RESUMEN
The T allele at rs7903146 in TCF7L2 increases the rate of conversion from prediabetes to type 2 diabetes. This has been associated with impaired ß-cell function and also with defective suppression of α-cell secretion by glucose. However, the temporal relationship of these abnormalities is uncertain. To study the longitudinal changes in islet function, we recruited 128 subjects with 67 homozygous for the diabetes-associated allele (TT) at rs7903146 and 61 homozygous for the protective allele (CC). Subjects were studied on 2 occasions, 3 years apart using an oral 75g glucose challenge. The oral minimal model was used to quantitate ß-cell function; the glucagon secretion rate was estimated from deconvolution of glucagon concentrations. Glucose tolerance worsened in people with the TT genotype. This was accompanied by impaired post-challenge glucagon suppression but appropriate ß-cell responsivity to rising glucose concentrations. These data suggest that α-cell abnormalities associated with the TT genotype (rs7903146) occur early and may precede ß-cell dysfunction in people as they develop glucose intolerance and type 2 diabetes.
RESUMEN
BACKGROUNDProglucagon can be processed to glucagon-like peptide1 (GLP-1) within the islet, but its contribution to islet function in humans remains unknown. We sought to understand whether pancreatic GLP-1 alters islet function in humans and whether this is affected by type 2 diabetes.METHODSWe therefore studied individuals with and without type 2 diabetes on two occasions in random order. On one occasion, exendin 9-39, a competitive antagonist of the GLP-1 Receptor (GLP1R), was infused, while on the other, saline was infused. The tracer dilution technique ([3-3H] glucose) was used to measure glucose turnover during fasting and during a hyperglycemic clamp.RESULTSExendin 9-39 increased fasting glucose concentrations; fasting islet hormone concentrations were unchanged, but inappropriate for the higher fasting glucose observed. In people with type 2 diabetes, fasting glucagon concentrations were markedly elevated and persisted despite hyperglycemia. This impaired suppression of endogenous glucose production by hyperglycemia.CONCLUSIONThese data show that GLP1R blockade impairs islet function, implying that intra-islet GLP1R activation alters islet responses to glucose and does so to a greater degree in people with type 2 diabetes.TRIAL REGISTRATIONThis study was registered at ClinicalTrials.gov NCT04466618.FUNDINGThe study was primarily funded by NIH NIDDK DK126206. AV is supported by DK78646, DK116231 and DK126206. CDM was supported by MIUR (Italian Minister for Education) under the initiative "Departments of Excellence" (Law 232/2016).
