Aims/hypothesis: Long-term trials in insulintreated subjects with type 2 diabetes have shown that adjunctive treatment with the amylin analogue pramlintide reduces HbA 1 c levels and elicits weight loss. While amylin reduces food intake in rodents, pramlintide's effect on satiety and food intake in humans has not yet been assessed. Methods: In this randomised, double-blind, placebo-controlled crossover study, 11 insulin-treated men with type 2 diabetes (age 60±9 years, BMI 28.9±4.8 kg/m 2 ) and 15 nondiabetic obese men (age 41±21 years, BMI 34.4±4.5 kg/m 2 ) underwent two standardised meal tests. After fasting overnight, subjects received single subcutaneous injections of either pramlintide (120 μg) or placebo, followed by a preload meal. After 1 h, subjects ate an ad libitum buffet meal. Energy intake and meal duration were measured, as were hunger ratings (using visual analogue scales), and plasma cholecystokinin, glucagon-like peptide-1 and peptide YY concentrations over time. Results: Compared with placebo, pramlintide reduced energy intake in both the type 2 diabetes (Δ−202±64 kcal, −23±8%, p<0.01) and obese (Δ−170±68 kcal, −16±6%, p<0.02) groups, without affecting meal duration. Hunger and hormonal analyte profiles provided evidence that pramlintide may exert a primary satiogenic effect, independently of other anorexigenic gut peptides. Conclusions/interpretation: The results indicate that enhanced satiety and reduced food intake may explain the weight loss observed in long-term pramlintide trials.

These results support continued evaluation of pramlintide as a potential treatment for obesity.

Evidence from rodent studies indicates that the β-cell-derived neurohormone amylin exerts multiple effects on eating behavior, including reductions in meal size, intake of highly palatable foods, and stress-induced sucrose consumption. To assess the effect of amylin agonism on human eating behavior we conducted a randomized, blinded, placebo-controlled, multicenter study investigating the effects of the amylin analog pramlintide on body weight, 24-h caloric intake, portion sizes, “fast food” intake, and perceived control of eating in 88 obese subjects. After a 2-day placebo lead-in, subjects self-administered pramlintide (180 μg) or placebo by subcutaneous injection 15 min before meals for 6 wk without concomitant lifestyle modifications. Compared with placebo, pramlintide treatment elicited significant mean reductions from baseline in body weight on day 44 (−2.1 ± 0.3 vs. +0.1 ± 0.4%, P < 0.001), 24-h caloric intake (−990 ± 94 vs. −243 ± 126 kcal on day 3, P < 0.0001; −680 ± 86 vs. −191 ± 161 kcal on day 43, P < 0.01), portion sizes, and caloric intake at a “fast food challenge” (−385 ± 61 vs. −109 ± 88 kcal on day 44, P < 0.05). Pramlintide treatment also improved perceived control of eating, as demonstrated by a 45% placebo-corrected reduction in binge eating scores ( P < 0.01). The results of this translational research study confirm in humans various preclinical effects of amylin agonism, demonstrating that pramlintide-mediated weight loss in obese subjects is accompanied by sustained reductions in 24-h food intake, portion sizes, fast food intake, and binge eating tendencies.

The microvascular dysfunction which occurs in sepsis involves all three elements of the microcirculation: arterioles, capillaries, and venules. In sepsis, the arterioles are hyporesponsive to vasoconstrictors and vasodilators. Sepsis also reduces the number of perfused capillaries, thereby impacting on oxygen diffusion to mitochondria. In the venules of some tissues (e.g., mesentery) there is an inflammatory response characterized by neutrophil infiltration and protein leakage. In addition, PMN-endothelial adhesive interactions occur in precapillary microvessels and capillaries in organs, such as, the lung and heart. Thus, all these elements of the microcirculation are involved in the sepsis-induced inflammation. In this review we address emerging views on the mechanisms involved in the microvascular dysfunction induced by sepsis within the framework of these three basic elements of the microcirculatory unit. Microcirculation (2000) 7, 83-101.