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

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