Regulation of hepatic glucose production and the role of gluconeogenesis in humans: is the rate of gluconeogenesis constant?

Nuttall, Frank Q.; Ngo, Angela; Gannon, Mary C.

doi:10.1002/dmrr.863

Cited by 126 publications

(146 citation statements)

References 133 publications

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“…In contrast, gluconeogenesis and its precursors (glycerol versus lactate/amino acids) was stable across 48 h of fasting, similar to other studies in fasting humans (as reviewed in Ref. 42 ). However, this fi nding differs from the expected transcriptional upregulation of genes, such as PEPCK by fasting ( 43 ).…”

Section: Discussionsupporting

confidence: 88%

“…Some individuals (women = 6, men = 5) were re-fed a low-fat meal (60% carbohydrate, 25% fat, and 15% protein; women = 567 and men = 667 kcal), and insulin and glucose excursion were assessed. In the 4 h after refeeding, peak insulin was signifi cantly higher in women (46 [37][38][39][40][41][42][43][44][45][46][47] vs. 20 [15][16][17][18][19][20][21][22][23][24][25] U/ml; P = 0.011), whereas peak glucose concentration did not differ between sexes ( P = 0.233). These fi ndings indicated reduced insulin sensitivity in women after short-term fasting.…”

Section: Insulin and Glucose Excursion After Refeedingmentioning

confidence: 99%

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The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men

Browning

Baxter

Satapati

et al. 2012

Journal of Lipid Research

116

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The primary substrates for energy metabolism in humans are glucose and fatty acids (FAs), with the relative importance of each dependent upon food availability (fed ↔ fasting ↔ starvation) ( 1, 2 ). In the fed state, insulin is elevated, glucose utilization predominates, and there is net fl ow of free FA from liver to adipose tissue. In the transition from fed to fasting, insulin falls, leading to increased release of free FAs from adipose tissue that are used by lean tissues (e.g., muscle and liver) for energy production or stored as triglyceride (TG). The rate of lipolytic release during fasting and starvation exceeds whole-body energy requirements in a sexually dimorphic manner, with women and men having release rates ‫ف‬ 64% and ‫ف‬ 50% greater than oxidation rates, respectively ( 3 ). This may result in sexually dimorphic lipid and glucose metabolism in muscle and liver.A signifi cant portion of whole-body FAs are reesterifi ed to TG in skeletal muscle and liver. In skeletal muscle this TG appears to function as a local energy source ( 4 ), whereas in liver most reesterifi ed FAs are exported as verylow-density lipoprotein-bound TG ( 5 ). Surprisingly little is known about the magnitude of lipid redistribution to liver and muscle during fasting or its metabolic consequences in humans. In liver, mouse models suggest that as much as a 14-fold increase in TG content during starvation may be normal ( 6 ). Such a degree of hepatic steatosis in humans has only been reported in pathological states such as obesity and insulin resistance, called nonalcoholic fatty liver disease ( 7 ). Intramyocellular TGs increase during fasting and starvation in women ( 8 ) and in endurance-trained male athletes ( 9, 10 ), but sexual dimorphism in this response has not been investigated. Moreover, the redistribution Abstract Fasting promotes triglyceride (TG) accumulation in lean tissues of some animals, but the effect in humans is unknown. Additionally, fasting lipolysis is sexually dimorphic in humans, suggesting that lean tissue TG accumulation and metabolism may differ between women and men. This study investigated lean tissue TG content and metabolism in women and men during extended fasting. Liver and muscle TG content were measured by magnetic resonance spectroscopy during a 48-h fast in healthy men and women. Whole-body and hepatic carbohydrate, lipid, and energy metabolism were also evaluated using biochemical, calorimetric, and stable isotope tracer techniques. As expected, postabsorptive plasma fatty acids (FAs) were higher in women than in men but increased more rapidly in men with the onset of early starvation. Concurrently, sexual dimorphism was apparent in lean tissue TG accumulation during the fast, occurring in livers of men but in muscles of women. Despite differences in lean tissue TG distribution, men and women had identical fasting responses in whole-body and hepatic glucose and oxidative metabolism. In conclusion, TG accumulated in livers of men but in muscles of women during extended fasting. This sexual dimo...

