RESEARCH & DEVELOPMENT

pir ti r m lin ? . ill

-Gill Higgins-

By investing considerable resources in amylin-related research, Glaxo and Amylin Pharmaceuticals are demonstrating their confidence in this new, and somewhat controversial, approach to diabetes treatment. Evidence for a therapeutic role is still scarce but interest remains high with several studies of amylin reported at the recent annual meeting of the American Diabetes Association. lnpharma reports on the latest developments.

Amylin [islet amyloid polypeptide] was discovered just a few years ago and was subsequently identified as the principal constituent of the amyloid deposits found in the pancreatic islets of 90% of patients with noninsulin-dependent diabetes mellitus (NIDOM). It appears to act in opposition to insulin in the regulation of glucose.' This finding led researchers to wondering whether the perfect explanation for insulin resistance in NIOOM had been found. Indeed, ill vitro and ill vivo studies showed that amylin: • inhibits insulin secretion from P cells • induces peripheral insulin resistance.

However, these effects have only been achieved with amylin concentrations thousands of times greater than normal blood levels in humans. At least one report has been published of elevated amylin concentrations in patients with NIOOM on oral hypoglycaemics, but there are no in vivo data in humans to confirm that infused amylin can produce insulin resistance or that physiological concen­trations are active. This is disappointing news which puts paid to the theory of amylin as the major cause of insulin resistance in NIOOM; and it has caused some researchers to doubt whether amylin acts as a circulating hormone at all. Nevertheless, a role for portal amylin or paracrine activity remains a possibility. 2 For this reason, amylin antagonists are still being pursued [see boxed text].

The idea that endogenous amylin limits the insulin response to glucose has been supported by an animal study' of the amylin antagonist, AC 187. In this study, AC 187 was infused as a primed! continuous IV infusion starting 10 min before an IV glucose bolus in fed and fasted rats. The insulin response was greater during AC 187 infusion compared with saline infusion in both fed and fasted animals (p < 0.03 and p < 0.05, respectively). This suggests that amylin antagonists could provide therapeutic improvement in 13 cell performance.

Lack of amylin in IDDM Quite a different picture exists for patients with

childhood-onset insulin-dependent diabetes mellitus (100M). These patients appear to have insufficient amylin, thus, when they receive insulin replacement therapy they are poorly equipped to deal with any associated hypoglycaemia.

Unlike other counter-regulatory hormones, such as glucagon and adrenaline, amylin is secreted simultaneously with insulin rather than in response to hypoglycaemia. Consequently, it may have a protective role when present in adequate amounts. Indeed, in animal models of 100M, recovery from

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hypoglycaemia has been demonstrated by amylin administration.

Amylin acts by limiting the ability of insulin to reduce glucose production by the liver and to promote the transfer of glucose into muscle glyco­gen, but it does not affect carbohydrate metabolism in adipose tissue. Thus, if given concomitantly witt insulin, it would allow the liver to synthesise and output glucose while insulin would act mainly to promote the conversion of carbohydrate into triglyceride for storage in adipose tissue.

There is no doubt that a new approach to the problem of hypoglycaemia in insulin-treated diabetes mellitus would be welcome. Studies are therefore continuing with synthetic forms of amylin, and more active preparations are being sought. I. Van laarsveld Be. et al. Plasma concentrations of islet amyloid polypeptide after glucagon administration in type 2 diabetic patients and non-diabetic subjects. Diabetic Medicine JO: 327-330, May 19932. Amiel S. Amylin and diabetes. Lancet 341: 1249-1250. 15 May 19933. Gedulin I et al. The selective amylin antagonist, AC 187, enhances the insulin respons during intravenous glucose tolerance tests in anesthetized rats. Diabetes 42 (Suppl. I): 229A, May 1993 ~XJ'1.l

INPHARMA"4 Sep 1993

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