Studies using RyR2-S2814D knock-in mice, which mimic constitutive phosphorylation of RyR2, show that chronic gain-of-function in RyR2 leads to basal hyperglycemia, impaired GSIS, and glucose intolerance—hallmarks of pre-diabetes and early T2DM [87]. The gene discussed is RYR2; the disease is Glucose intolerance.