Time course of hepatic gluconeogenesis during hindlimb suspension unloading

Abstract

New Findings What is the central question of this study?The rate of liver gluconeogenesis during hindlimb suspension unloading has not been determined. What is the main finding and its importance?Hepatic gluconeogenesis is significantly increased under conditions of hindlimb suspension unloading, which simulates the muscular atrophy occurring during spaceflight. This finding supports earlier hypothesis. This metabolic shift in the living animal warrants further study. The goal of this work was to determine the time‐dependent changes in fractional hepatic gluconeogenesis (GNG) during conditions of hindlimb suspension unloading (HSU), a ‘ground‐based’ method for inducing muscular atrophy to simulate space flight. We hypothesized that GNG would increase in HSU conditions as a result of metabolic shifts in the liver and skeletal muscle. A significant and progressive atrophy was observed in the soleus (30, 47 and 55%) and gastrocnemius muscles (0, 15 and 17%) after 3, 7 and 14 days of HSU, respectively. Fractional hepatic GNG was determined following the incorporation of deuterium from deuterated water (2H2O) into C–H bonds of newly synthesized glucose after an 8 h fast. Enrichment of plasma glucose with 2H was measured using the classic method of Landau et al. (the ‘hexamethylenetetramine (HMT) method’), based on specific 2H labelling of glucose carbons, and the novel method of Chacko et al. (‘average method’), based on the assumption of equal 2H enrichment on all glucose carbons (except C2). After 3 days of HSU, fractional GNG was significantly elevated in the HSU group, as determined by either method (∼13%, P < 0.05). After 7 and 14 days of HSU, gluconeogenesis was not significantly different. Both analytical methods yielded similar time‐dependent trends in gluconeogenic rates, but GNG values determined using the average method were consistently lower (∼30%) than those found by the HMT method. To compare and validate the average method against the HMT method further, we starved animals for 13 h to allow for hepatic GNG to contribute 100% to endogenous glucose production. The HMT method yielded 100% GNG, while the average method yielded GNG of ∼70%. As both methods used the same values of precursor enrichment, we postulated that the underestimation of gluconeogenic rate was as a result of differences in the measurements of product enrichment (2H labelling of plasma glucose). This could be explained by the following factors: (i) loss of deuterium via exchange between acetate and glucose; (ii) interference caused by fragment m/z 169, representing multiple isobaric species; and (iii) interference from other sugars at m/z 169. In conclusion, HSU caused a time‐dependent increase in hepatic gluconeogenesis, irrespective of the analytical methods used.

Morphology and Molecular Mechanisms of Hepatic Injury in Rats under Simulated Weightlessness and the Protective Effects of Resistance Training

“…This model has demonstrated that long-term weightlessness can cause systemic organ damages, such as bone loss, bone fracture, muscle loss and atrophy, cardiovascular disorders, and renal dysfunction [ 8 – 13 ]. Simulated weightlessness can decrease hepatic glycogen and increase hepatic gluconeogenesis [ 14 , 15 ]. Space flight can cause significant effects on liver glycogen, lipids, and enzymes in rats [ 16 ].…”

Intestinal microbiota contributes to altered glucose metabolism in simulated microgravity mouse model

“…The liver is one of the major metabolic organs in the control of systemic glucose homeostasis (47). Hepatic gluconeogenesis, as measured by transcription of key enzymes or incorporation of deuterated water into C-H bonds of newly synthesized glucose, was elevated in HU rats as early as 3 d after the initiation of HU (10,11). We also found up-regulated transcription of phosphoenolpyruvate carboxykinase 1, a key enzyme in gluconeogenesis, in the liver of HU mice (Fig.…”

“…Altered glucose and lipid metabolism have been observed in humans and rodents during short-or long-term spaceflights (1)(2)(3)(4)(5). Glucose intolerance and insulin resistance are also identified in ground-based microgravity analogs, such as head-down bed rest and dry immersion in human volunteers and hind limb unloading (HU) in rodents (2,3,(6)(7)(8)(9)(10)(11)(12). Although the clinical significance remains to be fully determined, these metabolic changes may contribute to muscular atrophy, bone loss, and cardiovascular disorders under simulated or real microgravity (3,13).…”

The Law of International Organizations and the Art of Reconciliation

“…67 It is noteworthy that, although such calls are heard at regular intervals in European scholarship, European scholars have balked at effectively putting forward new frameworks or paradigms meant to revolutionize the way we look at international organizations. 68 In that sense, such calls have remained rather 'romantic'.…”