particular do more poorly in measures of learning and memory [1].

It is important to note that in a hospital setting patients without diabetes can become hyperglycemic, and these patients have an increased mortality risk [2]. Stress induced hyperglycemia in patients without diabetes can occur during periods of acute illness and may be due to hormonal cascades, particularly increases in epinephrine, cortisol, growth hormone and glucagon [3]. Patients may have “pre-diabetes”, or may have frank diabetes that is undiagnosed. Among hyperglycemic patients in general medicine wards, one study found that 12% were undiagnosed, and that they had 18.3 times the mortality rate of their normoglycemic peers. These patients also had longer hospital stays, were admitted to the ICU more often, and largely had their hyperglycemia untreated throughout the course of their stay [4]. Similarly, in patients both with and without diabetes, hypoglycemia is associated with increased inpatient mortality and increased hospital length of stay [5][6].

A clinical awareness of a patient’s glycemic state, especially if the person has diabetes, is key to protecting higher neurological functioning, such as mood and cognition, as well as mitigating the risk of mortality. In this chapter, we will further discuss the acute and chronic effects of both hypoglycemia and hyperglycemia on the brain.

Acute Hyperglycemia

The effects of acute hyperglycemia on mood and cognition in people with diabetes are controversial. One study showed that people with type 2 diabetes may not exhibit changes in cognition or mood in short periods of mild hyperglycemia. Interestingly, patients may report feelings of well being and less anger during periods of brief mild hyperglycemia [7]. Other research contradicts this, reporting increased irritability and decreased feelings of well-being in people with type 1 and type 2 diabetes who are acutely hyperglycemic [8][9]. It appears that glucose level and not variability is the determinant of mood variation [9]. Patients with lower postprandial glucose, however, do better than those with higher postprandial glucose in cognitive testing [10].

In pragmatic studies involving people with diabetes whose driving abilities are assessed, acute hyperglycemia can lead to tiredness and decreased visual acuity. This can then cause incorrect treatment adjustment precipitating hypoglycemia [11]. People with type 1 diabetes have been shown to have lower verbal and overall IQ scores during periods of acute hyperglycemia [12]. Both people with Type 1 and Type 2 diabetes have exhibited lower cognitive scores when blood glucose increases past 15mmol/l [13]. Thus, acute hyperglycemia appears to have detrimental effects that may perturb day to day functions of both people with Type 1 and Type 2 diabetes.

Chronic Hyperglycemia

The effects of chronic hyperglycemia are more pronounced than those of acute hyperglycemia. Long term hyperglycemia as seen in people with diabetes appears to result in significant changes in their mood and cognitive state. For instance, type 2 diabetes is bidirectionally associated with depression [14]. Indeed, people with type 2 diabetes who have a hemoglobin HbA1c within the normal non-diabetic range exhibit fewer symptoms of depression than those with high HbA1c [15].

People with type 1 diabetes perform significantly worse than their non-diabetic peers in attention, psychomotor efficiency, cognitive flexibility, and general intelligence [16]. The etiology of these effects is unclear, and is the source of much research. Studies have found that high HbA1c levels predict cognitive deficit and its development over time in patients with and without diabetes [17]. Hyperglycemia and adiposity are associated with poor cognitive functioning in middle aged people without diabetes as well, which shows that these factors independently affect cognitive functioning outside of the usual complications of diabetes [18]. Children with type 1 diabetes may have poorer working memory as a result of hyperglycemia. Children with multiple risk factors, of which hyperglycemia was one, appeared to do worse in tests of verbal abilities, working memory, and mental efficiency. Children with other risk factors, such as earlier onset diabetes and hypoglycemia, in conjunction with hyperglycemia, did worse than peers in the same tests. Chronic hyperglycemia increases the risk of cognitive decline in those with diabetes by 60-100%. This is primarily due to a higher risk of vascular dementia rather than that of Alzheimer’s disease [19]. The risk of Alzheimer’s disease in people with diabetes, however, is elevated as well [20]. There is a 50-100% increased risk of stroke in people with diabetes versus a normal population, with a stroke relative-risk of 1.15 (95% CI 1.08 - 1.23) for every 1% (11 mmol/mol) rise in HbA1c [21]. The etiology of this is under study. Endocrine abnormalities, such as changes in insulin and amyloid metabolism, and increased oxidative stress may be at fault. Inflammatory phenomena, evidenced by an increase in CRP, IL6, and TNf-α concentration, have been studied in relation to this phenomenon as well [22].

