Diabetes Fatty acid synthesis

FIGURE 21-19 Regulation of triacylglycerol synthesis by insulin. Insulin stimulates conversion of dietary carbohydrates and proteins to fat. Individuals with diabetes mellitus lack insulin in uncontrolled disease, this results in diminished fatty acid synthesis, and the acetyl-CoA arising from catabolism of carbohydrates and proteins is shunted instead to ketone body production. People in severe ketosis smell of acetone, so the condition is sometimes mistaken for drunkenness (p. 909). 

D. Decreased insulin levels cause fatty acid synthesis to decrease and glucagon levels to increase. Adipose triacylglycerols are degraded. Fatty acids are converted to ketone bodies in liver a ketoacidosis can occur. There is increased decarboxylation of acetoacetate to form acetone, which causes the odor associated with diabetic ketoacidosis. 

Accumulating evidence indicates that SREBP-lc mediates the effect of insulin on transcriptional activation of genes involved in fatty acid synthesis (Horton et ah, 2002 Shimomura et al., 1999 Foretz et al., 1999). When mice are fed with a fat free high-carbohydrate diet, the liver SCD mRNA is induced about 50 fold (Ntambi, 1995 Sessler and Ntambi, 1998), however, the induction is blunted when SREBPl-c is disrupted. Because SDC and D6D mRNA expression were diminished in diabetic rats, and restored by insulin administration (Waters and Ntambi, 1994), the insulin effect on the desaturase genes is likely to be mediated by SREBP-lc. Studies with primary culture rat hepatocytes showed that the expression of a dominant negative SREBPl-c blocked the effect of insulin on the transcriptional activation of SCD, whereas expression of a dominant positive SREBPl-c mimicked the insulin effect (Foretz et al.,... 

Insulin thus appears to play a major role in the regulation of the quantity of carbohydrate which is utilized for fatty acid synthesis in adipose tissue. It corrects the decreased incorporation of glucose carbon into long-chain fatty acids, which is a characteristic of adipose tissue removed from starved or alloxan diabetic rats. There appears to be a difference in the effectiveness of insulin in vitro and in vivo with regard to adipose tissue from alloxan diabetic rats. This may reflect the fact that adipose tissue removed from alloxan diabetic rats 3 hours after the injection of insulin and then incubated for an additional 3 hours has actually been subjected to the influence of insulin for 6 hours a comparison with controls incubated with insulin in vitro for 6 hours has not been made. Aside from this and the different routes by which the hormone gains access to the tissue, the possibility remains that secondary hormonal adjustments to insulin in vivo may be responsible for its greater effectiveness. 

Otsuka Long-Evans Tokushima Fatty (OLETF) rats have hyperphagia because they lack receptors for cholecystokinin and become obese, developing hyperlipidemia, diabetes, and hypertension (29-31). We previously reported that CLA, especially Q)trans, 2cis (lOr, 12c) CLA, has anti-obese and hypolipidemic effects in OLETF rats. These effects were attributed to the enhancement of fatty acid 3-oxidation and the suppression of fatty acid synthesis (32,33). In the present study we evaluated the effect of CLA isomers (0.5% supplementation with 5% com oil) on the development of hypertension in OLETF rats. 

Thus, the whole process of phenol formation may be considered analogous, in an overall metabolic sense, to fatty acid synthesis in well-fed animals (with the resultant formation and storage of triacylglycerol in adipose tissue) or ketogenesis in the liver of starved or diabetic animals. These situations have effectively adapted to the demands of an imbalanced overproduction of acetyl-CoA. 

Following the administration of insulin to diabetic rats, fatty acid synthesis increases [90,100,102-104] as would be predicted, increases are observed in the citrate cleavage enzyme, fatty acid synthetase, and... 

Activation by fructose-1, 6-diphosphate offers an attractive possibility for regulation in view of the long-established relationship between glucose utilization and lipogenesis in a number of tissues [87,98,100, 101,244]. The levels of fructose-1, 6-diphosphate are known [245] to vary in the same direction as the rate of fatty acid biosynthesis for example, fructose-1, 6-diphosphate concentration in liver is lower in the fasted and diabetic state, conditions in which fatty acid synthesis is depressed. Further work will be necessary to determine whether activation of the synthetase by sugar phosphates has physiological significance. 

