Insulin secretion starts to decline months or years before clinical onset of type 1 diabetes, and individuals studied prospectively often pass through a stage of impaired glucose tolerance before symptoms appear. Insulin deficiency leads to increased glucose output by the liver and reduced glucose uptake by peripheral insulin sensitive tissues such as muscle and fat. Blood glucose rises and spills into the urine, producing an osmotic diuresis. Insulin lack promotes fat breakdown, with release of triacylglycerol, non-esterified fatty acids (NEFA) and glycerol into the circulation. Protein breakdown is also accelerated, with release of amino acids into the circulation; amino acids such as alanine and other 3-carbon molecules such as glycerol provide the liver with further precursors for gluconeogenesis. The 'accelerated starvation' of uncontrolled diabetes results in overproduction of acidic ketone bodies in the hepatic mitochondria, and culminates in the metabolic emergency of diabetic ketoacidosis.