Can the glyoxylate pathway contribute to fat-induced hepatic insulin resistance?

Song, Shujun

doi:10.1054/mehy.1999.0943

Cited by 20 publications

(19 citation statements)

References 86 publications

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“…1) Through the glyoxylate pathway, free acetate, which increases with elevated FFA oxidation, is converted to succinate (112). An increase in succinate could lead to elevation of glucose through the tricarboxylic acid cycle and the gluconeogenic pathway.…”

Section: Ffa and Gluconeogenesismentioning

confidence: 99%

Mechanisms of the free fatty acid-induced increase in hepatic glucose production

Lam

Carpentier

Lewis

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

237

149

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nisms of the free fatty acid-induced increase in hepatic glucose production. Am J Physiol Endocrinol Metab 284: E863-E873, 2003; 10.1152/ajpendo.00033.2003.-The associations between obesity, insulin resistance, and type 2 diabetes mellitus are well documented. Free fatty acids (FFA), which are often elevated in obesity, have been implicated as an important link in these associations. Contrary to muscle glucose metabolism, the effects of FFA on hepatic glucose metabolism and the associated mechanisms have not been extensively investigated. It is still controversial whether FFA have substantial effects on hepatic glucose production, and the mechanisms responsible for these putative effects remain unknown. We review recent progress in this area and try to clarify controversial issues regarding the mechanisms responsible for the FFA-induced increase in hepatic glucose production in the postabsorptive state and during hyperinsulinemia.lipid; hepatic insulin resistance FREE FATTY ACIDS (FFA), which are often elevated in obese individuals (6, 15, 29,70), have been implicated as an important causative link in the associations between obesity, insulin resistance, and type 2 diabetes mellitus (11,48,56,73,82). Elevated plasma FFA clearly impair the ability of insulin to stimulate muscle glucose uptake (45,98). This effect is associated with a reduction in insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity, an important step in the insulin-signaling cascade that has been shown to be inhibited by FFA-induced PKC activation in muscle (42,53). In contrast, although a number of studies have indicated that elevated plasma FFA and high-fat diets can increase postabsorptive (referred to throughout this manuscript as "basal") hepatic glucose production (HGP) (7, 14,67,68,113) and induce hepatic insulin resistance (i.e., reduce the ability of insulin to suppress HGP) (9, 13,51,67,68,74,91,97,102,111,125), the magnitude of these effects and the mechanisms involved remain controversial.Because elevated HGP and hepatic insulin resistance have been well documented in individuals with type 2 diabetes (12, 40,85), studies that examine the effects of FFA on hepatic glucose metabolism are essential in understanding the pathogenesis of insulin resistance in type 2 diabetes. In this brief review, the physiological effects of FFA on hepatic glucose metabolism and the putative mechanisms of these effects will be discussed. FFA AND BASAL HGP FFA and GluconeogenesisGlucose is produced by glycogenolysis and gluconeogenesis in the liver. FFA increase hepatic gluconeogenesis both in vitro and in vivo (11, 20,127). FFA stimulation of gluconeogenesis has been attributed to the production of 1) acetyl-CoA derived from FFA oxidation, which allosterically activates pyruvate carboxylase, 2) NADH, which is used for the formation of glyceraldehyde 3-phosphate from 1,3-bisphosphoglycerate, and 3) ATP, which is used as an energy source. Additionally, increased levels of citrate (product of acetyl-CoA derived from FFA o...

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Section: Ffa and Gluconeogenesismentioning

confidence: 99%

Mechanisms of the free fatty acid-induced increase in hepatic glucose production

Lam

Carpentier

Lewis

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

237

149

View full text Add to dashboard Cite

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“…The key enzymes associated with the glyoxylate cycle, isocitrate lyase and malate synthase, can become active in the human liver during periods of fasting [49] , allowing lipid to be converted into carbohydrate. It has already been suggested that activation of the glyoxylate cycle may contribute to the development of type 2 diabetes [50] . Furthermore, we have shown that alcohol may promote the development of a pseudo-diabetic condition as evidenced by a significant decrease in plasma insulin if consumed alone after a high carbohydrate meal [29] .…”

Section: Discussionmentioning

confidence: 99%

Effect of Moderate White Wine Consumption on Serum IgA and Plasma Insulin under Fasting Conditions

