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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #55: Incretin Physiology in Health and Disease Part 5 of 6

GIP

Similar to GLP-1, GIP acts through specific receptors belonging to the seven transmembrane-domain family of receptors. These receptors are expressed in the endocrine pancreas, on adipocytes, and in the brain [85]. The actions of GIP have been summarized in Figure 11.3.

ITDMChapt11Fig11.3

Islet hormone secretion

Intravenous administration of porcine or human GIP has led to a dose-dependent stimulation of insulin secretion in humans. These effects were found to be glucose-dependent, with negligible insulinotropic activity at normoglycemia. The physiologic importance of these effects has become apparent from experiments with immunoneutralization of circulating GIP or in GIP receptor knockout mice. Both ways to eliminate GIP signaling have led to glucose intolerance in the respective experimental animals [85]. Also, when the GIP plasma concentrations that are typically measured after meal ingestion were mimicked by exogenous infusion in humans, a significant insulinotropic activity was recorded [86]. Studies in β-cell lines have also suggested anti-apoptotic properties as well as β-cell proliferative effects for GIP.

Whereas GIP shares the insulinotropic properties with the other major incretin hormone GLP-1, the effects of both incretins on glucagon secretion differ largely from each other. Thus, in normoglycemic healthy volunteers, GIP even exerts a dose-dependent stimulation of glucagon release [9]. These effects are no longer detectable under conditions of hyperglycemia or in patients with diabetes. When GIP and GLP-1 were co-administered to patients with type 2 diabetes, the glucagonostatic actions of GLP-1 were fully abolished, suggesting that under normal conditions, the stimulation of glucagon release by GLP-1 overrides the glucagonstatic effect of GLP-1 [10]. In line with this, suppression of glucagon levels was found to be significantly more pronounced after intravenous compared to oral glucose administration.

Gastrointestinal effects

When GIP was initially discovered, a prominent role of the peptide as an inhibitor of gastric acid secretion was inferred from experiments in isolated canine stomach preparations. These studies gave rise to the initial name “gastric inhibitory polypeptide,” which was later replaced by the term “glucose-dependent insulinotropic polypeptide” [85]. Indeed, when GIP was administered to humans with and without type 2 diabetes in vivo, no significant effect on gastric acid secretion was found [87]. Also, no effects of exogenous GIP on gastric emptying were reported. Therefore, the peptide does not seem to play a major physiologic role in the control of gastrointestinal functions in humans.

Regulation of body weight

A potential role for GIP as a regulator of body weight became apparent from experiments in GIP receptor knockout mice. These animals were protected from developing obesity and insulin resistance on a high-fat diet [88]. In line with these experiments, studies using various GIP receptor antagonists have demonstrated improvements in glucose homoeostasis and weight gain in mice. Unfortunately, these findings have not yet been confirmed in humans or large animal species. There is also good evidence that GIP receptors are expressed abundantly on adipocytes, where the incretin is believed to induce lipoprotein lipase activity and to promote triglyceride accumulation [85]. These effects were shown to be partly mediated through increased secretion of resistin. In contrast to these experiments in rodent and cell culture models, administration of GIP to humans has had no significant effect on triglyceride or free fatty acid levels.

Other potential actions of GIP

In addition to the above-mentioned effects, there is some evidence for a stimulation of cortisol secretion by GIP [89]. Furthermore, GIP is believed to enhance bone formation through stimulation of osteoblast activity as well as inhibition of osteoclast resorptive activity.

Other gastrointestinal hormones with potential incretin function

Whereas various lines of evidence suggest that GIP and GLP-1 are the major incretin hormones in human physiology, some incretin-like activity has also been ascribed to several other gastrointestinal hormones.

Cholecystokinin (CCK)

Earlier studies, partly using rather nonspecific immunoassays, have reported reduced plasma concentrations of CCK in patients with type 2 diabetes, thereby suggesting a role for the peptide in the pathogenesis of diabetes. Indeed, CCK has been demonstrated to exert glucose-dependent insulinotropic effects in various experimental models [90]. However, at physiologic plasma concentrations, these effects were rather negligible, thereby questioning a true incretin function of the peptide. Furthermore, there appears to be a large interspecies variability regarding the insulinotropic effect of CCK, and experiments in humans did not reveal a strong stimulation of insulin secretion [90]. More importantly, the incretin effect was largely preserved after administration of the CCK receptor antagonist loxiglumide [91]. On that basis, even though CCK may exhibit some characteristics of an incretin hormone, it clearly cannot be considered a major physiologic mediator of the incretin effect [92].

Secretin   

Secretin is another gut peptide with potential incretin-like properties that is secreted from gastrointestinal S cells, which are primarily located in the duodenum and upper jejunum. Secretion of secretin is stimulated by nutrient ingestion, with fat and protein acting as strong stimulators, and glucose being a rather weak stimulus. Stimulation of insulin secretion has been described in response to secretin administration in various species, but at physiologic plasma concentrations the insulinotropic effect of the peptide is rather weak, thereby questioning an incretin role of the peptide [16,92].

Gastrin

The hormone gastrin is secreted from G cells located in the gastric antrum and duodenum. Gastrin secretion rises modestly in response to oral glucose administration [92]. However, circulating plasma levels are also strongly affected by many other factors, such as gastric pH. Some, but not all studies have demonstrated a glucose-dependent stimulation of insulin release in response to gastrin administration. More recently, a role for gastrin in β-cell growth and regeneration has also been implicated. Overall, the magnitude of the insulinotropic effect observed with physiologic gastrin levels does not appear to be sufficient to elicit a true incretin-like activity [16,92].

The incretin effect in patients with diabetes

The “size” of the incretin effect, that is, the percentage contribution of incretin hormones at total insulin responses to oral glucose, has been estimated at ∼35–75%, depending on the magnitude of the glucose load [6]. In a direct comparison of the incretin effect after 50 g of oral glucose between patients with type 2 diabetes and nondiabetic controls, the size of the incretin effect was 72.8 ± 6.9% in control subjects and 36.0 ± 8.8% in diabetic patients based on insulin measurements and 58.4 ± 7.6% and 7.6 ± 14.5%, respectively, based on C-peptide levels [93]. Because insulin concentrations are largely affected by hepatic insulin clearance, and oral glucose ingestion has been shown to reduce hepatic insulin clearance, it seems appropriate to primarily use C-peptide levels for the calculation of the incretin effect. On that basis it can be concluded that the incretin effect is almost completely absent in patients with type 2 diabetes. Given the importance of the incretin effect for the regulation of postprandial glucose homoeostasis, it has been speculated that a loss of the incretin effects may play a central role in the pathogenesis of type 2 diabetes [94].

The incretin effect has also been examined in patients with other types of diabetes. Interestingly, when GIP and GLP-1 were administered intravenously to patients with diabetes secondary to chronic pancreatitis, patients with MODY, LADA or early type 1 diabetes, the insulinotropic actions of the incretin hormones was reduced to a comparable extent as in patients with type 2 diabetes. In line with these observations, the size of the incretin effect was also found to be largely reduced in such patients. Taken together, these studies have lent strong support to the concept that the reduction in the incretin effect in patients with type 2 diabetes develops secondary to chronic hyperglycemia and goes along with a general decline in β-cell mass and function in these individuals [94,95].

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