GLP2R – Type 2 Diabetes Mellitus

This summary evaluates the association between GLP2R (HGNC:4325) and type 2 diabetes mellitus (MONDO_0005148) using evidence from large-scale genetic studies and functional assessments. The genetic investigations include multi‐patient cohorts with robust statistical associations and replication studies (PMID:30846969, PMID:28566273).

Overall, the clinical validity is rated as Strong. Large-scale meta-analyses involving up to 26,676 type 2 diabetes cases and data from a cross-sectional cohort of 2,929 subjects have demonstrated significant SNP × SNP interactions, notably between the incretin-associated variant in GLP2R and the well-established TCF7L2 marker (PMID:30846969, PMID:28566273). Although no additional affected relatives with segregating variants were reported (0 additional relatives), the genetic evidence remains compelling.

Genetic evidence stems from two independent analyses. One study identified a strong interaction between rs17681684 in GLP2R and rs7903146 in TCF7L2 impacting insulin secretion, while a meta-analysis flagged GLP2R among 13 novel loci associated with type 2 diabetes mellitus. These findings reinforce the gene’s involvement in incretin-mediated insulin regulation, a key pathophysiological mechanism in diabetes.

A reported variant, processed for clarity as c.1249C>T (p.Arg417Ter), was identified in a separate functional study (PMID:39610412). This variant was found in a patient with severe clinical illness marked by recurrent metabolic acidosis and intestinal dysfunction. Although the phenotypic context of this variant differs from the common type 2 diabetes presentation, its inclusion broadens the GLP2R mutation spectrum, hinting at allelic heterogeneity.

Functional evidence from animal and cellular models supports the biological relevance of GLP2R in intestinal physiology. In knockout models, GLP2R deficiency predisposes to intestinal injury and abnormal host-microbe interactions. However, the direct link between functional loss of GLP2R and type 2 diabetes remains limited, suggesting that while common variants confer diabetes risk, rare loss-of-function alleles may result in a distinct clinical picture.

In conclusion, the integration of genetic and experimental findings supports a strong association between GLP2R and type 2 diabetes mellitus. The genetic evidence, derived from robust multi-patient studies, provides valuable insights for diagnostic decision-making and commercial applications in risk stratification. Key take‑home: Variants in GLP2R represent clinically actionable markers that can enhance our understanding and management of type 2 diabetes mellitus.

References

• Frontiers in Endocrinology • 2019 • Gene x Gene Interactions Highlight the Role of Incretin Resistance for Insulin Secretion PMID:30846969
• Diabetes • 2017 • An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans PMID:28566273
• JPGN reports • 2024 • Novel homozygous nonsense mutation in glucagon-like peptide-2 receptor gene resulting in severe human illness PMID:39610412

Evidence Based Scoring (AI generated)