When there is insulin resistance the body begins an internal battle between acute survival and longevity. It is a long, subtle conflict that abruptly manifests itself as chronic conditions far beyond just hyperglycemia.
Let me walk you through how we develop insulin resistance and 3 ways it has overwhelmed society via its predominant role is obesity, infertility and diabetic ketoacidosis (DKA).
Insulin and GLUT 4 Transporters
When we eat, the digestive system breaks down complex food into simple molecules like amino acids, glucose and fats. These are then released into the blood stream to support biological processes.
For glucose to be useful to the body it requires the hormone insulin. Insulin binds to insulin receptors on cells. This interaction changes the conformation of the cell in a way that allows them to express the glucose transporter GLUT 4 on the cell surface.
The GLUT 4 transporter provides a entry point for glucose into the cell. It enables cells to take up glucose from the bloodstream.
GLUT 4 expression is increased in the presence of insulin and also during muscle contraction (i.e. exercise).
GLUT 4 is expressed largely on muscle, liver and fat cells.
- In the liver glucose is stored as glycogen
- In adipose cells glucose is stored as fat
- In muscle glucose is largely used immediately for energy
The video below explains how insulin facilitates transport of glucose into cells by stimulating GLUT 4 expression.
The Pancreas and Insulin
Insulin is released by beta cells on the pancreas in response to glucose in circulation. There should always be glucose in the circulation, our bodies need a constant supply to survive. The normal range of blood glucose when there is no active consumption (fasting blood glucose) is 70-99mg/dL.
A constant basal release of insulin from the pancreas maintains this narrow range of blood glucose. When we eat, the pancreas responds with “bolus” doses of insulin to maintain post prandial glucose ranges of less than 140mg/dL. The body is in a constant state of receiving and removing glucose from circulation.
Insulin Resistance
When insulin receptors are exposed to high levels of insulin over prolonged periods of time they lose sensitivity (desensitization). There is a decreased physiological response of these receptors to the presence of insulin. The pancreas is able to compensate to some degree by increasing the output of insulin but overtime the pancreas too will not be able to keep up.
A diminished response to insulin means a diminished expression of GLUT 4 transporters.
When this happens glucose enters the bloodstream and has no where to go. It just sits there. It is available but the body is no longer able to transfer it out of the bloodstream and into body tissue for use.
While it sits in the circulation it increases the osmolality of plasma, causes electrolyte disturbances, oxidative stress and a host of other disruptions of normal physiological processes.
Left untreated we advance from the development of hyperglycemia to diabetes which creates the potential for many other acute and chronic conditions.
Watch on YouTube
Subscribe for Access to Exclusive Content
Glucagon and Alternative Energy
Whether there is a true deficit or a perceived deficit in exogenous glucose the body will kickstart survival pathways starting with the secretion of glucagon to ensure that a source of energy is available.
Glucagon is secreted from the alpha cells in the pancreas in response to low blood glucose. Alpha cells also lose sensitivity to detect glucose when they are exposed to high levels over a prolonged period.
As a result, alpha cells become poorly calibrated for detection of blood glucose levels. Even though the concentration of glucose in circulation is high, they detect low levels and secrete glucagon. This initiates a series of pathways that increases endogenous production of glucose via glycogenesis and gluconeogenesis.
This further worsens the already high levels of glucose the blood stream.
Survival Pathways
The release of glucagon, in an otherwise healthy human, is intended to be a temporary fix to the lack of exogenous glucose until the next meal. It really is a survival situation for the body.
Glucagon release is accompanied by the release of “fight or flight” hormones like epinephrine, cortisol and growth hormone. Together these hormones are preparing the body for what it perceives to be a threat. In this case the threat is a lack of adequate energy.
With insulin resistance, sustained high blood glucose levels also means a sustained “fight or flight” response. Internally the body is in a constant state of stress.
This is why insulin resistance is associated with such a wide variety of syndromes including diabetic ketoacidosis, obesity and polycystic ovarian syndrome.
