Type 2 diabetes mellitus (T2DM) has been shown to be characterised by an almost abolished incretin effect. The incretin effect refers to the phenomenon of oral glucose eliciting a higher insulin response than intravenous glucose at identical plasma glucose profiles. It is conveyed by the two insulinotropic incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP are secreted from the small intestines in response to ingestion of nutrients. The incretin defect of T2DM has been characterised by a virtually lost insulinotropic effect of GIP. It is unknown whether the incretin defect is a primary event leading to T2DM or arises as a consequence of the diabetic state. To investigate this we studied patients with chronic pancreatitis (CP). Over time, CP leads to secondary diabetes mellitus (DM). If patients with CP and secondary DM exhibit the characteristic type 2 diabetic incretin deficiencies and patients with CP and normal glucose tolerance are normal in that regard, it is more likely that these deficiencies are consequences of the diabetic state rather than primary events leading to T2DM. On the other hand, if incretin physiology is preserved independently of the endocrine status of patients with CP, the incretin defect could represent a primary pathogenetic defect. Three protocols have been employed to investigate this. In a study investigating postprandial incretin responses in 8 patients with CP and exocrine pancreatic insufficiency, with and without pancreatic enzyme supplementation (PES), we observed preserved incretin responses as compared to matched healthy subjects; and, further, that PES increased postprandial incretin responses in these patients. This suggests not only that the secretion of incretin hormones is regulated by the mere presence of nutrients in the small intestine, but also that the assimilation of such nutrients is involved, as well. Furthermore, we gauged the incretin effect in 8 patients with CP and normal glucose tolerance and in 8 patients with CP and secondary DM. Eight healthy subjects and 8 patients with T2DM were studied for comparison. The incretin effect was shown to be preserved in normal glucose tolerant patients with CP, whereas it was strongly reduced in patients with CP and secondary DM, suggesting the incretin defect to be a consequence of the diabetic state. Lastly, we investigated the insulinotropic effect of the incretin hormones in 8 patients with CP and normal glucose tolerance and in 8 patients with secondary DM, and observed that patients with CP and secondary DM exhibit an impaired insulinotropic effect of GIP, and that this most likely occurs as a consequence of the diabetic state. In conclusion, we suggest that: 1) the postprandial secretion of incretin hormones is preserved among patients with CP; 2) assimilation of nutrients stimulates secretion of GIP and GLP-1; and 3) the characteristic incretin deficiencies of T2DM most likely are consequences of a deteriorating glucose homeostasis, rather than primary events leading to T2DM.