Discovery and Nomenclature

In 1900, Opie described a hyaline (homogeneous glassy) appearance within the islets of Langerhans from diabetic patients (Opie, 1900a,b) (Fig. 1). The hyaline material present in pancreata from diabetic patients was histologically identified to be amyloid, an extracellular proteinaceous material with characteristic staining properties (Ahronheim, 1943 Ehrlich and Ratner, 1961). Attempts at characterizing the amyloid material were frustrated by its low concentration and insolubility. Some...

Pharmacokinetics of Amylin in Rats

Subcutaneous bolus injections Plasma concentrations after different subcutaneous doses of rat amylin resulted in peak concentrations that were approximately linearly dependent upon dose (Young et al., 1996). The dose-concentration relationship following a subcutaneous bolus is quantified here as Cmax 10( '863*log dose)+2131, where concentration is in pM and dose is in mg. Such relationships have been useful in the interpretation of physiological relevance in a number of dose-response studies....

Amylin in Insulin Deficiency

Insulin-deficient animals showed reduction or absence of amylin, whether insulin deficiency was invoked chemically with streptozotocin (Bretherton-Watt et al., 1989 Inman et al., 1990 Jamal et al., 1990 Mulder et al., 1995b, 1996c Ogawa et al., 1990) or by autoimmune b-cell destruction, as with BB rats (Bretherton-Watt et al., 1991 Huang et al., 1991a,b). That is, loss of insulin secretion was associated with loss of amylin secretion. This indicates that any source of amylin that is outside of...

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Insulin dose (fjg s.c.) Insulin dose ( g s.c.) FIGURE 4 Insulin dose response for plasma glucose (a) and gastric emptying expressed as percent of gavaged contents remaining after 20 min (b). Supplementation with glucose to prevent insulin-induced changes (black triangles) also prevented changes in rate of gastric emptying. Data from Gedulin and Young (1998). remained 20 min after gavage. By pretreatment with various doses of insulin and or glucose, a range of plasma glucose concentrations was...

Clinical Studies

Recognizing that type 1 diabetes was characterized not only by insulin deficiency, but also by amylin deficiency, Cooper (Cooper, 1991) predicted that certain features of the disease could be related thereto, and he proposed amylin insulin co-replacement therapy. Although the early physiological rationale was flawed, the idea that glucose control could be improved over that attainable with insulin alone without invoking the ravages of worsening insulin-induced hypoglycemia was vindicated. The...

Effects on Bone

The actions of amylin on bone have been reviewed in several publications (MacIntyre, 1992a,b MacIntyre etal., 1991 Reid and Cornish, 1996 Tamura et al., 1992a,b Zaidi et al., 1990a,c, 1993b). MacIntyre proposed that amylin or its derivatives or agonists would be useful for treating bone disorders, such as osteoporosis, Paget's disease, or bone loss resulting from malignancy, endocrine disorders, autoimmune arthritides, breakage and fracture, immobility and disease, or hypercalcaemia (MacIntyre,...

Effects on Plasma Glucose and Lactate

Injection of amylin or amylin agonists, including human and rat amylin, pramlintide, salmon calcitonin, and calcitonin gene-related peptide (CGRP), increases the plasma levels of lactate and glucose in non-diabetic fasting rats and mice. This response can be useful in identifying and defining amylin agonists (amylinomimetic agents) (Cooper et al.) and has been investigated in several studies. Increases in plasma glucose and lactate are not present in all species. In humans, for example,...

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FIGURE 3 Opiate-sparing effect of amylin on morphine analgesia. Adding a small dose of amylin markedly reduced the morphine required to attain a given level of analgesia, as illustrated in the isobologram (left panel). From U.S. Patent 5,677,279 (Young, 1997) and unpublished data. The analgesic effect of amylin was not mediated via opiate receptors, since it was not diminished by the opiate antagonist naloxone (Young, 1997). On the other hand, there was a synergistic interaction between amylin...

References

Localization of calcitonin gene-related peptide and islet amyloid polypeptide in the rat and mouse pancreas. Cell Tissue Res. 269, 315-322. Akimoto, K., Nakazato, M., Matsukura, S., and Hayakawa, K. (1993). Plasma concentration of islet amyloid polypeptide in healthy children and patients with insulin-dependent diabetes mellitus. Acta Paediatr. 82, 310-311. Ardaillou, R., and Paillard, F. (1980). Metabolism of polypeptide hormones by the kidney. Adv. Nephrol....