Watch on YouTube
1. Diabetic Ketoacidosis and Insulin Resistance
DKA is an acute life threatening condition that can occur in patients with type 1 and type 2 diabetes. DKA occurs when the body does not have enough insulin to take up glucose as a source of energy.
There is usually some trigger, like infection or illness, that offsets the body’s ability to maintain homeostatic glucose levels.
Glucose is available in the bloodstream but it cannot be utilized because the body does not have enough insulin to overcome the resistance the cells have developed.
Gluconeogenesis and glycogenolysis are metabolic processes in the liver and muscles that provide a quick source of glucose in the perceived absence of exogenous sources. The body in now acutely saving itself by providing the immediate energy it needs but simultaneously exacerbating overall hyperglycemia. It is a viscous cycle.
Ketones in DKA
When the body runs out of glucose from gluconeogenesis and glycogenolysis it resorts to the use of ketones as the primary source of energy. Ketones are derived from the body’s breakdown of stored fat.
Again, while trying to save itself the body causes a rapid accumulation of ketones which leads to acidosis, hyperosmolality , dehydration , electrolyte imbalances and cognitive impairment which is the presentation of DKA.
In DKA we must provide exogenous sources of insulin at high doses to overcome insulin resistance.
2. Obesity and Insulin Resistance
If insulin resistance inhibits the uptake of glucose into cells (including fat cells) how could it possibly lead to obesity? Let me explain.
As insulin resistance persists and there is less glucose being taken up from the blood the body interprets this as a survival issue. The body thinks:
“Hey, its been a while since we’ve been able to get glucose from consumption! This could go on for a while. We better increase our storage!”
As the body uses the alternative routes of glycogenesis and gluconeogenesis to meet immediate glucose needs it will also produce some glucose for the purpose of long term storage.
Increasing fat increases the “storage space” for glucose. Fat is a building block for glucose via gluconeogenesis and also a direct source of energy in ketogenesis.
This increase in fat is seen predominantly around the abdomen (abdominal fat).
Over time this can progress from weight gain to obesity.
In obesity we can increase the expression of GLUT4 receptors via muscle contraction (exercise). The increase in uptake of glucose from the blood will signal that exogenous glucose is available and there is no need to further increase stores.
3. Infertility and Insulin Resistance
As we’ve established sustaining high levels in glucose in the blood and associated insulin resistance is a stressful condition for the body. In addition to increases in insulin, there is also an increase in the release of glucagon and stress hormones like epinephrine that sends the body into a “fight or flight” response.
Reproduction is not necessary for survival.
While externally we may seem at peace, internally the body is in a battle for viability.
During battle there is no concern for reproduction.
Insulin resistance affects several reproductive pathways beginning with decreased libido and certainly inhibition of conception.
In PCOS women express high levels of the hormone androgen. Androgen is the male sex hormones that is present in relatively low concentrations in otherwise healthy females.
Research has shown that androgen secretion increases in times of stress. Again when there is sustained insulin resistance the body sees this as a threat and activates stress responses. Androgen levels increase causing disruption in menstruations and ovulation with an overall decrease in fertility.
Insulin resistance is a significant public health concern. Our bodies are not designed to remain in prolonged periods of “fight or flight”. What we know for sure is that we can increase our GLUT4 transporter to facilitate uptake exogenous glucose via muscle contraction so let’s get moving!
The American Diabetes Association (ADA) and Centers for Disease Control (CDC) have a host of helpful resources whether you are a healthcare professional, diabetic or a caregiver of someone with insulin resistance.
If you’ve found this unit helpful I would love to hear from you! Leave a comment or question below.
Subscribe
Subscribe to get the latest study unit in your inbox.
The information on this website is intended to be used solely for educational and informational purposes. While the content may be about specific medical and health care issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions.
One thought on “Insulin Resistance: Its Role in Infertility, DKA and Obesity”