Amylin, or Islet Amyloid Polypeptide (IAPP), is a 37-residue
peptide hormonePeptide hormones are a class of peptides that are secreted into the blood stream and have endocrine functions in living animals. Peptide hormones are increasingly being identified in plants with important roles in cell-to-cell communication and plant defence...
secreted by
pancreaticThe pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as an exocrine gland, secreting pancreatic juice containing digestive enzymes that pass to...
β-cellsright|thumbnail|300px|A porcine islet of Langerhans. The left image is a brightfield image created using [[hematoxylin]] stain; nuclei are dark circles and the [[acinar]] pancreatic tissue is darker than the islet tissue...
at the same time as
insulinInsulin is a hormone that has extensive effects on metabolism and other body functions, such as vascular compliance. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle, and stopping use of fat as an energy...
(in a roughly 1:100 amylin:insulin ratio).
Islet, or insulinoma, amyloid polypeptide (IAPP, or amylin) is commonly found in
pancreatic isletsThe islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas...
of patients suffering
diabetes mellitus type 2Diabetes mellitus type 2 or type 2 diabetes is a disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency...
, or harboring an
insulinomaAn insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin.Beta cells secrete insulin in response to increases in blood glucose. The resulting increase in insulin acts to lower blood glucose back to normal levels at which point further secretion of insulin is...
. While the association of amylin with the development of type 2 diabetes has been known for some time, a direct causative role for amylin has been harder to establish.
Amylin, or Islet Amyloid Polypeptide (IAPP), is a 37-residue
peptide hormonePeptide hormones are a class of peptides that are secreted into the blood stream and have endocrine functions in living animals. Peptide hormones are increasingly being identified in plants with important roles in cell-to-cell communication and plant defence...
secreted by
pancreaticThe pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as an exocrine gland, secreting pancreatic juice containing digestive enzymes that pass to...
β-cellsright|thumbnail|300px|A porcine islet of Langerhans. The left image is a brightfield image created using [[hematoxylin]] stain; nuclei are dark circles and the [[acinar]] pancreatic tissue is darker than the islet tissue...
at the same time as
insulinInsulin is a hormone that has extensive effects on metabolism and other body functions, such as vascular compliance. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle, and stopping use of fat as an energy...
(in a roughly 1:100 amylin:insulin ratio).
Clinical significance
Islet, or insulinoma, amyloid polypeptide (IAPP, or amylin) is commonly found in
pancreatic isletsThe islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas...
of patients suffering
diabetes mellitus type 2Diabetes mellitus type 2 or type 2 diabetes is a disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency...
, or harboring an
insulinomaAn insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin.Beta cells secrete insulin in response to increases in blood glucose. The resulting increase in insulin acts to lower blood glucose back to normal levels at which point further secretion of insulin is...
. While the association of amylin with the development of type 2 diabetes has been known for some time, a direct causative role for amylin has been harder to establish. Recent results suggest that amylin, like the related beta-amyloid (Abeta) associated with
Alzheimer's diseaseAlzheimer's disease , also called Alzheimer disease, Senile Dementia of the Alzheimer Type or simply Alzheimer's, is the most common form of dementia. This incurable, degenerative, and terminal disease was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was...
, can induce
apoptotic cell-deathApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
in
insulinInsulin is a hormone that has extensive effects on metabolism and other body functions, such as vascular compliance. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle, and stopping use of fat as an energy...
-producing beta cells, an effect that may be relevant to the development of type 2 diabetes.. Finally, a recent study reported a synergistic effect for weight loss with leptin and amylin coadministration in diet-induced obese rats by restoring hypothalamic sensitivity to leptin .
Function
Amylin functions as part of the endocrine
pancreasThe pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as an exocrine gland, secreting pancreatic juice containing digestive enzymes that pass to...
and contributes to glycemic control. The peptide is secreted from the pancreas into the blood circulation and eventually excreted by the kidneys. Amylin's metabolic function is now somewhat well characterized as an inhibitor of the appearance of nutrient [especially glucose] in the plasma. It thus functions as a synergistic partner to insulin, with which it is cosecreted from pancreatic beta cells in response to meals. The overall effect to slow the rate of appearance (Ra) from the meal is mediated via a coordinate reduction of food intake, slowing of gastric emptying, inhibition of digestive secretion [gastric acid, pancreatic enzymes, and bile ejection]. Appearance of new glucose is slowed by inhibiting secretion of the gluconeogenic hormone
glucagonGlucagon is an important hormone involved in carbohydrate metabolism. Produced by the pancreas, it is released when blood glucose levels start to fall too low, causing the liver to convert stored glycogen into glucose and release it into the bloodstream, raising blood glucose levels and ultimately...
