Interestingly, though islets derived from chow-fed M4K4 iKO mice displayed similar insulin secretion (Fig. 5, D and E), islets isolated from HFD-fed M4K4 iKO mice displayed a significant attenuation in this 1st phase of insulin secretion (Fig. 5, F and G), which is one of the earliest detectable signs of β cell dysfunction in those destined to develop type 2 diabetes, which occurs prior to changes in plasma glucose levels (22, –, 24). The gene discussed is INS; the disease is type 2 diabetes mellitus.