Chapter 1 – Definition and Pathophysiology
The pancreas, an endocrine gland situated below and behind the stomach, weighs about half a pound and resembles an elongated cone lying on its side. The broad part, or head, is located next to a curve of the duodenum, the part of the small intestine just beyond the stomach. The pancreas tapers off to the left in the direction of the spleen and left kidney and ends in a portion known as the tail. Within the pancreas, especially at the tail, are the insulin-producing clusters of cells known as the islets of Langerhans. A normal adult human pancreas contains about 1 million such islets comprising about 1 gm of tissue, which contains about 8 mg or 200 units of insulin at any given time. Of the cell types found in these islets, it is the glucose-sensitive beta-cells that are key to glucose homeostasis. These cells are capable of measuring the blood glucose level within seconds with an accuracy to within 2 mg/dl and then of determining the quantity of insulin needed. Each islet contains between 1000 and 2000 beta-cells, and these cells, in aggregate, can rapidly secrete the precise amount of insulin required based on their measurement of the serum glucose level.
The islets of Langerhans also produce other substances. For example, alpha-cells produce and release glucagon, which, as noted above and in contrast to insulin, causes blood glucose levels to rise through mobilization of glucose stores in liver and muscle. This careful balance between insulin and glucagon secretion and action maintains normal blood glucose levels. Somatostatin, gastrin, vasoactive intestinal peptide (VIP), pancreatic polypeptide (PP), and ghrelin are also produced in the pancreas. There is ongoing research into the roles of these substances and how they influence diabetes. Hormones from the pituitary, adrenal, and thyroid glands also play a role, with an anti-insulin effect. Thus, glucose control in a normally functioning body actually reflects a balance among the actions of various hormones.
Definition and Pathophysiology
Insulin is a protein. It consists of two chains of 51 amino acids, the "A" and "B" chains, held together by two disulfide bridges. Within the beta-cell, insulin is manufactured in a multi-step process. In the step just prior to the final emergence of the complete insulin molecule, the precursor molecule is called proinsulin and is made up of the 51 amino acids of the future insulin molecule, plus 31 amino acids of the "connecting peptide" (or "C-peptide"). In the final manufacturing step, this C-peptide is cleaved off, leaving the remaining A and B chains of the insulin molecule. Insulin and C-peptide, in equal amounts, are packaged in secretory granules within the beta-cell cell, waiting to be used. The C-peptide itself is not thought to play a significant role in glucose homeostasis, but is released by the beta-cell into the circulation. The major use of C-peptide in clinical practice is as a "marker" for endogenous insulin production.
When the beta-cell senses a rise in glucose levels, it releases insulin in two phases. During the first phase, which is very rapid and occurs within the first 10 to 15 minutes after eating, insulin that was made earlier is released from insulin secretory vesicles that are already primed and docked. While during the second phase, new vesicles are likely primed and mobilized prior to their discharge. Other signals besides elevated glucose can cause insulin release into the blood, which can actually begin even before the blood glucose level becomes elevated.
Food entering the digestive tract stimulates the release of insulin from the beta-cells. This release depends on the amount and the type of food eaten. Carbohydrates are the most effective stimulators. The combined effects of hormones from the digestive tract and the increasing blood glucose level sustain the release and formation of insulin. Amino acids and proteins can also function as insulin secretagogues. Incretins such as GLP-1 and GIP are also produced in response to the presence of food in the GI tract.
In people who do not have diabetes, it is almost impossible to raise the blood glucose level above normal, regardless of what is eaten, because the insulin reserve is plentiful and is secreted in exactly the correct amount. In fact, if a person were to be given a slow intravenous infusion of a 5% glucose solution into an arm, the levels of glucose in blood drawn from a vein in the other arm would most often be normal. The person without diabetes can normally manufacture and release as much as 0.5 to 0.7 units/kg body weight per day.
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