Written by: Dr. Ryan Cedermark, DC, DACNB, RN, BSN, FNP Student (Chief Resident, CHC)

Reviewed by: Dr. Brandon Brock, MSN, BSN, RN, NP-C, DCN, DCM, DAAIM, BCIM, DACNB, FICC

Structural content edited by: Tara Brock

Post 2: Sweet Inflammation


Dysregulation of glucose has been shown to create inflammatory responses in the body and brain. Glucose is fuel for the brain and the brain is very dependent on a continuous, healthy supply from peripheral circulation. Glucose, along with oxygen and stimulation are necessary for neuronal survival. Without these three things being provided appropriately, the action potential of a neuron can shift closer to threshold. Another way to say it is that if neurons do not receive adequate oxygen, glucose and stimulation, they may become “excited” more easily and can constantly over-fire to low levels of stimulation, which can lead to neuronal cell death. Increases in neuronal cell death lead to decreases in synaptic activity and communication in the brain, which decreases the brain’s ability to perform at an optimal level. This is why maintaining consistent blood sugar levels throughout the day is so important for your body and brain.

Take Home

  • Low O2 equals a bad brain. ie: anemia and URI and COPD
  • Abnormal Blood sugar equals bad brain. ie: Insulin resistance and diabetes and hypoglycemia.

We have all felt the highs and lows of glucose consumption. If we eat too much at once, especially a meal that is high in carbohydrates and low in proteins, we can experience fatigue and a feeling of sleepiness after meals. On a personal note, if my wife (who I love) is not fed and her blood glucose levels begin to drop, she can develop a very scary condition (yes I found literature, see the Bushman article below) of becoming “hangry.” The term “hangry” is derived from the combination of “hungry” and “angry,” meaning that people who are hungry are usually angry (men suffer from this too). The results of the Bushman article shows that blood glucose levels play an important role on self-control and aggression. There are several mechanisms in place to prevent or try and correct hypoglycemia, such as decreased insulin secretion from the beta cells of the pancreas, increased glucagon secretion from the alpha cells of the pancreas and increased catecholamine secretion from the adrenal glands. Another important response comes from the central nervous system.

Take Home

  • Keep blood sugar stable.
  • Mood disorders need to have blood sugar investigated

Let’s take a look at the neurological consequences of chronically low blood sugar. When there is a drop in circulating blood glucose levels, a stress response is activated by the brain. Sensors in the lateral and dorsal medial nucleus of the hypothalamus communicate with the paraventricular nucleus to secrete corticotropin-releasing factor (CRF). CRF travels down the pituitary stalk to it’s receptors in the anterior portion of the pituitary gland. This binding allows the anterior portion of the pituitary gland to secrete adrenocorticotropic hormone (ACTH) into circulation. ACTH’s main goal is to travel all the way down to the adrenal cortex of the adrenal glands, allowing the release of glucocorticoids (cortisol), epinephrine and norepinephrine from an area in the adrenal glands called the zona fasciculata. This process of communication between the hypothalamus, pituitary and adrenal glands is known as the hypothalamicpituitary-adrenal axis (HPA). In a system of checks and balances, the glucocorticoids provide negative feedback to the brain to basically tell the brain that everything is ok and the HPA axis can take a break. The end result of this axis is to increase glucose in the circulation in times of low blood sugar.

Take Home

  • Keep your adrenals healthy and test with with sugar fluctuations.
  • Adequate hypothalamic output by activation, low inflammation and adequate transmitters is optimum.

When there are chronically low levels of glucose, the HPA axis can become overworked. Dysregulation of the HPA axis has been seen in patients suffering from depression. One possibility could be that dysregulation of the HPA axis correlates to an increase in peripheral immune activity. As mentioned in last week’s paper,peripheral immune activity can migrate to create central consequences due to dysregulation at the site of the NMDA receptor. Dysregulation at the site of the NMDA receptor can create mitochondrial oxidative phosphorylation uncoupling, leading to cellular excitotoxicity and eventual neuronal death. An increase in cellular death leads to decrease frequency of firing of neurons and neuronal pathways. This can lead to deactivation of frontal lobe activity which is a known cause of depression.

Take Home

  • NMDA receptor issues leads to excitotoxicity and neurodegeneration.
  • NMDA receptor over excitation can lead to seizures and so forth.

An important concept to keep in mind is that when neurodegeneration occurs, there can be an increase in glucose uptake from the cells. If a neuron that is undergoing neuroinflammation or degeneration gets activated, it has to recruit neurons from neighboring areas. This recruitment is an energy-demanding process that will essentially utilize more glucose and further create hypoglycemic episodes in the brain. These episodes create further neurodegeneration, decreased frequency of firing and can essentially create an increased susceptibility to depression.

Take Home

  • There is a brain blood sugar – blood sugar brain loop.
  • Low neuronal activity can lead to early signs (depression)

There are three inflammatory markers that have an affinity for the HPA axis. They are tumor necrosis factor-alpha, interleukin-1 and interleukin-6. If dysregulation of the HPA axis occurs due to chronically low peripheral glucose levels, inflammation can occur. Once inflammation occurs, the HPA axis will continue to try and pump out cortisol to dampen the inflammatory effect. So in this example, we now have two things driving and essentially fatiguing the HPA axis.

Take Home

  • Know your labs.
  • Correlate glucose – to C peptide – to adrenal function – to triglycerides to acute phase reactants to inflammatory markers for patterns of disease.

