Causes of the triglyceride-lowering effect of exercise training in rats.

Serum triglyceride (TG) levels are lower in exercise-trained (ET) compared with control rats throughout a 24-h period (P less than 0.01-0.001). To understand this phenomenon, the relationship between serum TG concentration and hepatic very low density lipoprotein (VLDL)-TG secretion rate was studied in intact rats. In addition, hepatic TG secretion was measured in isolated perfused liver and TG removal by isolated perfused hindlimbs at rest and during simulated exercise. In vivo, low TG levels are consistently associated with decreased serum insulin concentration and periodic decrease in free fatty acid (FFA) levels. At rest, with comparable FFA levels, VLDL-TG secretion was 50% lower in ET rats, proportionate to the reduction in serum TG levels. Hepatic TG secretion by perfused livers of ET and control rats was similar when studied at comparable FFA and insulin levels suggesting the fall in VLDL-TG secretion with exercise training was not the result of intrinsic change in the ability of the liver to esterify and secrete TG. Perfused muscle of ET and control rats remove TG at equal rates when perfused at rest. However, during simulated exercise, TG removal was increased only in hindlimbs from ET rats. Thus, low serum TG levels in ET rats seem to be due to a combined effect of decreased hepatic TG secretion, secondary to reduced substrate and insulin supply to the liver, and increased TG removal by muscle during exercise.

Mechanism of insulin resistance in fructose-fed rats.

Previous results from our laboratory demonstrated that chronic administration of fructose to normal rats led to both hyperinsulinemia and in vivo insulin resistance. To localize the major tissue site of insulin resistance in fructose-fed animals, we compared glucose uptake by perfused hindlimb skeletal muscle and liver from rats fed either a 60% fructose diet or laboratory chow. Glucose uptake by perfused muscle from chow and fructose-fed rats was comparable at perfusate insulin levels of 0 microunit/ml (15.2 versus 15.5 microliters/min/g muscle), 100 microunits/ml (18.3 versus 19.8), and greater than 500 microunits/ml (35.5 versus 33.4). In contrast, glucose outflow from livers of fructose-fed rats was significantly greater (p less than .02) than chow-fed animals perfused in the absence of added insulin (52.1 versus 36.5 mumol/g). Furthermore, the ability of insulin to suppress glucose outflow was less in livers from fructose-fed rats at perfusate insulin level of 165 microunits/ml (13.2 versus 41.4% as well as at insulin concentration greater than 900 microunits/ml, (32.5% versus 62.2%). These findings suggest that the insulin resistance resulting from chronic fructose feeding is due to the diminished ability of insulin to suppress hepatic glucose output, and not to a decrease in insulin-stimulated glucose uptake by muscle.

Effects of moderate increases in dietary polyunsaturated: saturated fat on plasma triglyceride and cholesterol levels in man.

1. The effects of two isoenergetic diets differing only in the values for polyunsaturated: saturated fat (P:S values of 0.2 v. 2.0) were studied in twenty adult human volunteers. 2. A period of 14 d on the high P:S diet failed to produce significant changes in fasting triglyceride levels, though there were individual variations. On the other hand, fasting cholesterol levels dropped by 10% (P less than 0.005). High-density-lipoprotein-cholesterol concentrations were not influenced by changes in the P:S value. 3. Investigations into the mechanism by which changes in the P:S value might affect plasma triglyceride values revealed no consistent effects on very-low-density-lipoprotein kinetics, insulin secretion, insulin sensitivity or free fatty acid concentrations. 4. The results of this study suggest that the largest increase in dietary P:S values that is likely to be obtained on a long-term basis may have only a small effect on plasma triglyceride and cholesterol concentrations.

Effect of differences in source of dietary carbohydrate on plasma glucose and insulin responses to meals in patients with impaired carbohydrate tolerance.

Two test meals, varying only in type of carbohydrate foods, were given to 12 volunteers with impaired glucose tolerance. The carbohydrate content of one meal was composed of potato and gelatin, while the other meals contained an equivalent amount of carbohydrate as rice and corn. The two meals were otherwise identical, and the additional constituents were turkey, green salad, and salad dressing. Plasma glucose and insulin responses were significantly lower after the meal containing rice and corn, with the change in the insulin response being the most dramatic. These results raise the possibility that variations in source of dietary carbohydrate may have therapeutic utility in patients with impaired glucose tolerance.

Age-related changes in very low density lipoprotein metabolism in normal rats.

