Extrapancreatic Effects Of Gip And

GIP receptor mRNA has been found in a variety of tissues outside the pancreas, including stomach, intestine, brain, heart, and adipose tissue. The function of GIP in many of these tissues remains unclear, but a role of GIP in adipose-tissue metabolism and a possible function in the development of obesity has recently generated much interest.

Fat is a potent secretagogue of GIP in humans, and functional GIP receptors have been identified on adipocytes [36]. Twenty-four-hour secretory patterns of GIP in humans closely parallel those of plasma triglyceride, suggesting a possible role in postprandial lipid clearance and metabolism [26], a hypothesis strengthened by the finding that infusion of GIP promotes the clearance of chylomicron triacyl-glycerol (TAG) in dogs [37]. Consistent with this hypothesis, hypertriglyceridemic subjects have been shown to exhibit disordered postprandial GIP secretion [38]. In various adipose-tissue preparations in vitro, GIP augments insulin-stimulated glucose transport [39], increases fatty-acid synthesis [40], and reduces glucagons-stimulated lipolysis [41], demonstrating a direct insulin-like anabolic role.

In man, accumulation of TAG in adipose tissue from dietary fat sources is quantitatively much more important than de novo lipogenesis. Adipose tissue lipo-protein lipase (LPL) plays a key regulatory role in postprandial TAG clearance by hydrolyzing chylomicron and very low density lipoprotein (VLDL) TAG and liberating fatty acids for uptake and storage within the adipocyte. GIP, in common with insulin, increases LPL activity in rat adipose-tissue explants, whereas GLP 1 is without effect [42]. The magnitude of the postprandial GIP response in humans is dependent on the size of the fat, as well as the carbohydrate load [43], and progressive increases in postprandial postheparin LPL activity in parallel with plasma GIP have been found when the fat content of the meal is increased [43]. These findings are consistent with GIP acting as a major hormonal signal linking meal size with LPL

activity in the physiological control of postprandial lipemia, in addition to its effects on postprandial glycemia.

These actions of GIP have led to the hypothesis that the hormone might play a role in the etiology of obesity. GIP secretion is sensitive to chronic changes in diet, in particular, to changes in the dietary fat content; diets high in fat content increase intestinal K cell number [44], GIP expression, and circulating GIP levels [45]. Obesity is typically associated with hyperinsulinemia, and the anabolic activity of GIP could combine with insulin to promote adipose tissue fat deposition. The gene encoding GIP could be considered a thrifty gene, maximizing nutrient storage and valuable to our hunter/gatherer forebears. However, this feature of GIP physiology could be maladaptive in people consuming energy-dense, fat-rich Western diets, and could contribute towards their obesity (Figure 2.2). The hypothesis has gained much recent support from studies of GIP-receptor knock-out mice (GIPR-/) in which GIP-receptor expression is disrupted. In contrast to normal control animals, these mice did not gain weight or become obese when placed on a high-fat diet. Food intake was not significantly different between the two groups, but the GIPR-/- mice exhibited a higher energy expenditure and appeared to oxidize triglycerides preferentially. In addition, crossing hyperphagic, genetically obese ob/ob mice with GIPR-/- mice reduced the severity of obesity by 23 percent in their homozygous offspring. These

Health Effects Overnutrition

FIGURE 2.2 Scheme linking overnutrition to the development of obesity, insulin resistance, and type 2 diabetes, via GIP From Gault, VA, O'Harte, FPM, and Flatt, PR, Glucose-dependent insulinotropic polypeptide (GIP): antidiabetic and antiobesity potential? Neuropeptides, 37, 253, 2003. With permission from Elsevier.

FIGURE 2.2 Scheme linking overnutrition to the development of obesity, insulin resistance, and type 2 diabetes, via GIP From Gault, VA, O'Harte, FPM, and Flatt, PR, Glucose-dependent insulinotropic polypeptide (GIP): antidiabetic and antiobesity potential? Neuropeptides, 37, 253, 2003. With permission from Elsevier.

findings collectively indicate that GIP is an important hormone in lipid metabolism, which links overnutrition with the development of obesity.

B. GLP 1 — A Spectrum of Antidiabetic Actions

GLP 1 is established as a physiological incretin, promoting insulin secretion and exerting trophic effects on the pancreas. However, it has other extrapancreatic biological actions, which could be highly desirable in the context of treating type 2 diabetes. GLP 1 delays gastric emptying [46], slowing down glucose absorption and thus reducing postprandial glucose excursions. It is also a potent inhibitor of gluca-gon secretion, and is able to lower glucose levels in insulin-requiring diabetic patients with no residual B cell activity (hence, no capacity for insulin secretion) by attenuating the hyperglycemic action of glucagons [47]. GLP 1 has also been shown to enhance glucose uptake and glycogen storage in liver and muscle [48]. All of these actions would contribute towards GLP 1's hypoglycemic effect in addition to its insulinotropic action. Moreover, GLP 1 is, in addition, a short-term inhibitor of appetite and food intake, and may contribute to glucose homeostasis by reducing food intake itself [49]. This satiety effect of GLP 1 would be desirable to support attempts at weight reduction in type 2 diabetic subjects, many of whom are also obese. The finding that glucose-stimulated GLP 1 secretion is reduced in obese subjects [50] is of obvious importance in its putative role as a satiety factor. The above spectrum of antidiabetic actions place GLP 1 in a potentially good position as a therapeutic agent in the treatment of diabetes.

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