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We also isolated pancreatic islets from ��TCF4KO and control mice on either NC (Figure?1G) or HF (Figure?S2K) diet for 8?weeks and tested insulin secretion in?vitro. Under both feeding conditions, insulin release was equal at low (1.6?mM) and high (16.7?mM) glucose concentrations between ��TCF4KO and control mice. Total insulin content did not differ PLX3397 molecular weight between islets isolated from ��TCF4KO and control mice in both feeding conditions (Figures 1H and S2L). Accordingly, histological analysis revealed no differences in pancreatic islets and in �� cell mass (Figure?1I). Ki67 staining also revealed no effect of TCF4 deletion on �� cell proliferation (Figure?1J). We also measured the mRNA levels of genes relevant for maintaining �� cell function in isolated pancreatic islets. As expected, Tcf7l2 mRNA levels were dramatically reduced in the pancreatic islets of ��TCF4KO mice (p?BMN 673 nmr and Ins2 and Gcg and Iapp were indistinguishable from that of control mice both on NC ( Figure?1K) and HF ( Figure?S2M) diets. Neither the mRNA levels for enzymes involved in glucose metabolism (Gck, Pklr, and G6pc2) nor receptors for insulin release and glucose sensing (Insr, Gipr, Glp1r, and Slc2a2) were affected by depletion of TCF4. Moreover, the expression of �� cell transcription factors (Pdx1, NeuroD1, Nkx2.2, Nkx6.1, Isl1, and FoxO1) was not affected in isolated pancreatic islets of ��TCF4KO mice (both on NC [ Figure?1K] and HF [ Figure?S2M] diets). Of interest, Axin2 and Sp5, two generic Wnt target genes ( Lustig et?al., 2002; Weidinger et?al., 2005), showed no change both on NC ( Figure?1K) and HF ( Figure?S2M) diets, implying ALOX15 that TCF4-dependent Wnt signaling is not operative in pancreatic �� cells. The lack of a metabolic phenotype of the ��TCF4KO mice prompted us to reassess the Tcf7l2?/? model. Tcf7l2?/? newborns appeared developmentally normal at birth yet displayed a reduced body weight ( Figure?2A). They became lethargic within hours after birth, presumably because of lack of energy to compete for nourishment, and typically died after 8?hr ( Figure?2D). Just after birth, glucose levels appeared indistinguishable between Tcf7l2+/+, Tcf7l2+/?, and Tcf7l2?/? newborns (data not shown). However, glucose levels were significantly lower at 3?hr postpartum (hpp) in the Tcf7l2?/? newborns ( Figure?2B) than in littermates. The hypoglycemia was caused neither by glycosuria (data not shown) nor by excessive insulin secretion, as plasma insulin levels were also significantly lower in Tcf7l2?/? mice than in their Tcf7l2+/+ and Tcf7l2+/? littermates ( Figure?2C). The Tcf7l2?/? newborns could be rescued for up to 32?hr by subcutaneous injections of 50?��l of 10% glucose at birth and every 6?hr thereafter (p?