Abstract: Tissue specific insulin receptor knockout mice have been employed to study the features of non-insulin-dependent diabetes mellitus (NIDDM) at Research Division, Joslin Diabetes Center, Boston, Massachusetts. The muscle insulin receptor knockout (MIRKO) mice display muscle insulin resistance but do not develop hyperisulinemia or diabetes. White adipose tissue of MIRKO mice have increased the sensitivity to insulin and its glucose uptake is dramatically elevated that activates fat accumulation and induces obesity which results from an increase in adipocyte number (hyperplasia) of the same size as well as individual cells in the control mice. MIRKO mouse adipose tissue increased secretion of adiponectin that increases the insulin sensitivity and do not alter the leptin production. The liver insulin receptor knockout (LIRKO) mice developed a syndrome like NIDDM with hyperinsulinemia and hyperglycemia, decreased liver size and its function since insulin is an important liver growth factor but they do not suffer with fat accumulation. The fat tissue insulin receptor knockout (FIRKO) mice become lean with the 50-60% reduction of fat masses. FIRKO mouse remains resistant to obesity with age and as a result it has high insulin sensitivity and normal glucose tolerance. They eat normal amount of food , increase the longevity of life and decrease the mortality. The β-cell insulin receptor knockout in combination with the insulin receptor substrates 1 or 2 both knockouts mice develop β-cells insensitivity to insulin and the insensitivity to the stimulation of insulin secretion by glucose. The animals show the alterations of β-cells growth and 20% of experimental mice develop II type diabetes. The brain insulin receptor knockout (BIRKO) mice are obese and insulin resistant. They have increased appetite, hyperinsulinemia, hypertrigliceridemia, and decreased responses of neurons to epinephrine. The endothelial cell insulin receptor knockout mice have the normal levels of insulin and glucose in the circulation, and the normal or decreased blood pressure. They look healthy but have decreased level of the vascular endothelial growth factor in blood which may prevent the development of retinopathy as NIDDM complication.