Yii-Der I. Chen

Hyperinsulinemia in fructose-induced hypertriglyceridemia in the rat.

Rats were fed diets containing (as percent of calories) 66% glucose or fructose, 22% casein, and 12% lard, for 1 wk. The effects of these diets on plasma triglyceride, glucose, and insulin concentrations were compared to those of control rats eating regular rat chow. Plasma triglyceride levels increased from a mean (+/- SE) control level of 85 +/- 7 to 142 +/- 9 (p less than 0.001) and 380 +/- 38 (p less than 0.001) mg/dl in dextrose- and fructose-fed rats, respectively. Plasma insulin concentrations demonstrated a similar increase, rising from a mean (+/- SE) control value of 29 +/- 4 microunits/ml to 55 +/- 10 microunits/ml in dextrose-fed rats and 85 +/- 12 microunits/ml in rats eating the fructose diet. Plasma glucose concentrations of the three groups were comparable. These results indicate that fructose-induced hypertriglyceridemia is associated with significant hyperinsulinemia.

Ability of exercise to inhibit carbohydrate-induced hypertriglyceridemia in rats☆

The ability of spontaneous running to prevent carbohydrate-induced hypertriglyceridemia was studied in young, nonobese rats. Exercise-trained and sedentary rats were fed a diet consisting of (as percent total calories) 12% fat, 22% protein, and 66% carbohydrate. The source of the carbohydrate was varied, and experiments were carried out with sucrose and glucose as the sole dietary carbohydrate. Plasma triglyceride (TG) levels rose in response to both forms of dietary carbohydrate in both sedentary and exercise-trained rats, but the magnitude of the elevation was greatly attenuated in the exercise-trained group. Plasma insulin concentrations were also significantly lower in exercise-trained rats. Measurements of hepatic very low density lipoprotein (VLDL)-TG secretion rate and adipose tissue lipoprotein lipase (LPL) activity were made in an effort to determine how exercise-training prevented the development of carbohydrate-induced hypertriglyceridemia. The results of these studies indicated that perfused livers of exercise-trained rats secreted significantly less VLDL-TG, whereas adipose tissue LPL activity of the two groups was similar. On the basis of these results, it is postulated that the ability of exercise-training to inhibit carbohydrate-induced hypertriglyceridemia is due to an increase in insulin sensitivity resulting from chronic exercise. As a result, the postprandial insulin responses to high carbohydrate diets would be relatively reduced in exercise-trained rats, leading to decreased hepatic VLD-TG secretion, and lower plasma triglyceride concentrations.

Comparison of Three Treatment Approaches to Decreasing Cardiovascular Disease Risk in Nondiabetic Insulin-Resistant Dyslipidemic Subjects

The efficacy of fenofibrate (FEN), rosiglitazone (RSG), or a calorie-restricted diet (CRD) to reduce cardiovascular disease risk was compared in 37 overweight/obese insulin-resistant nondiabetic subjects. Insulin sensitivity, fasting lipids and lipoproteins, and postprandial plasma glucose, insulin, free fatty acid, and triglycerides were measured before and after 3 months of treatment with FEN, RSG, or CRD. Weight decreased in the CRD group, but did not change significantly after treatment with either drug. Insulin sensitivity improved significantly in the CRD- and RSG-treated groups, but to a greater extent in those administered RSG, without a significant difference comparing FEN treatment with the CRD. Total cholesterol was significantly lower after FEN and CRD treatment. Fasting plasma triglycerides decreased significantly in the FEN- and CRD-treated groups, but postprandial concentrations decreased in only FEN-treated subjects. Significant decreases in postprandial glucose and insulin were seen in only the RSG- and CRD-treated groups. FEN administration improved dyslipidemia in these subjects without changing insulin sensitivity, whereas insulin sensitivity was enhanced in RSG-treated patients without improvement in dyslipidemia. Weight loss in the CRD group led to improvements in both insulin sensitivity and dyslipidemia, but the change in the former was less than in RSG-treated patients, and improvement in lipid metabolism not as great as with FEN. In conclusion, there did not appear to be 1 therapeutic intervention that effectively treated all metabolic abnormalities present in these patients at greatly increased risk of cardiovascular disease.

Is the Hypertriglyceridemia Associated with Insulin Deficiency Caused by Decreased Lipoprotein Lipase Activity

Questions have been raised as to whether reduced lipoprotein lipase (LPL) activity can account for the defect in plasma removal of very low density lipoprotein (VLDL) associated with insulin deficiency. In order to study this issue, streptozotocin-induced insulin deficiency was produced in 2-mo-old rats. Three groups of rats were studied: control, moderate diabetes (glucose > 200 < 350 mg/dl), and severe diabetes (glucose > 350 mg/dl). One week later food was withdrawn at 8 a.m., and the following measurements made at 2 p.m. (6 h after removal of food): (1) plasma glucose, insulin, and triglyceride (TG) levels; (2) VLDL-TG secretion rate; and (3) adipose tissue and skeletal muscle LPL activity. Rats with moderate diabetes had higher glucose and lower insulin levels than did control rats, and these differences were accentuated in rats with severe diabetes. Plasma TG levels were elevated (P < 0.001) in rats with moderate (↑99%) and severe diabetes (↑126%), and this was associated with a fall (P < 0.001) in VLDL-TG secretion. An increase in plasma TG levels, despite a decrease in VLDL-TG secretion, indicates the presence of a profound defect in VLDL-TG removal from plasma. However, muscle LPL of rats with severe diabetes and moderate diabetes was equal to that of control rats, and adipose tissue LPL was only moderately (P < 0.05) reduced (MD = ↓25%, SD = ↓32%). These results indicate that plasma TG levels rise in young, insulin-deficient rats as a result of a defect in removal of VLDL-TG from plasma. This removal defect is associated with normal muscle and only moderately reduced adipose tissue LPL activity, suggesting that the VLDL-TG removal defect associated with insulin deficiency may not be a simple function of a decrease in total (muscle + adipose tissue) LPL activity.

Benefits of Liraglutide Treatment in Overweight and Obese Older Individuals With Prediabetes

OBJECTIVE The aim was to evaluate the ability of liraglutide to augment weight loss and improve insulin resistance, cardiovascular disease (CVD) risk factors, and inflammation in a high-risk population for type 2 diabetes (T2DM) and CVD. RESEARCH DESIGN AND METHODS We randomized 68 older individuals (mean age, 58 ± 8 years) with overweight/obesity and prediabetes to this double-blind study of liraglutide 1.8 mg versus placebo for 14 weeks. All subjects were advised to decrease calorie intake by 500 kcal/day. Peripheral insulin resistance was quantified by measuring the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Traditional CVD risk factors and inflammatory markers also were assessed. RESULTS Eleven out of 35 individuals (31%) assigned to liraglutide discontinued the study compared with 6 out of 33 (18%) assigned to placebo (P = 0.26). Subjects who continued to use liraglutide (n = 24) lost twice as much weight as those using placebo (n = 27; 6.8 vs. 3.3 kg; P < 0.001). Liraglutide-treated subjects also had a significant improvement in SSPG concentration (−3.2 vs. 0.2 mmol/L; P < 0.001) and significantly (P ≤ 0.04) greater lowering of systolic blood pressure (−8.1 vs. −2.6 mmHg), fasting glucose (−0.5 vs. 0 mmol/L), and triglyceride (−0.4 vs. −0.1 mmol/L) concentration. Inflammatory markers did not differ between the two groups, but pulse increased after liraglutide treatment (6.4 vs. −0.9 bpm; P = 0.001). CONCLUSIONS The addition of liraglutide to calorie restriction significantly augmented weight loss and improved insulin resistance, systolic blood pressure, glucose, and triglyceride concentration in this population at high risk for development of T2DM and CVD.

Plasma Leptin Concentrations Do Not Appear to Decrease Insulin-Mediated Glucose Disposal or Glucose-Stimulated Insulin Secretion in Women With Normal Glucose Tolerance

The aim of this study was to test the hypothesis that plasma leptin concentrations contributed to the pathophysiology of NIDDM by decreasing both insulin-mediated glucose disposal and glucose-stimulated insulin secretion. The study was performed in 60 women with normal oral glucose tolerance. Differences in insulinmediated glucose disposal were determined by comparing the steady-state plasma glucose (SSPG) concentrations attained at the end of a 180-min constant infusion of somatostatin, glucose, and insulin, while comparisons of glucose-stimulated insulin secretion were based on the incremental increase in insulin concentration 30 min after an oral glucose challenge (ΔIns) as compared with the fasting value. The results showed that the higher the fasting plasma leptin concentration, the greater the degree of insulin resistance (r = 0.47, P < 0.01). Furthermore, multiple regression analysis indicated that the relationship between leptin and SSPG was independent of age and degree of obesity as estimated by BMI. However, since the total integrated plasma insulin response was highly correlated with both SSPG (r = 0.80, P < 0.001) and leptin (r = 0.55, P < 0.01), multiple regression analysis was repeated, adding total insulin response to the model. When this was done, the significant relationship between leptin and SSPG disappeared, whereas both BMI (P < 0.03) and insulin response (P < 0.001) were correlated with SSPG. A significant relationship between leptin and AIns was seen, but it was a positive one (r = 0.31, P < 0.02), not a negative one as would be expected if circulating levels of leptin inhibited glucose-stimulated insulin secretion. Furthermore, multiple regression analysis could only confirm an independent relationship between AIns and SSPG, but not between AIns and leptin. The results of these studies do not support the view that circulating leptin has a primary effect on either insulin action or secretion in normal female volunteers. It seems more likely that chronic hyperinsulinemia in insulin-resistant individuals acts to increase adipose tissue leptin synthesis and secretion, leading to higher ambient leptin concentrations.

Are the binding and degradation of low density lipoprotein altered in type 2 (non-insulin-dependent) diabetes mellitus?

SummaryStudies in vitro have shown that glycosylation of low density lipoprotein (LDL) will decrease its ability to bind to its receptor. We have evaluated the possibility that such an event might occur in vivo in diabetes by comparing the binding and degradation by normal fibroblasts and mouse peritoneal macrophages of LDL obtained from normal control subjects and patients with Type 2 (non-insulin-dependent) diabetes mellitus. When compared with control subjects, Type 2 diabetic patients had elevated fasting glucose (increased by 160%), haemoglobin A1c (increased by 75%), triglyceride (increased by 550%), and cholesterol (increased by 48%) levels. LDL from Type 2 diabetic patients displayed populations of particles with more heterogeneous hydrated densities than LDL from control subjects, with enrichment in the triglyceride content of the lighter population. 125I-LDL from normal and Type 2 diabetic subjects bound to fibroblasts with similar binding affinities and binding capacities. The kinetics of degradation of LDL from normal and Type 2 diabetic subjects by fibroblasts were also similar. Furthermore, all populations of LDL particles from Type 2 diabetic patients were bound and degraded by normal fibroblasts in identical fashions. In addition, 125I-LDL from normal and Type 2 diabetic subjects were not bound or degraded by mouse peritoneal macrophages. It is concluded that the LDL of patients with Type 2 diabetes with moderate hyperglycaemia are not modified sufficiently to alter their normal binding and degradation by human fibroblasts or to cause their uptake by mouse peritoneal macrophages.

In search of a relationship between physiologically-induced variations in adipose tissue lipoprotein lipase activity and very low density lipoprotein kinetics in normal rats

Abstract The relationship between total and heparin-releasable adipose tissue lipoprotein lipase (LPL) activity and very low density lipoprotein (VLDL0-triglyceride (TG) removal rate was studied in normal rats. Significant variation in both total and heparin-releasable adipose tissue LPL activity could be induced by changing diet and/or time of day at which the measurements were made. However, these maneuvers did not seem to modify VLDL-TG kinetics, and substantial variations (both increases and decreases) in LPL activity could be produced without altering VLDL-TG removal. These data indicate that quantitative variations in adipose tissue LPL activity as directly measured do not give rise to useful insights into VLDL-TG kinetics.

Hypertriglyceridemia and Lipoprotein Lipase Activity in Experimental Uremia

The relationship between changes in tissue lipoprotein lipase (LPL) activity and triglyceride (TG) concentration has been studied in chronically uremic rats. Uremic rats had a 6-fold increase in BUN and 75% rise in TG levels associated with a 50% reduction in adipose tissue heparin-releasable LPL activity. However, total LPL activity of adipose tissue and muscle was not significantly decreased. Furthermore, there was no significant correlation between the rise in plasma TG concentration seen in uremic rats and the reduction in heparin-releasable adipose tissue LPL activity. These data suggest that the TG removal defect associated with chronic uremia is not a simple function of a decrease in LPL activity.

Generation of antibodies against a human lipoprotein lipase fusion protein

Antibodies generated against specific proteins are useful tools for studying the physiology and cell biology of the protein of interest. Although antibodies have been successfully generated against lipoprotein lipase (LPL) and used to elucidate many aspects of its biology, there have been problems with the specificity, affinity and availability of these antibodies. To circumvent these problems, we have expressed a portion of human LPL as a bacterial fusion protein. The human LPL bacterial fusion protein was utilized to generate polyclonal antibodies in rabbits that recognize intact human, rat and bovine LPL. Using these antibodies, it was possible to demonstrate a direct correlation between LPL mass and LPL activity from different samples of human post-heparin plasma. In addition, these antibodies were used to develop an ELISA for the measurement of LPL in tissue or plasma. This is a useful means for obtaining polyclonal antibodies to LPL in sufficient quantity and without contaminating mammalian proteins.