Preserved incretin effect in type 1 diabetic patients with end-stage nephropathy treated by combined heterotopic pancreas and kidney transplantation

Abstract

Insulin secretion is stimulated better by oral than by intravenous glucose (incretin effect). The contribution of the autonomic nervous system to the incretin effect after oral glucose in humans is unclear. We therefore examined nine type 1 diabetic (insulin-dependent) patients with end-stage nephropathy, studied after combined heterotopic pancreas and kidney transplantation, and 7 non-diabetic kidney recipients (matched for creatinine clearance and immunosuppressive medication). The release of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) immunoreactivity and B cell secretory responses (IR insulin and C-peptide) to oral (50 g) and "isoglycaemic" intravenous glucose (identical glycaemic profile) were measured by radioimmunoassay. The difference in B cell responses between the two tests represents the contribution of the enteroinsular axis to the response after oral glucose (incretin effect). Insulin responses after the oral glucose challenge were similar in the two patient groups despite systemic venous drainage of the pancreas graft in the pancreas-kidney-transplanted group. In both groups GIP and GLP-1 increased after oral but not after intravenous glucose, and B cell secretory responses were significantly smaller (by 55.2 +/- 7.7% and 46.5 +/- 12.5%, respectively) with "isoglycaemic" intravenous glucose infusions. The lack of reduction in the incretin effect in pancreas-kidney-transplanted patients, whose functioning pancreas is denervated, indicates a lesser role for the nervous system and a more important contribution of circulating incretin hormones in mediating the enteroinsular axis in man.

Is the Diminished Incretin Effect in Type 2 Diabetes Just an Epi-Phenomenon of Impaired β-Cell Function?

“…3). This interpretation is further supported by the finding that a diminished incretin effect can also readily be observed in patients with other types of diabetes (45), and by the fact that it can be restored through pancreas transplantation in patients with type 1 diabetes (46). However, further studies will be required to substantiate this hypothesis.…”

Comparison of Pancreas-Transplanted Type 1 Diabetic Patients with Portal-Venous Versus Systemic-Venous Graft Drainage: Impact on Glucose Regulatory Hormones and the Growth Hormone/Insulin–Like Growth Factor-I Axis

“…However, the cephalic phase of insulin secretion lasts only a few minutes (24), which makes this explanation unlikely. Also, it has been reported that pancreas denervation does not interfere with pulsatile insulin secretion (25) or the overall incretin stimulation of insulin secretion after oral glucose (26), making it unlikely that these mechanisms contributed to the impaired insulin secretion observed in pancreas transplanted patients.…”

Impact of incretin hormones on β-cell function in subjects with normal or impaired glucose tolerance

“…In fact, GLP-1 is extensively degraded before entering the systemic circulation and may interact with sensory nerve fibers before making contact with endothelial dipeptidyl-dipeptidase IV (1,13). The importance of the neural pathway for the incretin function of GLP-1 is still unclear, because the incretin effect has been shown to be preserved in type 1 diabetic patients after combined pancreas and kidney transplantation (28). Parasympathetic efferences to the islets, on the other hand, seem to play a role not only in the early (cephalic) phase of insulin secretion, because (in rhesus monkeys) atropine infusion during a meal blunts both acute and second-phase insulin response without important changes in either GLP-1 and GIP plasma levels (5).…”