Arterial spin labeling MRI studies have shown that cerebral blood flow is poorer in people with diabetes, and that these people exhibit signs of cortical and subcortical atrophy [23]. Lacunar infarcts occur more frequently in people with diabetes, and there is a significant association between cognitive dysfunction, lacunar infarcts, and their prevalence in diabetes [24]. Hippocampal atrophy may be another cause of cognitive dysfunction, as its degree is predicted by HbA1c. A 10-15% loss in hippocampal volume has been documented in the elderly with pre-diabetes, and is associated with memory impairments [25]. The hippocampus is highly vulnerable to hypoglycemic damage, as would be expected in people with Type 1 diabetes, however, studies show that cortical atrophy in the hippocampus is more pronounced in those with Type 2 diabetes. This may be because people with Type 2 diabetes are older on average than people with Type 1 diabetes [26][27]. The reasons for the increased risk of dementia and/or cognitive deficit in those with diabetes may ultimately be multifactorial.

Acute Hypoglycemia

Despite the conflicting evidence regarding the effects of recurrent episodes of hypoglycemia on the brain, it is generally accepted that hypoglycemia causes neuronal injury and impairments in mood and cognition [28][29]. Moderate episodes of hypoglycemia have been shown to cause short term cognitive deficits, which increase the risk of motor vehicle accidents [29]. In a vehicle driving study on people with Type 1 diabetes, cognition was shown to return to baseline upon return to euglycemia [30]. The length of time it takes for one to recover cognitively from hypoglycemic episode is a matter of debate and may be related to the severity of the hypoglycemia. Cognitive recovery may take several days in those who have experienced severe hypoglycemia [31][32]. In healthy people without diabetes, acute episodes of hypoglycemia cause feelings of tiredness and increased tension [33]. In people with Type 1 diabetes, acute hypoglycemia causes deficits in cognitive task completion, increased anxiety, and decreased energy [34].

There is evidence that an extended episode of severe hypoglycemia causes direct neuronal necrosis [35]. The brain’s metabolism itself changes after repeated episodes of hypoglycemia in a short amount of time. Hypoglycemic episodes within 12-24h of each other result in a suppression of counterregulatory responses to subsequent hypoglycemic episodes [36]. As this is found in both type 1 and type 2 diabetes, it may also be an adaptive mechanism by which the brain better resists further hypoglycemic insult, and may be expressed even at the cellular level [37][38][39]. However, this increases the patient’s risk of subsequent hypoglycemia. The patient’s awareness of their own symptoms, as a result of these mechanisms, becomes impaired [39][40]. Poor hypoglycemia awareness in people with diabetes can be dangerous because affected individuals do not realize that their blood glucose is low, and extreme and uncorrected hypoglycemia may lead to unconsciousness and even death.

In people with type 1 diabetes, pulsed arterial spin labeling and BOLD fMRI studies have demonstrated increased blood flow in several brain regions such as the hypothalamus, brainstem, anterior cingulated cortex, uncus, and putamen during periods of mild hypoglycemia, which may suggest that these structures are especially sensitive to even small blood glucose changes [41][42]. Thus, even small acute glycemic changes may be of clinical importance.

Exposure to Recurrent Hypoglycemia

The effects of recurrent hypoglycemia on cognition are subject to debate. Multiple hypoglycemic episodes may be experienced in those with type 1 diabetes who undergo intensive insulin therapy. Repeated hypoglycemia in both type 1 and type 2 diabetes has been shown to cause impaired hypoglycemia awareness, and an alteration of the glycemic thresholds that the brain is used to [43]. As mentioned earlier, this poor awareness of hypoglycemia may lead to poor treatment adjustment practices, which could then lead to unconsciousness or death as the hypoglycemia becomes more severe.

Analysis of the 18 year DCCT trial showed no significant decline in cognition in persons with type 1 diabetes, despite high frequency of hypoglycemic coma and/or seizures [44]. There may, however, be adaptive changes that underlie reduced cerebral efficiency in people with Type 1 diabetes. People with Type 1 diabetes have been shown to have increased brain activation in several regions (bilateral frontal and parietal cortices, insula, thalamus, and cerebellum) during periods of hypoglycemia. Higher HbA1c was associated with lower activation in the right parahippocampal gyrus and amygdala as well, which could indicate compensatory recruitment. Thus, while cognitive differences may not be evident in those with a history of hypoglycemia, such people may require a higher level of brain activation to maintain the same level of cognitive function as their peers without diabetes [45].

Certain negative effects of recurrent hypoglycemia have been uncovered using neuroimaging techniques. Voxel Based Morphometry (VBM) studies suggest that a higher self-reported frequency of severe hypoglycemic events were associated with gray matter density losses, particularly in the left cerebrellar posterior lobe and the limbic unci [46]. There is evidence that the cerebellum is involved in higher executive functioning, language, and affect. Insult to this region may responsible for several cognitive deficits [47].

Persons with type 2 diabetes do not undergo repeated episodes of hypoglycemia as frequently as those with type 1 diabetes [48]. There is some debate as to the effects of recurrent hypoglycemia on the development of cognitive dysfunction and dementia in those with type 2 diabetes. Studies offer contradictory evidence regarding the relationship between hypoglycemic episodes and later dementia development[49][50][51]. Further research is needed to help elucidate the long term effects of recurrent hypoglycemic episodes on cognition, mood, and dementia development.

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