The enteroinsular axis may mediate the diabetogenic effects of TCF7L2 polymorphisms

Abstract

In an article in this issue of Diabetologia, Schafer et al. report that the acute insulin response to glucagon-like peptide-1 (GLP-1) is reduced in individuals with normal or impaired oral glucose tolerance undergoing a hyperglycaemic clamp experiment [1]. This effect was specific for individuals with the polymorphisms rs7903146 or rs12255372 in the gene sequence coding for transcription factor 7-like-2 (TCF7L2), polymorphisms associated with an increased risk of type 2 diabetes [2–4], and reduced insulin secretion [3, 5–11]. TCF7L2 plays a role in the WNT signalling pathway [12], which (among other things) influences the synthesis (and possibly secretion) of GLP-1 [13], and the embryological development of the endocrine pancreas [14]. It was therefore of interest to characterise the effect of GLP-1 upon insulin secretion in individuals with these polymorphisms. Schafer et al. started with the hypothesis that GLP-1 secretion, as tested following stimulation with oral glucose, would differ in those who carried diabetogenic TCF7L2 polymorphisms [3, 12]. This was not the case: TCF7L2 polymorphisms did not alter the pattern of GLP-1 secretion in response to oral glucose in any way. Although contrary to the expectations of the authors, this observation was nonetheless consistent with preliminary findings from another study [15]. The authors then went on to examine the influence of these polymorphisms on insulin secretion, using a standardised test that sequentially tested the insulin secretory responses to hyperglycaemia, exogenous GLP-1, and arginine, whilst separating the responses into early and second phases [1]. They found that carriers and controls produced identical responses to glucose and arginine, but the carriers had a reduced ability to secrete insulin in response to exogenous GLP-1. This confirmed that diabetes-associated TCF7L2 polymorphisms are associated with a lower incretin-mediated insulin secretory response. Contrary to the original hypothesis, however, this was mediated by under-responsiveness of endocrine pancreatic beta cells rather than an impairment in nutrient-stimulated GLP-1 secretion. This reduction in response appears to be specific to the insulinotropic action of GLP-1. Glucose and arginine apart, additional stimuli (e.g. β-adrenergic mimetics, sulfonylureas, leucine, gastric inhibitory polypeptide [GIP]) have yet to be studied. Such studies would help to separate specific defects in the response to GLP-1 from a more generalised beta cell secretory failure. Diabetologia (2007) 50:2413–2416 DOI 10.1007/s00125-007-0832-8