The effects of chronic uremia and dexamethasone on triglyceride kinetics in the rat.

The effects of chronic uremia and dexamethasone administration on triglyceride (TG) kinetics were studied in the rat. Uremia was produced by a two-stage, $\text{5}\text{6}$ nephrectomy, and resulted in a fourfold rise in BUN levels. The elevation in BUN level led to a rise in mean ( ± SE) TG levels from $\text{46 ± 4 to 62 ± 6 mg}\text{100 ml}$. The increase in TG levels was associated with a marked prolongation in very low density lipoprotein (VLDL) removal rate from plasma, without any change in triglyceride secretion rate (TG-SR). The combined effects of uremia and glucocorticoid treatment were evaluated by treating chronically uremic rats with either low (0.05 mg/kg body weight) or high (0.25 mg/kg body weight) doses of dexamethasone. The low dose of dexamethasone led to a further rise in mean TG levels of chronically uremic rats ($\text{107 ± 14 mg}\text{100 ml}$), and the hypertriglyceridemia was further accentuated when chronically uremic rats were treated with high-dose dexamethasone ($\text{179 ± 15 mg}\text{100 ml}$). The elevation of TG levels in uremic rats receiving the low dose of dexamethasone was associated with a prolongation of VLDL removal which was not statistically significant. Treatment with the higher dose of dexamethasone resulted in an increase in TG-SR and a further prolongation of VLDL removal, both of which were statistically significant. Thus, hypertriglyceridemia in the chronically uremic rat is due to a defect in VLDL removal. Dexamethasone treatment is capable of accentuating this removal defect, as well as increasing TG-SR. The combined effect of both is to lead to a marked degree of hypertriglyceridemia.     

Evidence that parathyroid hormone is not required for phosphate homeostasis in renal failure

Varying degrees of renal failure were produced by surgical reduction of renal mass in normal dogs and in thyroparathyroidectomized dogs (TPTX) in whom serum calcium levels were maintained in the normal range by the administration of vitamin D. Both groups of dogs maintained normal serum phosphate levels in spite of progressive decreases in glomerular filtration rates (GFR). Furthermore, both groups of dogs were able to increase the fractional excretion of phosphate as GFR decreased. Thus the same renal response to loss of GFR was maintained in the complete absence of parathyroid tissue. Finally, stable serum phosphate levels and increased fractional excretion of phosphate in response to a decrease in GFR were also demonstrated in acutely TPTX dogs who were not receiving vitamin D. These results indicate that phosphate homeostasis can be maintained in renal failure in the total absence of parathyroid hormone secretion.     

Use of estrogen-treated rats as a bioassay for evaluating catabolism of very low density lipoproteins

Estradiol-treated rats have markedly reduced circulating very low density lipoprotein (VLDL)-triglyceride (TG) pool sizes, and may provide a useful model to study the effect of differences in VLDL-TG composition on their in vivo catabolism. The results presented describe this approach, and its use to document impaired VLDL-TG catabolism of prelabeled VLDL in plasma injected from diabetic donor rats.     

Does day-long absolute hypoinsulinemia characterize the patient with non-insulin-dependent diabetes mellitus?

Plasma glucose and insulin responses to a standard oral glucose tolerance test (75 g of glucose) and to mixed meals were compared in 15 normal subjects and 15 patients with non-insulin-dependent diabetes mellitus (NIDDM). Fasting plasma glucose levels were above 140 mg/dL in all patients with NIDDM, and the two groups were weight matched. Plasma glucose levels were significantly higher in patients with NIDDM throughout the glucose tolerance test, and this was associated with a marked reduction in plasma insulin response. Plasma glucose levels were also higher in patients with NIDDM when measured hourly from 8 AM to 5 PM (mixed meals were consumed at 8 AM and 12 PM), but the plasma insulin concentration of the two groups were similar. Thus, the day-long circulating insulin levels of patients with NIDDM are not reduced. Consequently, these patients cannot be considered to be absolutely insulin deficient.     

Insulin-independent diabetes mellitus: Metabolic characteristics

Glucose intolerance in patients with insulin-independent diabetes mellitus can theoretically arise from a loss of normal tissue sensitivity to insulin (insulin resistance) and/or from a decrease in insulin secretory capacity. A review of available literature indicates that both of these defects can exist in these patients. Thus, patients with insulin-independent diabetes mellitus demonstrate a decrease in tissue sensitivity to insulin, and there is a significant relationship between the severity of the glucose intolerance and the magnitude of the insulin resistance in these patients. The relationship between glucose intolerance and insulin secretion in patients with insulin-independent diabetes is more complicated. Patients with mild glucose intolerance tend to have an insulin response to glucose equal to or greater than normal. As the severity of glucose intolerance increases, the insulin response becomes attenuated and patients with severe fasting hyperglycemia become hypoinsulinemic. On the basis of these changes in insulin resistance and insulin secretion, two formulations concerning the pathogenesis of insulin-independent diabetes seem possible. The first is based upon the premise that the basic defect in patients with insulin-independent diabetes is loss of normal tissue sensitivity to insulin. In an effort to maintain glucose homeostasis, increased amounts of insulin are secreted. However, as the need to augment insulin secretion continues, the beta cell may lose the ability to compensate, and frank hypoinsulinemia can supervene. Alternatively, patients with insulin-independent diabetes can be viewed as representing a metabolically heterogeneous group composed of individuals with various degrees of increased insulin resistance and decreased insulin secretory capacity. In this situation, the degree of glucose intolerance will vary as a function of the relative severity of the two metabolic defects. These relatively simple formulations are confounded by the fact that insulin deficiency can lead to insulin resistance, and vice versa, and that obesity will greatly affect insulin resistance and insulin secretion. Thus, the degree of glucose intolerance in any individual is the result of a complex series of relationships between both intrinsic and environmental factors controlling insulin resistance and insulin secretion. Our ability to understand the pathogenesis of insulin-independent diabetes mellitus will depend upon better understanding of these various relationships.     

Studies of the mechanism of fructose-induced hypertriglyceridemia in the rat

Carbohydrate-induced hypertriglyceridemia is easily produced in the rat, and fructose has been shown to be particularly potent in this regard. In this study we have compared the effects of feeding rats diets high (66% of total calories) in fructose or glucose on various aspects of carbohydrate and lipid metabolism. The results confirmed previous observations that fructose (456 +/- 276 mg/dl) was more potent (p less than 0.001) in raising plasma TG concentration than was glucose (242 +/- 13 mg/dl), and indicated that the difference in magnitude of hypertriglyceridemia produced by the two carbohydrates was closely related to the ability of the test diets to increase VLDL-TG secretion (r = 0.85, p less than 0.001). Both glucose and fructose feeding led to comparable degrees of hyperinsulinemia, and plasma TG concentrations increased before hyperinsulinemia evolved in fructose-fed rats. Therefore, it was concluded that fructose can act directly on the liver to increase VLDL-TG secretion, and that fructose-induced hypertriglyceridemia can occur in the absence of hyperinsulinemia. On the other hand, the rise in plasma TG concentration produced by fructose was reduced dramatically in exercise-trained rats, and this was associated with a decrease in plasma insulin concentration. Based upon these observations, we suggest that fructose feeding produces hypertriglyceridemia by directly stimulating hepatic VLDL-TG secretion, as well as by producing insulin resistance and hyperinsulinemia, and that it is the combined effect of these two separate actions which accounts for the magnitude of fructose-induced hypertriglyceridemia.