Amylin and hypoglycemic attacks

Question:

Diabetes Interview had an article about amylin the hormone last summer. You could wait until I figure out where my copy is and post it, or you could call Diabetes Interview at 415-750-1958 to get a copy of the article. BTW, DI’s January issue featured an interview with the guy who had that first transplant of islet cells encased in seaweed extract. After being unable to work for the last 8 years, now he only takes 1/2 unit of insulin if he’s over 100 (5.5?), and is currently down to a total of about 5 units a week and starting a new job publishing country and western music . Oh — and the cost of the transplant was a cool million bucks. In case you were going to check your financial reserves and sign up. OTOH, an attached interview with the surgeon, Dr. Soon-Shiong, says he has received FDA approval to conduct 19 more transplants, only to people who have also had prior kidney transplants, though. So I wonder when it becomes affordable for us not-totally-crippled types? Lyle, having trouble deciding whether to watch the Olympic closing ceremony or rewind my VCR enough to watch the Living With Diabetes segment taped this afternoon…

Response:

Type I diabetics (which I am a member for 28 years) have problems in both insulin production and also from unbalanced glucagon production at high levels during lows. CGRP and Amylin have been implicated in controlling aspects of this insulin/glucagon production. [...] The following are excerpts from a quick medline search. The last reference is the latest and greatest review from persons working at Amylin Corp. Many thanks for the summary and references! I was able to find the Amylin Corp. paper (TiPS April 1993) in my college library. The article is written in technical language I find difficult to decipher but I find a section towards the end quite informative: "AMYLIN DEFICIENCY IN IDDM Patients with IDDM have a double deficiency. In addition to their life-threatening lack of insulin, they have a significant amylin deficiency. The available data show that amylin expression and secretion by pancreatic $beta$-cells is absent or well below normal in IDDM. In several animal models of IDDM, pancreatic amylin secretion and gene expression are depressed. [...rats with IDDM also lack amylin] Measurements of plasma amylin in IDDM patients show that amylin is deficient in these patients after an overnight fast, and that a glucose load does not elicit any increase in amylin levels. PATHOLOGICAL CONSEQUENCES OF DEFICIENCY Our current understanding of amylin’s peripheral actions support the idea that amylin deficiency is associated with an increased risk of hypoglycaemia during insulin therapy, a risk that impedes the prescribing of higher doses of insulin aimed at achieving good glucose control. Because amylin stimulates the lactate flux important for post-prandial glycogen synthesis in the liver, a deficiency of amylin could lead to defective hepatic glycogen storage, and impairment of the counter-regulatory mechanisms that prevent hypoglycaemia. Indeed, recent data shows that glucagon raised glucose less effectively in IDDM patients than in matched healthy subjects. Amylin replacement experiments in $beta$-cell-deficient rats have provided evidence that hypoamylinemia could contribute to disturbances of hepatic gylcogen stores. In streptozotocin-treated [IDDM] rats on no therapy, liver glycogen was depleted by 73%. Treated animals receiving insulin replacement for five days had liver glycogen depleted by 42%. However, when a single daily dose of amylin (30$mu$g s.c.) was co-administered with their insulin, liver glycogen was normal. These results may indicate that amylin has chronic effects additional to the acute actions described above; the enhancement of liver glycogen was found more than 24h after the last dose of amylin." The article mentions that Phase II clinical trials are underway to assess its use in the treatment of IDDM. I look forward to reading about the results of these. Mark —

Response:

Amylin and closely related hormones calcitonin and calcitonin-gene-related-peptide (CGRP) are relatively new having been discovered since 1985. Calcitonin was discovered earlier mid sixties (??). Amylin was discovered as a major component in protein deposits in the islets of langerhans called amyloid plaques. CGRP was discovered first as an alternatively processed calcitonin gene product. These peptides act on widely distributed receptors in numerous tissues. The exact role of amylin and CGRP are unclear. Type I diabetics (which I am a member for 28 years) have problems in both insulin production and also from unbalanced glucagon production at high levels during lows. CGRP and Amylin have been implicated in controlling aspects of this insulin/glucagon production. Type II diabetics are affected by several possible problems. One is that amylin seems to increase muscle resistance to the effects of insulin, perhaps compounding the low or erratic levels of insulin production. Last month [August 1993], Glaxco, Britain’s largest