Kokavec

Crowe²

2006

Ann Nutr Metab

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Background/Aims: The present study aims to investigate the contribution of alcohol toxicity to the development of malnutrition by assessing the effect of consuming a moderate amount of white wine on plasma insulin and serum IgA under fasting conditions. Methods: A total of 5 non-alcoholic males aged between 19 and 22 years participated in the current investigation. The experimental procedure required participants to undergo a 6-hour fast before ingesting 4 standard units of alcohol (40 g) in the form of white wine over a 120-min period. The level of blood alcohol, plasma insulin and serum IgA was assessed at 30-min intervals across the 120-min experimental period. Results: Consuming alcohol promotes a significant increase in serum IgA in the absence of any change in plasma insulin or ketone production in fasted individuals. Conclusion: White wine prior to a meal does not promote glucose metabolism and utilization and may increase the risk of developing a transient diabetic condition due to an alteration in energy metabolism.

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“…Since insulin controls fat catabolism at the site of malonyl-CoA inhibition of CPT in mitochondria and hence regulates mitochondrial oxidation [34], it appears pertinent to propose that in lipodystrophy (probably also obesity-related) diabetes fat metabolism in peroxisomes may escape from insulin control rather than become resistant to it. Recently a possible role of gluconeogenesis in peroxisomes has been suggested [35], and the glyoxylate pathway has been suggested as a potential mechanism in diabetic hyperglycaemia [36]. With the phenotypes examined above, it appears that peroxisomal lipid metabolism and its putative gluconeogenic activity may play a key role in insulin resistance and type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…However, full operation of the glyoxylate Fatty Liver in Lipodystrophic Diabetes 9 pathway can never occur only by ISL and MS but requires the participation of other enzymes, such as acetate thiokinase (AT), malate dehydrogenase (MD), citrate synthase (CS), and aconitate hydratase (AH). Unfortunately, although many studies suggested the existence of the glyoxylate pathway in mammals, it has never been conclusively determined [36]. The reliability of these reports was challenged by criticisms of the sensitivity of the assays and the operativity of substrate concentration [43].…”

Section: Discussionmentioning

confidence: 99%

“…The reliability of these reports was challenged by criticisms of the sensitivity of the assays and the operativity of substrate concentration [43]. Nevertheless, the existence of the glyoxylate pathway in nematodes at the adult stage, in postembryonic larvae, and in embryos has been generally accepted, and incubation of peroxisomes from rat liver with 14 C-labeled dodecanedioic acid has indeed resulted in accumulation of succinate, a gluconeogenic precursor [36,43]. It is noteworthy that so far all evidence was obtained by anatomical, immunological, and biochemical means, whereas none was at the gene level.…”

Section: Discussionmentioning

confidence: 99%

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The role of increased liver triglyceride content: a culprit of diabetic hyperglycaemia?

Song

2002

Diabetes Metabolism Res

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The role of fat in the aetiology of insulin resistance and type 2 diabetes has been re-considered in the present review. This is because of the questions raised by recent created mouse models imitating human lipodystrophy diabetes. It appears that hepatic steatosis, which is shared by both lipodystrophy and most if not all obesity patients, may play a key role in the pathogenesis of insulin resistance and type 2 diabetes despite the fact that lipodystrophy is an extreme state and occurs more rarely than obesity. The possible link between lipid and glucose metabolisms via peroxisome activity has been examined and its role in determining hyperglycaemia is suggested. Moreover, new avenues towards a better understanding of insulin resistance at the genomic level have also been proposed. It appears that one of the most fundamental biological phenomena, fuel selection, may underlie the causes of diabetic hyperglycaemia and perplex the role of fat in the aetiology of insulin resistance.

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Can the glyoxylate pathway contribute to fat-induced hepatic insulin resistance?

Cited by 20 publications

References 86 publications

Mechanisms of the free fatty acid-induced increase in hepatic glucose production

Mechanisms of the free fatty acid-induced increase in hepatic glucose production

Effect of Moderate White Wine Consumption on Serum IgA and Plasma Insulin under Fasting Conditions

The role of increased liver triglyceride content: a culprit of diabetic hyperglycaemia?

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