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Amylin, or Islet Amyloid Polypeptide (IAPP), a peptide hormone secreted by pancreatic -cells at the same time as insulin (in the roughly 1:100 ratio of amylin to insulin).[1]

Clinical significance
Amyloid deposits deriving from islet amyloid polypeptide (IAPP, or amylin) are commonly found in pancreatic islets of patients suffering diabetes mellitus type 2, or containing an insulinoma cancer. While the association of amylin with the development of type 2 diabetes has been known for some time,[2] 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, can induce apoptotic cell-death in insulin-producing beta cells, an effect that may be relevant to the development of type 2 diabetes.[3] A recent study reported a synergistic effect for weight loss with leptin and amylin coadministration in dietinduced obese rats by restoringhypothalamic sensitivity to leptin.[4] 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.[5]

Amylin functions as part of the endocrine pancreas 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.[6]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) 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. These actions, which are mostly carried out via a glucose-sensitive part of the brain stem, the area postrema, may be over-ridden during hypoglycemia. They collectively reduce the total insulin demand.[7] Amylin also acts in bone metabolism, along with the related peptides calcitonin and calcitonin gene related peptide.[6] 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.

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.[8] Later amyloid 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.[9][10][11] It was also demonstrated by solid-state NMR spectroscopy that the fragment 20-29 of the humanamylin fragments membranes.[12] 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.

A synthetic analog of human amylin with proline substitutions in positions 25, 26 and 29, 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.[15] Amylin is degraded in part by insulin-degrading enzyme.[16]

Dawn phenomenon
Dawn phenomenon is defined as an increase in the blood sugar in the morning and is typically invoked in the context of diabetes. It is different from Chronic Somogyi rebound in that dawn effect is not associated with nocturnal hypoglycemia. It is possible that dawn effect is caused by the release of counterregulatory hormones such as cortisol, glucagon, or epinephrine, all of which can signal the liver to release glucose. In most of the cases, there is no need to change insulin dosing of patients who encounter dawn effect.[1] The "dawn effect," also called the "dawn phenomenon," is the term used to describe an abnormal early-morning increase in blood sugar (glucose) usually between 2 a.m. and 8 a.m. in people with diabetes. Some researchers believe it's due to the natural overnight release of hormones including growth hormones, cortisol, glucagon, and epinephrine that increase insulin resistance. Other causes may include insufficient insulin administration the night before, incorrect medication dosages, or eating carbohydrate snacks at bedtime.Dawn phenomenon can be treated by avoiding carbohydrate intake at bedtime, adjusting the dosage of medication or insulin, switching to a different medication, or by using an insulin pump to administer extra insulin during early-morning hours.

Chronic Somogyi rebound

Chronic Somogyi rebound, also called the Somogyi effect and posthypoglycemic hyperglycemia, is a rebounding high blood sugar that is a response to low blood sugar.[1] In context of managing the blood glucose level manually with insulin injections, this effect is counter-intuitive to insulin users who experience high blood sugar in the morning as a result of an overabundance of insulin at night. Compare with the dawn effect, which is a morning rise in blood sugar in response to waning insulin and a growth hormonesurge (that further antagonizes insulin).

A person with type 1 diabetes struggles to balance insulin delivery to manage their blood glucose level. Occasionally, insufficient insulin delivery can result in hyperglycemia. The appropriate response is to deliver a correction dose of insulin to reduce the blood sugar level, and to consider adjusting the insulin regimen to deliver additional insulin in the future to prevent hyperglycemia. Conversely, excessive insulin delivery may result in hypoglycemia. The appropriate response is to treat the hypoglycemia and to consider adjusting the insulin regimen to reduce insulin in the future. Somogyi and others[4] have claimed that if prolonged hypoglycemia is untreated, then stress due to low blood sugar can result in a high blood sugar level rebound. The physiological mechanisms driving the rebound are defensive. When the blood glucose level falls below normal, the body responds by releasing the endocrine hormone glucagon as well as the stress hormones epinephrine and cortisol. Glucagon facilitates release of glucose from the liver that raises the blood glucose immediately, and the stress hormones cause insulin resistance for several hours, sustaining the elevated blood sugar.

The first line of defense in preventing chronic Somogyi rebound is additional blood glucose testing. Continuous blood glucose monitoring would be a far better method to detect and prevent the Somogyi rebound, but the technology is not yet widely available due to acceptance in the medical insurance community. Testing blood sugar more often, 8 to 10 times daily with a traditional blood glucose meter, facilitates detecting the low blood sugar level before such a rebound occurs. Testing occasionally during the middle of the night is also important, particularly when high waking blood sugars are found, to determine if more insulin is needed to prevent hyperglycemia or if less insulin is needed to prevent such a rebound. Sometimes a person with diabetes will experience the Somogyi rebound when awake and notice symptoms of the initial low blood sugar or symptoms of the rebound. At night, waking with a night sweat (perhaps combined with a rapid heart rate) is a symptom of the adrenaline and rebound. Unfortunately, the evidence shows that patients with type 1 diabetes do not normally wake during nocturnal hypoglycemic episodes [1]. While reviewing log data of blood glucose after the fact, signs of Somogyi rebound should be suspected when blood glucose numbers seem higher after the insulin dosage has been raised, particularly in the morning.

In theory, avoidance is simply a matter of preventing hyperinsulinism. In practice the difficulty for a diabetic person to aggressively dose insulin to keep blood sugars levels close to normal and at the same time constantly adjust the insulin regimen to the dynamic demands of exercise, stress, and wellness can practically assure occasional hyperinsulinism. .Some practical behaviors which are useful in avoiding chronic Somogyi rebound are:

frequent blood glucose monitoring (810 times daily): continuous blood glucose monitoring: logging and review of blood glucose values, searching for patterns of low blood sugar values; conservative increases in insulin delivery; awareness to the signs of hypoglycemia; awareness to hyperglycemia in response to increased delivery of insulin. use of appropriate types of insulin (long-acting, short-acting, etc) in appropriate amounts