Hormonal Interactions
Endocrine tissue found in the pancreatic islets forms the basis of blood sugar control. This tissue secretes hormones that serve to either increase or decrease blood sugar, maintaining a delicate energy balance within the body. These hormones are called glucagon and insulin.
This interaction between our hormones is complicated. A delicate balance of input versus output must be maintained. Type I diabetics are missing a key player in this interaction. Without adequate insulin, the blood glucose level remains elevated. In addition, instead of responding to high blood sugar levels, glucagon will continue to try to increase blood sugar. This is because insulin levels control glucagon release. If insulin levels remain low even when blood sugar is high, glucagon will continue to try to raise blood glucose levels.
In Type II diabetes, the pancreas is trying to communicate with the cells, but the cells are no longer sensitive to the message. For this reason, Type II diabetes is also called insulin resistance. Typically, this lack of sensitivity to insulin by the cells is the result of years of high levels of simple carbohydrate consumption combined with a sedentary lifestyle. This causes the pancreas to produce excess amounts of insulin, but eventually the cells become ‘resistant’ to its effects, and the blood glucose rises. In essence, the pancreatic release of insulin resembles a ‘crying wolf’ effect, but the cells of the body are no longer listening, even though the situation has become an emergency because the blood glucose is elevated.
Stress hormone release exacerbates problems with blood glucose control. This is true for endogenous stress hormones (those released by the body’s own glands, such as cortisol and epinephrine) or exogenous stress hormones (those taken as medication, such as corticosteroids). Thus, for both types of diabetics, stress can at minimum make short-term control of blood sugar more challenging, but in the long term can be quite dangerous by contributing to the chronic complications that diabetics tend to develop.
The goal of diabetic therapy is to restore efficient communication between these systems. This can be achieved in some milder cases by strengthening the pancreas to produce more insulin or, more typically, by taking exogenous doses of insulin.
Glucagon and Glycogen
Pancreatic Alpha (A) cells in the periphery of the pancreas islet tissue secrete glucagon, a polypeptide hormone that increases blood sugar. When extra energy is consumed, it is stored as glycogen in the liver and muscles. Glycogen is essentially many glucose molecules bound together for storage. Glucagon works by binding to glycogen receptors on the liver and inducing the enzymatic breakdown of glycogen to glucose. Simply put, glucagon signals the liver to release stored glucose back into the bloodstream.
Glucagon also functions in the formation of glucose from amino acids in the liver through a process called gluconeogenesis. This allows some of the excess protein consumed in the diet to be shunted into energy production.
Insulin
Adjacent to the alpha cells in the pancreas are the beta cells. They constitute 70% of the islet cells and function to lower blood sugar with the secretion of insulin. Insulin is essential for the uptake of glucose from the blood into the majority of the body’s cells. Insulin manufacture and sensitivity plays the major role in diabetes. In Type I diabetes, beta cells are destroyed through what is thought to be an autoimmune response, resulting in insufficient insulin secretion. In Type II diabetes, there is usually a loss of sensitivity to insulin at the cellular level, compromising the cell’s ability to utilize glucose. In both Type I and Type II diabetes, glucose can no longer get from the blood into the cell efficiently, and levels of glucose in the blood rise.
Virtually all cells use insulin in order to absorb glucose, except for the tissues found in the retina of the eye, nerves, and kidneys. Insulin allows sugar to enter the cells by increasing the number of proteins that transport glucose across cell membranes, and by activating existing transport proteins. Insulin also increases the synthesis of glycogen from glucose in liver cells. In the tissues, where insulin is not required for the entry of glucose into the cell, the excess glucose that freely enters the cells is broken down into sugar alcohols (polyols). When in excess, these sugar alcohols contribute to the secondary complications of diabetes found in the retinas, nerves, and kidneys of diabetics.
The effects of insulin are numerous, including mediating storage of carbohydrates, fats, and proteins. Insulin also facilitates cellular growth and enhances liver, adipose, and muscle metabolism. Hence, while those with Type I diabetes tend to lose weight due to a lack of insulin, those with Type II are typically overweight due to the effects of excess insulin production. Excess insulin production tends to deposit weight around the trunk (producing the so called ‘spare tire’), which is a risk factor for a number of chronic diseases, including cardiovascular disease.
