Potential mechanisms of incretin dysfunction in type 2 diabetes
Various potential explanations have been expounded in order to explain the reduced incretin effect in type 2 diabetes [11,95]. One obvious factor to examine was the secretion of GIP and GLP-1. Regarding GIP, a number of studies have compared postprandial plasma concentrations between patients with and without diabetes. These studies have revealed increased, normal, or reduced GIP levels in patients with diabetes. Considering all studies together, there does not appear to be a general defect in GIP secretion  (Figure 11.4). If anything, a slight increase in postprandial GIP levels might occur in patients with early type 2 diabetes, but clearly the differences in GIP levels would not sufficiently explain any alterations in insulin of glucose concentrations .
There is some controversy regarding GLP-1 concentrations in patients with type 2 diabetes. One large cross-sectional study has reported a modest reduction in postprandial GLP-1 concentrations in patients with type 2 diabetes compared to nondiabetic control subjects. In this study, there was also a small reduction in GLP-1 levels in individuals with impaired glucose tolerance . However, upon closer analysis, the defects in GLP-1 secretion in type 2 diabetes found in this study were most apparent in the late postprandial period, that is, ∼120 – 240 min after meal ingestion. Because defects in insulin secretion in type 2 diabetes typically occur within the first 30 – 60 min after meal or glucose ingestion, such defect in GLP-1 levels would not plausibly explain the reductions in postprandial insulin secretion. A reduction in GLP-1 levels in patients with type 2 diabetes has also been reported in another study . In this study, reduced plasma concentrations of both total and intact GLP-1 were reported. These two studies reporting lower GLP-1 levels are contrasted by a number of other studies demonstrating normal or even increased GLP-1 concentrations in type 2 diabetes (Figure 11.4). In a formal meta-analysis of all these trials, there were no differences in GLP-1 concentrations between patients with and without type 2 diabetes . The discrepant results of these studies may be partly explained by different patient characteristics. In this regard, long diabetes duration and high glucagon plasma concentrations have been associated with modest reduction in GLP-1 levels . All aspects considered, a reduction in the secretion of GIP or GLP-1 does not explain the impaired incretin effect in type 2 diabetes.
The insulinotropic effect of the two major incretin hormones has been examined in a number of experiments (Figure 11.5). For GIP, a reduced insulinotropic effect in type 2 diabetes has already been reported in initial experiments using porcine GIP preparations . In a hyperglycemic clamp study directly comparing the insulinotropic effect of GIP at physiologic and supraphysiologic doses in patients with type 2 diabetes, the efficacy of GIP was reduced by ∼ 60% in the diabetic patients  (Figure 11.5). This finding has been subsequently confirmed in different studies. Notably, the loss of insulinotropic activity of GIP could not be overcome even by the administration of highly supraphysiologic doses . The efficacy of GIP was also found to be impaired to a lesser extent in first-degree relatives of patients with type 2 diabetes, along with a general reduction in β-cell function. The mechanistic reasons underlying the loss of GIP efficacy in type 2 diabetes have not been fully elucidated . Polymorphisms in the GIP receptor have recently been related to 2-h glucose concentrations during an OGTT in nondiabetic individuals. However, the effect size of this polymorphism is clearly insufficient to explain the marked abnormalities in GIP action in patients with type 2 diabetes. It has also been speculated that patients with type 2 diabetes may exhibit a reduced number of GIP receptors on pancreatic β cells, but until now, GIP receptor expression has not yet been quantified on islets from patients with type 2 diabetes. However, in rodents with diabetes a reduced expression of GIP receptors has been described, and the expression level of the GIP receptor was found to be modulated by the prevailing glucose concentrations. In line with these studies in rodent models, the insulinotropic action of the incretin hormones was found to be largely enhanced after reduction of chronic hyperglycemia by means of intensive insulin therapy in patients with type 2 diabetes. Therefore, at present the most plausible explanation for the loss of GIP efficacy in type 2 diabetes is a downregulation of GIP receptor expression secondary to chronic hyperglycemia .
