Sunday, July 23, 2017

New Paper on Glucose Dose and Suppression of Endogenous Glucose Production

Our research group recently published a paper in Diabetes titled ‘The Effect of Ingested Glucose Dose on the Suppression of Endogenous Glucose Production in Humans’.  The paper has been uploaded as an electronic form and will be properly published in an issue in a few weeks.  The paper requires a subscription to read so I’ll summarise it below:

The aim of the study was to get a better understanding of the regulation of endogenous glucose production (EGP) under physiological conditions, as most of the research on EGP has come from studies using the euglycemic-hyperinsulinemic clamp (a method that involves infusing glucose and insulin to maintain normal glucose levels and high insulin levels over time)

We used the dual tracer technique to accurately measure EGP before and after different glucose doses (25g, 50g, 75g) in healthy young males.  The dual tracer involves two stable (non-radioactive) labelled glucose tracers* – one that is included in the glucose drink, and the other is infused at a variable rate** to mimic the fall in endogenous glucose.  The dual tracer technique can also estimate the rate of glucose entering the bloodstream from the drink (Ra) and the rate of glucose exiting the bloodstream into tissues (Rd)***

The main findings are:

  • Consistent with previous research, different glucose doses produced a dose dependent insulin response but near identical glucose responses****
  • The 25g, 50g and 75g glucose doses all resulted in a near identical suppression of EGP*****
  • Whereas Ra and Rd were dose dependent, such that higher glucose doses results in a greater rate of glucose absorption and glucose disposal 

In the discussion we mention:

  • These results indicate that the suppression of EGP is likely the first line of defence (so to speak) to deal with oral glucose loads, which makes sense as inhibiting EGP is faster and requires less insulin than stimulating significant glucose disposal in muscle.  Minimising insulin secretion may also be the reason why we have a glucose response at all to low glucose doses (as healthy people clearly have the capacity to have almost no glucose response if their bodies were wired up to do that)
  • The fact that larger glucose doses result in greater insulin responses but near identical glucose responses means that something else besides the in blood glucose must be responsible for the difference in the insulin response, probably incretins 

So what are the practical implications of this paper?  This paper is mainly aiming to address textbook physiology type questions so, like many scientific papers, isn’t very actionable on an individual level.  Although it should go towards easing some of the anxiety of those who think that getting a glucose response from a banana or potato (~25g carbs) means that they are 'metabolically broken’, as this is normal and doesn’t necessarily mean that double or triple the carbohydrate intake will double or triple their glucose response.

* These are 1 and 2 atomic mass units heavier than regular glucose and this difference can be detected using gas chromatography-mass spectrometry (GC-MS)

** This avoids potential issues in calculating EGP such as paradoxical increases in EGP shortly after a glucose load and negative EGP during the euglycemic-hyperinsulinemic clamp.  There is a slightly amusing example of this in the following paper, where they find that one group of mice has negative EGP during the clamp, while the other group of mice has ‘impaired’ EGP because theirs is only ~0

*** Although this is more accurately done using the triple tracer technique, which involves infusing a second tracer at a variable rate to mimic the Ra

**** Previous studies have consistently found that different glucose loads (33g vs. 66g vs. 100g, 50g vs. 100g, etc*) produce a dose dependent insulin response but near identical glucose responses in healthy people.  In contrast, people with borderline or overt impaired glucose tolerance (2h glucose ≥ 7.8 mmol/l) have greater glucose responses from larger doses of glucose.  This begs the question, how is it that in healthy people, larger glucose doses don’t produce a greater glucose response?

***** EGP was suppressed by ~55% unlike the near complete suppression that is common from when using the euglycemic-hyperinsulinemic clamp.  This is because under physiological conditions insulin inhibits glycogenolysis but not gluconeogenesis, whereas the prolonged supraphysiological hyperinsulinemia from the clamp is necessary to persistently inhibit gluconeogenesis

1 comment:

  1. Hi Steven,

    Thanks for summarizing your study, I'll read it once it's out.

    Gabor Erdosi (of the Lower Insulin FB group) and I did a podcast discussing the apportioning of endogenous vs exogenous glucose to glycemic responses (Ep8 called "starch digestibility and limitations of the glycemic response" A summary of our views are available in the show notes on the podcast page.

    We looked at 2 studies, the first from 2012 was "Slowly and rapidly digestible starchy foods can elicit a similar glycemic response because of differential tissue glucose uptake in healthy men” ( and the second from 2015, most pertinent to your study, was "Plasma glucose kinetics and response of insulin and GIP following a cereal breakfast in female subjects: effect of starch digestibility” (

    I'm interested in your comment regarding our conclusions from these 2 studies. They were looking at different forms of starch refined in different ways (and to different degrees) rather than straight glucose.

    My understanding is that the degree of starch processing, probably acting through incretins, causes *disproportionate* insulin responses to a given glucose load. This seems in contradiction with your statement here saying "[...] different glucose doses produced a dose dependent insulin response but near identical glucose responses".

    Love to hear your thoughts on this :)

    Congrats on getting the paper published