Plasma triglyceride (TG) concentrations rise with age, and we have carried out studies of very low density lipoprotein (VLDL) kinetics in the rat in an effort to define the cause of this phenomenon. Efficiency of VLDL-TG secretion by perfused rat liver decreases at rats age from 1 1/2-12 mo. However, this is compensated for by an increase in liver weight, and VLDL-TG secretion per perfused liver does not change with age. In contrast, total VLDL-TG secretion by the interact rat increases significantly as rats grow from 1 1/2-12 mo of age, and this increase is proportionate to the age-related increase in liver weight. The ability of the older rat to maintain VLDL-TG secretion proportionate to liver weight is most likely due to the concomitant rise in plasma free fatty acid concentration that occurs with age. However, the efficiency with which VLDL-TG is removed from plasma is not maintained as rats age. Consequently, the age-related rise in plasma TG concentration is due to an increase in VLDL-TG secretion proportionate to secretory mass, accompanied by a relative decline in efficiency of VLDL-TG removal from plasma.

Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp.

Insulin resistance was quantified with two different methods in 30 subjects with varying degrees of glucose tolerance. One method, the insulin suppression test, is performed by continuously infusing epinephrine, propranolol, insulin, and glucose. Epinephrine and propranolol suppress endogenous insulin release, and steady-state plasma levels of exogenous insulin and glucose are reached in all individuals. Because the steady-state insulin level is the same in all subjects, the height of the steady-state plasma glucose level provides a direct estimate of insulin resistance. The other method, the euglycemic clamp technique, produces a steady-state level of exogenous hyperinsulinemia by means of a primed and continuous insulin infusion. Glucose is also infused at a rate sufficient to prevent an insulin-induced fall in glucose concentration, and the amount of glucose required to maintain the basal plasma glucose level provides the estimates of insulin resistance. The results indicated that estimates of insulin resistance generated by the two methods were highly correlated (r = 0.93). Furthermore, both methods of assessing insulin resistance indicated that the greater the degree of glucose intolerance, the more severe the insulin resistance. These results serve to further emphasize the importance of insulin resistance in the pathogenesis of hyperglycemia in type II diabetes.

Relationship between insulin resistance, insulin secretion, very low density lipoprotein kinetics, and plasma triglyceride levels in normotriglyceridemic man.

We have previously postulated that resistance to insulin-mediated glucose uptake was the basic metabolic abnormality in patients with endogenous hypertriglyceridemia. In this situation, glucose tolerance would tend to deteriorate, and could only be maintained by the increased secretion of insulin. Although the ensuing hyperinsulinemia might prevent the development of glucose intolerance, we suggested that it would also lead to increased hepatic very low density (VLDL) triglyceride (TG) synthesis and secretion. In the current study we have quantified these four metabolic variables in 16 nonobese human subjects with plasma TG concentrations less than 175 mg/dl. The results demonstrate the following degree of correlation: insulin resistance (Formula: see text) insulin response to food (Formula: see text) VLDL-TG secretion rate (Formula: see text) plasma TG concentration. These data indicate that nonobese subjects with normal TG levels have the same relationship between degree of insulin sensitivity, insulin response to food, VLDL-TG secretion, and TG concentration previously described in patients with endogenous hypertriglyceridemia.

Effect of age on plasma triglyceride concentrations in man.

Plasma triglyceride (TG) concentrations increase with advancing age. To determine if this phenomenon is due to age per se or to age-related changes in other metabolic variables, determination of fasting plasma TG, glucose, insulin, and free fatty acid (FFA) concentrations, as well as body mass index (BMI), were made on 167 normal subjects from 18 to 77 yr of age. Significant simple correlation coefficients (r) were found between TG concentrations and age (0.47), BMI (0.39) and fasting plasma glucose (0.40), insulin (0.24), and FFA (0.20) concentrations. Multiple regression analysis was used to determine the total amount of variability in TG concentration that could be accounted for by the combination of the examined metabolic parameters. A highly significant (p < 0.0001) total correlation of 0.57 was obtained, indicating that these variables could account for approximately one-third of the total variances. Partial correlation analysis (fixing four of the five variables) yielded a correlation coefficient of 0.35 (p < 0.001) between age and fasting TG concentration. Hence, age per se, or an age-dependent phenomenon, appears to be an independent factor with a role in determining plasma TG concentrations.

Effect of source of dietary carbohydrate on plasma glucose and insulin responses to test meals in normal subjects.

Plasma glucose and insulin responses were measured in 22 subjects after two meal tolerance tests that varied only in the food source of carbohydrate. Each meal contained 45% carbohydrate, 15% protein, and 40% fat and provided 40% of calculated daily caloric requirement. The meals elicited a similar glucose response; however, the insulin response was significantly lower when rice and corn supplied the carbohydrate as compared to potato and gelatin. The total insulin response, calculated as area under the response curve, was 60% (P less than 0.001) greater in the meal with potato and gelatin versus the rice and corn meal.