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 intravenously, suggesting that the effect was due to a deceleration of glucose uptake from the meal, rather than an acceleration of its metabolism (Kolterman et al., 1995). Since amylin did not affect the rate of glucose transit across exteriorized gut loops (Young and Gedulin, 2000), it was proposed that blunting of postprandial glucose profiles could reflect effects on gastric emptying. Rates of gastric emptying have been determined using three different approaches: (1) by measurement of remnant dye found in acutely excised stomachs, (2) by the systemic appearance of labels that are not significantly absorbed until they leave the stomach (e.g., labeled glucose, acetaminophen, 13C-labeled volatiles), and (3) by following the passage of radiolabeled meal components scintigraphically, with a gamma-camera. Amylin and/or pramlintide were shown to potently inhibit gastric emptying by the first method in animals (Clementi et al., 1996; Young et al., 1995a, 1996b), by the second method in animals (Gedulin et al., 1995; Young et al., 1995a, 1996a) and in humans, including those with type 1 and type 2 diabetes (Burrell et al., 2003b; Hücking et al., 2000; Kong et al., 1998; Lee et al., 2000; Vella et al., 2002), and by scintigraphy in patients with type 1 diabetes (Kong et al., 1997, 1998) and in nondiabetic subjects (Samsom et al., 2000). Depending upon dose, responses ranged from a slowing of emptying rate (e.g., by approximately 50%) to a complete cessation. In rats, amylin was 15-fold more potent on a molar basis than glucagon-like peptide-1 (GLP-1) and 20-fold more potent than cholecystokinin octapeptide (CCK-8) for inhibition of gastric emptying (Young et al., 1996b). It was the most potent mammalian peptide of 21 tested for this action (Gedulin et al., 1996b). Amylin inhibition of gastric emptying appears to be mediated by a central mechanism (Clementi et al., 1996; Dilts et al., 1997; Young et al.,2000). An intact vagus nerve (Jodka et al., 1996) and an intact area postrema (Edwards et al., 1998) are required for the effect. In rats that underwent total subdiaphragmatic vagotomy or surgical ablation of the area postrema, amylin was no longer effective at inhibiting gastric emptying (Edwards et al.,1998). The effect of amylin and amylin agonists (including pramlintide) to inhibit gastric emptying was reversed by insulin-induced hypoglycemia (Gedulin and Young, 1998; Gedulin et al., 1997b,c,d; Young et al., 1996a). This suggests the existence of a glucose-sensitive "fail-safe" mechanism that safeguards against severe hypoglycemia; nutrients ingested in response to the hunger that accompanies hypoglycemia can pass rapidly through the stomach for immediate digestion and absorption, unimpaired by the physiological restraint of amylin that would normally prevail at normal glucose concentrations. It seems likely that amylinergic control of gastric emptying is mediated via neurons in the area postrema shown in brain slices to be activated by amylin, and inhibited by low glucose (Riediger et al., 1999). Such neurons have been proposed to mediate glucoprivic gut reflexes (Adachi et al., 1995).