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Type 1 and Type 2 diabetes are characterised not only by postprandial insulin insufficiency but also by postprandial glucagon excess. Metabolism. 1975 Nov;24(11):1287-97;  Diabetologia. 1995 Mar;38(3):337-43. ;  N Engl J Med. 1992 Sep 3;327(10):707-13.     In normal individuals, pancreatic insulin is delivered into the portal vein with higher levels in the hepatic circulation than in the systemic. This is crucial in suppressing glucagon rise and hepatic glucose output in the post prandial period.  Delivery of insulin peripherally (subcutaneously)  to achieve higher systemic levels in diabetic patients cannot mimic the physiological delivery of insulin to suppress post prandial glucagon rise, N Engl J Med. 1971 Aug 19;285(8):443-9.   and hence the control of  post prandial hyperglycaemia using peripherally administered insulin remains under-achieved.

The hyaline degeneration of the Islets described in 1901 by E. L. Opie, was later identified as the islet associated amyloid polypeptide in 1986, with localisation of its  gene in 1988. Amyloid is a proteinaceous material with a dense meshwork of rigid fibrils containing a core of polypeptide chains.   At least 20 different types of amyloid fibril proteins have been described. Although different  diseases can produce amyloid fibrils with varying protein components,  Br J Haematol. 1997 Nov;99(2):245-56   the capacity to bind the normal plasma proteinserum amyloid P component (SAP) is a common property of all amyloid fibrils, making it possible to identify and quantify amyloid using SAP tracer scans. SAP which is related to CRP makes the amylin fibrils resistant to proteolytic degradation. SAP clearly has a role in systemic amyloidosis production, since knocking out the SAP gene decreases the severity and slows down development of systemic amyloidosis. Nat Med. 1997 Aug;3(8):855-9   Islet amyloid also contains other proteins, such as apolipoprotein E and the heparan sulfate proteoglycan perlecan. Diabetes. 1999 Feb;48(2):241-53.  Islet associated Polypeptide or Amylin  is a 37 amino acid residue peptide which is the building block of the islet amyloid fibrils.

Amylin Characteristics
Amylin,  a neuroendocrine hormone, is a 37 amino acid peptide, which resembles the calcitonin gene-related peptide a vasodilatory neuropeptide. Drugs Aging. 1996 Sep;9(3):202-12.  Amylin was initially purified from human insulinomas  Arch Pathol Lab Med. 1978 May;102(5):227-32.  and later the amyloid deposited in the pancreases of  type 2 diabetic patients.   Proc Natl Acad Sci U S A. 1987 Dec;84(23):8628-32.   Amylin, also known as islet amyloid polypeptide, is co-localised and co-secreted with insulin from the beta cells of the pancreas.  Proc Natl Acad Sci U S A. 1989 May;86(9):3127-30. and like insulin, amylin is secreted in response to carbohydrates (glucose)  and protein (amino acid) ingestion. Lancet. 1992 May 9;339(8802):1179-80. Amylin secretion is also stimulated by GLP-1, glucagon and cholinergic agonists, while insulin inhibits its secretion. Amylin is derived from an 89 amino acid preproamylin precursor molecule.  Amylin excretion is predominantly renal Diabetologia. 1994 Feb;37(2):188-94.  with a mean elimination half-life of 30–50 minutes. Am J Health Syst Pharm. 2005 Nov 15;62(22):2363-72
 Circulating amylin exists in glycosylated and non-glycosylated forms in normal subjects  and diabetics, with the non-glycosylated form being the biologically active compound.  Horm Metab Res. 1998 Apr;30(4):206-12.  Plasma levels of Amylin, like insulin, shows a diurnal pattern with low basal levels in the fasting state with rapid rise in response to meals.  Healthy humans have a fasting plasma amylin concentration of 4-8 pmol/L, and 15-25 pmol/L in the post prandial state with higher levels in insulin resistant states.  Drug Dev Res.1994;32:90-99. Amylin secretion shows a profile similar to that of insulin with a pulsatile component.  Am J Physiol Endocrinol Metab.2000 Mar;278(3):E484-90 Amylin complements the effect of insulin on post prandial glucose control through mechanisms detailed below. The gene for Amylin  is located on chromosome 12.   Proc Natl Acad Sci U S A. 1989 Dec;86(24):9662-6.  Amylin immunoreactivity has been demonstrated in islet delta cells (which normally produce somatostatin) lung, and in most parts of the gastrointestinal tract including the stomach, duodenum, jejunum, ileum, colon and rectum, as well as in the central nervous system. Endocr Rev. 1994 Apr;15(2):163-201.Amylin binding sites have been identified in various areas including the pancreatic beta cells, lung, skeletal muscles, brain and kidney.Peptides. 2001 Nov;22(11):1765-72.  Amylin receptors are produced through the co- expression of G-protein coupled calcitonin receptor gene and RAMPs (receptor activity- modifying proteins). Six different subtypes of amylin receptors with differing pharmacologic properties are made possible by the combination of calcitonin receptor isoforms with different RAMP. Biochem Soc Trans. 2004 Nov;32(Pt 5):865-7.
Amylin Actions

