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  • R406 receptor In the small intestine digestion and absorptio


    In the small intestine, digestion and R406 receptor of the nutrients are the next processes with an impact on the resulting plasma profile. Normally, neither carbohydrate digestion nor absorption are limiting factors, which is illustrated by the rapid and extensive absorption of glucose in conditions with accelerated gastric emptying (e. g. operations where pyloric function has been distorted) where rapid increases to abnormally high plasma levels may be seen [10]. For complex carbohydrates, the story is of course more complicated. However, the absorption rate is of great importance for the next-in-line regulator of glucose tolerance, the incretin effect. This is because the secretion of the incretin hormones is dependent on the absorption rate of the nutrients (glucose/amino acids) by the endocrine cells responsible for their secretion [11,12]. The incretin effects now sets in with its actions on the endocrine pancreas, and in particular insulin secretion [13]. The details of this will be discussed below. The next and final, important step in glucose tolerance is the disposition of the nutrients/glucose. The most important factor is of course insulin, which switches the liver from a site of glucose production in the fasting state to a site where part of the absorbed glucose may be taken up and stored as glycogen. Changes in glucagon secretion are also important for this change in the liver's metabolic function, with glucagon secretion normally being inhibited by the increasing plasma levels of glucose and some of the gastrointestinal hormones, in particular GLP-1. Impaired braking of hepatic glucose production (which is already elevated in T2DM) will clearly have untoward effects on glucose tolerance as discussed above. Most of the absorbed glucose, however, travels further on to the peripheral tissues, where two mechanisms are particularly important for the rate of glucose disposal: the mass action of the elevated glucose concentration (also sometimes referred to as glucose effectiveness) [14,15] and insulin's effect on glucose uptake in muscles and adipose tissue. Given the presence of glucose transporters in the tissues, it is clear that increases in the plasma concentration of glucose results in increased transfer of glucose to the intracellular compartment by facilitated diffusion. Insulin's effect on glucose transport involving the insertions of additional glucose transporters (GLUT4) in the plasma membranes of the fat and muscle cells will augment the diffusion even further. The postabsorption details and a discussion of the mechanisms of action of insulin receptor signaling are beyond the scope of this presentation, but clearly the intracellular fate of glucose may affect the rate of transfer, being dictated by the gradients driving the diffusion; thus removal of glucose from the relevant membrane areas (by phosphorylation) is essential for continued transport and, similarly, further metabolism of glucose-6-phosphate is important to prevent substrate inhibition of this process [16]. In the glucose tolerant individual, the final deposition of glucose comprises oxidation and/or storage as glycogen. These processes can be greatly accelerated in healthy individuals (suggesting surplus capacity) [17], but may be severely compromised in T2DM and may therefore influence postprandial glucose levels.
    The Incretin Effect
    Clinical Importance As briefly alluded to above, loss of the incretin effect is one of the fundamental characteristics of T2DM [89]. The loss is thought to particularly influence and augment postprandial plasma glucose levels, and it is due to lack of insulinotropic effect of physiological levels of both GIP and GLP-1, as clearly demonstrated in infusion studies with physiological doses which in healthy individuals would dramatically increase insulin secretion [90]. Whereas GIP remains inactive regardless of dose, slightly supraphysiological doses of GLP-1 may stimulate insulin secretion to levels similar to those observed in healthy individuals in response to glucose alone [46,91]. One could say that supraphysiological levels of GLP-1 are able to restore the beta cell's responsiveness to glucose. Why is the beta cell response to the two hormones impaired in T2DM? This is not known, and it is not known why the two hormones differ in this respect, but it seems reasonable to assume that the underlying mechanism is related to and perhaps identical to that responsible for the cells' lack of response to glucose (the reason for which is also unknown!). The deficiency develops very early in course of T2DM [19] and a similar deficiency occurs during the development of insulin resistance [92,93]. An improvement may be observed after beta cell rest, as for instance after optimized glucose control [90]. The ability of larger doses of GLP-1 to restore beta cell glucose sensitivity is the background for the development of the GLP-1 receptor agonists for diabetes therapy.