1. To evaluate the role of ketone bodies in diabetes-induced changes in hepatic cytochrome P450 composition, rats were treated with acetone, 3-hydroxybutyrate or 1,3-butanediol. 2. Treatment with acetone enhanced the rat hepatic O-dealkylations of ethoxyresorufin and methoxyresorufin, and the hydroxylation of p-nitrophenol, but had no effect on lauric acid hydroxylation and ethylmorphine N-demethylation. Neither 3-hydroxybutyrate nor 1,3-butanediol modulated the metabolism of the above substrates. 3. Immunoblot analysis of hepatic microsomal proteins revealed that treatment with acetone increased the apoprotein levels of P4501A2, P4502B1/2 and P4502E1. 4. It is concluded that acetone is responsible, at least partly, for the diabetes-induced increase in hepatic microsomal P4501A2, P4502B1/2 and P4502E1 proteins but does not mediate the increases in the P4503A1 and P4504A1 proteins. On the basis of work from our own and other laboratories a mechanism for the diabetes-induced changes in hepatic cytochrome P450 proteins is proposed.
1. The activities of hexokinase (EC 2.7.1.1) and phosphofructokinase (EC 2.7.1.11) have been studied in homogenates of adipose tissue taken from human diabetics, fasting and control patients. 2. Three isoenzymes of hexokinase were observed with apparent Km values for glucose of 1.04 × 10-5 m, 2.6 × 10-4 m and 2.9 × 10-4 m, respectively. 3. No change in activity of hexokinase was found in adipose tissue of untreated diabetics (n = 22), treated diabetics (n = 13) or non-diabetic controls. However, fasting was associated with a decrease of approx. 40% in the activity of hexokinase in adipose tissue. 4. In contrast, there was a marked decrease in the activity of phosphofructokinase in adipose tissue from untreated diabetics (n = 24) which was restored to normal by either insulin therapy or treatment by hypoglycaemic drugs. 5. There was a negative correlation between the phosphofructokinase/hexokinase ratio in adipose tissue and the fasting blood glucose (P = 0.01) and the 2 h blood glucose (P = 0.03) after an oral glucose load (50 g). 6. The functional significance of the changes in enzyme activities is discussed in relation to the glucose intolerance of diabetes.
1. The ability of fat-free homogenates of human adipose tissue to incorporate [l-14C]palmitate into neutral lipid and long-chain fatty acyl-CoA has been studied. Homogenates readily incorporated [ l-14C]palmitate into neutral lipid. Addition of L-glycerol 3-phosphate was required before synthesis of neutral lipid occurred whereas the system contained sufficient endogenous fatty acid for esterification with L-glycerol 3-phosphate.2. Glucose, glucose 6-phosphate and fructose 1,6-diphosphate could replace L-glycerol 3-phosphate if the system was supplemented with NADH. The order of efficiency of each substrate to support esterification of [l-'4C]palmitate was : L-glycerol 3-phosphate, fructose, 1 ,Qdiphosphate, glucose 6-phosphate and glucose.3. Factors known to alter the activity of phosphofructokinase (E.C.2.7.1.11) also altered the rates of incorporation of [l-14C]palmitate into neutral lipid. Thus citrate (10 mM) inhibited lipogenesis in this system when glucose 6-phosphate was used as initial substrate, but not when fructose 1,6-diphosphate was used. 3'5'-(cyclic)-AMP reversed the inhibition of lipogenesis by citrate. 4.Preparations of lipomata (benign tumours of adipose tissue) were found to be less sensitive to inhibition of lipogenesis by citrate (7 m) but inhibition was observed at higher concentrations of citrate (21 m). 3'5'-(cyclic)-AMP had no effect on lipogenesis in fat-free homogenates of lipomata in the presence of citrate (7 m). 5. AMP (1.2 mM) inhibited the synthesis of long-chain fatty acyl-CoA without altering the rate of synthesis of neutral lipid from L-glycerol 3-phosphate. When the concentration of AMP was increased to 4 m a concurrent decrease in lipid synthesis was observed.The clinical study of human adipose tissue is restricted by the small quantity that can be obtained by needle biopsy in the out-patient clinic or on the ward. It has been found that about
Several drugs were tested for their ability to inhibit lipogenesis in human adipose tissue. Only fenfluramine was found to inhibit the incorporation of T-palmitate and 14C_gtucose into neutral lipid in intact tissue. This effeet was observed at drug coneentrations above 1 mM. Fenfluramine inhibited lipogenesis in broken-cell preparations of human adipose tissue at concentrations of 1 mM and above. However, in this system the N-benzoyloxyethyl derivative of fenfluramine, S. 1513, was also found to inhibit lipogenesis. This drug was more potent than fenfluramine, a significant inhibition bdng observed at 0.4 mM. During inhibition of lipogenesis in homogenates of adipose tissue by fenfluramine radioaetitivity was found to aeeumulate in long-ehain aeyl-CoA whieh suggests that the drug may interfere with acylation of glycerol 3-phosphate. Evidence that fenfluramine may have a similar effeet in vivo was considered, but the results were not statistically significant.
Abstract. 1. The conversion of glucose and palmitate to neutral lipid by adipose tissue has been studied in a group of 30 adult diabetics and compared to a group of 30 non‐diabetic controls. — 2. Adipose tissue from both sources showed similar saturation characteristics for glucose; uptake of palmitate was linear up to 3 mM. — 3. Adipose tissue of diabetics incubated with glucose (14 mM) converted 270 ± 60 (90) mμmoles/mg protein/2 hours to neutral lipid compared to non‐diabetics who converted 380 ±70 (10) mμmoles/mg protein/2 hours. Similar results were obtained with a medium glucose concentration of 8 mM. No differences were found in glucose utilization between a group of 7 lean diabetics and 6 obese diabetics. — 4. Conversion of palmitate to neutral lipid by adipose tissue was inhibited by cyanide (1.5 mM), fluoride (50 mM) and was found to be temperature dependent. — 5. Adult diabetics converted 0.36 ± 0.06 (17) mμmoles palmitate/mg protein/2 hours into neutral lipid, compared to a group of non‐diabetics who converted 1.09 ± 0.35 (13) mμmoles/mg protein/2 hours.— 6. The significance of these observations is discussed in relation to the impaired glucose tolerance test of diabetes.
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