Amylin
Encyclopedia
Peptide hormone
Peptide hormones are a class of peptides that are secreted into the blood stream and have endocrine functions in living animals.Like other proteins, peptide hormones are synthesized in cells from amino acids according to an mRNA template, which is itself synthesized from a DNA template inside the...
secreted by pancreatic
Pancreas
The 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 a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
β-cells
Beta cell
Beta cells are a type of cell in the pancreas located in the so-called islets of Langerhans. They make up 65-80% of the cells in the islets.-Function:...
at the same time as insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. 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....
(in the roughly 1:100 ratio of amylin to insulin).
Clinical significance
Amyloid deposits deriving from islet amyloid polypeptide (IAPP, or amylin) are commonly found in pancreatic isletsIslets of Langerhans
The islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans at the age of 22, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas...
of patients suffering diabetes mellitus type 2
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
, or containing an insulinoma
Insulinoma
An 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...
cancer. While the association of amylin with the development of type 2 diabetes has been known for some time, its direct role as the cause has been harder to establish. Recent results suggest that amylin, like the related beta-amyloid (Abeta) associated with Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, can induce apoptotic cell-death
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
in insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. 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....
-producing beta cells, an effect that may be relevant to the development of type 2 diabetes.
A recent study reported a synergistic effect for weight loss with leptin
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
and amylin coadministration in diet-induced obese rats by restoring hypothalamic sensitivity to leptin. Finally, a recent proteomics study showed that human amylin shares common toxicity targets with beta-amyloid (Abeta), providing evidence that type 2 diabetes and Alzheimer's disease share common toxicity mechanisms.
Function
Amylin functions as part of the endocrine pancreasPancreas
The 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 a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
and contributes to glycemic control. The peptide is secreted from the pancreatic islets into the blood circulation and is cleared by peptidases in the kidney. It is not found in the urine.
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
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. 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....
, with which it is cosecreted from pancreatic beta cells in response to meals. The overall effect to slow the rate of appearance (Ra) of glucose from the meal is accomplished via coordinate slowing down gastric emptying, inhibition of digestive secretion [gastric acid, pancreatic enzymes, and bile ejection], and a resulting reduction in food intake. Appearance of new glucose is slowed down by inhibiting secretion of the gluconeogenic hormone glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
. These actions, which are mostly carried out via a glucose-sensitive part of the brain stem, the area postrema
Area postrema
The area postrema is a medullary structure in the brain that controls vomiting. Its privileged location in the brain also allows the area postrema to play a vital role in the control of autonomic functions by the central nervous system.-Anatomy:...
, may be over-ridden during hypoglycemia. They collectively reduce the total insulin demand.
Amylin also acts in bone metabolism, along with the related peptides calcitonin
Calcitonin
Calcitonin 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 . Calcitonin has been found...
and calcitonin gene related peptide.
Rodent amylin knockout
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is 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 anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
following food consumption. Because it is an amidated peptide, like many neuropeptide
Neuropeptide
Neuropeptides 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 amyloidAmyloid
Amyloids 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 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 amyloidAmyloid
Amyloids 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 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
A synthetic analog of human amylin with proline substitutions in positions 25, 26 and 29, or pramlintide (brand name SymlinPramlintide
Pramlintide acetate is a relatively new adjunct for diabetes , developed by Amylin Pharmaceuticals.-Pharmacology:...
), was recently approved for adult use in patients with both diabetes mellitus type 1
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
and diabetes mellitus type 2
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
. 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 receptorCalcitonin receptor
The calcitonin receptor is a G protein-coupled receptor that 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 protein
Receptor activity-modifying protein
Receptor 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.
See also
- Proislet Amyloid PolypeptideProislet Amyloid PolypeptideProislet Amyloid PolypeptideProislet amyloid polypeptide is the protein precursor for Islet amyloid polypeptide...
- PramlintidePramlintidePramlintide acetate is a relatively new adjunct for diabetes , developed by Amylin Pharmaceuticals.-Pharmacology:...
- Type II DiabetesDiabetes mellitus type 2Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...