High Carbs Diet Causes Hypoxia
Effect of Hypoxia on Blood Glucose, Hormones, and Insulin Receptor Functions in Newborn Calves
At between 7 and 11 h after delivery, 14 fasted calves were randomly divided into two groups to examine the effects of neonatal hypoxia on blood glucose metabolism and its mechanisms. One group was subjected to breathe a gas mixture containing 4.8-5.9% oxygen in nitrogen from a hood for 2 h. The second control group breathed atmospheric gas. Several possible causes of changes in blood glucose were assessed, including insulin, glucagon, and hydrocortisone as prereceptor factors, insulin binding as a receptor factor, and insulin receptor tyrosine kinase (IR-TK) activity as a postbinding factor. The hypoxic animals exhibited increased concentrations of blood glucose (from 5.47 ± 1.61 mmol/L to 7.97 ± 1.30 mmol/L), plasma insulin, and hydrocortisone, but decreased concentrations of glucagon. The percentage of specific binding activity decreased in the hypoxic group compared with the control group (12.71 ± 1.25% versus 15.14 ± 1.27%,p < 0.01). Several parameters of insulin receptor binding,i.e. affinity constants, high and low binding capacities, and numbers of binding sites, showed a tendency to decrease after hypoxia. Only lower affinity binding sites decreased significantly. At the postreceptor level, IR-TK activity was decreased in the hypoxic group compared with controls. It is concluded that hypoxia induced insulin resistance in these newborn calves. The results suggest that the primary mechanism for insulin resistance in the hypoxic newborn was reduced insulin receptor responsiveness with attenuated activity of IR-TK at the postreceptor level.
Carbohydrate metabolism is often deranged during severe stress such as hypoxia(11, 12), and this derangement is due, at least in part, to stimulated endocrine responses. This is commonly accepted and extensively described in adult humans and in animals, but there are limited data in the neonatal population. It is known, however, that hypoxia in the newborn is, arguably, the most common cause of severe, acquired brain injury(13). The incidence of hyperglycemia is most frequent in the first 24 h after birth and was related to low Apgar scores, respiratory distress syndrome(14), and hypoxia(15). Both hyperglycemia and hypoxia may have a potential impact on long-term neuralgic sequelae, morbidity, and mortality. Moreover, Vardi et al.(16) reported that, among 12 stressed children, four developed type I diabetes within 1 y.
The mechanism of hypoxia-induced hyperglycemia is still unclear. The major goal of this study was to describe changes in blood glucose metabolism, changes in insulin, glucagon, and hydrocortisone concentrations, and insulin receptor functions including IR-TK activity after hypoxia. The usual hypoxic model utilizes oxygen concentrations between 5 and 8% for 0.5-2 h(17). We used the calf as our animal model because a substantial amount of blood supply was needed in this and other related studies being conducted in our laboratory. Calves were exposed to 4.8-5.9% oxygen for 2 h to create hypoxia and acidosis, with serum lactate approximating 5.8-13.0 mmol/L. In this environment, blood glucose increased from 3.1-7.2 to 4.8-8.2 mmol/L at 1 h and 5.9-9.3 mmol/L at 2 h. Blood glucose levels in two of seven and in five of seven calves were more than 7 mmol/L at 1 and 2 h, respectively, in the hypoxic animals. Therefore, hypoxia, indeed, induced hyperglycemia in the newborn.
Hyperglycemia or insulin resistance may result from defects at a prereceptor, receptor, or postreceptor level. Insulin counterregulatory hormones such as hydrocortisone, glucagon, growth hormone, and epinephrine may affect blood glucose. Hydrocortisone as a major factor in stress reactions, and glucagon and insulin were measured in this study to assess their possible contribution to insulin resistance at a prereceptor level. Our results show that hypoxia increased plasma hydrocortisone and insulin levels. Hydrocortisone is an important mediator of the stress response and of hyperglycemia. High hydrocortisone levels have been reported in premature infants with hyaline membrane disease(18). Lilien et al.(19) has reported that hydrocortisone levels in stressed newborns are lower in hyperglycemic than in normoglycemic infants. As demonstrated in the present study, hydrocortisone values were significantly elevated in hypoxic newborn calves at 1 and 2 h after hypoxia relative to prehypoxic levels.
