The Effect on Metabolism, Food Intake and Preferences of a Knockout Gene Variant Involved in Carbohydrate Metabolism
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 38
- 试验地点
- 3
- 主要终点
- Glycemic variability during Inuit diet
研究概览
简要总结
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 A recent, unpublished study found the variant to be associated with lower BMI, body fat percentage, bodyweight, and lipid levels independent of the lower intake of refined sugar.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.
详细描述
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:
- HO have a lower glycemic variability on their habitual diet than WT+HE.
- HO have a lower glycemic variability on a starch and sucrose rich diet than WT+HE.
- 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Care Provider, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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.
结局指标
主要结局
Glycemic variability during Inuit diet
时间窗: During the 3 days of intervention with 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.
Glycemic variability during Western diet
时间窗: During the 3 days of intervention with 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.
次要结局
- 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 sweet 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))
- Perceived intensity of sugars(Baseline (to assess differences between genotypes, independent of the intervention))
- Plasma butyrate(The day before and the day after each dietary intervention period.)
- Fecal pH(Before and on the last day or on the day after each dietary intervention period.)
- Changes in gut microbiota composition(Before and on the last day or on the day after each dietary intervention period.)
- Low-fat sweet preference(Baseline (to assess differences between genotypes, independent of the intervention))
- Implicit wanting score: Low-fat savory foods(Baseline (to assess differences between genotypes, independent of the intervention))
- High-fat savory preference(Baseline (to assess differences between genotypes, independent of the intervention))
- Implicit wanting score: High-fat savory foods(Baseline (to assess differences between genotypes, independent of the intervention))
- Implicit wanting score: Low-fat sweet foods(Baseline (to assess differences between genotypes, independent of the intervention))
- Sweet liking(Baseline (to assess differences between genotypes, independent of the intervention))
- Plasma CRP(The day before and the day after each dietary intervention period.)
- Fecal butyrate(Before and on the last day or on the day after each dietary intervention period.)
- Implicit wanting score: High-fat sweet foods(Baseline (to assess differences between genotypes, independent of the intervention))
- Habitual diet(Baseline (to assess differences between genotypes, independent of the intervention))
- Plasma acetate(The day before and the day after each dietary intervention period.)
- HbA1c(Baseline)
- Fecal acetate(Before and on the last day or on the day after each dietary intervention period.)
- Fecal propionate(Before and on the last day or on the day after each dietary intervention period.)
- Serum insulin(The day before and the day after each dietary intervention period.)
- Glycemic variability during habitual diet(Measured during 7 days of wash-out)
- Intake in a snacking test meal(Baseline (to assess differences between genotypes, independent of the intervention))
- Plasma propionate(The day before and the day after each dietary intervention period.)
- Baseline gut microbiota composition(Before intervention (baseline).)
- Sucrose sweetness sensitivity(Baseline (to assess differences between genotypes, independent of the intervention))
- Plasma lipids(The day before and the day after each dietary intervention period.)
- Fecal carbohydrates(Before and on the last day or on the day after each dietary intervention period.)