So why is having low blood glucose bad? As mentioned above, it creates a stress response in your system. This stress response can become “plastic” in a negative fashion if not properly addressed. What that means is that this pathway can become more and more efficient, creating more problems for our body and brain. Another reason low blood sugar is bad for your body and brain is because glucose plays an essential role in creating ATP, which is necessary for maintaining a healthy neuronal membrane. Decreased ATP essentially means decrease function. An important clinical consideration for patients who have hypoglycemia is to understand why they have it. Are they not eating enough? Are they skipping meals throughout the day? Are they skipping breakfast? If on insulin, are they taking the correct dose? These are all important dietary and behavioral questions to ask the patient.

Take Home

  • Blood sugar issues can lead to autonomic issues that can be come plastic.
  • Know why hypoglycemia is present when it is.

Moving on to the neurological consequences of chronically elevated blood sugar. Chronically high blood sugar can cause peripheral and central inflammation. Low grade inflammation in obese subjects has been shown to contribute to peripheral insulin resistance. Insulin is a hormone released from the beta cells of the pancreas when blood sugar levels become high. Insulin will then “grab” the glucose molecules and store them away in cells of the muscle and liver. However, insulin has several other important jobs worth discussing. One very important concept when it comes to high blood sugar and depression is insulin’s job to take tryptophan from the peripheral areas of the body and deliver to the brain to be transformed into serotonin. Serotonin or 5-HT is a monoamine neurotransmitter that is important in regulating mood, sleep, appetite and even plays a role in memory and learning.

Take Home

  • Inflammation equals insulin resistance. Insulin resistance equals inflammation.
  • Blood sugar relates to transmitters. Transmitters control a lot.

What is interesting about serotonin is that about 90% of serotonin is located in the enterochromaffin cells of the gut. So if there is inflammation in the gut, there can be altered levels of serotonin located in the periphery. Ok, back to the brain. How do we get serotonin functioning well in the brain? Tryptophan is an essential amino acid, which means that our bodies can not create it. What we have to do is make sure the tryptophan is a part of our diet. Insulin will notice that there are circulating levels of tryptophan in the blood and carry it up to the brain for utilization. The problem is that there are other large neutral amino acids (LNAA) circulating in our system. These are leucine, isoleucine and valine. These three are competing with tryptophan for attachment to LNAA carrier proteins on brain capillaries through insulin. In regulated levels of blood glucose, insulin is smart enough to take normal levels of tryptophan to the brain and then grab the other three and disperse them in the periphery (so they can not compete for a spot on the carrier protein). In times of high glucose, insulin gets a little overexcited. There is so much insulin floating around since there is an increase in serum glucose. Insulin decides to take too much tryptophan to the brain. At first too much tryptophan may not be a bad thing as increased tryptophan can increase mood through conversion to serotonin. However, if this goes on for too long, the receptors and all of the mediators involved with converting tryptophan to serotonin become exhausted. This eventually leads to a decrease of serotonin, a change and mood, and eventually can lead to depression.

Take Home

  • Mood or mental disorders deserve labs, not just random trials with meds.
  • Do not lose your monoamines. It can cause problems with the end game, which is the neurotransmitter itself.

One way to fix problems with mood and depression is by taking medication. The problem is that some medications for depression are not as effective as they could be due to blood sugar dysregulation and inflammation. Between the years of 2005-2008, antidepressants were the third most common prescription drug taken by all ages of American citizens. There are several different types of antidepressants, however, relevant to this topic would be medications within the 5- HTP category. Let’s review the conversion of tryptophan to serotonin very briefly. Tryptophan is converted to 5-hydroxytryptophan (5-HTP) by tryptophan-5- hydroxylase which is then converted into serotonin (5-HT) by the enzyme aromatic L-amino acid decarboxylase. Do you see that taking a 5-HTP medication such as Prozac, Paxil or Zoloft while suffering from increased serum glucose levels and increased insulin can further exhaust this conversion pathway and eventually lead to depression, moodiness and even fatigue? Medications may absolutely be appropriate for a person, but making sure blood sugar is stable in the patient can make things a whole lot better.

Take Home

  • Know your meds and what they mean.
  • Know what meds can do to blood sugar and body content.

There are a few things to keep in mind before we wrap up this article. Communication between the brain and the rest of the body consists of several bidirectional loops. As I mentioned in my first article, the brain talks to the gut and the gut talks to the brain. This means that if something goes wrong in the brain, for example a head injury, then the rest of the body will most likely suffer. Continued suffering or inflammation in the rest of the body will further decrease healthy brain activation. On the other hand, if a person is suffering from blood sugar dysregulation, the brain can begin to suffer from consequences of inflammation from the periphery. Lifestyle modifications can help tremendously, as long as things like autoimmunity, infection, cancer etc. are ruled out. Eating small meals throughout the day, avoiding excessive carbohydrate and fat intake, and increasing exercise are all small but very important steps in the right direction. As mentioned above, medication is always an option if things like blood sugar dysregulation are ruled out, in my opinion.

Take Home

  • Diet is the key. Learn it and you fix a lot.
  • Brain activation for all you functional neurologists out there on someone with blood sugar issues is a bad idea with rapid fatigue problems.

Specific brain rehabilitation exercises as mentioned in the first article can positively impact the patient’s mood. However, you can not drive far in a car without enough gasoline. If there is decrease glucose in the system, there is less fuel to help activate neuronal membrane potentials which may create a more difficult time driving neuroplastic changes during brain rehabilitation exercises. Too much sugar and the system may already be in a depressed state, driving plastic pathways in a negative fashion. Next week I will talk about the cerebellum’s role in driving neuroplasticity, regulating immunity and dampening depressive moods.

Take Home

  • Never separate blood sugar from your exam when routine studies are needed.
  • Become multidimensional and learn to layer all the care patients need.


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