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GLP 1 shares many similarities with GIP in terms of its insulinotropic activity, and numerous studies have demonstrated its insulinotropic activity in vitro and in vivo [25]. It is a 30-amino-acid peptide secreted from the L-cells of the intestinal mucosa, which occur predominantly in the lower part of the small intestine and in the colon. In common with GIP, GLP 1 secretion is stimulated by carbohydrate and fat [26], but it is also stimulated by protein (2. 1). However, circulating levels of GLP 1(7-36)amide, the GLP 1 isoform that is bioactive, are severalfold lower than those of bioactive GIP. In contrast to GIP, GLP 1 secretion is not dependent upon nutrient absorption, and secretion can be elicited by the presence of nutrients in the gut lumen. Regulation of GLP 1 secretion by nutrients is complex and involves both direct and indirect mediators. While glucose and long-chain fatty acids in the lumen of the gut can exert direct stimulatory effects on the GLP 1 secretion, the physiological significance of this is questionable. GLP 1 secretion occurs very rapidly after nutrient ingestion, whereas the L-cells are located mainly in the distal part of the intestine, where, under normal conditions of feeding, lumenal glucose concentrations are far below the apparent limit of sensitivity of the L-cell. It therefore seems likely that the early GLP 1 response to ingested nutrients is mediated via a proximal-distal loop involving hormonal or neural signals generated from the upper small intestine [27]. Like GIP, GLP 1's insulinotropic activity is strictly glucose-dependent, and it has no effect on glucose concentrations below ~ 4.5 mmol/l [28]. GLP 1 also has trophic effects on pancreatic B cells. It stimulates all stages of insulin biosynthesis, as well as insulin-gene transcription [29], stimulates B cell proliferation, and enhances the differentiation of new B cells [30]. GLP 1 has also been shown to mediate endocrine proliferation in aging glucose-intolerant rats, with a resulting improvement in glucose tolerance [31], raising the exciting possibility that it might be capable of stimulating the growth of new cells in type 2 diabetic patients.

An intact N-terminal is also necessary to preserve GLP 1's insulinotropic activity, and the N-terminally truncated peptide, the product of DPP-IV cleavage, acts as a receptor antagonist [32]. GLP 1 is particularly sensitive to degradation by DPP-IV. Whereas approximately half an infusion of exogenous GIP remains intact in vivo, as little as 10 percent to 20 percent exogenous GLP 1 survives in intact form following infusion of the peptide. This rapid degradation of GLP 1 (and to a lesser extent, GIP) represents a major difficulty associated with attempting to utilize these hormones as potential therapeutic agents in diabetes.

The relative importance of GIP and GLP 1 in stimulating insulin secretion in healthy human subjects is difficult to resolve. Circulating levels of GIP following nutrient ingestion are some fourfold to fivefold higher than GLP 1, although in molar terms, GLP 1 has been shown to be a more potent insulin secretagogue than GIP [8]. Most current radioimmunoassays for GIP and GLP 1 measure precursors and inactive metabolites in addition to the biologically active hormone, making interpretation of physiological postprandial levels of the hormones difficult. A study using GIP-receptor antagonists in genetically obese mice concluded that GIP might be responsible for as much as 80 percent of the incretin effect in these animals [21]. However, similar studies in humans involving GLP 1 receptor antagonists [33] have shown that GLP 1 is responsible for a substantial part of the insulin response to oral glucose. Recent studies in humans, involving infusion of physiological concentrations of the biologically active hormones while circulating glucose levels were clamped at fasting, or slightly raised in order to mimic the postprandial state, have concluded that the two hormones contribute almost equally to the incretin effect of a meal, and do so in an additive manner [34]. This finding has been corroborated in recent experiments in mice with a double knock-out of both GIP and GLP 1 receptors [35], where preliminary results are consistent with the additive effects of the two hormones. However, GLP 1 is additionally very effective in minimizing changes in postprandial glycemia because of its capacity to delay gastric emptying and inhibit glucagon secretion (see next section). Thus, in the physiological setting of meal ingestion where whole-body glucose metabolism is considered, the insuli-notropic effect of GLP 1 can be obscured by these effects, demonstrating that the regulation of circulating glucose levels via the enteroinsular axis does not operate solely via the effects of the incretin hormones on insulin secretion.

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