Loss of Incretin Effect Is a Specific, Important, and Early Characteristic of Type 2 Diabetes

INCRETIN EFFECT IN TYPE 2 DIABETES—Whereas glucose-tolerant individuals are capable of adjusting their insulin secretion to their actual insulin sensitivity, people with type 2 diabetes are incapable of doing so (1). b-Cell failure is therefore the hallmark of this disease, although failure may be precipitated by the development of insulin resistance, typically as a consequence of obesity. In healthy subjects, a considerable part of the postprandial insulin response is due to the actions of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Together, the two hormones are responsible for the so-called incretin effect, i.e., the amplification of insulin secretion that is observed when glucose is taken orally as opposed to infused intravenously to provide identical plasma glucose concentrations (2). Although frequently ignored, the effect strongly depends on the dose of glucose (3). A convenient way of describing the effect is to calculate the gastrointestinally mediated glucose disposal (GIGD) (4). Here the amount of glucose required by intravenous infusion to copy the glucose excursions after the oral load is related to the oral load. Thus, if 25 g is required to copy a 75-g oral glucose load, the GIGD amounts to 100 3 (75 – 25)/ 75 = 66%. In other words, mechanisms associated with and activated by the oral ingestion resulted in a disposal of 75 – 25 = 50 g of the ingested glucose. In healthy subjects, most of the GIGD is accounted for by the actions of the incretin hormones, but inhibition of hepatic glucose production by suppression of glucagon secretion, hepatic uptake of glucose from the portal vein, and gut-brain or liver-brain reflex activity may also play a role. GIGD is particularly useful in the study of oral glucose handling in C-peptide–negative patients with type 1 diabetes, where the classical incretin definitions have nomeaning (4). In a study of oral administration of 25, 50, and 100 g glucose (3), the amounts of intravenous glucose required to match the excursions after oral administration amounted to ;20 g uniformly. Calculated as indicated above, the GIGD varied from 20% to as much as 80%. Thus, the healthy human body has a remarkable capacity to handle the intake of increasing amounts of glucose and is therefore capable of maintaining almost unchanged postprandial glucose excursions, regardless of the oral load. There is no doubt that the incretin hormones play a major role in GIGD in healthy subjects, and it can be concluded that the incretin effect plays a major role for normal glucose tolerance. In people with type 2 diabetes, this ability is dramatically reduced (5), as illustrated by calculation of the GIGD, which may be close to zero. Thus, if a patient with type 2 diabetes is given an oral glucose load of 50 g glucose, it typically takes close to 50 g intravenous glucose to copy the oral excursions (6). In other words, in these individuals, there is no mechanism available to dispose of the glucose taken in orally, or put in another way, the oral and the intravenous glucose loads are handled equally. The almost complete loss of GIGD is typically accompanied by a greatly reduced difference between the insulin responses to the oral and the intravenous glucose load, i.e., the incretin effect (5,6). This effect is often expressed as the integrated incremental insulin response (area under the curve [AUC]) to the oral glucose load [iAUCoral] minus the integrated incremental insulin response to the isoglycemic intravenous glucose infusion [iAUCiv] divided by the iAUCoral. When expressed in percent, this amounts to 100%3 (iAUCoral2 iAUCiv)/ iAUCoral. This value is typically around 70% (for 75 g glucose) in healthy subjects, whereas individuals with type 2 diabetes may have values around 30% (for 50 g glucose). As indicated by the almost complete loss of GIGD, the incretin effect (;30%) remaining in the patients with type 2 diabetes has little effect on glucose disposal, probably as a result of the simultaneously occurring insulin resistance. The loss of incretin effect is therefore likely to contribute importantly to the postprandial hyperglycemia in type 2 diabetes. In the present article, we review a number of central studies elucidating the mechanisms involved in the dramatic loss of ability to handle dietary carbohydrates in type 2 diabetes.