Interrelationships Of Nutrient Metabolism And The Effect On Glucose Homeostasis

Competition between nutrients as sources of metabolic fuel has been known for more than eight decades. However, quantitatively, the most important interaction is between glucose and fatty acids (5). As already mentioned above, if there is a perturbation of the energy-supply system in the body, such as an abundance of fatty acids, a competition ensues between glucose and fatty acids as sources of metabolic fuel. This phenomenon came to be significantly recognized when Randle and colleagues proposed the glucose-fatty-acid cycle to explain the metabolic interactions between glucose and fatty acids and their role in insulin sensitivity and diabetes (5). Essentially, the Randle hypothesis states that the metabolic relationship between glucose and fatty acids is reciprocal and not dependent (5-7). More recently, to explain this reciprocal relationship, Randle has proposed that oversupply of glucose would promote glucose oxidation and glucose and lipid storage while inhibiting fatty-acid oxidation. On the other hand, an abundance of free fatty acids would promote fatty-acid oxidation and storage while inhibiting glucose oxidation, and may possibly enhance glucose storage if glycogen reserves are incomplete (5). According to the original Randle hypothesis, an increase in fatty-acid availability results in increased fatty-acid oxidation with concomitant inhibition of glucose oxidation. Various mechanisms are involved in the inhibition of glucose oxidation during increased fatty-acid supply and oxidation, as illustrated in Figure 10.1. The

Glucose

FIGURE 10.1 Illustration of the original Randle hypothesis. Oversupply of lipids will lead to increased fatty-acid oxidation, the products of which include increased levels of acetyl CoA, which inhibits pyruvate dehydrogenase (PDH), and citrate, which inhibits phosphof-ructose kinase. Simultaneously, other products of fatty-acid oxidation, such as glycerol, are converted to glucose in a pathway that generates an abundance of Glucose-6-P (G-6-P), which inhibits hexokinase, and further impairs glucose utilization.

FIGURE 10.1 Illustration of the original Randle hypothesis. Oversupply of lipids will lead to increased fatty-acid oxidation, the products of which include increased levels of acetyl CoA, which inhibits pyruvate dehydrogenase (PDH), and citrate, which inhibits phosphof-ructose kinase. Simultaneously, other products of fatty-acid oxidation, such as glycerol, are converted to glucose in a pathway that generates an abundance of Glucose-6-P (G-6-P), which inhibits hexokinase, and further impairs glucose utilization.

accumulation of acetyl-CoA would result in the inhibition of pyruvate dehydrogenase (PDH), while the abundance of citrate would inhibit phosphofructokinase (PFK), and excess levels of glucose-6-phosphate (G-6-P) would inhibit the activity of hexokinase (HK) (7, 8).

There has also been an accumulation of evidence to show that increases in the glycolytic flux during glucose metabolism may decrease fatty-acid oxidation. It has been proposed that the potential sites of fatty-acid metabolism affected include the transport of fatty acid into the sarcoplasma, lipolysis of intramuscular triacylglycerol by hormone-sensitive lipase, and transport of fatty acids across the mitochondrial membrane (7). One scenario among the possible mechanisms of regulation of fatty-acid metabolism is an increase in malonyl-CoA concentration, which is formed from acetyl-CoA in a reaction catalyzed by acetyl-CoA carboxylase (ACC). Increased levels of malonyl-CoA will inhibit carnitine palmitoyl transferase 1 (CPT1) (9). Indeed, using muscle biopsies obtained from obese subjects for lipid analysis and reverse transcription-competitive polymerase chain reaction, it has been shown that down-regulation of ACC2 mRNA, induced by lowering plasma-insulin levels caused improvement in insulin sensitivity (10). Another possibility is increased levels of acetyl moiety that will result in acetylation of the carnitine pool decreasing the free carnitine concentration and thereby reducing fatty-acid transport into the mitochondria. It has also been suggested in some studies that CPT1 may be inhibited by small reductions in pH that may occur during glycolysis (7). Moreover, it has been shown that long-chain acyl-CoAs accumulate in the muscle during chronic glucose infusion, an observation that is consistent with malonyl-CoA-induced inhibition of fatty-acid oxidation. This phenomenon, by which glucose oxidation yield products that may regulate fatty-acid oxidation, has been referred to by some investigators as the reverse glucose-fatty-acid cycle (11, 12), in distinction from the original Randle hypothesis, which proposed that products of fatty-acid oxidation affect glucose metabolism.

Studies performed after the original Randle hypothesis was proposed have identified other mechanisms by which oversupply of fatty acids would affect glucose utilization. First, it has been shown that with adequate insulinization, increased fatty-acid levels effectively compete with glucose for uptake into peripheral tissues, regardless of the presence of hyperglycemia (13). Second, it has been reported that increased fatty-acid oxidation may inhibit glucose storage (14). Third, it has been suggested that the metabolic interactions between free fatty acid and glucose also involve impaired suppression of hepatic glucose output (HGP) by insulin (15). In addition, in a situation of enhanced lipolysis, increased levels of glycerol would promote gluconeogenesis (16). Furthermore, it has been shown that lipid-derived molecules, including diacylglycerol and ceramide, can inhibit glucose disposal by interfering with more than one pathway of the insulin-signal transduction system, depending on the prevailing species of fatty acids. These pathways include alteration of insulin action via chronic activation of protein kinase C (PKC) isoenzymes by long-chain acyl-CoA (17, 18). Putting together available information from the literature on the various mechanisms by which oversupply of lipids may impair glucose utilization and result in increased blood glucose, glucose-fatty-acid cycle today can be summarized by the various pathways shown in Figure 10.2.

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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  • Togo
    What are nutrients interrelationships in metabolism?
    23 days ago

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