73) The vicious metabolic cycles of HO and what can be done about it?

Please bear with me- this is a detailed and somewhat technical post but I promise it will be worth reading if you want to understand how hyperinsulinemia and leptin resistance play a large role in HO and how oxytocin may mitigate this vicious cycle.  In observing Sasha’s metabolic health over the last several years, I have become fascinated by the workings of the brain and body’s ability to achieve health and homeostasis.  As a beginner and informal student of neuro-endocrinology, I know my understanding is basic and that I am painting very broad brush strokes in my description.  For what it’s worth, here is my attempt at describing the relationships between some of these hormones important to metabolic health.

For the normal (non-HO) person:
1. Low blood sugar (hypoglycemia) triggers the hypothalamus to signal the sense of hunger.
2. When food (let’s say, a slice of pizza) is available, the hungry person eats it and this raises blood sugar, satisfying the person and making energy available for the person.
3. The pancreas produces and sends out insulin to facilitate blood glucose uptake into the cells to be immediately used for energy. Excess glucose is stored in fat cells as free fatty acids for later use.
4. In the absence of food, hunger triggers the person to secrete corticosteroids to convert stored glucose (glycogen), proteins, fats and carbs to raise blood glucose.
5. Corticosteroids also act like a traffic cop for glucose, slowing the flow of glucose into the cell, and preventing blood glucose from dropping too quickly.
6. In sum, the normal person's hypothalamus behaves in a way to respond to the low blood sugars using the feedback loop between his/her corticosteroids and insulin, creating a balanced system: insulin makes it possible for glucose to be used for energy as needed and any extra glucose to be stored as free fatty acids to be saved for another time when energy is needed in the absence of food. This process makes if possible for a person’s weight to remain stable.

For the HO person with hyperinsulinemia (who also has AI, Adrenal Insufficiency):
1. Low blood sugar (hypoglycemia) triggers the hypothalamus to signal a sense of hunger.
2.  When food is available (pizza), the HO/AI hungry person eats it and this raises blood sugar (same as above).
3.  Insulin does its job by sending glucose into the working cells and fat storage cells.  However,  in the case of the HO person, there is an oversecretion of insulin in response to the amount of glucose in the blood.  See* below #5 for the explanation why HO person may hypersecrete insulin.
3. Glucose leaves the blood quickly as soon as insulin arrives but insulin takes longer to clear from the blood. As long as insulin is still in the blood, free fatty acids (stored in fat cells) cannot be accessed or released in the blood for later use.
4.  The HO/AI person feels hungry (again), eats in response to the hunger, and the cycle continues with the insulin never being cleared from the body and more fatty acids being stored/trapped in the fat cells (making the person fatter).
5.  In the absence of food, corticosteroids are not available to convert stored glucose, proteins, fats, and carbs to raise blood glucose.  Unlike the normal person who can utilize corticosteroids to raise the blood glucose levels under the stressful conditions of hunger, the HO/AI person’s blood glucose drops further. *This state of low blood glucose is physically stressful and it causes insulin to increase because demand for energy in cells is greater.
 6. In this low blood sugar state, the HO/AI person feels hungrier and is driven to eat.  If s/he eats (esp carbs), glucose spikes, insulin rises in response and stays elevated, glucose drops again, fatty acids cannot be accessed for energy and the person becomes fatter. This becomes the vicious cycle familiar to HO sufferers.

Role of Leptin:
Known as the “satiety hormone”, leptin, a hormone released from the fat cells located in adipose (fat) tissues, sends signals to the hypothalamus in the brain. This particular hormone helps regulate and alter long-term food intake and energy expenditure, not just from one meal to the next like insulin. The primary design of leptin is to help the body maintain its weight.

Because it comes from fat cells, leptin amounts are directly connected to an individual’s amount of body fat. When the body is functioning properly, excess fat cells will produce leptin, which will trigger the hypothalamus to lower the appetite, allowing the body to dip into the fat stores to feed itself which keeps the person at a normal, stable weight. Unfortunately, when someone is obese, that individual will have too much leptin in the blood. This can cause a lack of sensitivity to the hormone, a condition known as leptin resistance and the person’s appetite does not get lowered. Because the individual keeps eating, the fat cells produce more leptin to signal the feeling of satiety, leading to increased leptin levels, more leptin resistance, more weight gain, etc. Similarly, if a person decreases fat/calories (by dieting, for example), leptin will also decrease and appetite will increase.  Leptin may be the reason why it is impossible to keep weight off in the long run after initially losing weight from a diet. Dieting may in fact, drive down leptin and drive UP appetite.

Between the vicious cycle of glucose, hyperinsulin secretion, overeating and weight gain, the weight maintaining function of leptin, and weight gaining effects of leptin resistance, it is not looking good for the sufferer of HO.

WHAT TO DO?

When it comes to an eating regimen, the low carbohydrate diet is known as one of the best choices for people with HO.  By keeping the sugar levels from precipitously rising (and falling and this prevents the triggering of the glucose/insulin roller coaster), rapid weight gain can be stopped or slowed.  Maintaining a more stable weight also prevents the overproduction of leptin and the development of leptin resistance.

Bariatric surgery and many drugs have been tried to find a cure and stop the scourge of HO but still, to my knowledge, this is still a work in progress.

So, where does oxytocin fit in as a possible therapeutic agent for HO, and in particular, hyperinsulinemia and leptin resistance?

1. Oxytocin may be an effective treatment against impaired leptin signaling or leptin resistance.
http://journal.frontiersin.org/article/10.3389/fendo.2015.00119/full
2. Oxytocin may cause increased sensitivity to satiety signals:
http://ajpregu.physiology.org/content/287/1/R87.short
3. Leptin targets a specific subpopulation of oxytocin neurons and that this action may be important for leptin’s ability to reduce body weight in both control and obese rats:
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059625
4. Oxytocin and its analogs have multi-level effects in improving weight control, insulin sensitivity and insulin secretion, and that oxytocin has a potential role in treating obesity and diabetes:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658979/
5. Therapeutic levels of oxytocin may raise blood glucose levels: http://www.karger.com/Article/Abstract/181018

These are but a few research papers reporting on oxytocin's potential role in decreasing appetite, weight, and the phenomena of hyperinsulinemia and leptin resistance.  Have hope!

P.S.  Sasha used to be a hyperinsulin secreter (OGTT with insulin tested two years ago indicated that he had this common problem associated with HO).  His last OGTT with insulin test at the end of December showed that he is no longer hypersecreting insulin- due in part to his weight loss from oxytocin?