The increase in circulating insulin could be due to several mechanisms: (a) HFD-induced insulin resistance in extrarenal tissues; (b) direct nutrient stimulation of β cells of the islets secondary to increased caloric intake (48, 49); (c) stimulation of insulin secretion by the gut-derived incretin hormones; (5) decreased metabolic clearance rate of insulin by the liver due to hepatic insulin resistance; (6) reduced renal insulin degradation due to proximal tubular IR knockout; and (7) a combination of the above. The gene discussed is INS; the disease is Insulin resistance.