Amylin reduces  postprandial glucagon secretion, thus decreasing endogenous hepatic glucose output,  Metabolism. 1997 Jan;46(1):67-70.  with improved post prandial glycaemia. This effect on glucagon might be mediated through central effects or peripheral effects namely delayed gastric emptying  Diabetologia. 1995 Jun;38(6):642-8    with resultant reduced exposure to proteins that would normally stimulate glucagon secretion. Amylin may regulate gastric emptying through a vagal mechanism via the area postrema which has an abundance of amylin binding sites.   Mol Pharmacol. 1993 Sep;44(3):493-7.  It is possible that a lack of blood brain barrier at this site might facilitate central sensing of the peripheral changes in glucose and amylin concentrations with appropriate responses in gastric emptying  Destruction of the area postrema results in abolishment of the effect of amylin on gastric empting.   A direct effect on alpha cells in the pancreas to decrease glucagon release is also probable.  The delay in gastric emptying induced by amylin seems to be independent of GLP-1, which is another hormone with similar action. Diabet Med. 2002 Sep;19(9):790-2. The delay in gastric emptying reduces the rate of entry of nutrients into the distal intestine, thus regulating the exogenous component of the post prandial glucose rise, while the reduction in glucagon rise regulates the endogenous contribution.

Amylin deficiency, not surprisingly,  is associated with increased glucagon and faster gastric emptying in the post prandial period. This is characteristic of type I diabetic patients and type 2 diabetic patients with beta cell failure. Although amylin hypersecretion has been noted in the early stages of type 2 diabetes,  both type 1 and type 2 diabetic patients,  ultimately tend to have total or relative amylin deficiency respectively.  Lancet. 1992 May 9;339(8802):1179-80.  First degree relatives of type 2 diabetics have also been noted to have a reduced  amylin secretion.  Diabetes Care. 2002 Feb;25(2):292-7    Hence amylin replacement has the potential to reverse these defects with improved glycaemic control in diabetic patients. 


Amylin infusion, producing as high as 50-100 times normal postprandial concentrations, failed to  produce any significant effect on glucose uptake in the skeletal muscle  Diabetologia. 1990 Feb;33(2):115-7.  Studies in type 2 diabetic patients using amylin antagonists suggest no influence of endogenous amylin on insulin sensitivity. Diabetes Metab Res Rev. 2002 Mar-Apr;18(2):118-26. Amylin infusion produced only a blunted insulin response at high doses. Clin Endocrinol Metab. 1992 May;74(5):1032-5.

Amylin infusion results in an increase in renin and aldosterone levels in healthy humans  Hypertension. 1995 Sep;26(3):460-4.  accompanied by a mild rise in diastolic blood pressure, and interestingly a plasma glucose rise at 60 minutes post infusion. CGRP also increases plasma renin, and it remains possible that the stimulatory effect on renin production in the kidney by amylin may be mediated through binding to CGRP receptors. In fact, hypertensive as well as obese subjects have been reported to have higher amylin levels.Diabetologia. 1994 Feb;37(2):188-94..  These findings could suggest a possible role for amylin in the pathogenesis of insulin resistance.

Amylin is also recognised to have calcitonin like functions on osteoclasts in the bone. Biochem Biophys Res Commun. 1989 Jul 31;162(2):876-81. with amylin deficiency resulting in low bone mass due to increased bone resorption.  J Cell Biol. 2004 Feb 16;164(4):509-14.     Central or peripheral administration of amylin in rats has effects on the pituitary with a significant reduction in serum Prolactin concentrations Neuro Endocrinol Lett. 2005 Dec 28;26(6)
Amylin and Body weight

Amylin deficient (-/-) mice have increased body weight compared to controls. Chronic inhibition of central amylin signalling in rats increased food intake with increased fat mass.  Endocrinology. 2001 Nov;142(11):5035.  Blockade of amylin receptors in rats using antagonists also produces increased food intake by up to 171%.  Am J Physiol Regul Integr Comp Physiol. 2004 Sep;287(3):R568-74  The meal size and frequency were increased by amylin receptor antagonism suggesting that amylin may normally exert an effect on satiety regulation.   The increased weight gain in amylin deficient mice could be mediated by the reduced responsiveness of these rats to the anorectic actions of cholecystokinin and bombesin. Peptides. 2003 Jan;24(1):91-8

