Hyperinsulinemia in obesity syndromes: its metabolic consequences and possible etiology.

Animal models with genetic or experimentally produced (lesions of hypothalamus) obesities are numerous and unlikely to ever be reduced to a single pathophysiologic entity. However, obese animals have many similar traits in common. They are all hyperinsulinemic, an abnormality that occurs early in the development of these syndromes and appears to be of prime importance in producing most of the metabolic changes observed both in the early and late phases of the obesity syndromes. In all instances, obesity is an evolutional syndrome in which the early phase is different from the later one. The early phase is principally characterized by increased hepatic very low density lipoprotein (VLDL) output, increased adipose tissue lipogenesis and VLDL uptake, hence, increased fat accretion and fat cell size. These abnormalities are secondary to hyperinsulinemia and can be reversed toward normal by normalizing circulating insulin levels. The late phase is characterized by the continuation of the disorders of the early one plus a superimposed abnormality, the insulin resistance state, that is detectable particularly at the level of adipose and muscle tissues, and eventually brings about hyperglycemia. Insulin resistance is a multifactorial pathological condition that includes at least: (a) a decrease (more or less marked) in insulin binding to target tissues that is responsible for the decrease in tissue sensitivity to the hormone; (b) intracellular defects that are probably responsible for the decreased insulin responsiveness of target tissues. The origin of hyperinsulinemia in animal obesities is still ill-defined. Lesions of the ventromedial hypothalamus (VMH) produce rapid and lasting hyperinsulinemia. Such lesions produce, in addition, increased secretion of insulin and glucagon and changes in pancreatic insulin, glucagon, and somatostatin content in subsequently perfused pancreases. The locus responsible for these effects is not defined and may actually involve a series of interrelated loci. Whatever the latter may be, one of the routes of CNS influence upon endocrine pancreas is the vagus nerve, although a humoral factor has also been claimed. The etiology of hyperinsulinemia in genetically obese animals is unknown. Genetic inheritance could bear primarily upon some hypothalamic or other CNS sites, with secondary alterations in the endocrine pancreas function, or primarily on the islets of Langerhans with possible alteration in the respective function of the A, B, and D cells with resulting excessive insulin secretion.