WHAT IS DIABETES MELLITUS??
Diabetes is a systemic disease characterized by hyperglycemia, hyperlipidemia, and hyperaminoacidemia. Diabetes alters the metabolism of all the energy nutrients (carbohydrates, fats and proteins) and affects most organ systems, often leading to specific problems with microcirculation, neuropathic disorders, and an increased predisposition to atherosclerosis. In that, Diabetes can contribute to or cause the development of blindness, kidney disease, heart disease, leg pains and ulcers (often requiring amputation), complications of pregnancy etc.
The two major forms of diabetes are Type I (insulin dependent or juvenile onset) and Type II (non-insulin dependent or maturity onset). They share a central feature: elevated blood sugar levels due to absolute or relative insufficiencies of insulin and/or cellular resistance to the actions of insulin.
So, in order to better understand Diabetes, we need to better understand Insulin.
WHAT IS INSULIN??
Insulin is a hormone that is produced and released by the pancreas; a small gland that lies between the stomach and the spleen.
WHAT ARE HORMONES??
Hormones are chemical messengers. They are chemical compounds that circulate through the body, affecting target cells and organs (“target” referring to specific cells and organs with receptor sites matching that hormone).
A single hormone may have different effects in different tissues and/or any given body function may be influenced by more than one hormone.
Hormones assist in regulation and integration of body functions but do not initiate any body reactions.
Their release is triggered by specific events or stimuli, often part of complex feedback loops between many receptors, organs, releasing factors etc.
The endocrine, nervous, and immune systems work together to regulate body responses to both internal and external environments.
The greatest effects of the endocrine system itself include regulation of digestion, body growth and development, electrolyte and water metabolism, and reproductive functions.
5 Functions of the Endocrine system:
1. Differentiation of the reproductive and CNS systems in the developing fetus
2. Stimulation of sequential growth and development during childhood and adolescence.
3. Co-ordination of male and female reproductive systems, making reproduction possible
4. Maintenance of an optimal internal environment throughout the lifespan
5. Initiation of corrective and adaptive responses when emergency demands occur.
THE PANCREAS AND IT’S HORMONES
The pancreas, located between the stomach and the spleen, is both an endocrine gland that produces hormones and an exocrine gland that produces digestive enzymes. It plays a strong role in metabolism in the body.
Structures within the pancreas, known as Islets of Langerhans contain three different types of hormone secreting cells:
Alpha Cells: secrete Glucagon
Beta Cells: secrete Insulin
Delta Cells: secretes somatostatin
Glucagon:
Is released in response to low blood glucose levels, high amino acid levels, and by sympathetic nervous system stimulation.
Its release is inhibited by high blood glucose levels.
Effects:
The primary action of glucagon is at the liver, where it facilitates the conversion of glycogen to glucose. It also stimulates lypolysis.
It is an antagonist to insulin!
Insulin:
Is released in response to high blood glucose levels, high amino acid levels, gastrointestinal enzymes, and parasympathetic stimulation of Beta cells.
Effects:
1) Facilitates entry of glucose into cells.
Note: the brain and red blood cells do not require insulin for glucose uptake.
2) Increases uptake of amino acids by cells
3) Converts glucose to glycogen in the liver and skeletal muscle
4) Converts excess glucose to fatty acids
5) Converts amino acids into proteins in the liver
6) Converts fatty acids to triglycerides
The net effect of insulin in most cells is to stimulate cell metabolism (primarily in the liver, skeletal muscle and fat cells), but its major action is in decreasing blood glucose levels.
Somatostatin:
Is released in response to high blood glucose or amino acid levels.
Effects:
Causes contraction of the pyloric sphincter preventing entry of more food/sugar into the digestive tract.
Allows periodic entry of nutrients to the small intestine
INSULIN
Insulin is a key regulator of blood glucose levels. After a meal, food is digested in the stomach and intestines; carbohydrates are broken down in to glucose (and other sugars), and proteins are broken down into amino acids. Glucose and amino acids are absorbed directly into the bloodstream, and their blood concentration levels rise. Normally, this triggers release of insulin from the beta cells of the pancreas. Insulin, in turn, increases the permeability of cells (especially muscle cells) to glucose and amino acids, where there are burned for energy, converted into proteins, or stored for later use. Insulin also facilitates storage of excess glucose as glycogen in the liver and muscle for later use when food nutrients are not available. As blood glucose levels fall to pre-meal levels, the pancreas reduces its production of insulin and the body uses its stored energy until the next meal provides additional nutrition.
INSULIN AND GLUCOSE METABOLISM AND STORAGE:
At rest, muscle cells are only slightly permeable to glucose, and therefore typically rely on fatty acids as their energy source.