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Section: Discussionsupporting

confidence: 88%

Section: Insulin and Glucose Excursion After Refeedingmentioning

confidence: 99%

The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men

Browning

Baxter

Satapati

et al. 2012

Journal of Lipid Research

116

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“…The glucagon rise is more persistent. In addition, our review of the literature indicated that the gluconeogenic rate is relatively constant under most circumstances (12).…”

Section: Dietary Protein Effect On Plasma Insulin and Glucagonmentioning

confidence: 89%

“…As we have pointed out previously, the role of glucagon in regulation of the glucose concentration is uncertain and appears to play only a minor role, with the exception of emergencies when additional glucose production is needed (12).…”

Section: Our Laboratory's Interest In Amino Acids In People With Typementioning

confidence: 90%

Amino acid ingestion and glucose metabolism—A review

2010

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SummaryInterest in the effect of proteins or amino acids on glucose metabolism dates back at least a century, largely because it was demonstrated that the amino acids from ingested protein could be converted into glucose. Indeed, these observations influenced the dietary information provided to people with diabetes. Subsequently it was shown that ingested protein did not raise the blood glucose concentration. It also was shown that proteins could stimulate a rise in insulin and glucagon but the response to various proteins was different. In addition, it was shown that individual amino acids also could stimulate a rise in insulin and in glucagon concentrations. When individual amino acids are ingested by normal subjects, there is an ordering of the insulin and glucagon responses. However, the order is not the same for insulin and glucagon. In addition, the metabolic response cannot be predicted based on the functional groups of the amino acids. Thus, empirical prediction of the metabolic response to ingested single amino acids is not possible. IUBMBIUBMB Life, 62(9): [660][661][662][663][664][665][666][667][668] 2010

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“…Hepatic gluconeogenesis is regulated within a narrow range by a number of hormonal signals translated into intracellular molecular signals (15). Among these, PGC-1a and AMPK are critical regulators of gluconeogenesis.…”

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confidence: 99%

Dietary Iron, Circadian Clock, and Hepatic Gluconeogenesis

Kalhan

Ghosh

2015

Diabetes

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Circadian rhythms in energy metabolism and behavior have been examined at the molecular level with the identification of key clock genes that synchronize the endogenous rhythms in metabolism to external cues (zeitgebers), primarily day-night cycle and activity. These rhythms are temporally orchestrated and rigorously regulated by the central oscillators located in the suprachiasmatic nuclei and are synchronized with peripheral cell autonomous clocks resident in individual tissues that regulate specific functions. Among the peripheral organs, the hepatic clock is also entrained by nutrients; major metabolic processes in the liver have been found to be under circadian control (1). Disruption of the hepatic clock by change in behavior or specific nutrients could lead to metabolic disorders, such as obesity and type 2 diabetes, by affecting specific metabolic functions (2,3).In the current issue of Diabetes, Simcox et al. (4) have examined the impact of dietary iron on hepatic circadian rhythms of glucose production in mice and in isolated hepatoma cells. By administering different amounts of iron in the diet, they achieved hepatic iron levels within the range observed in healthy humans under usual variations in dietary iron and without iron toxicity. In a series of elegant studies, they show that higher iron intake, and consequently higher hepatic iron, was associated with the change in the circadian rhythm of glucose and gluconeogenesis mediated by the repression of key gluconeogenic enzymes, PEPCK and glucose-6-phosphatase (G6Pase). The effects of iron were mediated by increased oxidative stress, resulting in increased peroxisome proliferatoractivated receptor g coactivator 1a (PGC-1a) transcripts and protein levels; induction of aminolevulinic acid synthase 1 (ALAS1), the first enzyme for heme synthesis; and an increase in total heme and heme B in the liver. The mechanism of the repressive effect of iron was shown to be the requirement of heme for nuclear receptor subfamily 1 group d member 1 (Rev-Erba) to bind nuclear receptor corepressor 1 (NCOR) to form a repressor complex without any change in its protein levels, instead of increasing hepatic heme by administering aminolevulinic acid, thus bypassing ALAS1 or by feeding heme repressed gluconeogenesis.The study by Simcox et al. (4) underscores an important feature of chronobiology. The change in dietary iron did not perturb the periodicity of the chronome and it only impacted the amplitude of expression. The periodicity of expression of transferrin receptor, ferritin, PGC-1a, ALAS1, PEPCK, or G6Pase did not change and peaked at zeitgeber time (ZT) 10 and is likely related to activity and food intake. The sequence of peak expression of ALAS1 at ZT10, followed by heme concentration at ZT12 and of heme oxygenase 1 (HO1) at ;ZT18 ensures the tight regulation of cellular concentration of heme. High dietary iron was associated with higher peak expression of PGC-1a, ALAS1, HO1, and the total heme in the liver. The antioxidants (SOD1 and catalase) peaked at ZT6. These...

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Regulation of hepatic glucose production and the role of gluconeogenesis in humans: is the rate of gluconeogenesis constant?

Cited by 126 publications

References 133 publications

The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men

The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men

Amino acid ingestion and glucose metabolism—A review

Dietary Iron, Circadian Clock, and Hepatic Gluconeogenesis

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