Additionally, to test the hypothesis that cumulative endogenous insulin is adversely associated with microvascular integrity only in the presence of metabolic insulin resistance, as suggested by experimental studies investigating the microvascular effects of exogenous insulin (7, 8), we further study whether the associations of cumulative adulthood insulin with retinal microvasculature are different in those participants with clustering of metabolic risk factors (“metabolic syndrome”) and those defined as being metabolically healthy. The gene discussed is INS; the disease is Insulin resistance.