WHY IS AMYLIN, A PRODUCT OF THE INSULIN-PRODUCING BETA-CELLS OF THE PANCREAS,
NOT REDUCED OR EFFECTED??
Amylin is produced by the Beta-Cells that are allegedly destroyed in T-1-Diabetics
The human organism consists of trillions of cells all working together for the maintenance of the entire organism. While cells may perform very different functions, all the cells are quite similar in their metabolic requirements. Maintaining a constant internal environment with all that the cells need to survive (oxygen, glucose, mineral ions, waste removal, and so forth) is necessary for the well-being of individual cells and the well-being of the entire body. The varied processes by which the body regulates its internal environment are collectively referred to as homeostasis.
What is Homeostasis?
Homeostasis in a general sense refers to stability, balance or equilibrium. It is the body’s attempt to maintain a constant internal environment. Maintaining a stable internal environment requires constant monitoring and adjustments as conditions change. This adjusting of physiological systems within the body is called homeostatic regulation.
Homeostatic regulation involves three parts or mechanisms: 1) the receptor, 2) the control center and 3) the effector.
The receptor receives information that something in the environment is changing. The control center or integration centerreceives and processes information from the receptor. And lastly, the effector responds to the commands of the control center by either opposing or enhancing the stimulus. This is an ongoing process that continually works to restore and maintain homeostasis. For example, in regulating body temperature there are temperature receptors in the skin, which communicate information to the brain, which is the control center, and the effector is our blood vessels and sweat glands in our skin.
Because the internal and external environment of the body are constantly changing and adjustments must be made continuously to stay at or near the set point, homeostasis can be thought of as a synthetic equilibrium.
Since homeostasis is an attempt to maintain the internal conditions of an environment by limiting fluctuations, it must involve a series of negative feedback loops.
The human pancreas is an amazing organ with two main functions:  to produce pancreatic endocrine hormones (eg, insulin & glucagon), which help regulate many aspects of our metabolism and  to produce pancreatic digestive enzymes. The hormone function of the pancreas is the emphasis of this portion of EndocrineWeb ~ this is referred to as the Endocrine Pancreas. Pancreatic production of insulin, somatostatin, gastrin, and glucagon plays an important role in maintaining sugar and salt balance in our bodies, and therefore, any problem in the production or regulation of these hormones will manifest itself with problems with blood sugar and fluid / salt imbalances.
The digestive portion of the pancreas makes up more than 90% of its total cell mass. The digestive (or exocrine) pancreas is responsible for making digestive enzymes which are secreted into the intestines to help digest (break down) the food we eat. These enzymes digest proteins, fats, and carbohydrates into much smaller molecules so our intestines can absorb them. The picture above is an accurate representation of the pancreas which lies next to the duodenum (the first part of the small intestine right after the stomach). The actual size of the pancreas is similar to a banana which has been stepped on…it has a slight curve to it, and its about the same length, width, and thickness. The yellow “tube” running through the middle of the pancreas is called the pancreatic duct. It drains all the digestive enzymes from the pancreatic cells where they are made into the duodenum where they mix with food as it comes out of the stomach.
The Endocrine Pancreas
The emphasis of the remainder of these pages within EndocrineWeb is on the Endocrine Pancreas. Approximately 5% of the total pancreatic mass is comprised of endocrine cells. These endocrine cells are clustered in groups within the pancreas which look like little islands of cells when examined under a microscope. This appearance led to these groups of pancreatic endocrine cells being called “Pancreatic Islets.” Within pancreatic islets are cells which make specific pancreatic endocrine hormones, of which there are only a few (the most famous, of course, being insulin). These cells within the islets are called “Pancreatic Islet Cells.”
Pancreatic islets are scattered throughout the pancreas. Like all endocrine glands, they secrete their hormones into the bloodstream and not into tubes or ducts like the digestive pancreas. Because of this need to secrete their hormones into the blood stream, pancreatic islets are surrounded by small blood vessels. This relationship is shown in the picture of a pancreatic islet where islet cells are secreting their hormones into nearby blood vessels. Remember, the purpose of endocrine cells is to make hormones which are secreted into the blood stream where they gain access to other cells very far away with the goal of making those cells respond in a specific fashion.
