The bulk of the pancreas is an exocrine gland secreting pancreatic fluid into the duodenum after a meal. 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
- 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 totake up glucose and convert it into glycogen. Insulin also take up amino acids from the blood and convert them into protein. It
- acts on liver cells
- stimulating them to take up glucose from the blood and convert it into glycogen while
- inhibiting production of the enzymes involved in breaking glycogen back down ("glycogenolysis") and
- inhibiting "gluconeogenesis"; that is, the conversion of fats and proteins into glucose.
- 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 and 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. One possibility: peptides derived from insulin may bond to unrelated peptides to form a "neoantigen"; that is, an antigen that was not present when tolerance to self-antigens was being established.
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.
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). 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
- 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.
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.
Amylin is a peptide of 37 amino acids, which is also secreted by the beta cells of the pancreas. Some of its actions include 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.
X-Ray Crystal Structure of Glucagon based on PDB 1GCN. Image used with permission (CC BY-SA 3.0; Truthortruth).
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, which 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. Somatostatin is also secreted by the hypothalamus and by the intestine.
The gamma cells of the islets secrete a 36-amino-acid pancreatic polypeptide, which reduces appetite.