DHEA and Cortisol
Imbalances of DHEA and cortisol influence blood sugar control and are contributing factors to the development of diabetes. In general, insulin resistance is associated with low DHEA levels, especially in men. Insulin resistance in women is usually associated with adrenal hypersecretion and polycystic ovary syndrome. High levels of DHEA and cortisol are typical of this subset of patients.
Cortisol is released in response to physical, metabolic, or psychological stress and raises blood sugar by stimulating gluconeogenesis in hepatic and skeletal muscle tissues. Thus, chronically high levels contribute to insulin resistance, abdominal fat deposits (apple-shaped obesity), and lipid abnormalities — the constellation of imbalances associated with metabolic syndrome X.
DHEA is a precursor of testosterone and estrogen synthesis. DHEA is also an important hormone with its own receptors and physiological properties. DHEA stimulates increased lean muscle mass and reduced abdominal fat. It also appears to play an important role in glucose regulation. Most importantly, experimental studies show that DHEA administration increases insulin sensitivity. DHEA levels are typically higher in men. High levels in women may be associated with hirsutism and insulin resistance.
Insulin Like Growth Factor (IGF-I)
Produced in the liver in response to growth hormone stimulus, IGF-1 (insulin-like- growth-factor-1) plays an important role in regulating glucose metabolism. IGF-1 helps to increase insulin sensitivity. It also works in the body to increase lean muscle mass, enhance fat metabolism, and improve cardiovascular function. Research studies indicate that IGF-1 cuts the rate of diabetes by nearly 50% in laboratory animals by protecting pancreatic beta cells from autoimmune destruction. In addition, low levels of IGF-1 have been associated with atherosclerosis, aging, obesity, and the development of diabetic neuropathy.
Hormonal Conversations
One way to understand the relationship between blood sugar metabolism and diabetes is to imagine a daily ‘conversation’ between our hormones. Each and every day, a balancing act is carried out within our endocrine system. The central players are:
Pancreas: gland that contains the pancreatic islets, tissue responsible for producing and secreting insulin and glucagon.
Adrenal glands: glands that secrete stress hormones, including cortisol and epinephrine.
Glucagon: a pancreatic hormone that releases stored glycogen from the muscles and liver back into the blood.
Insulin: a pancreatic hormone that allows glucose to be moved across cell membranes for energy production.
Cortisol: an adrenal gland hormone released when stress is chronic and long-term.
Epinephrine: an adrenal gland hormone also known as adrenaline that is released during a ‘fight or flight’ response.
Act 1, Scene 1: In the early morning while you’re still sleeping, your blood glucose level hovers near 70 mg/dl. When your alarm clock sounds, your blood sugar rises in response to the secretion of cortisol and epinephrine.
Act 1, Scene 2: When you arrive at work, your boss blames you for someone else’s mistake. You become agitated and frustrated, and your blood sugar increases again as stress hormones surge from your adrenal glands. You sit down at your desk and play your favorite relaxation tape. As you calm down, your stress hormone levels decrease, reducing your blood sugar.
Act 2, Scene 1: By lunchtime, your blood sugar has dropped again to about 50 mg/dl. You eat lunch and treat yourself to a scoop of ice cream for dessert. Your blood sugar rises to 100 mg/dl and your pancreas responds by secreting insulin. This pushes the glucose into your cells, returning your blood sugar levels to a normal range.
Act 2, Scene 2: After work, you spring to your bus stop to catch an early bus. Glucagon enables the quick release of stored glycogen to fuel your energy burst. Once you arrive home, your hormones continue their ‘conversation’ as you relax, exercise, eat, and prepare for bed. Tomorrow morning, their interaction will continue to monitor your blood sugar as it rises and falls while you carry on with your daily life. In fact, these interactions between hormones are taking place every minute of every hour of your life.
Coda: People with diabetes mellitus are missing something in their hormonal conversation. Their ability to produce or use insulin is diminished. The hormones that tell the body to increase the blood sugar may be working, but the insulin that brings blood sugar down does not respond. Glucagon responds to low insulin levels, but it does not respond to low blood sugar levels. This is why the one-way conversation of the counter regulatory hormones can be quite dangerous in a diabetic. Glucagon will keep on increasing blood sugar by responding to low insulin levels, rather than responding to the high blood sugar levels, which can eventually lead to a coma.
Diabetic Therapy: The goal of diabetic therapy is to restore the communication in the body between these systems. This can be achieved by strengthening the pancreas to produce more insulin, by restoring peripheral metabolism of insulin, or by taking exogenous insulin.
