Insulin was the first peripheral signal shown to regulate food intake through interaction with central-hypothalamic neurons (87). Protagonists of popular diets have claimed in the lay press that limitation of insulin secretion is the mechanism for hunger control in subjects fed low-carbohydrate, ketotic diets. Yet, the scientific
Inhibition of food intake (55-57) Stimulation of physical activity (53-55)
Induction of fat-mass loss (55-57) Preservation of lean-muscle mass (55-57) Preservation of bone mass (55-57)
Improvement in insulin sensitivity (54, 57, 72, 84) Improvement in glucose tolerance (54, 57, 84)
Reversal of hepatic steatosis (73, 84)
evidence strongly disputes that claim. Insulin fulfills the role (shared by leptin) of serving as a marker of adipose tissue mass and is secreted in direct proportion to fat mass. Insulin secretion also serves as an acute response to caloric influx: Increased secretion begins within minutes of initiation of feeding, is maintained for the duration of food intake, and returns to basal secretory rate in the postabsorptive period. If insulin were an appetite stimulant (like ghrelin), its secretion would have preceded, not followed, ingestion of food.
The timing and pattern of postprandial insulin secretion suggest a role in the regulation of satiety and meal termination. Indeed, direct administration of insulin to the central nervous system suppresses food intake in rodents (88). Since circulating insulin reaches the central nervous system via receptor-mediated transport across the blood-brain barrier, it is possible that peak insulin levels attained during feeding trigger central mechanisms that mediate satiety. Postprandial insulin secretion also is a potent signal for leptin secretion (48). Thus, in addition to a direct effect, insulin could exert anorectic effects via a leptin-mediated mechanism. Paradoxically, diabetic patients treated with exogenous insulin or medications that increase insulin secretion or sensitivity tend to gain weight. Although several mechanisms explain the weight gain during intensive diabetes therapy, additional putative mechanisms include "central" insulin resistance and diabetic dysleptinemia (78-80).
Pancreatic polypeptide (PP) is secreted by specialized endocrine cells located within the pancreatic islets of Langerhans. Plasma levels of PP increase after meals in proportion to meal size, as well as during insulin-induced hypoglycemia. The increased plasma PP level during insulin-induced hypoglycemia is a marker of cholinergic or parasympathetic activation and may have little bearing on the metabolic role of PP under normal physiological conditions. Postprandial PP levels probably add to the physiological satiety-signaling cascade that limits hyperphagia and helps maintain interprandial intervals. In this regard, systemic administration of PP has been shown to reduce food intake in rodents (89). Furthermore, administration of PP in patients with chronic pancreatitis has been shown to improve glucose tolerance (90).
Thus, circulating PP levels, though not a major determinant of caloric balance, may be part of the afferent signals that transmit metabolic information to higher centers. However, little mechanistic information is available for the possible anor-exigenic action of PP. The related peptides PP, PYY, and NPY bind to G-protein-coupled transmembrane receptors Y1-Y5 that have different affinities for each of the ligands: PP binds to Y4 and Y5 receptor subtypes expressed in the hypothalamus and other tissues (7, 8, 91). Thus, it is possible that circulating PP levels exert their effects through interaction with central receptors in a manner that antagonizes the orexigenic effects of NPY.
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