When excess pantothenic acid is administered to diabetic rats, the excretion of sugar and ketone bodies is markedly reduced, and cholesterol accumulates in the liver, adrenals, and blood. Therefore, pantothenic acid administration to diabetic rats appears to stimulate the use of acetate and acetoacetate for cholesterol and fatty acid synthesis. The role of coenzyme A in diabetes is discussed in greater detail in the chapter devoted to that disease. 

Because cholesterol and phospholipid synthesis is likely to be necessary for the maintenance of the integrity of the structural lipoproteins in nervous tissue, especially in the Schwann cells and the oligodendrocytes, and also because cholesterol and fatty acid synthesis is decreased in livers of diabetics, cholesterol and fatty acid synthesis has been measured in the central and peripheral nervous tissue of animals made diabetic with alloxan. The synthesis of both compounds is decreased in diabetic animals in the central but not in the peripheral nervous system. Whether the extension of such studies will someday lead to the elucidation of the pathogenesis of diabetic neuropathy remains to be seen. 

The rate of fatty acid synthesis is reduced in diabetes, and, as a result, more acetyl CoA may be available for other metabolic reactions, such as the formation of ketone bodies. 

However, these observations provide only indirect evidence for a role of NADPH in the development of ketosis in diabetes. When attempts were made to measure directly the ratio of NAD to NADH in tissues of diabetic and normal animals, no significant differences were found. This old theory must be evaluated in the light of new information on fatty acid synthesis. Wakil [140] has clearly established that the carboxylation of acetyl CoA is the rate-limiting reaction in fatty acid synthesis. This is a reaction in which acetyl CoA is converted to malonyl CoA in the presence of acetyl CoA carboxylase, a biotin enzyme. 

Another mechanism by which fatty acid synthesis could be inhibited in diabetic rats is a feedback inhibition of the acetyl CoA carboxylase by the longer chain length fatty acid. Fatty acid synthesis in crude liver and avocado homogenates can be blocked by adding free fatty acid or albumin-bound fatty acid to the media. But the acyl-CoA derivative of the free fatty acid rather than the free fatty acid appears to be the inhibitor. The acetyl CoA accumulation could result from the inhibition of citrate synthetase by palmityl CoA described by Lynnen. In any case diabetic ketosis is unlikely to result from retarded fatty acid synthesis because a similar and sometimes greater retardation of fatty acid synthesis is observed in starvation, and ketone body accumulation in starvation does not compare to such accumulation in diabetes. 

Gellhorn and Benjamin (1966) have demonstrated that oxidative desaturation of saturated fatty acids becomes depressed in the diabetic state and that this enzymatic impairment is reversed by insulin. Since insulin can also reverse the diabetic depressed llpogenlc activity, it is fair to assume that the insulin-Induced rise in hepatic desaturase activity could be mediated by the increase in de novo fatty acid synthesis. Mercurl et al. (1974) demonstrated that dietary fructose or glycerol was able to partially restore the A9 desaturase activity depressed by the diabetic state. Since utilization of these carbohydrates by the liver is not insulin dependent (Takeda et al , 1967 and Howard and Lowenstein, 1967) and the fatty acid synthetase activity is increased by a fructose or glycerol supplemented diet (Volpe and Vagelos, 1974 and Bruckdorfer et al., 1972), further research in this area may increase our understanding of these metabolic relationships. 

It was possible to synthesize medium chain length fatty acids through a proper combination of jS-oxidation enzymes (Seubert et al. 1957). However, alloxan diabetic rats with an intact jS-oxidation in liver have an extremely depressed fatty acid synthesis (Brady et al. 1956). Also the unfavorable equilibrium of the jS-ketothiolase reaction, which is far on the side of cleavage, made the synthesis by reversal of the jS-oxidation steps appear very unlikely (Lynen et al. 1957). 

Long chain acyl-CoA esters cause a competitive inhibition of acetyl-CoA-carboxylase. The elevated levels of long chain fatty acid Co-A esters in diabetes and on starvation may be the basis of the keto-acidosis (Bobtz et al. 1963). Citrate synthase (condensing enzyme) is also inhibited by long chaiii acyl-CoA esters (Wieland et al. 1963 a, b). It appears therefore that the product of fatty acid synthesis is able to regulate the synthesis by means of a feed back mechanism. 

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