^^^^^^ Spelled "Glaxo". This company is the number 2 pharm company closely behind Merck in sales. Glaxo’s biggest product is Zantax (sp). They are multinational with US headquarters in Research Triangle Park near Durham, NC. This is not an area where the sites of action and the effects are completely understood. It is a very attractive area for both further research and drug development. There is not all that much literature available on the function and actions of these peptide hormones. All are active in a fashion apparently unrelated to insulin or glucagon production in the brain. Amylin receptors are abundant in a region of the brain called the nucleus accumbens. The following are several academic references to amylin’s properties. These may be too technical inorder to get the theme, but the bottom line is that the amount of publicly known info says to me that more research is needed. There is evidence that amylin itself may be a mild neuotoxin as well as all the good aspects. The following are excerpts from a quick medline search. The last reference is the latest and greatest review from persons working at Amylin Corp. AU - Leffert JD AU - Newgard CB AU - Okamoto H AU - Milburn JL AU - Luskey KL TI - Rat amylin: cloning and tissue-specific expression in pancreatic islets. SO - Proc Natl Acad Sci U S A 1989 May;86(9):3127-30 AU - Ferrier GJ AU - Pierson AM AU - Jones PM AU - Bloom SR AU - Girgis SI AU - Legon S TI - Expression of the rat amylin (IAPP/DAP) gene. SO - J Mol Endocrinol 1989 Jul;3(1):R1-4 AU - Roberts AN AU - Leighton B AU - Todd JA AU - Cockburn D AU - Schofield PN AU - Sutton R AU - Holt S AU - Boyd Y AU - Day AJ AU - Foot EA AU - et al TI - Molecular and functional characterization of amylin, a peptide associated with type 2 diabetes mellitus. SO - Proc Natl Acad Sci U S A 1989 ;86(24):9662-6 AU - Nishi M AU - Bell GI AU - Steiner DF TI - Islet amyloid polypeptide (amylin): no evidence of an abnormal precursor sequence in 25 type 2 (non-insulin-dependent) diabetic patients. SO - Diabetologia 1990 Oct;33(10):628-30 AU - Steiner DF AU - Ohagi S AU - Nagamatsu S AU - Bell GI AU - Nishi M TI - Is islet amyloid polypeptide a significant factor in pathogenesis or pathophysiology of diabetes? SO - Diabetes 1991 Mar;40(3):305-9 AU - Rink TJ AU - Beaumont K AU - Koda J AU - Young A TI - Structure and biology of amylin. AD - Amylin Pharmaceuticals Inc., San Diego, CA 92121. SO - Trends Pharmacol Sci 1993 Apr;14(4):113-8 — Frank Kolakowski O US Mail: Lee F. Kolakowski Renal Unit, 8th Flr. O O Massachusetts General Hospital Charlestown Navy Yard O O 149 13th Street FAX : 1-617-726-5669 O O Charlestown, MA 02129 Phone AT&T: 1-617-726-5666 O O The home of the G-Protein-Coupled Receptor Database (GCRDb) O

Response:

The following article appeared in the Sunday Times during September last year. It claims that a new drug is being developed to avoid hypoglycemic attacks in Type I diabetics. Does anyone have more information on this and Amylin Pharmaceuticals? I’d also like to find out more about the function of the hormone "Amylin". "ESCAPE FROM UNDER THE SHADOW OF DIABETES", Sunday Times ?th September 1993 THERE may be light at the end of the tunnel for diabetics who have to endure the grim routine of insulin shots and the ever-present shadow of life-threatening attacks caused by dangerously low levels of glucose in the bloodstream. Last month [August 1993], Glaxco, Britain’s largest pharmaceuticals manufacturer, won an American patent protecting a new drug that experts believe could be the biggest breakthrough in diabetes treatment since insulin was discovered in the 1920s. [...] In collaboration with its joint-venture partner, Amylin Pharmaceuticals of California, it has turned new theories about how the disease is created into a drug with the potential to treat adult diabetes. Amylin, working by itself, is also developing a drug to prevent hypoglycemic attacks in young people. [...] The research by Glaxco and its Californian partner is concentrating on another natural hormone, amylin. Dr Gareth Cooper, a scientist at Oxford University who went on to become one of the founders of Amylin Pharmaceuticals, first identified the hormone in 1987. He noticed that abnormal levels of the hormone, produced naturally in the pancreas, were common in diabetics. The levels of amylin differed, however, for sufferers of Type I and Type II diabetes, suggesting that the hormone was palying a key role in the disease. Type I diabetics [...] were found to have very low levels of amylin. Later research found that by stimulating the level of amylin in the body, diabetics could prevent the hypoglycemic attacks they still suffer even when taking insulin. [...] The product Amylin is developing on its own is codenamed AC137 and will stimulate the hormone and prevent hypoglycemic attacks [...] It has already begun to be tested on humans – it has completed its first phase of trials and will start the second this month [September 1993]. The initial trials of a new drug only test whether a product is safe, rather than whether it works or not, but the comany has said that all indications are that the drug will be effective in treating diabetics. [...] [The article goes on to describe an oral "Amylin antagonist", codenamed AC253 being developed by Glaxco, for Type II sufferers who have too much amylin in their blood.]

Response:

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