Genetic variants in the ghrelin peptide gene, its receptor (GHSR), and telomere maintenance genes were differentially distributed across BMI categories in type 2 diabetes patients, providing the first molecular distinction between obese and non-obese diabetics.
17.8% vs 40.4% ACYP2 CC genotypeThe ACYP2 telomere gene variant was dramatically less common in obese diabetics than non-obese diabetics, providing the first molecular marker distinguishing these two groups.
What the researchers found
The ACYP2 rs6713088 CC genotype was the standout finding: it was significantly under-represented in obese diabetics (17.8%) compared to non-obese diabetics (40.4%, p=0.01) and showed a gradient across 4 BMI grades (p=0.025). Paradoxically, the same genotype was over-represented in obese non-diabetics compared to non-obese non-diabetics (50% vs 27.6%, p=0.04), suggesting its role differs depending on diabetes status.
Ghrelin (GHRL rs27647C/T), ghrelin receptor (GHSR rs509030G/C), and TERC (rs12696304G/C) minor allele frequencies were significantly lower in normal-BMI diabetic patients (p=0.034, 0.008, and 0.011, respectively), suggesting these variants may contribute to obesity susceptibility within the diabetic population.
Why it matters
Understanding why some diabetics become obese while others don't could enable more personalized treatment. The finding that ghrelin-related genetic variants differ across BMI categories in diabetes is particularly interesting because ghrelin is a peptide hormone that could be therapeutically targeted. If specific genetic profiles predict obesity risk in diabetes, treatments could be tailored accordingly — for example, choosing GLP-1RA therapy for patients with high-risk ghrelin variants.
How the study worked
Two cross-sectional studies conducted in Saudi Arabia (2013) and Kuwait (2019) enrolling 216 type 2 diabetes patients and 193 non-diabetic controls. Participants were grouped by obesity status and sub-grouped into 4 BMI categories (normal, overweight, obese, severely obese). Eight SNPs in 5 genes (ghrelin, GHSR, ACYP2, TERC, and others) were genotyped by real-time PCR from fasting blood samples.
What this study cannot tell us
The cross-sectional design cannot establish causation. Sample sizes were moderate (216 T2DM patients, 193 controls), limiting statistical power for subgroup analyses. The study was conducted in two Middle Eastern populations and may not generalize to other ethnic groups. The two study sites used different gene panels, limiting direct comparison. Multiple testing correction was not described. The functional significance of the identified SNPs needs further investigation.
How to read the evidence
This is a cross-sectional genetic association study with moderate sample size from two Middle Eastern populations. While the findings are novel and statistically significant, the cross-sectional design and lack of replication in independent cohorts limit the evidence strength.
When this study was published
Published in 2022, this study represents early exploration of the genetic basis for obesity variation within type 2 diabetes. Larger genomic studies may have since expanded on these findings.
The bigger picture
Ghrelin — the peptide hormone that stimulates appetite — is known to interact with the GLP-1 system in regulating metabolism and body weight. Finding that genetic variations in ghrelin and its receptor differ between obese and non-obese diabetics adds a genetic dimension to our understanding of peptide hormone signaling in metabolic disease. This could inform pharmacogenomic approaches to selecting diabetes and obesity therapies.
Questions still open
- Could ghrelin or GHSR gene variants predict which diabetes patients will respond best to GLP-1RA therapy?
- What is the functional mechanism by which the ACYP2 variant influences obesity risk differently in diabetics versus non-diabetics?
- Would these genetic associations replicate in larger, more diverse populations?
Common questions
Why does ghrelin genetics matter for diabetes and obesity?
Why are some people with diabetes obese while others are not?
Read the original research
Association of obesity in T2DM with differential polymorphism of ghrelin, growth hormone secretagogue receptor-1 and telomeres maintenance genes.
Hormone molecular biology and clinical investigation, 43(3), 297-306
Citation
Giha, Hayder A; Joatar, Faris E; AlDehaini, Dhuha M B; Malalla, Zainab H A; Ali, Muhalab E; Al Qarni, Ali A. (2022). Association of obesity in T2DM with differential polymorphism of ghrelin, growth hormone secretagogue receptor-1 and telomeres maintenance genes.. Hormone molecular biology and clinical investigation, 43(3), 297-306. https://doi.org/10.1515/hmbci-2021-0063