Whilst Glis3 is upstream of Ngn3 in the foetal pancreas and loss of Glis3 during embryonic development produces neonatal diabetes, a consequence of defective Ngn3-mediated islet differentiation (Yang et al, 2011), in the adult animal, Ngn3 appears to play little or no role in the diabetogenic effect of loss of Glis3. Loss of Glis3 directly causes drastically reduced insulin expression, leading to hyperglycaemia which subsequently induces beta cell apoptosis probably via glucotoxicity, triggering a vicious cycle that culminates in severe fulminant diabetes. This evidence concerns the gene INS and diabetes mellitus.