Central  Brain Res. 1991 Jan 25;539(2):352-4.    or peripheral   Physiol Behav. 1995 Dec;58(6):1197-202  amylin administration reduces food intake with reduction in body weight.  The reduction in food intake may be mediated through central and peripheral effects (deceleration of gastric emptying).    Intracerebroventricular injection of Amylin into rats produced a 30% reduction in food intake over a 24 hour period  Endocrinology. 2000 Feb;141(2):850-3. with effects lasting for up to 7 days. Chronic Amylin infusion for 10 days resulted in weight reduction mainly attributable to a reduction of retroperitoneal fat.  Amylin's effect seems to be mediated through directstimulation of neurons in the area postrema of the brain.  Peptides. 1998;19(2):309-17     The ability of amylin to reduce meal size is potentiated by the presence of increasing insulin levels.  Horm Metab Res. 2000 Feb;32(2):62-5. 

Zucker obese rats have amylin resistance with a hyper-amylinemic state. Despite amylin c0- secretion with insulin, insulinomas are not usually associated with high amylin levels although a case has been reported. Diabetologia. 1993 Sep;36(9):843-9.
Pramlintide

Human amylin being insoluble with a tendency to self aggregate with amyloid fibril formation,   J Struct Biol. 1997 Jun;119(1):17-27 necessitated a synthetic analog for clinical use. Pramlintide was thus developed as an equipotent analog,  with three proline residues substituted at positions 25, 28 and 29.  J Clin Pharmacol. 1996 Jan;36(1):13-24  Pramlintide has a half life of 50 minutes, and is administered subcutaneously pre meals. Curr Pharm Des. 2001 Sep;7(14):1353-73.   Physiologic levels of amylin as in healthy subjects are reproducible using subcutaneous Pramlintide injections in diabetic patients, with a single dose producing peak concentrations at 20 minutes with levels lasting for 3 hours. Pre meal injections of subcutaneous Pramlintide achieving physiological plasma levels has been shown to produce substantial reduction in post prandial hyperglycaemia in type1  Metabolism. 1999 Jul;48(7):935-41    and type 2 diabetic patients,   Diabet Med. 1997 Jul;14(7):547-55    totally abolishing the glucose surge in the first 60 minutes after  meal ingestion.  This improved post meal glycaemia is demonstrable even with short acting insulin analogs as insulin lispro. Diabetes Care. 2003 Nov;26(11):3074-9.


While Pramlintide achieves improvement in post prandial glycaemia through glucagon suppression, Metabolism. 2002 May;51(5):636-41.   the secretion of glucagon in response to hypoglycaemia remains intact preserving this protective counter regulatory response. J Clin Endocrinol Metab. 1996 Mar;81(3):1083-9.     On a similar note, the effect on gastric emptying also seems to be glucose dependent such that in the presence of hypoglycaemia, gastric emptying is not delayed by amylin.   Diabetes. 1998 Jan;47(1):93-7.  Despite prolongation of the half gastric emptying time to about 90 minutes, inter-meal gastric emptying remains reassuringly complete. Diabetologia. 1998 May;41(5):577-83  Studies in type I diabetics   suggest that Pramlintide has no effect on insulin sensitivity in the liver or peripheral tissues.J Clin Endocrinol Metab. 1996 Mar;81(3):1083-9.


Studies for up to an year have shown that Pramlintide when used as an adjunct to insulin therapy in type 1   Diabetes Care. 2002 Apr;25(4):724-30      and type 2 diabetics    Diabetes Technol Ther. 2002;4(1):51-61    improves glycaemic control, [view HbA1c response] with HbA1c reductions of 0.5-1.0% from baseline, with lower insulin requirements in the amylin treated groups.  Importantly, the improved glycaemia was achieved without an increase in weight, and in fact was associated with an average weight loss of 1.6 kilograms in those with BMI>27 and 2.4 kgs in those with BMI>35. Short term studies in type I diabetic patients have shown reduction insulin dose requirements by up to 17%, and better 24 hour profile with reduced triglyceride excursions.  Diabetes Care. 2003 Jan;26(1):1-8   Pramlintide has minimal side effects, the most common of which are nausea and vomiting of a mild to moderate degree, dose dependent and self limiting. Whether the glycaemic benefits induced by Pramlintide will be sustained in the longer term, its effect on satiety and feeding, and the ideal way of gradual up-titration of doses to avoid side effects remain to be determined. Pramlintide precipitates at a pH above 5.5 and hence is not available as a co-formulation with insulin yet.  Symlin [amylin pharmaceuticals]  as meal time injections, has been approved by the US FDA in March 2005  for use in type 2 diabetic patients poorly controlled on insulin.