The Effect on Metabolism, Food Intake and Preferences of a Knockout Gene Variant Involved in Carbohydrate Metabolism

Around 10% has type 2 diabetes in Greenland, despite being a practically unknown disease only six decades ago. The drastic increase is of great concern, especially considering the transition that have occurred during the same decades going from a fisher-hunter lifestyle towards a more western lifestyle. Today, traditional marine foods are still increasingly being replaced by imported foods high in refined sugar (sucrose) and starch. Furthermore, recent studies discovered that the Greenlandic population harbors a different genetic architecture behind type 2 diabetes. Hence, obtaining more knowledge on interactions between lifestyle, genetics, and metabolism is therefore crucial in order to ameliorate the growing curve, or maybe even turn it around.

Sucrose intolerance is in general rare; however, it is a common condition in Greenland and other Inuit populations. Here it is caused by a genetic variant in the sucrase-isomaltase (SI) gene, resulting in complete loss of enzyme function and hence an inability to digest sucrose and some of the glycosidic bonds in starch, both carbohydrates that are not part of the traditional Inuit diet. A recent, unpublished study found the variant to be associated with lower BMI, body fat percentage, bodyweight, and lipid levels independent of the lower intake of refined sugar. This might be explained by differences in the metabolism of carbohydrates and in the gut microbiota. The healthier phenotype was confirmed by a SI knockout mouse model, which furthermore interestingly indicated that the variant might alter food and taste preferences.

It is anticipated that the drastic increase in type 2 diabetes in Greenland can be explained at least partly by the complex interaction between lifestyle and genetics. Therefore, the aim is to investigate if metabolic and microbial differences can explain the healthier phenotype of the homozygous carriers of the SI variant than wildtype individuals amd perform a 3-day cross-over dietary intervention using assigning subjects to a traditional Greenlandic diet and a Western diet. Moreover, the aim is to assess whether their food and taste preferences are different. The study will help us to understand the complex interactions between lifestyle, behavior, genetics, the microbiota and the host metabolism.

In this human study, effects of the SI knockout variant on metabolism, dietary habits and food preferences will be quantified. The study will be unique by being the first assessing the effect of a complete loss of SI function, which it is only feasible in Arctic populations.

Differences between homozygous (HO) carriers and heterozygous (HE)/wildtype (WT) individuals are suspected to be large on a carbohydrate-rich diet and small on a traditional diet. The following hypotheses will be addressed:

HO carriers metabolize carbohydrates differently than HE+WT individuals:

1. HO have a lower glycemic variability on their habitual diet than WT+HE.
2. HO have a lower glycemic variability on a starch and sucrose rich diet than WT+HE.
3. HO have a glycemic variability similar to WT+HE on a traditional diet low in carbohydrates.

   HO carriers have different food preferences than HE+WT individuals:
4. HO have a lower sweet taste preference compared to WT+HE.
5. HO perceive iso-intense solutions of sucrose, fructose, and glucose differently in sweet taste intensity and WT+HE will perceive them iso-intense.
6. HO consume less high-sugar-low-fat foods than WT+HE.
7. HO have similar intake and preference for high-sugar-high-fat foods as WT+HE.

   HO carriers have a microbiota different from HE+WT individuals:
8. Diversity and abundance of starch-fermenting bacteria is higher in HO than in WT+HE and the abundance of Parabacteroides is lower.
9. The increase in starch-fermenting bacteria as well as fecal and circulating levels of short chain fatty acids is larger for HO than in WT+HE on a starch and sucrose rich diet.
10. A diet low in carbohydrates will alter the microbiota similarly for HO and WT+HE.

Eligibility Criteria:
Inclusion Criteria:

* Homozygous carriers of the c.273_274delAG variant in the SI-gene (cases)
* Homozygous non-carriers of the c.273_274delAG variant in the SI-gene (controls)

Exclusion Criteria:

* Diagnosis of diabetes or pharmacological treatment of diabetes.
* Gastrointestinal diseases such as inflammatory bowel disease, gastrointestinal cancer, and ulcer. Persons with mild gastrointestinal problems are not excluded, e.g. persons with lactose-intolerance who normally do not have any gastrointestinal problems.
* Homozygous carriers of the TBC1D4 risk variant p.Arg684Ter.
* Lack of compliance with the procedures in the study protocol, judged by Investigator.
* For the homozygous carriers of the c.273_274delAG variant: rise in blood glucose in an oral sucrose tolerance test.