Evidence for a causative relationship between prolonged tissue hypoxia and diabetic retinopathy and glomerulosclerosis are presented. Based on the assumption that one of the most fundamental requirements for optimal cellular metabolism is a constant cellular oxygen tension, the "three-in-one concept" for the development of diabetic microangiopathy is formulated. The term "three-in-one" is employed because this concept partly or completely includes "the glycoprotein-", "the hypoxia-", and "the growth hormone hypothesis". Diabetics show evidence of variability in the tissue oxygen availability/demand ratio which is compensated by three self-regulating factors: 1) an increase in local flow, 2) an increase in red cell 2,3-DPG leading to a shift to the right of the oxyhaemoglobin dissociation curve, and 3) an increase in the oxygen-binding capacity or the haemoglobin concentration. The level of plasma inorganic phosphate (Pi) is of importance in maintaining high 2,3-DPG levels. However, since Pi fluctuates depending upon changes in the control of diabetes, the regulatory mechanism of the 2,3-DPG modulated unloading of oxygen from the erythrocytes often becomes insufficient, and therefore in poorly regulated diabetics with less than optimal 2,3-DPG levels, the main load of compensation against tissue hypoxia is placed on an adjustment in the microcirculation of the organ involved. However, in order for the microvascular dilatation to occur, the cells must experience a hypoxic stimulus. The summation of the infinite number of discrete and occasionally pronounced hypoxic injuries to the tissue cells in association with the adverse effect of local vasodilatation with increased plasma permeation through the vessel walls might over the years lead to diabetic microangiopathy. Based on this theory the high level of Pi in diabetes becomes of particular significance. Our experience with a high phosphate diabetes diet in the treatment of diabetics is presented. This dietary regimen leads to a significant increase in the oxygen release capacity of the erythrocytes, suggesting an improvement in tissue oxygenation, and may therefore become of value in the prophylaxis of diabetic microangiopathy.