Genetic Variant Modulates Dietary Impact on Glucose Control: Inuit Study Reveals Key Insights

Introduction

The sucrase-isomaltase (SI) gene plays a critical role in digesting sugars and starches. A specific loss-of-function variant (c.273_274delAG) is common in Indigenous Arctic populations like the Greenlandic Inuit and has been linked to improved metabolic health. This variant prevents carriers from digesting sucrose and certain starches, naturally reducing sugar intake. Despite this advantage, how it interacts with different diets to affect glucose homeostasis—a key factor in diabetes—remains unclear. This study investigates whether the SI genotype modifies the impact of traditional versus Western diets on glucose control and lipid metabolism in Inuit individuals, offering potential pathways for diabetes management.

Study Design and Methods

A genotype-based randomized crossover trial was conducted in Greenland, involving participants from Nuuk and Maniitsoq. It included 17 homozygous SI carriers and 16 non-carriers, all aged 18 or older, with no gastrointestinal disorders, diabetes, or high-risk TBC1D4 gene variants. The trial featured two 3-day dietary interventions separated by a 7-day washout period. Diets were: 1) A traditional Greenlandic diet rich in fish and meat, and 2) An isoenergetic Western diet with 11% energy from sucrose. Participants randomized the diet order using a dice, with no blinding for participants or personnel. Primary outcomes focused on glucose variability measured as coefficient of variation (CV). Fasting blood samples analyzed lipids, insulin, and C-reactive protein before and after each intervention. Statistical analyses used linear mixed models to assess genotype × diet interactions, adhering to CONSORT 2010 and CONSIDER guidelines for ethical reporting in Indigenous health research.

Key Findings on Glucose and Insulin

Non-carriers showed significantly higher glucose variability (CV) on the Western diet versus the Greenlandic diet (β = 5.23%, 95% CI 3.02–7.45). In contrast, carriers exhibited no such increase (β = 1.27%, 95% CI -0.86–3.4), with carriers displaying 20% lower CV on the Western diet than non-carriers (p for interaction = 0.015). At baseline, carriers had lower fasting insulin levels, and the Greenlandic diet reduced insulin by 22.7 pmol/l (95% CI 5.1–40.3) in non-carriers but not in carriers (p for interaction = 0.009). These results highlight the variant’s protective effect on glucose stability under high-sugar conditions, with minimal impact on lipids.

Implications and Treatment Potential

The findings suggest that SI loss-of-function carriers inherently manage glucose more effectively, likely due to reduced sucrose digestion. This positions SI enzyme inhibition as a promising therapeutic target for type 2 diabetes, mimicking the variant’s effects. Such inhibitors could improve glycemic control in broader populations, particularly those on high-sugar diets. However, cultural context is vital—integrating traditional diets rich in omega-3 fatty acids from fish may benefit non-carriers by lowering insulin resistance. Future research should explore long-term SI inhibition safety and scalability, emphasizing community-based approaches to honor Indigenous health practices.

Conclusions and Broader Impact

This trial demonstrates that genetic factors like the SI variant can profoundly modulate dietary responses, with carriers showing superior glucose homeostasis on Western diets. Clinically, this underscores personalized nutrition strategies for diabetes prevention. The study, published in Diabetologia, also sets a precedent for ethical Indigenous health research, advocating for culturally respectful interventions that address disparities. Funding from the Independent Research Fund Denmark, Greenland Research Council, and Brugseni underscores its societal relevance. For more details, refer to the full article at ClinicalTrials.gov (NCT05375656) or PubMed (PMID: 41995844).