We propose that, while the immediate feed forward stimulatory actions of insulin on its own secretion might be mediated via the IRs, at high concentrations of insulin, either during the glucose stimulation of insulin secretion (short-term negative feedback) or during states of insulin resistance and hyperinsulinemia (long-term negative actions), negative actions of insulin might be mediated via insulin binding to IR/IGF-1R hybrids and/or IGF-1Rs. The gene discussed is INSR; the disease is Insulin resistance.