Glucagon-like peptide 1 and dysglycemia: Conflict in incretin science

Although GLP-1 (glucagon like peptide-1) based therapies (GLP-1 agonists and dipeptidyl peptidase-4 inhibitors) is currently playing a cornerstone role in the treatment of type 2 diabetes, dilemma does exist about some of its basic physiology. So far, we know that GLP-1 is secreted by the direct actions of luminal contents on the L cells in distal jejunum and proximal ileum. However, there is growing evidence now, which suggest that other mechanism via “neural” or “upper gut” signals may be playing a second fiddle and could stimulate GLP-1 secretion even before the luminal contents have reached into the proximities of L cells. Therefore, the contribution of direct and indirect mechanism to GLP-1 secretion remains elusive. Furthermore, no clear consensus exists about the pattern of GLP-1 secretion, although many believe it is monophasic. One of the most exciting issues in incretin science is GLP-1 level and GLP-1 responsiveness. It is not exactly known as to what happens to endogenous GLP-1 with progressive worsening of dysglycemia from normal glucose tolerance to impaired glucose to frank diabetes and furthermore with increasing duration of diabetes. Although, conventional wisdom suggests that there may be a decrease in endogenous GLP-1 level with the worsening of dysglycemia, literature showed discordant results. Furthermore, there is emerging evidence to suggest that GLP-1 response can vary with ethnicity. This mini review is an attempt to put a brief perspective on all these issues.