Hepatic metabolism of free fatty acids in normal and diabetic dogs

Basso, Laurence V.; Havel, Richard J.

doi:10.1172/jci106264

Cited by 204 publications

(104 citation statements)

References 36 publications

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“…In dogs given insulin antiserum the most immediate effect observed in liver perfusion studies, in which radiolabeled palmitate was provided as substrate, was an increase in the secretion of labeled triglycerides (50) consistent with the present findings that insulin has an inhibitory effect on secretion. In similar experiments, in which insulin replacement therapy had been withdrawn for 2 d from pancreatectomized dogs, triglyceride secretion was found to be low (51). However, reduced triglyceride synthesis in more chronic insulin deficiency, whether a primary or secondary effect, must inevitably reduce VLDL triglyceride secretion.…”

Section: Discussionmentioning

confidence: 93%

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: 93%

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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“…Basso and Havel recently reported decreased utilization of ketone-bodies across the hind leg (mainly muscle) of depancreatinized dogs (52). Thus, there appears to be impaired ketone-body utilization by skeletal muscle in both prolonged starvation and depancreatinized diabetes.…”

Section: Discussionmentioning

confidence: 95%

Human forearm metabolism during progressive starvation

Owen¹,

Reichard²

1971

J. Clin. Invest.

168

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A B S T R A C T Forearm muscle metabolism was studied in eight obese subjects after an overnight, 3 and 24 day fast. Arterio-deep-venous differences of oxygen, carbon dioxide, glucose, lactate, pyruvate, free fatty acids, acetoacetate, and P-hydroxybutyrate with simultaneous forearm blood flow were measured. Rates of metabolite utilization and production were thus estimated. Oxygen consumption and lactate and pyruvate production remained relatively constant at each fasting period. Glucose, initially the major substrate consumed, showed decreased consumption after 3 and 24 days of fasting. Acetoacetate and P-hydroxybutyrate consumption after an overnight fast was low. At 3 days of fasting with increased arterial concentrations of acetoactate and P-hydroxybutyrate, consumption of these substrates rose dramatically. At 24 days of fasting, despite further elevation of arterial levels of acetoacetate and P-hydroxybutyrate, the utilization of acetoacetate did not increase further and if anything decreased, while five out of eight subjects released P-hydroxybutyrate across the forearm. Acetoacetate was preferentially extracted over P-hydroxybutyrate. At 24 days of starvation, free fatty acids were the principal fuels extracted by forearm muscle; at this time there was a decreased glucose and also ketone-body consumption by skeletal muscle.

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“…iO126 A. tI. Kissebah et al : Insulin Secretion, Plasma FFA and TG Transport Kinetics in diabetic dogs the incorporation of plasma free fatty acid into plasma VLDL triglycerides was decreased [5]. In human juvenile diabetes early reports suggested that the hepatic production of triglyceride was normal [14,42].…”

Section: Discussionmentioning

confidence: 99%

Inter-relationship between insulin secretion and plasma free fatty acid and triglyceride transport kinetics in maturity onset diabetes and the effect of phenethylbiguanide (Phenformin)

1974

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Summary. The plasma free fatty acid and triglyceride transport kinetics in 16 non-obese and 7 obese maturity onset diabetics with hypertriglyceridaemia have been compared with results obtained in 27 control subjects. Changes in glucose and insulin responses were evaluated in relation to the lipid parameters. All the diabetics showed elevated plasma FFA levels and turnover rates. In the non-obese diabetics the plasma triglyceride turnover rate was within the normal range and their hypertriglyceridaemia was due to impaired trigleeride clearance. In the obese diabetics the plasma trig]yceride turnover rate was increased and they also had some impairment of triglyceride clearance, so that in them a double mechanism was observed to account for their hypertriglyceridaemia. The insulin levels in the diabetics were similar to, or greater than, those found in the controls. Our results suggested that the enhanced lipolysis and impaired triglyceride clearance observed in the diabetic patients were a manifestation of insulin unresponsiveness in adipose tissue and that the changes in insulin and glucose relationship could be secondary to elevated FFA and triglyceride levels. Further confirmation was obtained by the finding of an exaggerated insulin response to a glucose challenge in normal subjects infused with Intralipid.Treatment with phenethylbiguanide (Phenformin) significantly lowered the plasma FFA and triglyceride concentration in both diabetic groups. This was associated with normalisation of both plasma FFA turnover and triglyceride clearance. It also reduced the triglyceride turnover rate to the normal range in the obese diabetics. These changes were associated with a fall of plasma glucose and insulin levels to within the normal range. These results suggested an effect of Phenformin in reducing the rate of lipolysis leading to improved glucose tolerance.

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Hepatic metabolism of free fatty acids in normal and diabetic dogs

Cited by 204 publications

References 36 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

Human forearm metabolism during progressive starvation

Inter-relationship between insulin secretion and plasma free fatty acid and triglyceride transport kinetics in maturity onset diabetes and the effect of phenethylbiguanide (Phenformin)

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