Observations on humans, on rats in vivo, and on isolated perfused rat livers indicate that insulin stimulates hepatic very-low-density lipoprotein (VLDL)-TAG secretion when the liver is chronically exposed to the hormone. They suggest that frequent stimulation of insulin secretion throughout the diurnal cycle may result in a chronic stimulation of VLDL secretion and increased delivery of acyl moieties to the periphery, particularly to muscle, the most important site of insulin-sensitive glucose disposal. If acyl groups are provided in excess of the oxidative needs of the tissue, this may lead to induction of insulin resistance, irrespective of whether obesity is established concomitantly. Dietary factors that stimulate hepatic VLDL secretion may have the same effect and contribute to the induction of a vicious spiral leading to the development of the full-blown Metabolic Syndrome and its pathological consequences, including type-2 diabetes, stroke, and cardiovascular disease.