Pancreatic Endocrine Hormones and Their Purpose
- Purpose: Regulate blood glucose (sugar) in the normal range (lots more about this)
Action: Forces many cells of the body to absorb and use glucose thereby decreasing blood sugar levels
Secreted in response to: High blood glucose
Secretion inhibited by: Low blood glucose
Disease due to deficient action: Diabetes
Disease due to excess action: Hypoglycemia
Tumor called: Insulinoma
- Purpose: Assist insulin in regulating blood glucose (sugar) in the normal range (actions are opposite of insulin)
Action: Forces many cells of the body to release (or produce) glucose (increasing blood sugar)
Secreted in response to: Low blood glucose
Secretion inhibited by: High blood glucose
Disease due to deficient action: Some times nothing, sometimes hypoglycemia
Disease due to excess action: Hyperglycemia
Tumor called: Glucagonoma
- Purpose: Regulate the production and excretion of other endocrine hormones
Action: Slows down production of insulin, glucagon, gastrin, and other endocrine hormones
Secreted in response to: High levels of other endocrine hormones
Secretion inhibited by: Low levels of other endocrine hormones
Disease due to deficient action: Poorly defined
Disease due to excess action: Diabetes, gallstones, and dietary fat intolerance
Tumor called: Somatostatinoma
- Purpose: Assist in digestion within the stomach
Action: Induce acid producing cells of the stomach to produce acid
Secreted in response to: Food in the stomach and intestines
Secretion inhibited by: Absence of food in stomach and intestines
Disease due to deficient action: Poorly defined, some times no symptoms at all
Disease due to excess action: Stomach ulcers due to excess stomach acid
Tumor called: Gastrinoma (also called Zollinger Ellison Syndrome)
- Vasoactive Intestinal Peptide (VIP)
- Purpose: Help control water secretion and absorption from the intestines
Action: Causes intestinal cells to secrete water and salts into the intestines (inhibit absorption)
Secreted in response to: Unclear
Secretion inhibited by: Unclear
Disease due to deficient action: No symptoms at all
Disease due to excess action: Severe watery diarrhea and salt (potassium) imbalances
Tumor called: VIPoma
However, scattered through the pancreas are several hundred thousand clusters of cells called islets of Langerhans. The islets are endocrine tissue containing four types of cells. In order of abundance, they are the:
- beta cells, which secrete insulin and amylin;
- alpha cells, which secrete glucagon;
- delta cells, which secrete somatostatin, and
- gamma cells, which secrete pancreatic polypeptide.
Insulin is a small protein consisting of
- an alpha chain of 21 amino acids linked by two disulfide (S—S) bridges to a
- beta chain of 30 amino acids.
Beta cells have channels in their plasma membrane that serve as glucose detectors. Beta cells secrete insulin in response to a rising level of circulating glucose (“blood sugar”).
Insulin affects many organs. It
- stimulates skeletal muscle fibers to
- take up glucose and convert it into glycogen;
- take up amino acids from the blood and convert them into protein.
- acts on liver cells
- acts on fat (adipose) cells to stimulate the uptake of glucose and the synthesis of fat.
- acts on cells in the hypothalamus to reduce appetite.
In each case, insulin triggers these effects by binding to the insulin receptor — a transmembrane protein embedded in the plasma membrane of the responding cells.
Taken together, all of these actions result in:
- the storage of the soluble nutrients absorbed from the intestine into insoluble, energy-rich products (glycogen, protein, fat)
- a drop in the level of blood sugar
Diabetes mellitus is an endocrine disorder characterized by many signs and symptoms. Primary among these are:
- a failure of the kidney to efficiently reclaim glucose so that glucose spills over into the urine
- a resulting increase in the volume of urine because of the osmotic effect of this glucose (it reduces the return of water to the blood).
|Diabetes mellitus is a disorder quite distinct from the similarly-named diabetes insipidus. They both result in the production of large amounts of urine (diabetes), but in one the urine is sweet while in the other (caused by ADH deficiency) it is not. Before the days of laboratory tests, a simple taste test (“mellitus” or “insipidus”) enabled the doctor to make the correct diagnosis.|
There are three categories of diabetes mellitus:
- Type 1
- Type 2
- Inherited Forms of Diabetes Mellitus
Type 1 Diabetes Mellitus
(also known as Insulin-Dependent Diabetes Mellitus or IDDM)
- is characterized by little (hypo) or no circulating insulin;
- most commonly appears in childhood.
- It results from destruction of the beta cells of the islets.
- The destruction results from a cell-mediated autoimmune attack against the beta cells.
- What triggers this attack is still a mystery, although a prior viral infection may be the culprit.
Type 1 diabetes is controlled by carefully-regulated injections of insulin. (Insulin cannot be taken by mouth because, being a protein, it would be digested. However, the U.S. FDA has approved [in January 2006] an insulin inhaler that delivers insulin through the lungs and may reduce the number of daily injected doses needed.)
For many years, insulin extracted from the glands of cows and pigs was used. However, pig insulin differs from human insulin by one amino acid; beef insulin by three. Although both work in humans to lower blood sugar, they are seen by the immune system as “foreign” and induce an antibody response in the patient that blunts their effect and requires higher doses.
Two approaches have been taken to solve this problem:
- Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version. This approach is expensive, so now the favored approach is to
- Insert the human gene for insulin into E. coli and grow recombinant human insulin in culture tanks. Insulin is not a glycoprotein so E. coli is able to manufacture a fully-functional molecule (trade name = Humulin). Yeast is also used (trade name = Novolin).
