Chronic hyperglycaemia promotes lipogenesis and triacylglycerol accumulation in human skeletal muscle cells

Aas, Vigdis; Kase, Eili Tranheim; Solberg, Rigmor; Jensen, Jørgen; Rustan, Arild C.

doi:10.1007/s00125-004-1465-9

Cited by 57 publications

(63 citation statements)

References 44 publications

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“…The effects we observed are therefore not simply a result of benfotiamine abolishing the previously documented inhibitory effects of hyperglycemia on glucose uptake in myotubes (Aas et al 2004). However, we also found that 200 lM benfotiamine was able to reverse the inhibitory effect of hyperglycemia on glucose oxidation.…”

Section: Discussionsupporting

confidence: 47%

“…In addition to the harmful effects on the vasculature, hyperglycemia also contributes to insulin resistance in skeletal muscle (Richter et al 1988). We have previously shown that myotubes exposed to chronic hyperglycemia have increased lipogenesis and intramyocellular triacylglycerol (IMTG) accumulation (Aas et al 2004). The mechanisms by which these effects occur are complex and remain unknown but might involve mitochondrial dysfunction (Aas et al 2011).…”

Section: Introductionmentioning

confidence: 99%

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Benfotiamine increases glucose oxidation and downregulates NADPH oxidase 4 expression in cultured human myotubes exposed to both normal and high glucose concentrations

et al. 2011

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The aim of the present work was to study the effects of benfotiamine (S-benzoylthiamine O-monophosphate) on glucose and lipid metabolism and gene expression in differentiated human skeletal muscle cells (myotubes) incubated for 4 days under normal (5.5 mM glucose) and hyperglycemic (20 mM glucose) conditions. Myotubes established from lean, healthy volunteers were treated with benfotiamine for 4 days. Glucose and lipid metabolism were studied with labeled precursors. Gene expression was measured using real-time polymerase chain reaction (qPCR) and microarray technology. Benfotiamine significantly increased glucose oxidation under normoglycemic (35 and 49% increase at 100 and 200 lM benfotiamine, respectively) as well as hyperglycemic conditions (70% increase at 200 lM benfotiamine). Benfotiamine also increased glucose uptake. In comparison, thiamine (200 lM) increased overall glucose metabolism but did not change glucose oxidation. In contrast to glucose, mitochondrial lipid oxidation and overall lipid metabolism were unchanged by benfotiamine. The expression of NADPH oxidase 4 (NOX4) was significantly downregulated by benfotiamine treatment under both normo-and hyperglycemic conditions. Gene set enrichment analysis (GSEA) showed that befotiamine increased peroxisomal lipid oxidation and organelle (mitochondrial) membrane function. In conclusion, benfotiamine increases mitochondrial glucose oxidation in myotubes and downregulates NOX4 expression. These findings may be of relevance to type 2 diabetes where reversal of reduced glucose oxidation and mitochondrial capacity is a desirable goal.

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Section: Discussionsupporting

confidence: 47%

Section: Introductionmentioning

confidence: 99%

Benfotiamine increases glucose oxidation and downregulates NADPH oxidase 4 expression in cultured human myotubes exposed to both normal and high glucose concentrations

et al. 2011

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“…(ii) In another recent study by Aas et al 48 to evaluate the potential effects of hyperglycemia on glucose and lipid metabolism in human muscle cells, it was shown that glucose oversupply leads to increased triglyceride accumulation and the incorporation of glucose into triglycerides, concomitantly with a reduced insulinstimulated glucose uptake and glycogen synthesis, without alterations in fatty acid oxidation. In other words, the increased intramyocellular lipid storage did not result from decreased fatty acid oxidation but from de novo lipogenesis.…”

Section: Stimulatory Effects Of Glucose On Muscle De Novo Lipogenesismentioning

confidence: 99%

“…Glucose plays a central role in this cycle as a source of acetyl-CoA, Krebs cycle intermediates and NADPH molecules, which are required for the synthesis of FAs. It might also function as a stimulator of de novo lipogenesis, based upon the above-mentioned recent demonstrations in muscle satellite cells 47,48 that glucose, even in the absence of insulin, stimulates the gene expression of SREBP-1c as well as key genes encoding glycolytic and lipogenic enzymes, leading to an increased lipogenic flux.…”

