The Effect on Metabolism, Food Intake and Preferences of a Knockout Gene Variant Involved in Carbohydrate Metabolism
Condition: Diabetes Mellitus, Type 2; Metabolic Disease; Sucrose Intolerance Congenital; Sucrase Isomaltase Deficiency
MeSH terms: Diabetes Mellitus, Type 2; Metabolic Diseases
Study type: Interventional

Summary: 
      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 A recent, unpublished study found the variant to be associated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.
    

Detailed description: 
      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.
    

Intervention name(s): Cross-over study
Intervention type(s): Other
Intervention description(s): Traditional Inuit Diet and Western Diet.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: A cross-over design will be applied to the intervention. Participants will be randomized to first receive either a diet high in starch and relatively high in sucrose, resembling a western diet, or a diet low in carbohydrate with many marine foods, resembling a traditional Inuit diet. There will be a wash out period of 7 days between the two diets.
Each participant will throw a dice in order to randomize the order of which the participants receive the two intervention diets.
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Inuit; Greenlandic diet; Diabetes; Microbiota; Glucose variability; Food preference; SI