This chapter is related to Section U1(iii) from the 2017 CICM Primary Syllabus, which asks the exam candidate to "explain the control of blood glucose". Which is hilarious, because if a normal person working in the ICU were asked to explain the control of blood glucose, they would surely explain it by answering "it's controlled by the intensivist, who wants it between 5 and 10 mmol/L". Though technically accurate, that response is more in keeping with the theme of the Second Part exam revision chapter, titled "Glycaemic control among the critically ill" for obscure SEO reasons. For the First Part exam candidates, the college mainly wanted to know about the roles of endogenous insulin and glucagon, the activities of the liver as a "glucostat", and the effects of giving a bolus of 50% dextrose:
- Normal blood glucose concentration
- Normal BSL is on average 5 mmol/L during the fasting state.
- It increases to no more than 9-10 mmol/L following a meal
- There is a balance between tissue utilisation, release from stores, and production from dietary carbohydrates and gluconeogenesis
- Glucose sources in the post-absorptive state
- Release from storage:
- glycogen and fat in the liver,
- glycogen in skeletal muscle
- fat in adipose tissue
- De novo synthesis:
- Gluconeogenesis by the liver (80%) and kidney (20%)
- Glucose sensing
- Mainly by pancreatic islet β-cells and α-cells
- The molecular mechanism involves glucokinase, which has an affinity for glucose concentrations higher than 3-4 mmol/L
- Glucokinase activity leads to the production of ATP and DAG
- ATP inhibits ATP-sensitive potassium channels, depolarising the β-cell membrane and producing insulin release ( or suppressing glucagon release)
- Minor role is played by hypothalamus and midbrain, which regulate satiety and the autonomic responses to hyper and hypoglycaemia
- Response to increased blood glucose
- Glucagon release is suppressed
- Insulin release is directly stimulated (biphasic pattern)
- Insulin produces effects which promote the storage, and inhibit the release, of glucose:
- Reduced gluconeogenesis, glycogenolysis, free fatty acid oxidation and ketone production by the liver
- Increased glycogen synthesis and increased VLDL synthesis
- Increased glucose uptake by insulin-sensitive tissues which express GLUT4 glucose transport channels (skeletal muscle and adipose tissue)
- Response to decreased blood glucose:
- Insulin release is suppressed, and glucagon release is stimulated
- Glucagon stimulates glucose mobilisation:
- Hepatic glycogenolysis increases, liberating stored glucose
- Hepatic and renal gluconeogenesis is stimulated
- Glucagon inhibits the transfer of glucose into storage forms:
- Glucagon inhibits glycolysis and hepatic glycogen synthesis
- Glucagon also inhibits the synthesis of VLDLs and triglycerides, and stimulates the beta-oxidation of fatty acids in the liver, which promotes ketogenesis.
For something as fundamental as this one might expect there to be copious papers and review articles written about this topic, but no - it was actually much easier to find information about somatostatin receptors. "Glucose homeostasis" appears to be the search string with the greatest yield. Gerich (2000) is probably the most succinct overview of this material, and at under five pages will not overwhelm even the most flustered of exam candidates. Unfortunately, PubMed doesn't even have it as an abstract. Sohn & Ho (2020) would be another great recommendation, if only suitable for the paying subscribers of Pflügers Archiv. As is often the case, the financially unfortunate reader is left to choose between piracy and Wikipedia.
"State the range of normal blood glucose" is a common expectation of the college examiners, as if demonstrating this basic med-school-level memory is somehow important for the assessment of a middle-career ICU trainee. For the record, this range has an unfairly random distribution among different regulatory bodies, as if everyone looked at a slightly different combination of population studies, but not at each others' work. Here is a handful of values for normal fasting BSL from whatever various online resources appear on the first page of Google results, as an example:
So. Which of these should the confused reader write in their exam paper? It seems like the Australian trainee should probably be going with whatever the Australian Diabetes Society says is normal, because it would be perilous to go against such a powerful organisation. Unfortunately, they don't seem to have settled on a normal value range, but their position statements seem to suggest that a fasting glucose > 7.0 is abnormal, that a BSL of more than 5.0 mmol/L is safe enough to drive with, and that a BSL of 3.9 falls within the lowest 5% centile for ambulatory monitoring, which gives the exam candidate something to work with.
Is this a law of nature? Does the blood sugar level have hard physical limits that make a certain range of values mandatory to sustain multicellular life? At a risk of alienating the reader who is mainly interested in relevant information, it is probably worth noting that in the animal kingdom, at least among the vertebrates, blood glucose is correlated fairly strongly with metabolic rate. In this fashion, resting amphibian and fish BSLs are among the lowest, with the American bullfrog Rana catesbeiana operating normally at a BSL of 0.8 mmol/L. On the other range of the scale, most birds tend to enjoy being hyperglycaemic, with the domestic turkey normally having a BSL of around 11.0 mmol.L (Umminger, 1977). With increasing body size there is a subtle trend to lower BSLs , but it is not especially exciting - a fall in average BSL from 9 mmol/L to 6 mmol/L is noted over a mass range from 10g to 10,000 kg (Kjeld and Ólafsson, 2008). As always, everything is much weirder with invertebrates. For example, crabs and molluscs tend to favour an extremely low range of BSL values (1.7-3.4 mmol/L), whereas insects rock trehalose instead of glucose, and their blood trehalose level (BTL?) can range from 5 mmol/L to 50 mmol/L.
With that awkward digression behind us, we can now look at how the normal BSL is maintained in the normal human organism. This normal value, whatever you decided it was (let's say on average something like 4-5 mmol/L) is observed during the fasting state, otherwise known as the known as the post-absorptive state - the period of time during which you are not eating mainly because for a large proportion of it you are asleep. Because glucose is essential for the function of basically everything, there is a constant uptake of it from the blood by metabolically active tissues, and so it follows logically that there should also be a matching amount of glucose release from sites of storage and synthesis, which are mainly the liver and kidneys. Yes, though conventional teaching of the hepatocentric patriarchy has convinced you sheeple that the liver is the main "glucostat" organ, in fact the kidneys contribute a substantial amount of glucose to the circulation, to the point where the proximal tubule can contribute about 20% of the total glucose supply inder normal postabsorptive conditions, and up to 40-50% after prolonged fasting (Legouis, 2020, and Stumvoll et al, 1997).
As this is a fasting state, and no new carbohydrate is being consumed, basically all glucose is either being synthesised de novo from amino acids and lactate, or coming from some stored glucose source (let's call it glycogen). In case you need some sort of numbers, it appears that about 50% of the glucose supply is being produced by each mechanism (Landau et al, 1996), at least under the conventional Western definition of fasting (where you're never more than fifteen minutes away from a glazed donut). When you're really fasting, gluconeogenesis gradually overtakes glycogenolysis as the main source of circulating glucose, and Landau et al were able to demonstrate that after 42 hours of starvation about 93% of the glucose supply is dependent on gluconeogenesis. Without revisiting any more material from the chapter on the physiological adaptation to starvation it will suffice to leave the reader with a confusing diagram to describe the comings and goings of major macronutrients during a day spent in a post-absorptive state:
Anyway: the point is that at any given moment, there is some obligatory glucose consumption happening, and so there needs to be a constant mobilisation of glucose to meet that demand. In this state, no storage of nutrients is occurring. The opposite is true during the postprandial state.
Considering that it takes about 5-6 hours to completely absorb the nutrients from a meal, and expecting three meals a day for most people even in this economy, we can safely say that most of the waking day is actually spent in the postprandial state. During this time there is a next influx of glucose and other nutrients. As the glucose consumption by the organ systems can be assumed to remain relatively stable, this means the total nutrient supply exceeds demand. In this scenario the excess of nutrients is stored in various sites, pto be released later during the postabsorptive state.
A single Western meal could contain up to 100g of rapidly available carbohydrate (over 550 mmol, or same as two 1L bags of 5% dextrose), and it would clearly be unsafe to dump it all into the bloodstream right away (consider what might happen if the BSL were abruptly rise to 100 mmol/L). In actual fact the postprandial blood glucose level rarely exceeds 9 mmol/L (and anything in excess of 11.1 mmol/L is considered "impaired glucose tolerance"). The main reason for this is the massive first pass effect of the liver. A large proportion of the carbohydrate load is used to replenish the hepatic glycogen reserve (perhaps 20% of the ingested glucose, to keep a an intrahepatic stash of about 400 kcal), and the excess (a further 10-20g) is sunk into fat. The rest of the glucose does end up in the systemic circulation, where it is rapidly sucked up by insulin-sensitive tissues like adipose tissue and skeletal muscle, with a rate of uptake so rapid that the BSL never increases beyond the abovementioned modest values. At the same time, the reader is reminded that this whole process takes some 3-4 hours to complete, and during that time all the glucose-hungry tissues continue consuming glucose, which helps dispose of a few more grams. In case a flowchart is somehow easier to follow , the metabolic fate of an ingested glucose load can be depicted in this reapproximation of a diagram from Gerich (2000). The original had images of the liver, skeletal muscle brain and kidneys, which have been omitted because it is assumed the readers know what those organs look like.
From the above, it follows that the systems of glucose control need to be able to:
This is the role played by insulin, glucagon, and to a lesser extent by the catecholamines.
The first step is the detection of glucose concentration, which occurs at two main levels:
For the purposes of the CICM first part exam, it is only essential to recall that direct glucose sensing by the pancreatic β-cells and α-cells is the dominant mechanism.
To bring all of the abovementioned material together, as well as various sections of the chapters on insulin and glucagon, we can now create a point-form checklist of the endocrine response to changes in blood glucose. From the CICM examiner comments to Question 4(p.2) from the second paper of 2007 and Question 1 from the second paper of 2011, it seems they wanted the candidates to take a "sensors, integrators, effectors" structured approach. Trying to integrate this into an answer which one could write in under 10 minutes was challenging to say the least. Instead of writing everything that could possibly be written about this topic and presenting that as a preposterously long "model" answer, a short summary is created for the questions themselves, and a much longer and more elaborate version is presented here, with all the working shown.
Without further ado, the effect of giving 50% dextrose:
With a decrease in blood glucose:
As glucose concentration increases due to the activity of glucagon, glucagon secretion is decreased, and insulin secretion is increased. The two competing influences and their mutual inhibition maintain the homeostatic setpoint and regulate the balance of glucose storage and release.