Inhibition of Gastric Emptying

In studies aimed at defining the role of amylin in glucose control, elevations of postprandial glucose concentration were blunted in subjects infused with the human amylin analog, pramlintide (Kolterman et al., 1995, 1996). An effect similar to blunt glucose excursions was observed by Brown and others during infusions of amylin in dogs trained to drink glucose (Brown et al., 1994). The effect of pramlintide in humans was present when glucose was administered orally, but not when administered...

Effects on Digestive Secretions

Area Postrema Rat

Rat amylin subcutaneously injected into rats dose-dependently inhibits pentagastrin-stimulated gastric acid secretion and protects the stomach from ethanol-induced gastritis. The ED50s for these actions (0.050 and 0.036 mg, respectively) are the lowest for any dose-dependent effect of amylin thus far described, and their similar potencies are consistent with a mechanistic (causal) association. At higher amylin doses, inhibition of gastric acid secretion was almost complete (93.4 ). Gastric...

Inhibition of Glucagon Secretion

This chapter describes a physiological and profound effect of amylin to inhibit meal-related glucagon secretion. Glucagon is processed from a large precursor, proglucagon, in a tissue-specific manner in pancreatic a-cells. In addition to amino acid nutrient stimuli, glucagon is also secreted in response to stressful stimuli, such as hypoglycemia and hypovolemia. Glucagon primarily acts on liver to initiate glycogenolysis and gluconeogenesis, resulting in a rapid increase in endogenous...

Effects in

Amylinomimetic

Biological actions in adipocytes can be mediated directly via circulating hormones or indirectly via sympathetic innervation of fat. Direct effects can be usefully assessed in preparations in which adipocytes have been dissociated from each other, and are therefore directly exposed to substrate and hormones. Amylin appears to have no direct effects in isolated adipocytes. II. Effects of Amylin in Isolated Adipocytes_ Only four reports address the effects of amylinomimetic agents in isolated...

Inhibition of Food Intake

Amylinomimetic

Over 100 publications, principally from five groups, describe an effect of amylin and amylin analogs in inhibition of food intake in animals and humans. The major groups contributing to this area are those of the following Chance and Balasubramaniam Balasubramaniam et al., 1991a,b Chance et al., 1991a,b, 1992a,b, 1993 Morley, Flood, and Edwards Edwards and Morley, 1992 Flood and Morley, 1992 Macintosh et al., 2000 Morley and Flood, 1991,1994 Morley et al., 1992, 1993, 1994, 1995, 1996, 1997...

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FIGURE 1 Insulin dose response for the incorporation of radiolabeled glucose into glycogen in isolated stripped soleus muscle from rats. From Young et al. 1992 . 1990 Pittner et al., 1994a,b, 1995a, 1996 Rink et al., 1993 Weiel et al., 1993 Young et al., 1991, 1992a,b, 1993b Fig. 1 . Impairment of insulin-stimulated glucose storage as glycogen in muscle is a key feature Lillioja et al., 1986 Young et al., 1988 and a predictor Bogardus et al., 1986 of insulin resistance in humans. This feature...

Effects in Liver

Amylin and calcitonin gene-related peptide CGRP were each shown to stimulate endogenous glucose production in vivo in rats. Neither peptide had any effect on any of several measures of intermediary carbohydrate metabolism in isolated hepatocytes or isolated perfused liver in rats. The possibility exists that augmentation of endogenous glucose production was secondary to release of lactate from muscle into the plasma, thereby stimulating gluconeogenesis by increasing the availability of...

Amylin in Insulin Resistance

In insulin-resistant animals, amylin expression and plasma amylin concentrations were elevated Bretherton-Watt et al., 1989 Gill and Yen, 1991 Huang etal., 1991b, 1992 Koranyi etal, 1992 O'Brien etal., 1991 Pieber et al., 1994 Tokuyama et al., 1991,1993 . This was especially true if insulin resistance was invoked with dexamethasone Hiramatsu et al., 1994 Jamal et al., 1990, 1991 Koranyi et al., 1992 Mulder et al., 1995a O'Brien et al., 1991 Pieber etal., 1993 . In insulin-resistant humans and...

Table

Johnson et al., 1990 Kogire et al., 1991 Marco et al., 1990 Murakami et al., 1990 Ohsawa et al., 1989 Peiro etal., 1991 Silvestre etal., 1990a,b hren and Pettersson, 1990 Ar'Rajab and hren, 1991 Bretherton-Watt et al., 1990 Broderick and Gold, 1991 Broderick etal., 1991 Fehmann et al., 1990 Ghatei etal., 1990 Gilbey etal., 1989 Gold et al., 1990 Nagamatsu et al., 1990a,b O'Brien et al., 1990 Pettersson and Ahren, 1990 Tedstone etal., 1989, 1990 1993, 1994 Bloom, 1994 Bretherton-Watt et al.,...