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

NCT05375656 | Completed

• 1 other identifier: F15319-03
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 2

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 A recent, unpublished study found the variant to be associated with lower BMI, body fat percentage, bodyweight, and lipid levels independent of the lower intake of refined sugar.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.

Conditions

Diabetes Mellitus, Type 2; Metabolic Disease; Sucrose Intolerance Congenital; Sucrase Isomaltase Deficiency

Keywords

Inuit; Greenlandic diet; Diabetes; Microbiota; Glucose variability; Food preference; SI

Outcome Measures

Primary Outcomes (2)

• Glycemic variability during Western diet

  Glycemic variability will be measured by mean amplitude of glycemic excursions (MAGE) during the whole study period, i.e. during both Western and Inuit diet and the wash-out period in between.

  During the 3 days of intervention with Western diet.

• Glycemic variability during Inuit diet

  Glycemic variability will be measured by mean amplitude of glycemic excursions (MAGE) during the whole study period, i.e. during both Western and Inuit diet and the wash-out period in between.

  During the 3 days of intervention with Inuit diet.

Secondary Outcomes (30)

• Sweet Bias Score

  Baseline (to assess differences between genotypes, independent of the intervention)

• Fat Bias Score

  Baseline (to assess differences between genotypes, independent of the intervention)

• High-fat savory preference

  Baseline (to assess differences between genotypes, independent of the intervention)

• Low-fat savory preference

  Baseline (to assess differences between genotypes, independent of the intervention)

• High-fat sweet preference

  Baseline (to assess differences between genotypes, independent of the intervention)

Other Outcomes (11)

• Body weight

  Baseline (participant characteristics)

• Height

  Baseline (participant characteristics)

• Hip circumference

  Baseline (participant characteristics)

Study Arms (2)

Traditional Inuit Diet

ACTIVE COMPARATOR

The traditional Inuit diet will consist of local foods, being primarily of animal origin, e.g. fish, marine mammals, caribou, and lamb. The diet will be supplemented with eggs, potatoes, and berries, and/or other foods low in starch and with no sucrose content. The diet will therefore have a high content of fat and protein, a low content of carbohydrate and no content of sucrose. The participants will receive foods that will cover at least 100% of their energy requitement. Each participant will throw a dice in order to randomize the order of which the participants receive the two intervention diets.

Other: Cross-over study

Western Carbohydrate-Rich Diet

EXPERIMENTAL

The Western diet will have high amounts of grain products, e.g. bread, pasta, rice, as well as fruits and vegetables and some foods with a high sucrose content, e.g. cake and sweet snacks and/or drinks, and cereal products with added sucrose. The diet will have a low amount of meat. Hence, the diet will be high in carbohydrates, starch, and some sucrose and have a lower content of protein and fat. The participants will receive foods that will cover at least 100% of their energy requitement. Each participant will throw a dice in order to randomize the order of which the participants receive the two intervention diets.

Other: Cross-over study

Interventions

Cross-over study OTHER

Traditional Inuit Diet and Western Diet.

Traditional Inuit Diet; Western Carbohydrate-Rich Diet

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• Steno Diabetes Center Copenhagen: lead
• The Novo Nordisk Foundation Center for Basic Metabolic Research: collaborator
• University of Copenhagen: collaborator
• Steno Diabetes Center Greenland: collaborator

Study Sites (2)

Maniitsoq Healthcare Center

Maniitsoq, Greenland

Location

Pikialaarfik, Greenland Institute of Natural Resources

Nuussuaq, 3905, Greenland

Location

Related Publications (1)

• Senftleber NK, Skott Pedersen K, Schnoor Jorgensen C, Pedersen H, Bjerg Christensen MM, Kabel Madsen E, Andersen K, Jorsboe E, Gillum MP, Frost MB, Hansen T, Jorgensen ME. The effect of sucrase-isomaltase deficiency on metabolism, food intake and preferences: protocol for a dietary intervention study. Int J Circumpolar Health. 2023 Dec;82(1):2178067. doi: 10.1080/22423982.2023.2178067. Epub 2023 Feb 22.

  PMID: 38113483 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Metabolic Diseases; Sucrase-isomaltase deficiency, congenital; Diabetes Mellitus; Food Preferences

Interventions

Cross-Over Studies

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Nutritional and Metabolic Diseases; Endocrine System Diseases; Feeding Behavior; Behavior

Intervention Hierarchy (Ancestors)

Epidemiologic Research Design; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Study Officials

• Marit E Jørgensen, Prof.

  Steno Diabetes Center Greenland

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: The study will be blinded with respect to the genotype of the participants for everyone involved in the study except for the investigator. The dietary intervention will not be blinded.
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: September 27, 2021
• First Posted: May 17, 2022
• Study Start: January 8, 2022
• Primary Completion: May 7, 2022
• Study Completion: May 7, 2022
• Last Updated: May 31, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

GR (2)