Plasma Triglyceride and Fatty Acid Metabolism in Diabetes mellitus

Lewis, Barry; Mancini, Mario; Mattock, M. B.; Chait, Alan; Fraser, T. Russell

doi:10.1111/j.1365-2362.1972.tb00676.x

Cited by 84 publications

(33 citation statements)

References 49 publications

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“…However, reduced triglyceride synthesis in more chronic insulin deficiency, whether a primary or secondary effect, must inevitably reduce VLDL triglyceride secretion. The reduction in serum triglyceride when insulin is administered to patients with either type I or type II diabetes (52) and primary hypertriglyceridemia (53,54) is consistent with an inhibitory effect of insulin on triglyceride secretion, although a major contribution to this effect may be the reduction in serum free fatty acid levels or effects on lipoprotein lipase levels.…”

Section: Discussionmentioning

confidence: 92%

Effects of Insulin and Glucose on Very Low Density Lipoprotein Triglyceride Secretion by Cultured Rat Hepatocytes

Durrington¹,

Newton²,

Weinstein³

et al. 1982

J. Clin. Invest.

215

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A B S T R A C T The effect of insulin on hepatic triglyceride synthesis and secretion is controversial. Previously, we have described a cell culture system of adult rat hepatocytes that synthesize and secrete very low density lipoprotein (VLDL) triglycerides with small and irreproducible effects of insulin on triglyceride metabolism. To study the primary effects of insulin on hepatic triglyceride metabolism a method was developed utilizing fibronectin-coated culture dishes that allowed adhesion, spreading, and maintenance of hepatocytes for 2-3 d in the absence of serum and insulin. This culture system allowed mass measurements of both cellular and secreted VLDL triglycerides for long time periods after the addition of physiological concentrations of insulin to hormone-free culture medium. In the absence of insulin and after an initial 4 h in culture, the medium was replenished and triglyceride mass was measured at the end of 18-h incubations. VLDL triglyceride accumulated in the culture medium at a linear rate over this time-course with increasing accumulation as the medium glucose concentration was raised from 2.5 to 25 mM glucose (1.77±0.24 to 3.09±0.76 yg triglyceride/mg cell protein per h). There was no apparent significant lipolysis or hepatocellular reuptake of secreted VLDL triglycerides. In the absence of insulin cellular triglyceride levels were unchanged between 3 and 24 h in culture while insulin (50-500 gU/ml) significantly increased cellular triglyceride content at all glucose concentrations tested (0-25 mM). The addition of insulin to the culture medium progressively reduced the rate of VLDL triglyceride secretion accompanied by an increase in cellular triglyceride at insulin concentrations > 50 ,U/ml. Most or all of the observed increase in cell triglyceride content could in all experiments be accounted for by the insulin-induced inhibition of VLDL secretion. Incorporation of [2-3H]glycerol into cellular and VLDL triglycerides as a function of insulin concentration was also measured. Glycerol incorporation data at 20-22 h after plating of the cells closely paralleled the insulin-induced changes in cellular and VLDL triglyceride as determined by mass analysis. The observed effects of insulin occurred at concentrations close to the physiological range and suggest that the direct hepatic effect is to suppress VLDL secretion although the net effect in vivo will clearly reflect many additional accompanying changes.

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Section: Discussionmentioning

confidence: 92%

Effects of Insulin and Glucose on Very Low Density Lipoprotein Triglyceride Secretion by Cultured Rat Hepatocytes

Durrington¹,

Newton²,

Weinstein³

et al. 1982

J. Clin. Invest.

215

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“…The abnormalities in serum lipoprotein pattern of insulin-deficient diabetic patients are partly accounted for by the decrease of tissue LPL activity. Thus, it is likely that the increase of VLDL and probably also the increase of LDL-triglyceride is caused by impaired removal of triglyceride from these particles at peripheral tissues even though an increase in splanchnic production of VLDL may also be present and contribute to the rise of triglycerides [4][5][6]. The decrease of HDL-cholesterol could also be related to the LPL deficiency and to concomitant reduction in the plasma clearance of triglyceride-rich lipoproteins.…”

Section: Discussionmentioning

confidence: 99%

“…Kinetic analyses have suggested that the increase of triglyceride and VLDL concentrations in uncontrolled insulin-dependent diabetes is chiefly accounted for by a combination of increased splanchnic production of triglycerides and their inefficient removal [4,5]. The defect in removal of VLDL triglycerides has been attributed to low activity of lipoprotein lipase (LPL), and, indeed, clearly decreased LPL activities have been demonstrated in postheparin plasma of untreated juvenile diabetic patients [6].…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein lipase activity of adipose tissue and skeletal muscle in insulin-deficient human diabetes

