Sunday, 17 January 2016

Being Human 2 - Is the newly discovered human variability in postprandial (postmeal) glycemic response genetically based and is it therefore similar to the genetically based Lactose Persistence found in Europeans?


I think we are all aware that when we eat, our body breaks down carbohydrates to glucose and therefore our blood sugar (glucose) level rises after eating. A really interesting paper about this came out in Cell in November (1). The paper is open access and can be found here. Here’s the summary:
 
“Elevated postprandial blood glucose levels constitute a global epidemic and a major risk factor for prediabetes and type II diabetes, but existing dietary methods for controlling them have limited efficacy. Here, we continuously monitored week-long glucose levels in an 800-person cohort, measured responses to 46,898 meals, and found high variability in the response to identical meals, suggesting that universal dietary recommendations may have limited utility. We devised a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota measured in this cohort and showed that it accurately predicts personalized postprandial glycemic response to real-life meals. We validated these predictions in an independent 100-person cohort. Finally, a blinded randomized controlled dietary intervention based on this algorithm resulted in significantly lower postprandial responses and consistent alterations to gut microbiota configuration. Together, our results suggest that personalized diets may successfully modify elevated postprandial blood glucose and its metabolic consequences.”
 
Image credit: Zeevi et. al. 2015 (1).
 
Not very interesting or informative is it? Nothing to interest those of us wading through the tsunami of data in the scientific literature and searching for meaning about the state of being human?
 
Well, I wouldn’t have hunted the paper down at all if it wasn’t for an interview I heard with Eran Elinav (one of the authors), on BBC Radio 4 (- I live in the UK), waxing lyrical about the HUGE variability the team had found in Postprandial Glycemic Response (PPGR) in humans. In particular he mentioned that humans had an unexpectedly massive range in rise of blood glucose concentration in response to standardised meals but ALSO to a range of foods including beer, ice cream, dark chocolate, bread and even sushi!
Basically he was saying that, when all outside factors are controlled for there was STILL an absolutely unexplainable difference in response to the same foods.
 
In their introduction the authors outline the problems that high postprandial glucose response (PPGR) can cause and the methods previously used to estimate it:
 
“Blood glucose levels are rapidly increasing in the population, as evident by the sharp incline in the prevalence of prediabetes and impaired glucose tolerance.. Prediabetes, characterized by chronically impaired blood glucose responses, is a significant risk factor for type II diabetes mellitus (TIIDM).. It is also linked to other manifestations, collectively termed the metabolic syndrome, including obesity, hypertension, non-alcoholic fatty liver disease, hypertriglyceridemia, and cardiovascular disease. Thus, maintaining normal blood glucose levels is considered critical for preventing and controlling the metabolic syndrome.
Dietary intake is a central determinant of blood glucose levels, and thus, in order to achieve normal glucose levels it is imperative to make food choices that induce normal postprandial (postmeal) glycemic responses. Postprandial hyperglycemia is an independent risk factor for the development of TIIDM, cardiovascular disease, and liver cirrhosis and is associated with obesity, and enhanced all-cause mortality in both TIIDM and cancer.
Despite their importance, no method exists for predicting PPGRs to food. The current practice is to use the meal carbohydrate content even though it is a poor predictor of the PPGR. Other methods aimed at estimating PPGRs are the glycemic index, which quantifies PPGR to consumption of a single tested food type, and the derived glycemic load. It thus has limited applicability in assessing the PPGR to real-life meals consisting of arbitrary food combinations and varying quantities, consumed at different times of the day and at different proximity to physical activity and other meals.”
 
Frankly I found this absolutely ASTOUNDING! Basically doctors have NO adequate tools for adequately assessing an individual patient’s response to food in the REAL world! It would seem, to me, that we have at present, little hope in dealing with this worldwide problem!
 
The current paper attempts to address these linked problems.
 
Here is how they collected their data:
 
“Each participant was connected to a continuous glucose monitor (CGM), which measures interstitial fluid glucose every 5 min for 7 full days (the ‘‘connection week’’), using subcutaneous sensors (Figure 1D). CGMs estimate blood glucose levels with high accuracy and previous studies found no significant differences between PPGRs extracted from CGMs and those obtained from either venous or capillary blood. We used blinded CGMs and thus participants were unaware of their CGM levels during the connection week. Together, we recorded over 1.5 million glucose measurements from 5,435 days. While connected to the CGM, participants were instructed to log their activities in real-time, including food intake, exercise and sleep, using a smartphone-adjusted website.”
 
Image credit: Zeevi et. al. 2015 (1).
 
Here is some of the detail on what they found:
 
“As expected, the PDP of carbohydrates (Figure 4A) shows that as the meal carbohydrate content increases, our algorithm predicts, on average, a higher PPGR. We term this relation, of higher predicted PPGR with increasing feature value, as non-beneficial (with respect to prediction), and the opposite relation, of lower predicted
PPGR with increasing feature value, as beneficial (also with respect to prediction; see PDP legend in Figure 4). However, since PDPs display the overall contribution of each feature across the entire cohort, we asked whether the relationship between carbohydrate amount and PPGRs varies across people. To this end, for each participant we computed the slope of the linear regression between the PPGR and carbohydrate amount of all his/her meals. As expected, this slope was positive for nearly all (95.1%) participants, reflective of higher PPGRs in meals richer in carbohydrates. However, the magnitude of this slope varies greatly across the cohort, with the PPGR of some people correlating well with the carbohydrate content (i.e., carbohydrates ‘‘sensitive’’) and that of others exhibiting equally high PPGRs but little relationship to the amount of carbohydrates (carbohydrate ‘‘insensitive’’; Figure 4B). This result suggests that carbohydrate sensitivity is also person specific.”
 
“The large interpersonal differences in PPGRs are also evident in that the type of meal that induced the highest PPGR differs across participants and that different participants might have opposite PPGRs to pairs of different standardized meals (Figures 2D and 2E).”
Here are some of their graphs:
 

 
 
Image credits: Zeevi et. al. 2015 (1).
 
Lastly the authors state that the gut Microbiome data (the microbe faunal composition of an individual’s digestive system) could be correlated with an individual’s PPGR. Essentially some gut bacteria are associated with risk factors for high PPGR. Proteobacteria and Enterobacteriaceae both exhibit positive associations with a few of the standardized meals PPGR (Figure 2H). These taxa have reported associations with poor glycemic control, and with components of the metabolic syndrome including obesity, insulin resistance, and impaired lipid profile. RAs of Actinobacteria are positively associated with the PPGR to both glucose and bread, which is intriguing since high levels of this phylum were reported to associate with a high-fat, low-fiber diet.
 
A good table showing the glycemic index for some foods is shown in the supplemental Information:
 
 Image credits: Zeevi et. al. 2015 (1).
 
Of particular note are all the carbohydrate containing foods from bread onwards. Bread, Greek pastries, wholemeal bread, rolls, and wholemeal rolls are all derived from wheat. Human exposure to processed wheat and its associated gluten is extremely recent and dating to the advent cereal growing in the Middle East ca. 10000 years ago. Other foods on this list include Potatoes, Rice and Cereal (in this case Cornflakes containing entirely maize flour). All these plants are also those which have entered human diets over same time-span.
 
Interestingly Persimmons from south china are also high in carbohydrates and soluble dietary fibre known as FODMAPs which have been implicated causing digestive issues (2).
 
Some speculations
I find it quite startling and also very suggestive that this variability in human response to carbohydrate is SO varied.
 
Many of the foods causing the greatest PPGR are foods that have entered human diets during an extremely recent evolutionary interval. Indeed the great proportion of evolutionary changes that have happened to make us humans (the HARs of our genome, see here) date to just after our ancestors split from chimpanzees.
 
Thus my question is are all humans as equally adapted to eating these grains/sources of carbohydrates and their processed derivatives? Indeed the authors note genetic factors as a likely source of PPGR in humans, in their introduction.
 
Therefore I find it extremely plausible that it is possible that some humans carry an allele regulating PPGR similar to that responsible for Lactose Persistence in Europeans.
 
 
References
1. Zeevi, D. et. al. 2015. Personalized Nutrition by Prediction of Glycemic Responses. Cell 163, 1079–1094, (November 19).
 
2. Kris Gunnars at Authority Nutrition. Retrieved from http://authoritynutrition.com/foods/persimmons/
 

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