The Dynamic Incretin Adaptation and Type 2 Diabetes

Abstract

In 1932, Dr. Jean La Barre (1) of Belgium introduced “incretin” as the name of a substance in the gut mucosa that produces hypoglycemia when injected in normal but not in pancreatectomized experimental animals. He and Dr. Hans Heller (2) of Austria suggested almost simultaneously that this could be the basis for diabetes therapy. The incretin concept was further developed in the early 1960s when it became possible to determine the insulin level in blood. Then thefamousexperimentscomparingthe influenceof ivvs.oral glucoseadministrationoninsulinsecretionwereundertaken. The results showed that oral glucose elicited a much larger insulin response than an iv glucose infusion (3, 4). This was confirmed in a study when glucose levels were the same after oral vs. iv glucose administration (5) and, with similar technique, has also been demonstrated to exist in mice (6), providing a tool for investigating incretin mechanisms in more detail. The incretin function has key physiological impact on glucose homeostasis after oral glucose. This is illustrated by results in healthy humans that the glucose excursion is very similar after ingestion of 25, 50, or 100 g due to an increase in the incretin effect matching the increased glucose load and preventing hyperglycemia (5). The incretin effect is largely attributed to the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). They are both released from enteroendocrine cells after oral glucose, and they both augment glucose-stimulated insulin secretion (7). GIP and GLP-1 are also released after ingestion of nonglucose macronutrients (both proteins and lipids) (8). This may suggest that the incretin concept is broader than only augmenting insulin secretion after oral glucose. However, whether the incretin hormones are of importance for the insulin response to nonglucose stimuli also remains to be established. Duringrecentyears, the interest inthe incretinconcepthas been intensified because pharmacological therapy of type 2 diabetes has been developed based on the antidiabetic action of GLP-1 (9). In addition to stimulated insulin secretion, these actions include inhibited glucagon secretion, induction of satiety, and delay in gastric emptying. Today, clinically introduced incretin-based therapy exists in terms of injectable GLP-1 receptor agonists and of orally available inhibitors of the enzyme dipeptidyl peptidase-4 (DPP-4), which raise endogenous GIP and GLP-1 levels by preventing inactivation of the incretin hormones (9). An important discussion has evolved as to whether the incretin function is impaired in type 2 diabetes and, if so, whether this contributes to the pathophysiology of the disease. A first study on this topic compared the insulin and C-peptide responses to oral glucose (50 g) vs. iv glucose when plasma glucose levels were matched, and the study was performed in both healthy subjects and subjects with type 2 diabetes (10). The results showed that more than 70% of the insulin response to oral glucose was mediated by the incretin hormones in healthy subjects,whereas the corresponding figure in subjectswith type 2 diabetes was less than 40%, i.e. the results suggested that incretin function is markedly impaired in type 2 diabetes. At the same time, the study showed that the GIP response to oral glucose was the same in healthy and diabetic subjects (GLP-1 was not determined). Therefore, this study suggested that it is impaired action of incretin hormones rather than impaired incretin hormone secretion that explains the defective incretin function in type 2 diabetes. This conclusion was supported by other results showing that the insulin secretory response to iv GIP is indeed markedly impaired in type 2 diabetes (11). It was later shown that the insulinotropic action of iv GLP-1 is also impaired in type 2 diabetes, albeit not as much as the response to GIP (12). Other studies have, however, shown defective incretin hormone secretion in type 2 diabetes, making this