1979

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Summary.We have previously shown that lipoprotein lipase (LPL) activity of tissues is an important determinant not only of plasma VLDL levels but also of HDL-cholesterol. Studies were designed to investigate whether the serum lipoprotein alterations in uncontrolled insulin-deficient diabetes can be accounted for by changes in LPL activity of tissues. The heparin-releasable LPL activity was determined from biopsy samples of adipose tissue and skeletal muscle in 16 patients with newly detected untreated insulin-deficient diabetes and in 16 age-, sex-and body weight-matched healthy control subjects. Repeat assays were carried out after the patients had been on insulin treatment for an average of two weeks and when the diabetes was well controlled. When untreated the patients had increased concentrations of triglycerides and cholesterol in whole serum and in VLDL and LDL while the HDL cholesterol level was lower than that of controls (p < 0.01). The cholesterol/triglyceride ratio in each of the three lipoproteins was similar in patients and controls. While untreated the diabetic patients had significantly reduced mean LPL activity both in adipose tissue (average 34% of control mean, p < 0.001) and in skeletal muscle (average 45% of control mean, p < 0.05). In the whole group HDL-cholesterol was positively correlated with adipose tissue LPL activity (r = + 0.58, p < 0.001) while log serum total triglyceride and log VLDL-triglyceride showed significant negative correlations with LPL activity of both adipose tissue and skeletal muscle. After initiation of insulin treatment the LPL activity increased significantly (p < 0.01) in both tissues but was still subnormal after 2 weeks. At the same time the VLDL and LDL concentrations had returned to normal while the ItDL-cholesterol remained low. The results suggest that the increase of VLDL and LDL triglyceride and the decrease of HDL-cholesterol present in uncontrolled insulin-deficient diabetes are, at least partly, accounted for by decreased LPL activity of tissues. The restoration of tissue LPL and of serum HDL-eholesterol by insulin are relatively slow processes. The results are consistent with the hypothesis that HDL-cholesterol concentration is dependent on the efficiency of removal of triglyceride-rich lipoproteins from the circulation.

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“…Reaven and Reaven [36] come to a similar conclusion in studies on the development of hypertriglyceridaemia in acute and chronic streptozotocin-diabetic rats. In diabetic patients, Lewis et al [37] noted the importance of reduced extra-hepatic catabolism in controlling VLDL levels. In support of this, a reduction in lipoprotein lipase activity has been observed in insulin-deficient diabetes mellitus [3840] as well as a defect in VLDL removal [41].…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein secretion by isolated perfused livers from streptozotocin-diabetic rats

1981

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Summary. In liver perfusion from sucrose-fed, streptozotocin-diabetic rats there was in comparison with normal animals, a decrease in very low density lipoprotein concentration in the perfusion medium (38.6 ___ 6.3 versus 64.4___ 8.4 ixg. g liver -1 3 h-1 p < 0.05) and an increase in high density lipoprotein concentration (33.5 ___ 6.5 versus 14.0 ___ 1.9 Ixg. g liver -1 3h -1, p <0.005), which was paralleled by enhanced secretion of apoprotein A-I. The triglyceride: protein ratio was lower in very low density lipoprotein from diabetic animals (8.8 versus 13.4). Analysis of the apoprotein composition showed that diabetic very low density lipoprotein lacked arginine-rich protein (apo-E) and apo-C peptides; diabetic high density lipoprotein also lacked arginine-rich protein but contained more A-IV and apo-C-peptides. This may indicate net transfer of C peptides to high density lipoprotein from the degradation of very low density lipoprotein particles. The ratio of 3H-leucine: a4C-glucosamine incorporation was decreased in all diabetic lipoprotein classes suggesting increased glycosylation of apoproteins. These changes in particle composition may influence lipoprotein metabolism in diabetes through their effects on lipoprotein lipase and lecithin cholesterol acyl transferase activity, plasma half-life and tissue binding. Key words: Sucrose-feeding, streptozotocin diabetes, lipoprotein secretion, apoprotein composition, liver perfusion, incorporation of leucine, glucosamine.It has previously been found that in experimental diabetes mellitus in the sucrose-fed rat there are increased plasma levels of very low density (VLDL), low density (LDL) and high density (HDL) lipoproteins [I]. Subsequent studies on the half-life of injected HDL showed that the increase in HDL was due to an augmented synthetic rate with a secondary decrease in catabolism [2]. The mechanism for the increased VLDL levels is thought to be due to a defect in removal caused by decreased activity of extrahepatic lipoprotein lipase [3]. Recently the presence of a plasma factor which interferes with the removal of VLDL-triglyceride has been demonstrated in experimental diabetes mellitus [4]. The parallel increase in both VLDL and HDL concentrations is of interest since there is usually an inverse relationship between these lipoproteins [5] and because the HDL particle is partially derived from the metabolism of VLDL [6]. We have previously shown that in the perfused liver from diabetic rats the incorporation of leucine into protein was decreased whilst that of glucosamine was unchanged or even enhanced [7]. We therefore wished to extend this work by examining the incorporation of these labels into the specific lipoproteins in the study of the hyperlipidaemia of experimental diabetes.We have measured the secretion of lipoproteins by isolated perfused livers in streptozotocin-diabetic rats to assess how much hepatic synthesis determines the levels of circulating lipoproteins without the influence of peripheral catabolism by lipoproteins lipase. Materials ...

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Plasma Triglyceride and Fatty Acid Metabolism in Diabetes mellitus

Cited by 84 publications

References 49 publications

Effects of Insulin and Glucose on Very Low Density Lipoprotein Triglyceride Secretion by Cultured Rat Hepatocytes

Effects of Insulin and Glucose on Very Low Density Lipoprotein Triglyceride Secretion by Cultured Rat Hepatocytes

Lipoprotein lipase activity of adipose tissue and skeletal muscle in insulin-deficient human diabetes

Lipoprotein secretion by isolated perfused livers from streptozotocin-diabetic rats

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