Section: Substrate Cycling Between De Novo Lipogenesis and Lipid Oxidmentioning

confidence: 99%

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

et al. 2004

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Life is a combustion, but how the major fuel substrates that sustain human life compete and interact with each other for combustion has been at the epicenter of research into the pathogenesis of insulin resistance ever since Randle proposed a 'glucose-fatty acid cycle' in 1963. Since then, several features of a mutual interaction that is characterized by both reciprocality and dependency between glucose and lipid metabolism have been unravelled, namely:(i) the inhibitory effects of elevated concentrations of fatty acids on glucose oxidation (via inactivation of mitochondrial pyruvate dehydrogenase or via desensitization of insulin-mediated glucose transport), (ii) the inhibitory effects of elevated concentrations of glucose on fatty acid oxidation (via malonyl-CoA regulation of fatty acid entry into the mitochondria), and more recently (iii) the stimulatory effects of elevated concentrations of glucose on de novo lipogenesis, that is, synthesis of lipids from glucose (via SREBP1c regulation of glycolytic and lipogenic enzymes).This paper first revisits the physiological significance of these mutual interactions between glucose and lipids in skeletal muscle pertaining to both blood glucose and intramyocellular lipid homeostasis. It then concentrates upon emerging evidence, from calorimetric studies investigating the direct effect of leptin on thermogenesis in intact skeletal muscle, of yet another feature of the mutual interaction between glucose and lipid oxidation: that of substrate cycling between de novo lipogenesis and lipid oxidation. It is proposed that this energy-dissipating substrate cycling that links glucose and lipid metabolism to thermogenesis could function as a 'fine-tuning' mechanism that regulates intramyocellular lipid homeostasis, and hence contributes to the protection of skeletal muscle against lipotoxicity.

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“…Furthermore, there is some indication that the human muscle may constitute another possible site for DNL. 37 Today, the effect of obesity on the magnitude of DNL is not clear since it may depend upon several factors related to this Fat balance and de novo lipogenesis Y Schutz heterogenous condition such as hyperinsulinemia and insulin resistance, which may influence the expression of lipogenic markers. The medical and nutritional conditions and the metabolic disturbance occurring in the host may play a role in the magnitude of the DNL process.…”

Section: Do Obese Women Convert More Cho To Fat Than Lean Women?mentioning

confidence: 99%

Concept of fat balance in human obesity revisited with particular reference to de novo lipogenesis

Schütz

2004

Int J Obes

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The measurement of fat balance (fat input minus fat output) involves the accurate estimation of both metabolizable fat intake and total fat oxidation. This is possible mostly under laboratory conditions and not yet in free-living conditions. In the latter situation, net fat retention/mobilization can be estimated based on precise and accurate sequential body composition measurements. In case of positive balance, lipids stored in adipose tissue can originate from dietary (exogenous) lipids or from nonlipid precursors, mainly from carbohydrates (CHOs) but also from ethanol, through a process known as de novo lipogenesis (DNL). Basic equations are provided in this review to facilitate the interpretation of the different subcomponents of fat balance (endogenous vs exogenous) under different nutritional circumstances. One difficulty is methodological: total DNL is difficult to measure quantitatively in man; for example, indirect calorimetry only tracks net DNL, not total DNL. Although the numerous factors (mostly exogenous) influencing DNL have been studied, in particular the effect of CHO overfeeding, there is little information on the rate of DNL in habitual conditions of life, that is, large day-to-day fluctuations of CHO intakes, different types of CHO ingested with different glycemic indexes, alcohol combined with excess CHO intakes, etc. Three issues, which are still controversial today, will be addressed: (1) Is the increase of fat mass induced by CHO overfeeding explained by DNL only, or by decreased endogenous fat oxidation, or both? (2) Is DNL different in overweight and obese individuals as compared to their lean counterparts? (3) Does DNL occur both in the liver and in adipose tissue? Recent studies have demonstrated that acute CHO overfeeding influences adipose tissue lipogenic gene expression and that CHO may stimulate DNL in skeletal muscles, at least in vitro. The role of DNL and its importance in health and disease remain to be further clarified, in particular the putative effect of DNL on the control of energy intake and energy expenditure, as well as the occurrence of DNL in other tissues (such as in myocytes) in addition to hepatocytes and adipocytes.

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Chronic hyperglycaemia promotes lipogenesis and triacylglycerol accumulation in human skeletal muscle cells

Cited by 57 publications

References 44 publications

Benfotiamine increases glucose oxidation and downregulates NADPH oxidase 4 expression in cultured human myotubes exposed to both normal and high glucose concentrations

Benfotiamine increases glucose oxidation and downregulates NADPH oxidase 4 expression in cultured human myotubes exposed to both normal and high glucose concentrations

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

Concept of fat balance in human obesity revisited with particular reference to de novo lipogenesis

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