The observed elevation of insulin levels may have been secondary to hyperglycemia or insulin resistance. Long et al.(20) noticed that insulin concentrations are either normal or increased, and that increases in plasma glucose are common in stressed patients in association with decreased sensitivity to insulin. Insulin is a major anabolic and anticatabolic hormone. Despite the rise in plasma insulin concentrations, the effects of insulin may be antagonized by glucagon and hydrocortisone or by reduced insulin action at the receptor binding site. Surprisingly, plasma glucagon values during 2 h of hypoxia were decreased, although it has been reported that pancreatic alpha cells in newborn infants at 2 h after birth are able to release glucagon(21) and that plasma glucagon levels rise after delivery and remain elevated throughout the first days of life(22). It may be noted that the simultaneous infusion of glucose and insulin can inhibit glucagon secretion(23, 24). The alpha cell is capable of responding to both amino acids and glucose(22). Glucose infusion in full-term and preterm newborn infants results in a prompt and sustained suppression of glucagon secretion(25). This observation may explain why the elevated glucose and insulin resulted in a fall of plasma glucagon levels in the present study.
Insulin receptor binding was measured in this study to assess its possible contribution to insulin resistance. A decrease in lower affinity receptor sites in liver tissue was observed after 2 h of hypoxia. It has been reported that decreased insulin binding was not related to insulin resistance in normal newborn dogs(26), and insulin receptors in fetal tissue were not down-regulated by hyperinsulinemia(27). One possible explanation for our result is that insulin reduced the insulin receptor response as a result of endocytosis or internalization(28). Another explanation is the possible effects of hormones such as hydrocortisone or glucagon.
The mechanism of insulin signal transformation after insulin binding remains unclear. Potential mechanisms have been proposed, including phosphorylation cascade, second messenger at the cell surface, and insulin-receptor interaction with other organelles(29). It has been reported that insulin binding stimulates insulin receptor autophosphorylation and subsequent insulin receptor activation(30). It is generally believed that the insulin receptor tyrosine kinase activity is essential for insulin action(30, 31). There is, however, little or no information about newborn infants or animals(10), especially after hypoxia. Johnston et al.(26) has reported that insulin binding (numbers and affinity) is not the limiting factor in neonatal insulin action and that an insulin receptor postbinding defect exists in insulin resistant newborns. IR-TK activity in normal newborn rat liver was reported to be similar in neonatal and adult rats(10). The present study showed that IR-TK activity was reduced in hypoxia, and that blood glucose levels increased in spite of an increase of insulin secretion. The possibility of decreased of IR-TK activity as a major contributing factor to insulin resistance in newborn calves cannot be excluded, because the decrease of insulin binding occurs only in lower affinity receptor sites, and it has been reported that the “spare” insulin receptor can be activated for the insulin reaction(32). The possible explanation for the decreased IR-TK activity is likely the decrease in insulin binding by the insulin receptor, and inhibition of IR-TK activity by certain molecular species changed or produced during hypoxia. It has been reported that the production of tumor necrosis factor-α increased in human mononuclear cells during hypoxia(33). This factor, in turn, can convert insulin receptor substrate-1 into an inhibitor of insulin receptor tyrosine kinase activity in culture cells(34). The mechanism of the postreceptor effect, however, needs further investigation.
The present study demonstrates that insulin resistance is associated with hyperglycemia and changes of endocrine metabolism in hypoxic newborn calves, and suggests that blood glucose levels should be closely monitored when stressed newborn infants receive a high dose glucose infusion and glucocorticoid infusion. Based on the mechanisms of decreased IR-TK activity, certain strategies may be developed for the prevention and management of hyperglycemia and insulin resistance in stress.