Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass.
Bottom Line: Single nucleotide polymorphisms in the T-cell factor 7-like 2 (TCF7L2) gene, associated with T2D by genome-wide association studies, lead to impaired β cell function.Tcfl2(fl/fl)::Ins1Cre islets displayed defective glucose- and GLP-1-stimulated insulin secretion and the expression of both the Ins2 (∼20%) and Glp1r (∼40%) genes were significantly reduced.These data demonstrate that Tcf7l2 plays a cell autonomous role in the control of β cell function and mass, serving as an important regulator of gene expression and islet cell coordination.
Affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine.Show MeSH
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Mentions: To determine whether the imposition of a metabolic stress may affect the glucose intolerance observed in Tcf7l2fl/fl::Ins1.Cre+mice, animals were maintained for the indicated times on a high fat (∼60% total calories) diet. Null animals under these conditions gained weight similarly to wildtype littermates, albeit with a small increase versus controls apparent from 20 weeks (Supplementary Material, Fig. S1). While glucose intolerance was not apparent at 12 weeks (Fig. 1B), the dysglycemia observed at 16 and 20 weeks was further exaggerated compared with that apparent in animals maintained on regular chow (Fig. 1C and D). Insulin tolerance did not differ between genotypes (Fig. 1G), and fasting glucagon levels were identical (Fig. 1H). Nonetheless, in vivo insulin release prompted by IP injection of 1 g/kg glucose was markedly impaired in the mice (Fig. 2A).Figure 2.
Affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine.