Fuelling Life and Managing Surplus: Revisiting Type 2 Diabetes

Abstract

Type 2 Diabetes (T2D) is becoming an increasing global health challenge. Despite intensive efforts to understand its pathophysiology we seem still to be scratching on the surface. Starting from first principles this essay attempts to explore new ways to approach T2D. The premise is that a prolonged nutrient surplus lies at the heart of T2D. Given that homeostasis relies on steady states that require a balance between in- and efflux to maintain the milieu interieur, imbalances between energy uptake and utilisation can only be reconciled by storing unused energy. This explains the link between obesity and T2D. But putting on unlimited reserves is impractical. This is the dilemma the body faces. The natural conclusion is to reduce energy intake or increase expenditure to regain balance. The essay further explores rates of change of fluxes as the medium through which homeostatic control occurs. Steady states are maintained by resisting perturbations and in that way create corridors of control. In closing the essay advocates a pluralistic integrated approach to studying the multi-faceted phenomena that underlie T2D.

“The narrative is biology, the language is chemistry, the alphabet is physics.”

1. Introduction

The purpose of this chapter is to revisit the disease mechanisms and dynamics underlying T2D starting from first principles to come closer to an understanding of what is causing the condition and how best to approach it therapeutically. Nutrition therapy or “diet” that is limiting energy intake and being more physically active, thereby increasing energy expenditure are widely considered cornerstones in the treatment of women and men with type 2 diabetes mellitus (T2D) [1]. These interventions also delay the onset of T2D in patients with pre-diabetes [2, 3]. Why is this so? Why do they work? What can we learn from them as we make therapeutic choices as we care for women and men with T2D?

2. Fuelling life

“The alphabet is physics” – on the energetics of life itself.

To find answers to these questions it helps to remind ourselves of the energetics of life itself. Life is a self-organising energy dissipative system driven by the flow of energy and entropy [4, 5, 6]. Common to all autonomously living organisms is proton flux [7]. In photoautotrophic organisms such as plants photon energy from the sun is translated into a proton flux which is converted into chemical bond energy. Non-photosynthetic or heterotrophic organisms release bond energy via molecular rearrangement and electron transfer onto oxygen as the final electron acceptor to generate a proton gradient and flux. This then transfers the bond energy (releases Gibbs free energy) into smaller energy units such as high energy phosphate bonds of ATP in a process we call oxidative phosphorylation. This is the common fate of all substrates utilised for energy production: catabolic breakdown and liberation of Gibbs free energy as outer electrons of carbon and hydrogen atoms are “donated” to oxygen [8]. The energetics of life are firmly anchored in bond energy and quantum physics [9]. The various substrate classes carbohydrates, lipids and ketone bodies are all carriers of bond energy, and regarding them in isolation when considering energy balance in humans with T2D is probably misleading (Figure 1).

Figure 1.

Turning bond energy into ATP.

“I believe seeing biology as a thermodynamic process governed by the most fundamental laws of physics brings clarity and an understanding of life, its structures, evolution and meaning, which cannot be obtained from other perspectives.” [6]

“The language is chemistry” – chemical bonds hold the energy.

Aside from the interchangeability of the various bond-energy sources at the most fundamental level, biochemical pathways that allow the interconversion of energy rich metabolites also propose a wholistic perspective when contemplating energy balance. Of particular importance is the synthesis of fatty acids from carbohydrate precursors as well as the interplay between fatty acid flux and glucose utilisation [10]. The interdependency between carbohydrate and lipid metabolism is also given credence by ectopic lipid deposits characteristic of chronic hyperglycaemia [11].

Three substrate classes stand out with respect to energy provision in humans: the hexose or pentose sugars and their polymers, the fatty acids and their glycerol esters, and ketone bodies derived from the latter.

Glucose is the molecule that has received the most attention with respect to the syndrome we call T2D. A PubMed search for the term “type 2 diabetes mellitus and glucose” yielded more than 72,000 records whereas a query for “type 2 diabetes and fatty acids” just under 7000. (July 2023) Why does glucose receive so much more attention? One possible explanation is that historically it has been easy to detect the sweet taste of glucosuria [12]. Chemically glucose has a 6-carbon skeleton with alcohol groups attached to every aside from the terminal carbon, which carries an aldehyde group. The molecule combines non-polar C-C and C-H bonds with polar side groups. These readily form hydrogen bonds rendering glucose water soluble. The carbon backbone can fold back upon itself to form a ring structure, in which the oxygen of the aldehyde group links up with the terminal carbon at its other end. The ring persists upon polymerisation of glucose to starch, cellulose, or glycogen.

Glucose combines water solubility with energy content, reactivity, compact packaging (ring form) and an avidity for polymer formation. With this catalogue of features, it is indeed a remarkable molecule. Unsurprisingly, it is one of the most represented molecular entities in nature.

The remarkable features of glucose bring with it intriguing challenges. Glucose is osmotically active, requiring cells to store it intracellularly as a polymer: glycogen in animals or starch in plants. Glucose is not inert as a molecule and attaches itself spontaneously to proteins (why glycosylated haemoglobin can be used to monitor metabolic control) [13]. Finally, chronically elevated plasma glucose concentrations predict the complications of long-standing T2D [14, 15, 16].

Carbohydrates including glucose are not the major contributor to energy supply. Only an estimated 2% of total on-body energy reserves in humans are stored as carbohydrate. Lipids constitute the principal energy store [17]. This preponderance suggests that focussing only on glucose when contemplating energy utilisation in women and men with T2D may be inappropriate. The advantages of lipids as energy sources stem from a combination of density and metabolic efficiency. Due to their hydrophobic nature lipids are stored in a non-hydrated form. Accordingly, most of the mass of adipocytes is derived from pure triacylglycerol. Free fatty acids (FFA) carry fewer partially oxidised carbon atoms (e.g., OH functional groups) when compared to carbohydrates thus carrying more energy normalised per carbon. Glycogen, the predominant carbohydrate storage form in animal cells is hydrophilic. More than half of the mass of hydrated cellular glycogen is water that does not provide utilizable bond energy. Furthermore, glucose carbons are partially oxidised carrying oxygen bearing functional groups. In terms of the terminal pathway, the products of both FFA and glucose catabolism enter the citric-acid cycle as acetyl-CoA, from whence on they share a common fate. From an energy balance point of view carbohydrates are important but lipids perhaps more so (Figure 2).

Figure 2.

Carbohydrates above and lipids below the “iceberg” waterline.

Triacylglycerols (TAG) and their component FFA chains are not without issues. Long-chain FFA are not water soluble and must be transported attached to albumin in the blood stream, or when conjugated to TAG in lipoprotein transport vehicles. Long-chain FFA do not pass readily through the blood brain barrier and cannot be used by the brain as an energy source [18]. Unlike glucose that is amenable to glycolysis FFA cannot be metabolised anaerobically. Finally, not all tissues can utilise FFA, e.g., erythrocytes which lack mitochondria.

The limitations of long chain fatty acids are not prohibitive, as nature has found a work around in the form of ketone bodies. Acetoacetate, beta-hydroxybutyrate and acetone are small soluble molecules synthesised by partial oxidation of fatty acids in hepatic mitochondria. Production and utilisation correspond to a continuation of the catabolic lipid pathway: triacylglycerols to fatty acids to ketone bodies to acetyl-CoA [17]. In clinical practice ketone bodies signal a prolonged catabolic state or the life-threatening complication of ketoacidosis. a focus that does not give credit to their beneficial role in human energy supply, making lipid energy more accessible [19]. Beta-hydroxybutyrate that represents 70% of the blood borne ketone bodies provides an alternative source of energy for tissues when glucose concentrations are low, or tissue function is compromised [20]. In healthy subjects ketonemia is in the range of 0.1–0.4 mmol/l after an overnight fast, accompanied by a high synthesis rate and flux of 0.2–0.4 mmol/min. During a prolonged fast of 5 days ketone body flux rises to 1.5–2.5 mmol/min with concentrations reaching 7–10 mmol/l [21]. Ketone bodies exemplify again how closely carbohydrate and lipid metabolism are linked and interdependent.

Energy in human catabolism is derived to a large part from the oxidation of C∙C and C∙H bonds, which may be sourced from a variety of substrates [22]. If energy needs are met through the catabolism of one substrate, there is less demand for another. As both the oxidation of glucose and fatty acids delivers acetyl-CoA for the citric acid cycle they are competitive providers of bond energy in many tissues. Energy sourced from one, need no longer be supplied by the other. When enjoying a set menu that involves a choice of the main dish, after having selected and eaten the preferred dish one is satiated and will not wish to eat another. Once a need has been met, the demand abates. Focussing on glucose in isolation without accounting for energy sourced from FFA (or ketones) ignores the fundamentals of supply and demand (Figure 3).

Figure 3.

Competing sources of primary energy: Carbohydrates and lipids.

“The narrative is biology” – of fluxes and buffers.

Flux drives the motor of life [9]. It is the throughput of bond energy providing substrates that keeps cells running, just as the flow of petrol through a combustion engine keeps a motor running. Catabolic pathways capture free energy released from continuous biological combustion. This continuity of throughput requires that at least one step in a catabolic pathway is sufficiently removed from chemical equilibrium [23]. Let us consider a series of connected ponds as an analogy. When all ponds are at the same height the water levels in the individual ponds are the same (at equilibrium). Water moves back and forth at random between the ponds, but there is no net movement of water in any one direction. However, if the first pond in the series is elevated or the last pond is lowered there is a directed flow of water (Figure 4).

Figure 4.

Connected ponds analogy.

A directed flux as seen in catabolic pathways requires non-equilibrium states. Non equilibrium states are achieved either by a “push”- (provision of reactants or substrates) or a “pull”-mechanism (removal of reactants) so that a balance cannot set in and there is constant flow through the pathway. Modifying the pond analogy by introducing an inflow into the first and an outflow from the last pond results in a steady stream of water through the ponds. Introducing mill wheels that are turned by the directed flow of water creates a system that captures the flow energy to do work. This is very similar to how a hydroelectric power plant works and resembles the logic of a metabolic pathway (Figure 5).

Figure 5.

Modified connected ponds analogy.

The essential role of flux through metabolic pathways as emphasized by Eric Newsholme at Oxford half a century ago reflects a fundamental understanding of biology itself. An understanding that has been more recently echoed in a chapter title “Reconceptualizing the organism: From complex machine to flowing stream” from the book “Everything flows: Toward a processual philosophy of biology [23, 24]”. The dissipative nature of biological systems requires a constant flow of energy. Just as the wind, the movement of air allows boats to sail and drives wind turbines, movement of substrates through catabolic pathways fuels life [25].

In medical practice we are often looking at absolute concentrations (e.g., of glucose in the blood) rather than flux rates or throughput. This is also true when considering T2D. In doing so we may be missing important information. For similar concentrations of metabolites in the blood stream may be associated with different flux rates and thus provision of energy [26]. A steady state level is an expression of a balance between in- and outflow. It is not an expression of a specific flux rate. This may be illustrated by a bathtub. If water inflow from a tap and the outflow into the drain are in balance the level in the bathtub remains the same and a steady state is maintained. At the same time the volumes of water entering and leaving may differ considerably: the same level associated with very different flow rates (Figure 6). If energy supply to cells follows nutrient flux, focussing on steady state levels (e.g., blood glucose concentrations) may miss important relevant information with respect to the dynamics of T2D (e.g., plausibly altered fluxes in the pre-diabetic state).

Figure 6.

Different possible flux rates underlying a common steady state level.

There is a fundamental connection between flux, the milieu interieur, and homeostasis. Homeostasis serves to assure an internal environment regulated within bounds, the milieu interieur. Balanced flux rates create the steady states which constitute homeostasis [27]. The milieu interieur represents a network of steady states, each kept within boundaries by balancing as much as necessary respective in- and outflows so controlled levels can be maintained (Figure 7).

Figure 7.

Balanced flux rates create the steady states of homeostasis.

As noted with the bathtub analogy however, balanced flux rates underlying a given steady state may be very different. In- and outflow through a system may not be comparable although on the surface in terms of concentrations everything looks the same. This is a critical idea to hold onto for the further discussion.

Cells are the principal organisational unit of biology that must be supplied with sufficient energy to sustain the energy dissipative system of life [28]. Cellular energy demands are continuous and variable. Coordinative efforts are directed at enabling uninterrupted cellular fluxes of substrates under the caveat that whole body uptake of nutrients is discontinuous and that energy demands are variable. This implicates buffers that can absorb and supply substrate on demand (Figure 8). The movement in and out of buffers playing an essential role in securing adaptive flux continuity. A network of substrate depots that stockpile nutrients and subsequently release them is intuitive from a systems design perspective. Glycogen and triglyceride depots at the cellular level and the liver and adipocytes at the organ level qualify as dynamic substrate buffers.

Figure 8.

The critical role of buffers in maintaining steady states.

Human biology qualifies as a complex system of systems [29, 30]. In which component systems organise into self-regulating sub-systems. The flux of energy, the supply and provision of matter (from which structure evolves), the exchange of information within and between systems (allowing for cooperation and adaptation) etc., requires coordination. Metabolic pathways self-regulate via the concentrations of the reactants and products of the chemical reactions, the flow rates through the system, availability and activities of enzymes and the availability of co-factors [31]. These in turn are modifiable by mechanisms such as hormone signalling induced de-or phosphorylation of a rate limiting enzyme or gene expression. Information may be encoded in constellations and relationships of molecules to one another and their synchronous shifts (rates of change) rather than individual concentrations. In an adaptive self-correcting system, dynamics and rates of change carry the relevant information. Synchronicity or coordination of rates of change being the actual control medium. Homeostatic set points in biology are plausibly phenomena of counter-regulation to perturbations of the internal environment and system inertia rather than the directed attainment of a defined set point. It is the resistance to perturbation that results in convergence toward set points. Response lag times and overshoot manifest as a control interval or homeostatic corridor representing performance characteristics of a self-correcting system. In this understanding rates of change define biological regulation. What we observe when measuring plasma glucose or serum insulin are the cumulative effects of ongoing instantaneous rate adjustments. Figuratively, as we are looking at the water level in a bathtub biology is turning the taps to adjust the inflows and playing with the drains to manipulate the outflows. The water level is an expression of the net effects of these ongoing adjustments.

Multicellular organisms represent collaborative communities. With increasing organisational complexity more sophisticated mechanisms are applied to facilitate their cooperation. Signalling molecules such as hormones and the information flow they support serve this purpose. Homeostatic substrate regulation serves to assure that all the cells of the body are adequately supplied with energy rich metabolites. In this understanding the purpose of blood glucose regulation is a “means to end, and not an end in itself”. The controlled variable is the provision of nutrient to critical tissues. If this understanding is applied what is regulated are not substrate concentrations rather adequate cellular substrate fluxes. These must suffice to meet energy demands, accounting for differential substrate utilisation by diverse cell populations. The system provides a flow of energy rich metabolites that allows cells to meet their needs. Human biology follows a multi-fuel model in which a mix of substrates is on offer. Homeostatic adaptation involves adjusting the blend of circulating energy rich substrates at the flux level, which reflects itself in their circulating concentrations.

Glucose is the by far the preferred substrate of the central nervous system. The selfish brain hypothesis gives priority to the brain’s substrate needs proposing that prevention of neuroglycopenia is the objective of blood glucose homeostasis [32]. Coordinating access to systemic glucose supply between tissues that can clear large quantities of glucose from the blood stream is intuitive in the light of the threat that neuroglycopenia represents. Loss of consciousness when escaping from a predator due to increased muscle glucose uptake is unlikely to confer an evolutionary advantage. Following this line of reasoning one or more fuel gauges that monitor and inform of substrate availability in the central compartment and signal glucose surplus above the limits needed to secure brain function carries engineering elegance (Figure 9). The pancreatic islet qualifies as such a device. If structure follows function, then anatomical location can point to functional purpose. Islets of Langerhans are found in the tail of the pancreas in proximity to the aorta. Blood perfusing the pancreatic artery can be considered providing an informative sample of central aortic blood representative of that flowing through the carotids. Sensing glucose content in these samples and sharing this information through the systemic circulation provides a means to synchronize supply and demand; to coordinate between major actors in the regulation of substrate availability liver, muscle and adipose tissue. This in such a way that it assures adequate substrate availability for the brain. It informs cells of systemic substrate availability, for example, glucose available to the brain [33, 34, 35]. Plausibly, a well-fed brain is at the heart of glucose homeostasis and insulin helps to make this happen. Insulin concentrations constituting the permissive signal for glucose uptake. Rates of change in glucose availability may be the pertinent signal that is responded to directly by changing rates of glucose uptake correspondingly. The concept deserving consideration is that substrate regulation is more appropriately represented by calculus (rates of change) than by algebra (absolute concentrations). Computationally the coordination and callibration of rates of change may be more straight forward than working with concentrations. As in the former only the direction of change and proportionality suffice to engineer a tailored response [36].

Figure 9.

Insulin a figurative fuel gauge?

Cellular signalling serves the receipt, integration, and distribution of information. Intercellular communication involves attachment of a ligand to a molecular docking site on target cells resulting in a conformational change of the latter. Binding alters the spatial arrangement of atoms in the target changing its properties by exposing or hiding a catalytic site, opening or closing a channel, etc. These conformational changes alter the molecule’s behaviour modifying its catalytic activity, allowing or preventing in- or outflow of ions etc. Such effects subsequently trigger downstream events resulting in the multi-step relay of information, culminating in a terminal effector step for example, the phosphorylation of an enzyme, changing the site at which a molecule is found (translocation of GLUT 4 to the plasma membrane), or initiation of gene expression and subsequent synthesis of a peptide or protein. All regulation traces back to arrangements and associations of atoms and resulting alterations in molecular behaviour.

This is relevant when contemplating one of T2D’s hallmarks, insulin resistance. If insulin is contended to “mandate” glucose uptake, as is suggested by the concept of “insulin resistance” there must be a corresponding molecular mechanism in place. The argument deserving consideration is that insulin provides a permissive rather than mandatory signal. Metabolic flux rates are generally regulated by a “push-pull”. The “push” represented by the concentrations of reactants and the “pull” by the passing on of products to the next step in a sequence. The additive effects of push and pull driving the flux rate subject to bottlenecks such as the activities of rate limiting enzymes or availability of transporters. Similarly cellular nutrient uptake can be envisaged to respond to a push-pull logic, subject to bottlenecks [37, 38]. Research in T2D has emphasised the push side of this logic, represented by blood glucose concentrations and the ambient concentrations of insulin. An example of modifying pull given by improvements of insulin-mediated glucose uptake in muscle following exercise. The logic of fluxes proposes a “pull me - push you” analogous to the fable animal “pushmi-pullyu” in Hugh Lofting’s Doctor Dolittle. Why should cells take up glucose if their energy requirements are met and their buffers full? The construct of insulin resistance hints that glucose uptake at the cellular level is independently regulated by insulin without accounting for cellular substrate needs or storage capacity. This may represent a too narrow view.

3. Managing surplus

The increasing prevalence of obesity in many parts of the world provides indirect evidence that energy intake for many of us is above our requirements. How much energy do we really need? Resting energy expenditure (REE) which corresponds to the energy consumed when inactive equates to approximately 4.2 KJ/kg (1 Kcal/kg) per hour in humans. For a sedentary 70 kg male an intake of approximately 7000 kJ (1700 kcal) balances daily resting energy needs with expenditure [39]. The same energy is contained in 3 Big Mac Hamburgers (590 Kcal or 2468 KJ). (McDonalds) [40] For a sedentary woman of 58 kg about 5800 kJ (1400 kcal) per day suffice [39]. The energy contained in the main nutrient classes are 37 kJ/g (9 kcal/g) for fat, 3.75 kcal (16 kJ)/g for carbohydrates and 17 kJ/g (4 kcal/g) for protein [41]. Thus about 200 g of fat meet the daily requirements of a sedentary 70 kg male. A handful of peanuts (about 300 g) at 2400 kJ/g (570 kcal/g) meet these energy needs for a day [42].

In parallel to an increasing availability of nutrients in many regions the need to be physically active decreases. It is estimated that labour saving household devices alone decrease domestic energy expenditure by about 110 kcal/day [43].

Assuring an adequate energy flux is essential to maintaining life. What if energy supply exceeds demand? The dilemma facing human biology in many regions of the world today is a persistent positive energy balance. The energy content of ingested nutrients exceeds energy expenditure. A situation resembling a bathtub where inflow is greater than outflow. If maintained for long enough the bathtub will overflow (Figure 10).

Figure 10.

Persistent surplus leads to overflow.

Applied to T2D, homeostatic mechanisms strive to maintain a controlled milieu interieur by balancing influxes and effluxes to create steady states. Critical herein are holding devices. When nutrient intake consistently exceeds demand transient buffers are repurposed to provide permanent storage. Energy assimilated in the form of nutrients must either be consumed by doing work (e.g., thermoregulation, anabolic synthesis, locomotion, fuelling of host defences etc.) or stored. With a more sedentary life-style energy expenditure declines. If coupled with an unchanged or even greater intake of nutrients a surplus sets in. Energy not used must be excreted (e.g., glucosuria) or stored. In humans with T2D renal glucose loss is usually modest. Most of the excess in energy providing substrates must be stored. Adipocytes are the principal energy storing cells. Consequently, adipose tissue mass increases, as reflected in the increasing global prevalence of obesity (Figure 11) [44].

Figure 11.

Expansion of adipose tissue.

Storing excess energy for times of lack is essential for survival. However, there comes a point where the benefits of securing reserves are plausibly offset by the cost of warehousing, as illustrated by the Pickwick Syndrome. For an ambulatory species large on-body energy reserves compromise the ability to hunt and forage or escape from predators. Accordingly, from an evolutionary point of view a case can be made for putting a limit on long-term stockpiling. The evolutionary objective lying in finding a compromise, that secures reserves for times of lack, while not putting survival at risk. This reminds of the children’s story of Goldilocks and the 3 Bears, in which the moral of the story was to get it “just right”; to avoid excesses to either side of too much or not enough. Extending this line of thought, the additional functions that more recently are being attributed to adipose tissue also suggest that expanding total body fat mass limitlessly is not expected to be otherwise innocuous. Also when accounting for the heterogeneity of fat depots [28].

The focus in seeking to understand T2D often concentrates on the triumvirate pancreatic islet, liver, and muscle. In 1994 at the EASD meeting in Düsseldorf Gerald Reaven proposed that in so doing a major tissue showing GLUT4 insulin mediated glucose uptake, was being under-represented [45]. Adipocytes represent the body’s principal energy warehouse, holding about 4500 kcal/19000 kJ (men) and about 5500 kcal/23200 kJ (women) of energy per kg [46]. The total amount of stockpiled energy depending on the fat mass. Adipose tissue is the “energy buffer” of the body. This deserves to be kept in mind when reflecting upon chronic energy surplus.

Let us consider the following thought experiment. What if adipocytes behaved similarly to balloons? When a balloon is empty and there is no wall tension, no resistance is encountered when blowing air into it. As the balloon fills and its walls stretch resistance increases, and it may become impossible to blow it up further (without bursting it). The resistance of balloons to further stretching depending on their natural size, the properties of the materials used and the wall thickness. In practice we need to blow harder to fill more air into a progressively more filled balloon (Figure 12).

Figure 12.

As a balloon inflates blowing it up becomes more difficult.

If human adipocytes were to show similar properties, long-standing nutrient surplus over time would be expected to lead to increasing resistance to the uptake of further nutrients (mirroring a balloon’s resistance to further distension) [47]. In this situation the balance between FFA uptake and esterification versus hydrolysis and FFA release by adipocytes shifts. The driving force for the shift is a property of the adipocyte itself and its willingness to store additional substrate. The increase in the proportion of large abdominal adipocytes seen in patients with T2DM matches these considerations [48]. As does data linking enlarged subcutaneous abdominal adipocytes with hyperinsulinaemia, insulin resistance, glucose intolerance and an increase in in vitro lipolysis [49, 50].

To draw on a related analogy. If a parking lot is full the next car can only enter once a car leaves. Storage facilities generally show a maximal uptake capacity. In a biological system this may be a probabilistic rather than a deterministic limit. The preponderance to to take up and store further nutrients depending on a variety of variables including cross-membrane concentration gradients. Beyond the carrying capacity of adipocytes with increasing body-mass other organs also increase in size leading to a further increase in stockpiling ability. Resting energy expenditure also increases leading to a greater tolerance for energy surplus [46]. However, despite a catalogue of noteworthy adaptive mechanisms the ability to deal with a chronic excess in nutrients is likely to show limits. Limits that differ between individuals [51].

If the above thought experiment has merits, with a prolonged surplus in energy intake and a progressive unwillingness of adipocytes to take up additional energy rich substates, clearance of these substrates from the blood stream decreases. Until now we have considered adipocytes in isolation and ignored any signals concerning systemic substrate availability. Let us continue to do so. As the figurative lorries laden with supply are turned away from the warehouses, they go back on the road eventually returning to the dispatcher. In the human body this is the liver, which is confronted with an increase in returning uncleared energy rich substrate, primarily FFA. FFA are the principle aerobic energy substrate at the whole-body level at rest. This increased FFA supply does not leave glucose uptake unaffected [52]. If energy requirements remain unchanged glucose utilisation is expected to decrease [53]. Implicitly it becomes more difficult to maintain the steady state in blood glucose and blood glucose concentrations rise. Insulin concentrations which track blood glucose also rise. This constellation of increased blood glucose and insulin concentrations reminds of T2D.

Circumstantial evidence suggests that T2D may qualify as an unwillingness to warehouse high energy substrates to the extent needed to assure normoglycaemia [54]. Maintaining a steady state requires that efflux balances influx. If nutrient influx increases and energy utilisation decreases, balance can only be secured by shunting surplus into buffers. Once the storage capacity of these is reached or they otherwise throttle uptake a steady state can no longer be maintained, as clearance no longer matches inflow. Such an aetiological scenario is supported by epidemiological data demonstrating a strong correlation between T2D and adiposity. While not all obese women and men develop T2D with increasing excess body fat the proportion rises.

The natural history frequently shown by humans when moving from impaired glucose tolerance (IGT) to frank T2D is consistent with such a model. In healthy individuals ingested glucose is rapidly cleared from the blood stream and stored. In settings of IGT analogous to trying to find a parking spot in peak times, complete storage of a glucose load is delayed. Finally, in frank T2D not all ingested substrates can be removed before the next meal. This is not unlike the situation in populated metropolitan areas where the availability of parking is chronically below demands. Cars that cannot find a regular place to park either continue circling looking for an empty spot or park illegally (Figure 13). While the trivial nature of this analogy is recognised it may be illustrative of what we are facing when contending T2D.

Figure 13.

No where to park: Keep circling or park illegally.

At the heart of T2D is plausibly an attenuated tendency to expand fat cell mass in an environment of chronic nutrient surplus [55].

This thought experiment anticipates observations seen in T2D and is consistent with much of the evidence that has been published concerning insulin resistance and hyperglycaemia [56]. It also explains why decreasing energy intake and/or increasing energy expenditure are effective in managing women and men with T2D [47]. In the former the storage demands on adipocytes decrease and in the latter storage space is freed up as more energy rich substrate is being consumed.

A wealth of data has been published showing numerous alterations in patients with T2D. Many of these showing associative or correlative phenomena that seem to be coupled with chronically increased blood glucose. A putative mechanism to limit on-body storage of energy rich substrate that puts a cap on body fat depots is consistent with much of this evidence (Figure 14).

Figure 14.

A systems biology perspective on limiting substrate storage.

While the diagnostic criteria for T2D are widely agreed upon, biology may have a different perspective on the matter. The diagnostic limits are possibly historically motivated, influenced by the thresholds for glucosuria. Epidemiological evidence however suggests that the increase in risk of macrovascular complications begins at a lower threshold, in the realm of pre-diabetes [57]. Additional support also comes from interventions directed at post-prandial glucose in patients with pre-diabetes that reduced cardiovascular events [58, 59]. Observations that agree with a role of fluxes in the pathophysiology of T2D. The prediabetic state being indicative of altered substrate fluxes, leading to difficulties in maintaining the steady state.

As an aside, the current discussion intentionally does not include the gut, − islet – liver axis and the complex distributed biocomputing realised therein. The role of the gut, pancreatic islet, liver network is understood as primarily to secure efficient nutrient absorption. It lies upstream of dealing with an established chronic surplus of nutrients.

Looking now at the other end of the disease lifecycle. With increasing duration of chronic nutrient surplus, the glucoregulatory system seems to be adversely affected [55, 56, 60]. If homeostatic control is achieved through synchronicity of rates of change, then a signalling system would need to maintain a dynamic range that allows for rate changes to be monitored and relayed when the baseline shifts. Increases in serum insulin in response to chronic rises in blood glucose concentrations may not passively follow blood glucose, but rather be actively readjusted to maintain a dynamic range. Such a mechanism would allow ongoing signalling of rates of change of blood glucose concentrations despite a shift in baseline blood glucose concentrations. Beta cell failure in such an understanding represents less the inability of insulin secretion to keep up with rising blood glucose, rather blood glucose concentrations moving out of the physiological insulin response curve. Unless the glucose-insulin response curve adjusts as blood glucose rises chronically, insulin secretion will concentrate on the top of the dose response curve. The result is a compromised ability to effectively signal changes (Figure 15A). If the whole curve moves right to adjust for the change in baseline the dynamic range for insulin would be regained (Figure 15B). However, only shifting the same curve horizontally does not account for the greater spread of blood glucose concentrations seen in T2D. Which is achieved by stretching the curve (Figure 15C). These adjustments in insulin secretion kinetics moving from normal glucose tolerance to T2D are what is observed experimentally [61]. There is one more aspect to consider. To draw on the analogy of travelling in a vehicle, the faster one is travelling the more difficult it becomes to accelerate. Plausibly, the beta cell is facing the same dilemma. While it is striving to signal the dynamics in blood glucose, the adjusted high baseline insulin secretion needed to calibrate to the shifted dynamic range of blood glucose makes it difficult to secrete even more insulin. What we paraphrase with “beta cell failure” in patients with T2D may have less to do with failing of the beta cell as such than with blood glucose concentrations moving out of the physiological response range of the glucose sensor. To draw on another analogy. When using a thermometer to measure temperature, not one size fits all. An oven thermometer will measure at a different temperature interval than a freezer thermometer. Using a freezer thermometer to measure body temperature cannot give the desired read-out as the dynamic range is unsuited. This is not a failing of the thermometer.

Figure 15.

Maintaining the dynamic range of insulin signalling.

4. Conclusions

The discussion above reemphasizes the merits of restoring energy balance by reducing energy uptake or increasing energy expenditure when striving to prevent or delay progression of T2D. This is most promising in pre- or early diabetes before long-standing hyperglycaemia has taken its toll on the glucoregulatory apparatus. All the while it must be recognised that eating less and moving more is a lot easier said than done. Energy expenditure while walking equates on average to about 4.8 kJ (1.15 kcal) /kg/1600 m, running expends about 7.15 kJ (1.71 kcal) /kg/1600 m and cycling about 2.5 kJ (0.6 kcal) kg/1600 m [62]. To lose 500 g of adipose tissue by jogging alone requires running for about 16 km. For many this is neither attractive nor feasible. To include bouts of physical activity in our everyday lives such as walking a stop when taking a bus, climbing one or two flights of stairs rather than taking an elevator or escalator and parking the car a little further away from the shops is practical and in the long run adds up. Physical activity used in this way serves to reduce energy surplus and not primarily to acutely lower blood glucose concentrations. The latter has repeatedly been shown to have only modest and short-lived effects in adults with T2D [63].

If a patient is unable reduce energy input or increase energy output directly, pharmacological support should be considered. If the above reasoning is followed, agents that emulate diet and exercise have the greatest theoretical footing. In this respect, the merits of overriding a stipulated hesitancy to store additional surplus energy, as suggested by the gain in body mass during therapy with sulfonylureas and thiazolidinediones seems counterintuitive. With progressive beta cell failure blood glucose control in patients with T2D is no longer as amenable to “diet and exercise”, other therapeutic concepts must be adapted [64]. In practical terms, when endogenous insulin secretion is no longer able to replicate glucose dynamics extending the range of the insulin signal by exogenous insulin supplementation should not be unduly delayed.

Returning to the onset of our journey. Could we look at glucose and the other high-energy substrates and their interrelationships differently? Could revisiting the physiological role of insulin help us come closer to answers to the open questions we still face concerning the enigma of T2D? Could a revised understanding of the mechanisms leading to the increasing number of glucose molecules circulating in the blood stream (looking for a place to park) bring us closer to treatments that halt the progression of T2D seen in many patients. Could such a perspective bring us closer to treatments that put an end to the complications that result from persistent exposure of blood vessels to uncleared glucose moeities? Is it only glucose or not the overall balance of energy-rich substrates that deserves consideration in humans with T2D? Does glucose not only represent the tip of an iceberg of energy rich substrates, in which lipids make up much of what is under the water line? Are not fluxes and flows at the heart of metabolic control rather than concentrations? Does insulin serve to inform more than to command? Are not rates of change the medium through which homeostatic control is negotiated?

Biological organisms are system of systems, within which structure, function, energy, and information flow are intertwined and mutually interdependent [65]. To fully appreciate an organism’s dynamics these interrelated aspects deserve to be considered simultaneously. Regarding each aspect in isolation can provide valuable insights, but often provides only an approximative cut-out. As we study T2D further holding multiple lines of thought in parallel may be needed to solve the puzzles we still face. The life mission of the polymath Edward de Bono, who is most famously known for coining the term “lateral thinking”, was to develop and teach thinking techniques. Aside from lateral thinking he also advocated parallel thinking. In two popular books six thinking hats or six action shoes he emphasised the merits of regarding issues simultaneously from multiple perspectives [66, 67]. By looking at T2D from multiple complementary vantage points simultaneously such as supply chain, energy balance, information exchange, control logic, etc. insights may become apparent that remain hidden when each aspect is considered in isolation.

The purpose of this essay is to remind of the fundamentals of energy metabolism when considering T2D. This leads naturally to the merits of matching energy intake to expenditure as has been repeatedly advocated over decades. The goal is also to encourage an unorthodox look at the condition. Rather than provide ready-made answers this essay hopes to stimulate exploration down the road less travelled. By questioning generally accepted facts and revisting taken for granted premises we may come to a revised understanding of a syndrome that is increasing in prevalance globally due to a greater availability of nutrients, a more widespread sedentary lifestyle and aging populations. An understanding that will help us better tackle this insidious syndrome that threatens to become an unsurmountable public health challenge world-wide in terms of the condition itself and its long term complications.