Clinical trial NCT05375656: The Effect on Metabolism, Food Intake and Preferences of a Knockout Gene Variant Involved in Carbohydrate Metabolism
Official title: The Effect on Metabolism, Food Intake and Preferences of a Knockout Gene Variant Involved in Carbohydrate Metabolism
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes Mellitus, Type 2
Metabolic Disease
Sucrose Intolerance Congenital
Sucrase Isomaltase Deficiency
Keywords: Inuit
Greenlandic diet
Diabetes
Microbiota
Glucose variability
Food preference
SI
Lead sponsor: Steno Diabetes Center Copenhagen
Sponsor class: OTHER
Collaborators: name: The Novo Nordisk Foundation Center for Basic Metabolic Research
name: Department of Food Science, University of Copenhagen
name: Steno Diabetes Center Greenland
First posted: 2022-05-17
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: PREVENTION

Brief 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.

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.

Primary outcomes:
measure: Glycemic variability during Western diet
timeFrame: During the 3 days of intervention with Western diet.
measure: Glycemic variability during Inuit diet
timeFrame: During the 3 days of intervention with Inuit diet.
Secondary outcomes:
measure: Sweet Bias Score
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: Fat Bias Score
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: High-fat savory preference
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: Low-fat savory preference
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: High-fat sweet preference
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: Low-fat sweet preference
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: Implicit wanting score: High-fat savory foods
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: Implicit wanting score: Low-fat savory foods
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: Implicit wanting score: High-fat sweet foods
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: Implicit wanting score: Low-fat sweet foods
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: Habitual diet
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: Intake in a snacking test meal
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: Sucrose sweetness sensitivity
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: Sweet liking
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: Perceived intensity of sugars
timeFrame: Baseline (to assess differences between genotypes, independent of the intervention)
measure: Plasma lipids
timeFrame: The day before and the day after each dietary intervention period.
measure: Serum insulin
timeFrame: The day before and the day after each dietary intervention period.
measure: Plasma CRP
timeFrame: The day before and the day after each dietary intervention period.
measure: Plasma acetate
timeFrame: The day before and the day after each dietary intervention period.
measure: Plasma propionate
timeFrame: The day before and the day after each dietary intervention period.
measure: Plasma butyrate
timeFrame: The day before and the day after each dietary intervention period.
measure: HbA1c
timeFrame: Baseline
measure: Fecal acetate
timeFrame: Before and on the last day or on the day after each dietary intervention period.
measure: Fecal propionate
timeFrame: Before and on the last day or on the day after each dietary intervention period.
measure: Fecal butyrate
timeFrame: Before and on the last day or on the day after each dietary intervention period.
measure: Fecal pH
timeFrame: Before and on the last day or on the day after each dietary intervention period.
measure: Changes in gut microbiota composition
timeFrame: Before and on the last day or on the day after each dietary intervention period.
measure: Baseline gut microbiota composition
timeFrame: Before intervention (baseline).
measure: Fecal carbohydrates
timeFrame: Before and on the last day or on the day after each dietary intervention period.
measure: Glycemic variability during habitual diet
timeFrame: Measured during 7 days of wash-out
Other outcomes:
measure: Body weight
timeFrame: Baseline (participant characteristics)
measure: Height
timeFrame: Baseline (participant characteristics)
measure: Hip circumference
timeFrame: Baseline (participant characteristics)
measure: Waist circumference
timeFrame: Baseline (participant characteristics)
measure: Body composition
timeFrame: Baseline (participant characteristics)
measure: Plasma lipodomics.
timeFrame: The day before and the day after each dietary intervention period.
measure: Plasma metabolomics.
timeFrame: The day before and the day after each dietary intervention period.
measure: Plasma proteomics.
timeFrame: The day before and the day after each dietary intervention period.
measure: Fecal lipodomics
timeFrame: The day before and the day after each dietary intervention period.
measure: Fecal metabolomics.
timeFrame: The day before and the day after each dietary intervention period.
measure: Fecal proteomics.
timeFrame: The day before and the day after each dietary intervention period.
Locations:
city: Maniitsoq
country: Greenland
facility: Maniitsoq Healthcare Center
city: Nuussuaq
country: Greenland
facility: Pikialaarfik, Greenland Institute of Natural Resources
Study officials:
affiliation: Steno Diabetes Center Greenland
name: Marit E Jørgensen, Prof.
role: PRINCIPAL_INVESTIGATOR
References: