Amylin

Amylin, or Islet Amyloid Polypeptide (IAPP), is a 37-residue peptide hormone secreted by pancreatic β-cells at the same time as insulin (in a roughly 100:1 ratio).

Islet, or insulinoma, amyloid polypeptide (IAPP, or amylin) is commonly found in pancreatic islets of patients suffering diabetes mellitus type II, or harboring an insulinoma. While the assosciation of amylin with the development of type II 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) assosciated with Alzheimer's disease, can induce apoptotic cell-death in particular cultured cells, an effect that may be relevant to the development of type II diabetes.^[1]

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Function

Amylin functions as part of the endocrine pancreas and contributes to glycemic control. 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 glucagon. These actions, which are mostly mediated via a glucose-sensitive in the brain stem, the area postrema, may be over-ridden during hypoglycemia. They collectively reduce the total insulin demand.^[2][3]

Rodent amylin knockouts are known to fail to achieve the normal anorexia following food consumption. Because it is an amidated peptide, like many neuropeptides, 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. The peptide is secreted from the pancreas into the blood circulation and eventually excreted by the kidneys. IAPP is capable of forming amyloid fibrils in vitro. Within the fibrillization reaction, the early prefibrillar structures are extremely toxic to insuloma cells cultures. Later amyloid fibril structures also seem to have some cytotoxic effect on cell cultures. 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 unique since it is the only non fibril forming IAPP form.

History

IAPP was identified independently by two groups as the major component of diabetes-associated islet amyloid deposits in 1987.^[4][5]

Pharmacology

Synthetic amylin, or pramlintide (brand name Symlin), was recently approved for adult use in patients with both diabetes mellitus type 1 and diabetes mellitus type 2. Insulin and pramlintide, injected separately but both before a meal, work together to control the post-prandial glucose excursion. (Amylin Pharmaceuticals, Inc, , . Retrieved on 2007-05-05)

Receptors

There appears to be at least three distinct receptor complexes that bind with high affinity to amylin. All three complexes contain the calcitonin receptor at the core, plus one of three Receptor activity-modifying proteins, RAMP1, RAMP2, or RAMP3.^[6]

References

Further reading

Notes

1. ^  Chronic Oxidative Stress as a Central Mechanism for Glucose Toxicity in Pancreatic Islet Beta Cells in Diabetes. JBC Vol. 279, Issue 41, 42351-42354, October 8, 2004
2. ^  Amyloidosis in cats from Petdiabetes wiki.