When directly compared to nondiabetic individuals, the insulinotropic effect of GLP-1 has also been found to be reduced in patients with type 2 diabetes . However, the extent of this defect is clearly less pronounced than the respective impairment in GIP action. Thus, in a hyperglycemic clamp study examining individuals with and without type 2 diabetes, the insulinotropic effect of GLP-1 was reduced by ∼30% in the diabetic patients . Of note, this impairment in GLP-1 action appears to be less than what would be expected in such patients, assuming a ∼50 – 65% β cell deficit in type 2 diabetes . Moreover, the impairment in GLP-1 action can easily be overcome by administration of supraphysiologic doses. Thus, even though in absolute terms the insulinotropic effect of GLP-1 is reduced in type 2 diabetes, this incretin hormone still appears to stimulate insulin secretion to a much greater extent than GIP or other secretagogues. The largely preserved insulinotropic activity of GLP-1 in patients with type 2 diabetes may be secondary to the recruitment of additional β cells, as demonstrated in a series of elegant experiments in isolated β cells .
Although the impairment in incretin activity in type 2 diabetes primarily affects their insulinotropic effect, it is still conceivable that the actions of GIP or GLP-1 on glucagon secretion may also be affected. However, in a direct comparison between patients with and without type 2 diabetes, the glucagonostatic effect of GLP-1 was fully preserved . In this regard it is worth mentioning that GLP-1 has been found to normalize glucagon levels even in patients with type 1 diabetes . For GIP, a glucagonotropic effect has been described in healthy individuals at normoglycemia . These effects were no longer detectable at hyperglycemia or in patients with type 2 diabetes. Therefore, alterations in glucagon secretion do not seem to contribute to the loss of incretin activity in type 2 diabetes.
An alternative explanation to the concept of GIP receptor downregulation as a mechanism for the loss of incretin activity in type 2 diabetes would be a general decline in β-cell mass and function in these patients . According to this hypothesis, the reduction in GIP activity in type 2 diabetes largely goes along with a general decline in β-cell function. Indeed, the insulinotropic effect of GIP is closely correlated to the insulin responses after intravenous glucose administration. Also, a gradual decline insulin secretion with chronic hyperglycemia has been described for both glucose-stimulated and GIP-induced insulin secretion. It is also worth considering the fact that the isoglycemic clamp design may lead to an underestimation of the incretin effect in individuals with a general reduction in their functional β-cell capacity . Thus, because oral glucose represents a relatively large β-cell stimulus (which comprises the actions of 50 g or absorbed glucose plus the insulinotropic effects of GIP and GLP-1), whereas the β-cell stimulation by an isoglycemic i.v. glucose infusion is relatively weak (∼20–25g of glucose only), it is likely that in individuals with a general impairment in β-cell function the insulin response to the oral glucose stimulus is reduced to a greater extent than the response to the i.v. glucose infusion. On that basis, one would plausibly expect that the incretin effect, that is, the difference in insulin responses between oral and i.v. glucose, diminishes with declining β-cell mass. In line with such argumentation, an inverse relationship between fasting glucose concentrations and the size of the incretin effect has been described. Thus, even though the insulinotropic effect of the incretin hormones, especially GIP, is clearly diminished in patients with type 2 diabetes, it is likely that the degree of impairment of the incretin effect is overestimated because of the experimental conditions .
Summary and conclusions
The incretin hormones GIP and GLP- play a predominant role in the postprandial augmentation of insulin secretion, thereby largely contributing to the maintenance of glucose homeostasis after meal ingestion. Incretin-like properties have also been ascribed to other gut hormones, such as CCK or secretion, but the importance of these other peptides is rather negligible under physiologic conditions. In addition to their insulinotropic effects, GIP and GLP-1 exhibit numerous other actions in various other organs and tissues, such as the central nervous system, the gastrointestinal tract, and the cardiovascular system. In patients with diabetes, the incretin system is markedly altered, which appears to be primarily due to loss of insulinotropic activity of GIP. Therefore, the incretin system represents a central regulatory element in the interplay between nutrient absorption and glucose homeostasis, which is of critical importance for the physiologic control of energy homeostasis.