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.

Hyperinsulinemia in obesity syndromes: Its metabolic consequences and possible etiology

Tolbutamide, gliclazide and glibenclamide failed to stimulate glucose oxidation in rat pancreatic islets. Tolbutamide also failed to stimulate pyruvate and palmitate oxidation and decreased the islet content of NAD(P)H and ATP. Tolbutamide stimulated 45Ca net uptake, inhibited 86Rb net uptake and tended to increase 22Na net uptake by the islets. The effect of theophylline upon islet function differed from that of tolbutamide by the magnitude of its insulinotropic action as a function of the glucose concentration, by its stimulant action upon the utilization of endogenous nutrients in islets deprived of glucose and by the lack of gross alteration in 45Ca and 86Rb net uptake. It is concluded that the insulinotropic effect of hypoglycemic sulfonylureas cannot be merely equated to a facilitation of nutrient metabolism or inactivation of phosphodiesterase in the islet cells. The primary action of these drugs could be to affect cations transport across the B-cell membrane.

Metabolic, cationic and secretory effects of hypoglycemic sulfonylureas in pancreatic islets

The relationship between obesity and hypersecretion of insulin by the pancreas was studied. We found that pancreata from obese Zucker rats secrete significantly more insulin than do pancreata from lean Zucker rats. At a glucose stimulation of 300 mg/dL, the overall dynamic biphasic insulin secretory profiles from obese and lean rats were similar. Further studies to investigate the glucose-insulin dose response relationship in obese and lean rat pancreata demonstrated insulin hypersecretion by pancreata from obese rats which was particularly pronounced at normoglycemic and hypoglycemic levels (by factors as much as 14-fold). This hypersecretion is so striking as to suggest that in the intact state the obese animal may lack the ability to readily "shut off" its insulin secretion under normoglycemic conditions, whereas lean animals possess such an ability. Under hypoglycemic conditions (75 mg/dL), the hypersecretion is transient and insulin secretion returns to normal basal levels after 30 minutes of perfusion. Thus the degree to which this hypersecretory phenomenon may occur in vivo remains to be established.

Dynamics of insulin hypersecretion by obese Zucker rats

The obese-hyperglycemic syndrome is well characterized in adult mice. However, little is known about islet morphology and function at an early age when obese mice islets start to proliferate. We have now studied islet morphology and functional development in obese-hyperglycemic mice (Umea ob/ob) and their lean littermates at ages < or = 38 days. The weight of obese mice began to increase more than that of the lean littermates at days 8 to 12. At day 18, clinical diagnosis of the ob/ob syndrome could be made with 100% certainty. Islets from obese mice started to show enhanced growth rate during week 4, coinciding with the time of onset of hyperglycemia. 3H-thymidine labeling index is enhanced in ob/ob mice from day 22. Insulin secretion in islets from mice aged 18 to 21 days was the same in obese and lean mice from the same litter. At days 30 to 33, second-phase release and islet insulin content were decreased in islets from obese animals, but were restored after an overnight fast. It is likely that the hyperglycemia rather than increased insulin demand triggers increased beta-cell growth.

Development of insulin secretory function in young obese hyperglycemic mice (Umeå ob ob )

A number of characteristics are common to the differing forms of rodent obesity. An increased efficiency of energy utilisation is accompanied by, but not dependent upon, hyperphagia and hypoactivity. An impairment in thermogenic processes may be responsible for the increase in efficiency in a number of the obese models. The developmental sequence of the obesity varies between the differing models, recessively inherited obesities being associated with early pre-weaning excess fat deposition, whereas obesity in other forms of rodent obesity develops at a later age and is of a more moderate type. The rodent models also differ in the type of adipose tissue expansion between hypertrophic and hypertrophic-hyperplastic growth. The hyperinsulinaemia characteristic of all obesities is together with the hyperphagia the major stimulus for the enhanced hepatic and adipose tissue lipogenesis. The obese-hyperinsulinaemic state produces secondary effects which include changes in pancreatic morphology, insulin resistance, enhanced gluconeogenesis, increased basal lipolysis and loss of responsiveness to lipolytic hormones. Hyperadrenocortism and sterility observed in the recessively inherited obesities may result from hypothalamic dysfunction. The possible metabolic basis of the obesities is discussed.

The characteristics of genetically obese mutants

Pancreatic insulin content and insulin secretion, from the pancreas of obese mice fed ad lib (ob/ob), obese mice maintained on a restricted diet (ob/ob RD) and lean mice has been studied using incubated pieces of pancreas in vitro and in a perifusion system. The ob/ob mice pancreas contained approximately twice as much insulin as the lean mice pancreas, whereas the ob/ob RD mice had a normal insulin content. Increasing the glucose concentration had a marked and prolonged stimulating effect on insulin secretion in the pancreas of the ob/ob and ob/ob RD mouse, but not in the lean mouse. Leucine stimulated insulin secretion in all three groups of animals both in the absence and presence of glucose in a biphasic manner; in the presence of glucose the insulin secreted from the pancreas of the ob/ob and ob/ob RD mice was abnormally high. Arginine stimulated insulin secretion from the lean mouse pancreas in the absence of glucose, whereas in the obese mouse pancreas stimulation was observed only in the presence of glucose, and the effect increased with increasing glucose concentration. The large amounts of insulin which can be secreted by the pancreas of the ob/ob and ob/ob RD mice under stimulation suggest that an abnormal response of the pancreas to biological stimuli of insulin secretion could be a primary defect in these animals.

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In vitro studies on insulin secretion in the genetically obese mouse

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In vitro studies on insulin secretion in the genetically obese mouse