Pathogenic mechanisms in ischemic damage: a computational study.

The pathogenesis of penumbral tissue infarction during acute ischemic stroke is controversial. This peri-infarct tissue may subsequently die, or survive and recuperate, and its preservation has been a prime goal of recent therapeutic trials in acute stroke. Two major hypotheses currently under consideration are that penumbral tissue is recruited into an infarct by cortical spreading depression (CSD) waves, or by a non-wave self-propagating process such as glutamate excitotoxicity (GE). Careful experimental attempts to discriminate between these two hypotheses have so far been quite ambiguous. Using a computational metabolic model of acute focal stroke we show here that the spatial patterns of tissue damage arising from artificially induced foci of infarction having specific geometric shapes are inherently different. This is due to the distinct propagation characteristics underlying self-regenerating waves and non-wave diffusional processes. The experimental testing of these predicted spatial patterns of damage may help determine the relative contributions of the two pathological mechanisms hypothesized for ischemic tissue damage.

Spreading depression in focal ischemia: a computational study.

When a cerebral infarction occurs, surrounding the core of dying tissue there usually is an ischemic penumbra of nonfunctional but still viable tissue. One current but controversial hypothesis is that this penumbra tissue often eventually dies because of the metabolic stress imposed by multiple cortical spreading depression (CSD) waves, that is, by ischemic depolarizations. We describe here a computational model of CSD developed to study the implications of this hypothesis. After simulated infarction, the model displays the linear relation between final infarct size and the number of CSD waves traversing the penumbra that has been reported experimentally, although damage with each individual wave progresses nonlinearly with time. It successfully reproduces the experimental dependency of final infarct size on midpenumbra cerebral blood flow and potassium reuptake rates, and predicts a critical penumbra blood flow rate beyond which damage does not occur. The model reproduces the dependency of CSD wave propagation on N-methyl-D-aspartate activation. It also makes testable predictions about the number, velocity, and duration of ischemic CSD waves and predicts a positive correlation between the duration of elevated potassium in the infarct core and the number of CSD waves. These findings support the hypothesis that CSD waves play an important causal role in the death of ischemic penumbra tissue.

Increased insulin receptors in carbohydrate-sensitive subjects: a mechanism for hyperlipaemia in these subjects?

Twenty male subjects, 11 normal and 9 carbohydrate-sensitive, participated in a study in which the effect of feeding diets low in copper (1.03 mg/d) on the number and affinity of insulin receptors was determined. Since carbohydrate-sensitive subjects are hyperinsulinaemic, it was anticipated that they would demonstrate a down-regulation of insulin receptors. The subjects were fed a low copper diet for 11 weeks and then replenished with copper (3 mg/d) for 3 weeks. Regardless of diets fed, carbohydrate-sensitive subjects showed increased insulin binding. The increase was due to the number of receptors without any change in their affinity. This unusual and unexpected observation in carbohydrate-sensitive subjects suggests an altered response of the insulin receptor, namely the failure of plasma insulin to down-regulate the number of receptors. It is possible that such an alteration could lead to a shift of the biological response curve of insulin to the left in some target tissues thereby causing hyperlipaemia by diverting glucose into triglyceride. The exact mechanism of hyperlipaemia in carbohydrate-sensitive subjects remains to be clarified.

A study on Asian Indian and American vegetarians: indications of a racial predisposition to glucose intolerance.

Sixty-two Asian Indian and American vegetarians participated in a 3-h glucose tolerance test after an overnight fast to study clinical indices of glucose homeostasis. The Asian Indians had a higher (p less than 0.0035) insulinogenic score than the Americans. The Asian Indians had significantly higher insulin levels than the Americans at every sampling time during the glucose tolerance test except for the 3-h sample. The Indian men had significantly higher (p less than 0.05) plasma glucose than the other three groups at 2 h after the glucose load. American subjects had higher (p less than 0.0008) insulin binding to erythrocytes than the Asian Indian subjects. Scatchard analysis and competition-inhibition plots of the insulin-receptor data indicated that decreased binding in the Indian group results from a lowered number and decreased affinity of erythrocyte receptors. These results suggest that Asian Indians exhibit several clinical indications associated with an increased risk for the development of insulin-independent diabetes.

Effect of dietary carbohydrates on glucagon and insulin receptors in genetically obese female Zucker rats.

Obese Zucker rats are hyperlipemic and mildly hyperglycemic. Because insulin and glucagon are involved in lipid and carbohydrate metabolism and they act via their receptors, we investigated the role of insulin and glucagon receptors in obese and lean female Zucker rats. Because dietary sucrose is more lipogenic than starch, we also studied the effect of dietary carbohydrates on the receptors. Significant phenotypic effect (obese greater than lean) was observed on plasma levels of glucose, triglyceride and insulin. Binding of insulin and glucagon to liver plasma membranes was significantly lower in obese rats than in lean rats. Lower insulin binding was due to a lower number of receptors as well as a lower affinity, whereas the lower glucagon binding was due only to a lower receptor number. Insulin binding in lean rats but not in obese rats was lower in sucrose-fed than in starch-fed rats. Diet had no effect on glucagon binding. We propose that in obese Zucker rats, in addition to hyperinsulinemia, impaired glucagon activity as manifested by decreased glucagon binding to target tissues may be an important contributor to the hyperlipemia and obesity.

Genetic obesity and dietary sucrose decrease hepatic glucagon and insulin receptors in LA/N-corpulent rats.

A catabolic and hypolipemic effect of glucagon has been described in normal animals. We therefore studied the role of glucagon in genetically obese, hyperlipemic rats. Twelve genetically obese hyperlipemic LA/N-cp/cp (corpulent) rats and 12 lean littermates were fed either 54% starch or 54% sucrose for 12 weeks. Plasma glucagon and insulin levels and glucagon and insulin binding to liver membranes were measured. Comparing all corpulent and lean animals regardless of diet, a significant (P less than 0.0001) phenotypical effect (cp/cp greater than lean) was observed in plasma insulin levels (464 +/- 54 vs 70.3 +/- 7.6 muu/ml, mean +/- SEM). Insulin binding (2.68 vs 16.1%/50 micrograms protein) and glucagon binding (25.6 vs 47.3%/50 micrograms protein) were both significantly lower (P less than 0.0001) in corpulent rats as compared to their lean littermates. Sucrose feeding had marginal effect on plasma insulin or insulin binding. It, however, decreased glucagon binding in corpulent rats but not in their controls. A significant negative correlation was observed between plasma insulin and insulin binding, while a positive correlation was seen for plasma glucagon and glucagon binding. A significant negative correlation was observed between plasma glucagon and lipogenic enzymes (glucose-6-phosphate dehydrogenase and malic enzyme) in liver and between glucagon binding and these enzymes. We propose that in these genetically obese rats, in addition to hyperinsulinemia, impaired glucagon activity as manifested by decreased glucagon binding to target cells may be an important contributor to the hyperlipemia and obesity. A further decrease in glucagon binding in rats fed sucrose indicates that sucrose, per se, may be an additional contributory factor.