. These actions, which are mostly mediated via a glucose-sensitive part of the brain stem, the area postrema, may be over-ridden during hypoglycemia. They collectively reduce the total
insulinInsulin is a hormone that has extensive effects on metabolism and other body functions, such as vascular compliance. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle, and stopping use of fat as an energy...
demand. Amylin also acts in bone metabolism, along with the related peptides
calcitoninCalcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . It has been found in fish,...
and calcitonin gene related peptide..
Rodent amylin
knockoutA gene knockout is a genetic technique in which an organism is engineered to carry genes that have been made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...
s are known to fail to achieve the normal
anorexiaAnorexia is the decreased sensation of appetite...
following food consumption. Because it is an amidated peptide, like many
neuropeptideNeuropeptides are small protein-like molecules used by neurons to communicate with each other. They are neuronal signaling molecules, influence the activity of the brain in specific ways and are thus involved in particular brain functions, like analgesia, reward, food intake, learning and...
s, it is believed to be responsible for the anorectic effect.
Structure
The human form of IAPP has the amino acid sequence KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY, with a disulfide bridge between cysteine residues 2 and 7. Both the amidated C-terminus and the disulfide bridge are necessary for the full biological activity of amylin. IAPP is capable of forming amyloid fibrils
in vitro. Within the fibrillization reaction, the early prefibrillar structures are extremely toxic to beta-cell and insuloma cell cultures. Later
amyloidAmyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various other neurodegenerative diseases.-Definition:...
fiber structures also seem to have some cytotoxic effect on cell cultures. Studies have shown that fibrils are the end product and not necessarily the most toxic form of amyloid proteins/peptides in general. A non-fibril forming peptide (1-19 residues of human amylin) is toxic like the full-length peptide but the respective segment of rat amylin is not.. It was also demonstrated by solid-state NMR spectroscopy that the fragment 20-29 of the human-amylin fragments membranes. Rats and mice have six substitutions (three of which are proline substitions at positions 25, 28 and 29) that are believed to prevent the formation of amyloid fibrils. Rat IAPP is nontoxic to beta-cells, even when overexpressed.
History and Nomenclature
IAPP was identified independently by two groups as the major component of diabetes-associated islet
amyloidAmyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various other neurodegenerative diseases.-Definition:...
deposits in 1987.
The difference in nomenclature is largely geographical; European researchers tend to prefer IAPP whereas American researchers tend to prefer Amylin. Some researchers discourage the use of "Amylin" on the grounds that it may be confused with the pharmaceutical company.
Pharmacology
Synthetic amylin, or pramlintide (brand name
SymlinPramlintide acetate is a relatively new adjunct treatment for diabetes , developed by Amylin Pharmaceuticals.-Pharmacology:...
), was recently approved for adult use in patients with both
diabetes mellitus type 1Diabetes mellitus type 1 is a form of diabetes mellitus. Type 1 diabetes is an autoimmune disease that results in destruction of insulin-producing beta cells of the pancreas...
and
diabetes mellitus type 2Diabetes mellitus type 2 or type 2 diabetes is a disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency...
. Insulin and pramlintide, injected separately but both before a meal, work together to control the post-prandial glucose excursion.
Amylin is degraded in part by insulin-degrading enzyme.
Receptors
There appears to be at least three distinct receptor complexes that bind with high affinity to
amylin. All three complexes contain the
calcitonin receptorThe calcitonin receptor is a G protein-coupled receptor which binds the peptide hormone calcitonin and is involved in maintenance of calcium homeostasis, particularly with respect to bone formation and metabolism ....
at the core, plus one of three
receptor activity-modifying proteinReceptor activity-modifying proteins are a class of protein which interact with and modulate the activities of several Class B G Protein-Coupled Receptors including the receptors for secretin, calcitonin , glucagon, and vasoactive intestinal peptide...
s, RAMP1, RAMP2, or RAMP3.
Further reading
External links