Gip

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GIP is a 42 amino-acid peptide secreted from specific endocrine cells, the K cells, which have the highest density in the upper part of the small intestine. In man, GIP-release studies in response to glucose stimulation have confirmed the proximal small intestine to be the major, but not exclusive, site of endogenous GIP release, as small quantities of GIP are also released from the distal small intestine, by cells in which GIP and GLP 1 are colocalized [11]. In addition to carbohydrate, GIP secretion is also stimulated by fat and amino acids [12], though in practice, protein ingestion, per se, is not an important nutritional stimulus for GIP release, as protein is largely absorbed as dipeptides or tripeptides, which do not stimulate release of the hormone (Figure 2.1). Its secretion is dependent upon the absorption of nutrients rather than their mere presence in the gut lumen, and monosaccharide perfusion studies in rats have shown that it is only those sugars actively transported via the SGLT1 transporter that stimulate GIP secretion [13]. Studies in pigs fitted with mesenteric and hepatic portal cannulae have shown that the rate of GIP secretion is proportional to the rate of glucose absorption from the gut [14]. The magnitude of the GIP response increases with the glucose load ingested, thus the contribution of the enteroinsular axis to insulin secretion is proportionately greater when large carbohydrate loads are ingested, or when mixed meals of fat and carbohydrate are consumed. GIP is insulinotropic both in vitro, in isolated islets, or perfused pancreas, and in vivo in both animals and humans, provided that the prevailing circulating glucose concentration is above a threshold of approximately 6 mmol/l [15]. This glucose dependence of GIP provides a safeguard against inappropriate insulin secretion and hypoglycemia as a consequence of fat-stimulated GIP secretion. In addition to insulin secretion, GIP also enhances insulin-gene expression [16], the growth, differentiation, and

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FIGURE 2.1 Plasma GIP and GLP 1 in healthy human subjects following 375 Kcal meals of glucose (■), protein (A) or fat (•). (Mean + SEM, n = 8). From Elliott, RM, et al., Glucagon-like peptide (7-36) amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post prandial and 24h secretion patterns, J. Endocrinol, 138, 159, 1993. Reproduced by permission.

30 60 90 120 150 Time (min) after start of meal

FIGURE 2.1 Plasma GIP and GLP 1 in healthy human subjects following 375 Kcal meals of glucose (■), protein (A) or fat (•). (Mean + SEM, n = 8). From Elliott, RM, et al., Glucagon-like peptide (7-36) amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post prandial and 24h secretion patterns, J. Endocrinol, 138, 159, 1993. Reproduced by permission.

proliferation of pancreatic B cells [17, 18], and acts as a B cell mitogenic and antiapoptopic factor [19], thus acting as a true insulinotropic agent.

An intact N-terminal is necessary to preserve GIP's insulintropic activity, but studies with synthetic GIP/GLP 1 chimeric peptides have indicated that the entire GIP sequence is important for receptor recognition [20]. The truncated peptide GIP(3-42)amide has been shown to act as a receptor antagonist and contains a high-affinity receptor-binding region [21]. These factors are important, as both GIP and GLP 1 are rapidly and extensively degraded in vivo by the ubiquitous enzyme dipeptidyl peptidase IV (DPP-IV) to produce their respective N-terminally truncated metabolites [22], thus diminishing the biological activity of the two hormones (see also the following section). The receptor for GIP is distinct from that for GLP 1, but both belong to the superfamily of G-protein-coupled receptors and are functionally coupled to the adenylate cyclase system. Interaction of GIP with its receptor on the pancreatic B cells increases intracellular calcium concentrations and enhances exocytosis of insulin-containing granules. Activation of mitogen activated protein (MAP) kinase and P13 kinase/protein kinase B signaling pathways have been implicated, secondary to the rise in cyclic adenosine monophosphate (AMP) in this process [23, 24].

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