To increase muscle cell membrane permeability to glucose we normally rely on the actions of insulin, but between meals, insulin levels are too low to facilitate glucose transport.
There are two main ways the body increases glucose permeability in muscle cells:
1) During moderate to heavy exercise, for reasons unknown, muscle cells become highly permeable to glucose, even in the absence of insulin!
2) Otherwise, we must wait until a meal is eaten. Intestinal absorption of glucose and amino acids from food we eat stimulates the release of insulin from the beta cells of the pancreas.
If muscles are not active after a meal is eaten, the excess glucose is stored as glycogen for future use (especially for short bursts of anaerobic activity).
Most glycogen (up to 60%) is stored in the liver, where is can be accessed later and converted back into glucose for use between meals when food is not available.
When the quantity of glucose exceeds what can be stored in the liver as glycogen, insulin promotes its conversion to fatty acids. These fatty acids are then packaged as triglycerides and LDL’s (the bad one’s) and are stored in adipose tissue as fat.
Release of Glucose from the Liver Between Meals:
Decreasing blood glucose levels inhibit insulin secretion from the pancreas.
The lack of insulin de-facilitates glycogen storage in the liver, preventing further uptake of glucose into the liver from the blood.
The lack of insulin facilitates glycogenolysis, allowing glycogen to be converted back into glucose to diffuse back into the blood.
INSULIN AND FAT METABOLISM:
In the absence of Insulin, all aspects of fat breakdown for energy use are greatly enhanced. This is a normal occurrence between meals but becomes extreme in Diabetes Mellitus.
In the absence of Insulin, stored triglycerides are converted into free fatty acids and glycerol. Blood free fatty acid concentration levels rise within minutes, becoming the main energy source for body tissues.
Fatty acid metabolism converts fatty acids into chemical called ketone bodies. Ketones are toxic to the body at high levels. As ketone levels rise, severe “ketoacidosis”, as seen in Diabetes Mellitus can cause death.
The excess free fatty acid levels also stimulates production of plasma lipoproteins and cholesterol, which promotes development of atherosclerosis.
INSULIN AND PROTEIN METABOLISM:
Insulin is also required to facilitate storage of proteins after meals. The mechanism of interaction is not as clearly understood as with carbohydrates and fats.
Insulin shares, with growth hormone, the ability to increase the uptake of amino acids into cells.
Insulin has a direct effect on activating the intracellular formation of proteins.
Insulin also inhibits the breakdown of proteins, thus decreasing the release of amino acids from cells, especially muscle.
Insulin suppresses gluconeogenesis. In that, amino acids are conserved in protein stores in the body (amino acids are the primary substrates for gluconeogenesis).
With Insulin Lack:
Virtually all protein storage comes to a complete halt when insulin is not available.
Protein catabolism is increased and protein synthesis stops. Large quantities of amino acids, therefore, enter the bloodstream. Excess amino acids are either used directly for energy or as substrates for gluconeogenesis. Manipulation of amino acids results in increased urea, which must be excreted by the kidneys.
Protein wasting is one of the most serious effects of Diabetes Mellitus. It can lead to extreme weakness and/or altered function of organs.
SUMMARY OF BLOOD GLUCOSE REGULATION
In a normal person, blood glucose concentrations are very narrowly controlled, either by factors that facilitate excess blood glucose absorption into cells for energy or storage or by factors that release stored glucose back into the blood stream in states of starvation or hypoglycemia.
Factors involved in this fine control are:
Liver Function:
In periods of hyperglycemia, in the presence of Insulin, up to two thirds of absorbed glucose is almost immediately stored as glycogen. Over time, as blood glucose levels decrease (between meals) and Insulin secretion decreases, the liver releases the stored glucose back into the blood.
Insulin and Glucagon:
Insulin is released in response to high blood glucose levels, and causes levels to reduce toward normal levels. Conversely, decreases in blood glucose, stimulate glucagon release. Glucagon, in turn, causes blood glucose levels to rise.
Hypothalamus and the SNS:
During periods of hypoglycemia, the hypothalamus and SNS are simulated. In turn, epinephrine from the adrenal glands further facilitates the release of glucose from the liver.
Growth Hormone and Cortisol:
Over prolonged periods of hypoglycemia (hours to days), growth hormone and cortisol are released. Both act to decrease the rate of glucose utilization by cells, thus preserving glucose stores in the bloodstream.
Why is it so important to maintain constant blood glucose levels??
The brain, retina and some glandular tissues rely solely on glucose for energy (cannot revert to use of fats or proteins for energy). In that, blood glucose levels must be maintained to provide constant energy for these cells.