Dietary Energy Partition: The Central Role of Glucose

Abstract

Humans have developed effective survival mechanisms under conditions of nutrient (and energy) scarcity. Nevertheless, today, most humans face a quite different situation: excess of nutrients, especially those high in amino-nitrogen and energy (largely fat). The lack of mechanisms to prevent energy overload and the effective persistence of the mechanisms hoarding key nutrients such as amino acids has resulted in deep disorders of substrate handling. There is too often a massive untreatable accumulation of body fat in the presence of severe metabolic disorders of energy utilization and disposal, which become chronic and go much beyond the most obvious problems: diabetes, circulatory, renal and nervous disorders included loosely within the metabolic syndrome. We lack basic knowledge on diet nutrient dynamics at the tissue-cell metabolism level, and this adds to widely used medical procedures lacking sufficient scientific support, with limited or nil success. In the present longitudinal analysis of the fate of dietary nutrients, we have focused on glucose as an example of a largely unknown entity. Even most studies on hyper-energetic diets or their later consequences tend to ignore the critical role of carbohydrate (and nitrogen disposal) as (probably) the two main factors affecting the substrate partition and metabolism.

Keywords: body energy interchanges; diet; dietary protein as energy substrate; disposal of excess nitrogen; energy metabolism; energy storage; glucose; handling of dietary lipids; inter-organ energy relationships.

Figure 1

Different structures of the glucose molecule present in biological systems. From Oliva et al. 2019 [10].

Figure 2

Paths of conversion of glucose (6C) to 3C fragments.

Figure 3

Relationship between the main groups of dietary nutrients driving to the formation of 2C and 3C fragments. In red, the irreversible decarboxylative oxidation path of pyruvate (3C) to acetyl-CoA (2C).

Figure 4

The pyruvate dehydrogenase complex. Upper panel: mechanism of action of the pyruvate dehydrogenase complex, showing why the reaction catalyzed by the E1 enzyme unit is irreversible. Lower panel: kinase/phosphatase regulation of the E1 subunit. Main factors regulating its activation/inhibition.

Figure 4

The pyruvate dehydrogenase complex. Upper panel: mechanism of action of the pyruvate dehydrogenase complex, showing why the reaction catalyzed by the E1 enzyme unit is irreversible. Lower panel: kinase/phosphatase regulation of the E1 subunit. Main factors regulating its activation/inhibition.

Figure 5

Inter-organ substrate cycles (6C-3C). The first and second panels present the Cori cycle and glucose-alanine cycle [89]. The lower panel shows an “open” inter-organ relationship (6C-3C) such as that found between the adipose tissue and peripheral organs [49].

Figure 6

Summary of the final conversion of dietary protein amino acids in 1C, 2C, 3C, 4C, and 5C fragments, which revert essentially into 3C and 2C, during the human catabolism of amino acid hydrocarbon-skeletons. The pathways used to prepare this graph are the most common, including the main alternate pathways [105]. The green lines show the carbon paths for each amino acid, the brown lines represent the relationship between the core of the TCA cycle and pyruvate dehydrogenase (with the loss of one CO₂ between each substrate group box (marked in yellow). Non-standard abbreviations: Hyp = L-4-hydroxyproline; Orn = ornithine; “1C” = One-carbon fragment donor systems.

Figure 7

The nitrogen “gap: in rats. A “nitrogen gap” was found when analyzing all the components of the nitrogen balance in young rats: i.e., the N ingested, that excreted by urine and feces as well as the total N accrued, thus proving the existence of a sizeable part of the N excreted not as urea, or through the other possible ways and means shown in Box 1. Different complete (measuring both sides of the N balance equation) studies repeated these findings, dependent on diet, and with a magnitude (in rodents at least) in the range of 10–30% of all nitrogen excreted. Redrawn with data from Esteve et al. [130].

Figure 8

Hypothesis for the origin of ammonia and nitric-oxide generation of nitrogen gas in mitochondria. The coexistence in the liver mitochondrial matrix of both ammonia/ammonium and nitric oxide, within well-regulated pathways, in significant amounts, and related to the urea cycle, suggests the possibility of a reaction which may generate nitrogen gas at the expense of both. This is a speculative hypothesis, which has not been proven so far. In any case it is difficult to justify the presence of both reactants in a relatively high concentration without interacting, since the uncontrolled chemical reaction between them is spontaneous and exergonic. In this hypothesis, we include the findings of Kartal et al. [137] in their study of the mechanism of ammonia oxidation in anammox bacteria, which has an intermediate metabolite between them, hydrazine (N₂H₄). The two enzyme activities of the complex hydrazine synthase and hydrazine dehydrogenase are intimately related to membrane of the anammoxosome particle.

Figure 9

Partition-related substitution of nutrients in the diet to fuel the metabolic processes. This graph intends to explain the absence of a total/complete substitution capability between the three main groups of nutrients: Protein, carbohydrate and fat, which constitute most of our diet, at least from an energy point of view. Solid lines show the direct relationship between the groups of substrates. The large red line emanating from 2C represents the oxidation of acetyl-CoA in the TCA cycle to obtain most of the energy we use. The thinner red dash-lines indicate other main sources of cell ATP, adding up to the sum of energy available to cover our needs. Part of our food is made up of other components (minerals, organic micro-components, fiber, etc.). Their relationships with other compounds are marked with purple lines. SOBC stands for: “synthesis of other body components” from the building blocks provided by the four groups of nutrients analyzed. Their mixed paths have been marked in black. The lines in blue represent the metabolism of carbohydrates, including the part shared with amino acids and lipid. Protein-amino acid paths are marked in green. The lines in dark yellow represent the paths exclusive of lipids.

Figure 10

Simplified presentation of the main hormonal mechanisms that control the circulating concentrations of glucose. Black titles and arrows show the basic relationships between glucose and other substrates. Blue titles represent hormones and other regulating agents. Green lines indicate activation or increase effects of the regulator on the signaled path. Red lines show inhibitory or deactivation effects.