Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans.
The available evidence suggests that about two-thirds of the insulin response to an oral glucose load is due to the potentiating effect of gut-derived incretin hormones. The strongest candidates for the incretin effect are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). In patients with type 2 diabetes, however, the incretin effect is lost or greatly impaired. It is hypothesized that this loss explains an important part of the impaired insulin secretion in patients. Further analysis of the incretin effects in patients has revealed that the secretion of GIP is near normal, whereas the secretion of GLP-1 is decreased. On the other hand, the insulintropic effect of GLP-1 is preserved, whereas the effect of GIP is greatly reduced, mainly because of a complete loss of the normal GIP-induced potentiation of second-phase insulin secretion. These two features, therefore, explain the incretin defect of type 2 diabetes. Strong support for the hypothesis that the defect plays an important role in the insulin deficiency of patients is provided by the finding that administration of excess GLP-1 to patients may completely restore the glucose-induced insulin secretion as well as the beta-cells' sensitivity to glucose. Because of this, analogs of GLP-1 or GLP-1 receptor activations are currently being developed for diabetes treatment, so far with very promising results.
Department of Medical Physiology, The Panum Institute, University of Copenhagen, Denmark. Holst@mfi.ku.dk
Jens Juul
JJ
Holst
Jesper
J
Gromada
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D005768:Gastrointestinal Hormones / Q000502:physiology*; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D009490:Neurosecretory Systems / Q000503:physiopathology; D010446:Peptide Fragments / Q000378:metabolism*; D036361:Peptide Hormones / Q000378:metabolism* / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism*
D005768:Gastrointestinal Hormones; D007328:Insulin; D010446:Peptide Fragments; D036361:Peptide Hormones; D011498:Protein Precursors; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon