Diabetes: The Sweetener Paradox

22. December 2014

There are strong hints that helping oneself to sweetener in high doses increases the risk of developing glucose intolerance. Scientists at the Weizman Institute of Science in Israel have found valid reasons for this association, something which at first glance appears very contradictory.

Sweeteners are superior to ordinary sugar in many ways: they impart a stronger sweetness, have a very low physiological calorific value and they cannot be metabolised by caries-causing bacteria. Therefore these sweet “miracle substances” are among those around the world most commonly added to foods.
Yet time and again the synthetically produced sweeteners end up the subject of criticism. Studies have already indicated that sweeteners increase appetite and thus may be leading to obesity. In addition, an increased risk of bladder cancer and vascular disease has already been discussed in relation to sweeteners.

Paradoxical link

Scientists at the Weizman Institute of Science in Rehovot, Israel, have now found evidence that sweeteners may even induce glucose intolerance. This sounds paradoxical, since a low-sugar diet actually should have many advantages, especially with respect to glucose tolerance. Obviously though the gastrointestinal microbiota also plays an important role in the development of glucose intolerance. And consumption of sweeteners apparently has substantial effects on the gut microbiota’s composition.

Sweeteners given to various mice results in glucose intolerance

The scientists first subjected healthy, lean mice to a glucose tolerance test. This makes it possible to check how well an organism is able to process a large amount of orally ingested glucose. With humans as well this test helps in detecting incipient diabetes. Following this the scientists adjusted the drinking water of the animals by adding the maximum recommended daily consumption dose of saccharin, aspartame or Sucralose. The control animals drank sugar water or unsweetened water. After eleven weeks, the researchers repeated the glucose tolerance test – with a clear result: during the experimental time period, all sweetener-drinking mice developed glucose intolerance, whereas none of the control mice did. Among animals that had been drinking saccharin-containing water, the precursor stage of type 2 diabetes was particularly pronounced. Further experiments with obese mice and animals of varied strains showed the same result: the consumption of sweeteners always led to glucose intolerance, a misregulated glucose metabolism. How does this happen?
“Most sweeteners pass through the gastrointestinal tract without being digested”, the researchers write. Therefore the substances act directly on bacterial colonisation and on the composition of the gut. The gut microbiota’s composition in turn plays a central role in the regulation of many physiological processes, including the metabolism of sugar.

Antibiotics neutralise the effect

In order to test whether the gastrointestinal flora of the animals is actually involved in glucose intolerance, the researchers administered high dosage of the broad-spectrum antibiotics ciprofloxacin and metronidazole, which act on Gram-negative bacteria, to both the leaner and obese animal subjects. During the antibiotic treatment, the animals continue to drink sweetener-containing water. Already after four weeks of therapy the researchers were barely able to detect glucose-intolerance test differences between the fatter and leaner animals drinking sweetener and the control animals. What’s more, Vancomycin, targeted at Gram-positive bacteria, also led to this effect.
“These results suggest that the sweetener-induced glucose intolerance is caused by changes in the gut flora and the different proportions of its bacterial representatives”, the study authors conclude.
A further test was used to confirm this assumption: the scientists transferred the bacteria of the gastrointestinal flora of sweetener-drinking mice to microbe-free control mice. Already six days after the faecal transplant these mice were also suffering from glucose intolerance. Here was yet another indication for the researchers that sweeteners, via the modulation of the intestinal flora, lead to a precursor form of type 2 diabetes.

Species composition shifted

Next, the scientists put the microbiome composition of the variously fed mice under the microscope. One DNA sequencing showed: among the sweetener-fed mice more bacteria of the genus Bacteroides were present as well as were some representatives of the Clostridiales. Other subgroups of the Clostridiales on the other hand had fallen significantly in frequency, among these the lactic acid bacteria Lactobacillus reuteri, universally present in healthy humans and animals, the researchers report. In the sweetener-fed mice the researchers were also able to detect a multitude of active metabolic pathways which are responsible for increased energy intake from food and thus promote the development of obesity.
With mice it seems that sweeteners are obviously directly related to the onset of glucose intolerance. Is this also true for humans though?

Consumer survey

In order to address this question, the scientists analysed data from a consumer survey. From among 381 non-diabetic participants, 40 regularly consumed some amount of sweeteners. In this group of people the scientists found “a significant positive correlation between the sweetener consumption and several clinical parameters associated with this metabolic syndrome”, they write. These parameters include, for example, elevated fasting blood glucose and HbA1C levels as well as poorer results in the glucose tolerance test.

Small pilot study

In a small pilot study, the researchers tested their findings on seven subjects who normally consume no sweetener. The subjects were for a week given a daily intake of saccharin of 5 milligrams per kilogram of body weight, the maximum amount recommended by the FDA, administered in three daily doses. Already after four days, the initially normal glucose tolerance had significantly deteriorated in four participants. And similarly to that in the mice, the composition of their gut microflora had also changed. In three subjects both glucose tolerance and the composition of the gut microbiomes remained unchanged. When the researchers transferred stool samples of the subjects to gastrointestinally bacteria-free mice, only those which had received the stool from among the four subjects who had reacted to the consumption of saccharin then developed glucose intolerance. “Depending on the composition of the gut flora, humans apparently react differently to the consumption of sweeteners”, the researchers conclude from their data.
“Sweeteners are supposed to protect humanity from obesity and high blood glucose levels. Along with other changes in the human diet, the number of diabetics and obese people has increased concurrently with the mass consumption of sweeteners”, the researchers write. Thus sweeteners have exactly done what they were actually supposed to prevent. Future food strategies should be adapted to the different composition of the intestinal flora of people, the scientists urge.

Effects even with “normal” consumption?

Although the scientists were able through their research to provide a wealth of powerful evidence for the association of sweetener consumption and the development of glucose intolerance, it remains unclear whether these effects are to be expected with moderate sweetener consumption. Also, the matter remains to be clarified as to which “gut type” would be better off in the future by renouncing sweeteners.

Original publication of the article: http://www.nature.com/