The glucose paradox. Is glucose a substrate for liver metabolism?

Katz, Joseph; McGarry, Julie

doi:10.1172/jci111610

Cited by 265 publications

(135 citation statements)

References 60 publications

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“…Thus, under these experimental conditions hepatocytes exhibit both an abbreviated substrate cycle between glucose and glucose 6-phosphate and an extensive one involving the entire glycolytic/gluconeogenic sequence. This phenomenon is in keeping with the many studies that have demonstrated that much of the glycogen synthesized from glucose is formed indirectly via lactate or other 3-carbon derivatives [38][39][40][41].…”

Section: Discussionsupporting

confidence: 87%

Effects of fatty acid oxidation on glucose utilization by isolated hepatocytes

et al. 1993

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We have studied the inhibitory action of long-and short-chain fatty acids on hepatic glucose utilization in hepatocytes isolated from fasted rats. The rates of hepatic glucose phosphorylation and glycolysis were determined from the tritiated products of [2-'H] and [6-3H]glucose metabolism, respectively. The difference between these was taken as an estimate of the 'cycling' between glucose and glucose-6-phosphate. In the presence of 40 mM glucose this cycling was estimated at 0.68 pmol/min/g wet wt. Glucose phosphorylation was unaffected during palmitate and hexanoate oxidation to ketone bodies but glycolysis was inhibited. The rate of glucose cycling was increased during this phase to 1.25 pmol/min/g. Following the complete metabolism of the fatty acids, glycolysis was reinstated and cycling rates returned to control levels. Hepatic glucose cycling appears to be an important component of the glucose/fatty acid cycle.

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Section: Discussionsupporting

confidence: 87%

Effects of fatty acid oxidation on glucose utilization by isolated hepatocytes

et al. 1993

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“…Weight did not change and participants were instructed to maintain their habitual diet and exercise regimens during the study, suggesting that the increase in EGP seen in the placebo group represents the natural disease progression. In addition, increased fasting glucose clearance with colesevelam treatment could reflect direct uptake of glucose by the liver for storage in glycogen (the direct pathway [38,39]), which in turn could account for the apparent stabilisation of hepatic glycogenolysis. The significance of this stabilising effect of colesevelam on EGP and glycogenolysis must be interpreted with caution because the treatment effect did not reach statistical significance.…”

Section: Discussionmentioning

confidence: 99%

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

et al. 2011

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Aims/hypothesis The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis). Methods Participants with type 2 diabetes (HbA 1c 6.7-10.0% [50-86 mmol/mol], fasting glucose <16.7 mmol/l, fasting triacylglycerols <3.9 mmol/l and LDL-cholesterol >1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n=30) or placebo (n=30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment. Colesevelam increased cholesterol and bile acid synthesis and decreased FGF-19 concentrations. However, no effect was seen on fractional hepatic de novo lipogenesis. Conclusions/interpretation Colesevelam, a non-absorbed bile acid sequestrant, increased circulating incretins and improved tissue glucose metabolism in both the fasting and postprandial states in a manner different from other approved oral agents.Trial registration: ClinicalTrials.gov NCT00596427 Funding: The study was funded by Daiichi Sankyo.

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“…40%o of body mass in man and is the major site at which exogenous glucose is taken up (reviewed by Katz & McGarry, 1984). Initial studies suggested that lipid fuels do not inhibit glucose utilization in incubated or perfused muscle (Beatty & Bocek, 1971;Jefferson et al, 1972;Goodman et al, 1974;Reimer et al, 1975;Berger et al, 1976), with the possible exception of diaphragm (reviewed by Ruderman et al, 1969), but that they inhibit glucose oxidation at the pyruvate dehydrogenase step (Berger et al, 1976;Hagg et al, 1976).…”

Section: Introductionmentioning

confidence: 99%

Effects of starvation and exercise on concentrations of citrate, hexose phosphates and glycogen in skeletal muscle and heart. Evidence for selective operation of the glucose-fatty acid cycle

Zorzano¹,

Balon²,

Brady³

et al. 1985

Biochemical Journal

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1. Concentrations of citrate, hexose phosphates and glycogen were measured in skeletal muscle and heart under conditions in which plasma non-esterified fatty acids and ketone bodies were physiologically increased. The aim was to determine under what conditions the glucose-fatty acid cycle might be operative in skeletal muscle in vivo. 2. In keeping with the findings of others, starvation increased the concentrations of glycogen, citrate and the fructose 6-phosphate/fructose 1,6-bisphosphate ratio in heart, indicating that the cycle was operative. In contrast, it decreased glycogen and had no effect on the concentration of citrate or the fructose 6-phosphate/fructose 1,6-bisphosphate ratio in the soleus, a slow-twitch red muscle in which the glucose-fatty acid cycle has been demonstrated in vitro. 3. In fed rats, exercise of moderate intensity caused glycogen depletion in the soleus and red portion of gastrocnemius muscle, but not in heart. In starved rats the same exercise had no effect on the already diminished glycogen contents in skeletal muscle, but it decreased cardiac glycogen by 2530% . 4. After exercise, citrate and the fructose 6-phosphate/fructose 1,6-bisphosphate ratio were increased in the soleus of the starved rat. Significant changes were not observed in fed rats. 5. The data suggest that in the resting state the glucose-fatty acid cycle operates in the heart, but not in the soleus muscle, of a starved rat. In contrast, the metabolite profile in the soleus was consistent with activation of the glucose-fatty acid cycle in the starved rat during the recovery period after exercise. Whether the cycle operates during exercise itself is unclear.

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The glucose paradox. Is glucose a substrate for liver metabolism?

Cited by 265 publications

References 60 publications

Effects of fatty acid oxidation on glucose utilization by isolated hepatocytes

Effects of fatty acid oxidation on glucose utilization by isolated hepatocytes

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

Effects of starvation and exercise on concentrations of citrate, hexose phosphates and glycogen in skeletal muscle and heart. Evidence for selective operation of the glucose-fatty acid cycle

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