- Recombinant DNA technology has also made it possible to manufacture slightly-modified forms of human insulin that work faster (Humalog® and NovoLog®) or slower (Lantus®) than regular human insulin.
Injections of insulin must be done carefully. Injections after vigorous exercise or long after a meal may drive the blood sugar level down to a dangerously low value causing an insulin reaction. The patient becomes irritable, fatigued, and may lose consciousness. If the patient is still conscious, giving a source of sugar (e.g., candy) by mouth usually solves the problem quickly. Injections of glucagon are sometimes used.
Type 2 Diabetes Mellitus
Type 2 is also known as Non Insulin-Dependent Diabetes Mellitus (NIDDM) and adult-onset diabetes. However, this type eventually leads to insulin dependence and also is now appearing in many children so those terms are no longer appropriate.
Many people develop Type 2 diabetes mellitus without an accompanying drop in insulin levels (at least at first).
In many cases, the problem appears to be a failure to express a sufficient number of glucose transporters in the plasma membrane (and T-system) of their skeletal muscles.
Normally when insulin binds to its receptor on the cell surface, it initiates a chain of events that leads to the insertion in the plasma membrane of increased numbers of a transmembrane glucose transporter (called GLUT4).
|Discussion of how transmembrane proteins are moved to the surface of the cell in which they are synthesized.|
This transporter forms a channel that permits the facilitated diffusion of glucose into the cell.
Skeletal muscle is the major “sink” for removing excess glucose from the blood (and converting it into glycogen). In type 2 diabetes, the patient’s ability to remove glucose from the blood and convert it into glycogen may be only 20% of normal. This is called insulin resistance. Curiously, vigorous exercise seems to increase the expression of the glucose transporter on skeletal muscle and this may explain why type 2 diabetes is more common in people who live sedentary lives.
Type 2 diabetes mellitus usually strikes in adults and, particularly often, in overweight people. However, over the last few years in the U. S., the incidence of type 2 diabetes in children has grown to the point where they now account for 20% of all newly-diagnosed cases (and, like their adult counterparts, are usually overweight).
Several drugs, all of which can be taken by mouth, are useful in restoring better control over blood sugar in patients with type 2 diabetes.
However, late in the course of disease, patients may have to begin to take insulin. It is as though after years of pumping out insulin in an effort to overcome the patient’s insulin resistance, the beta cells become exhausted.
Inherited Forms of Diabetes Mellitus
Some cases of diabetes result from mutant genes inherited from one or both parents. Examples:
- mutant genes for one or another of the transcription factors needed for transcription of the insulin gene (5 mutant versions have been identified).
- mutations in one or both copies of the gene encoding the insulin receptor. These patients usually have extra-high levels of circulating insulin but defective receptors. The mutant receptors
- may fail to be expressed properly at the cell surface or
- may fail to transmit an effective signal to the interior of the cell.
- a mutant version of the gene encoding glucokinase, the enzyme that phosphorylates glucose in the first step of glycolysis.
- mutations in the gene encoding part of potassium channels in the plasma membrane of the beta cell. The channels fail to close properly causing the cell to become hyperpolarized and blocking insulin secretion.
- mutations in several mitochondrial genes which reduce insulin secretion by beta cells. These diseases are inherited from the mother as only her mitochondria survive in the fertilized egg.
While symptoms usually appear in childhood or adolescence, patients with inherited diabetes differ from most children with type 2 diabetes in
- having a history of diabetes in the family and
- not being obese.
Amylin is a peptide of 37 amino acids, which is also secreted by the beta cells of the pancreas.
Some of its actions:
- inhibits the secretion of glucagon;
- slows the emptying of the stomach;
- sends a satiety signal to the brain.
All of its actions tend to supplement those of insulin, reducing the level of glucose in the blood.
A synthetic, modified, form of amylin (pramlintide or Symlin®) is used in the treatment of type 2 diabetes.
The alpha cells of the islets secrete glucagon, a polypeptide of 29 amino acids.
Glucagon acts principally on the liver where it stimulates the conversion of
- glycogen into glucose (“glycogenolysis“) and
- fat and protein into intermediate metabolites that are ultimately converted into glucose (“gluconeogenesis”)
In both cases, the glucose is deposited in the blood.
Glucagon secretion is
- stimulated by low levels of glucose in the blood;
- inhibited by high levels, and
- inhibited by amylin.
The physiological significance of this is that glucagon functions to maintain a steady level of blood sugar level between meals.
Injections of glucagon (which is readily available thanks to recombinant DNA technology) are sometimes given to diabetics suffering from an insulin reaction in order to speed the return of normal levels of blood sugar.
The delta cells secrete somatostatin. This consists of two polypeptides, one of 14 amino acids and one of 28.
Somatostatin has a variety of functions. Taken together, they work to reduce the rate at which food is absorbed from the contents of the intestine.
The gamma cells of the islets secrete a 36-amino-acid pancreatic polypeptide, which reduces appetite.
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