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Type 2 Diabetes Remission in Patients with Heterozygous Variants in the Leptin-Melanocortin Pathway after Roux-en-Y Gastric Bypass: A Matched Case–Control Study

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Abstract

Background

Roux-en-Y gastric bypass (RYGB) is associated with a high rate of type 2 diabetes (T2D) remission. Carriers of heterozygous variants in the leptin-melanocortin pathway (LMP) are more likely to experience weight recurrence after RYGB. Our aim was to investigate if carrier status and associated weight regain affects the rate of T2D remission after RYGB.

Methods

Carriers of LMP variants with a diagnosis of T2D prior to RYGB (N = 16) were matched to non-carriers (N = 32) based on sex, age, and BMI. We assessed for post-operative T2D remission status post-surgery on a yearly basis, for up to 15 years. Our primary endpoint was the proportion of patients achieving T2D remission at 1 year. We conducted a survival analysis for all patients that achieved remission at least at one time-point to evaluate for maintenance of T2D remission by using a log-rank test.

Results

Both carriers and non-carriers had similar baseline and procedural characteristics. The proopiomelanocortin gene in the LMP pathway had the most variants (n = 5, 31%). Carriers had a lower total body weight loss percentage at nadir (28.7% ± 6.9) than non-carriers (33.7% ± 8.8, p = 0.04). The proportion of patients achieving T2D remission at 1 year was 68.8% for carriers and 71.9% for non-carriers (p = 1.0). Survival curves for maintenance of first remission were similar for both groups (p = 0.73), with a median survival of 8 years for both carriers and non-carriers.

Conclusions

Despite inferior weight loss outcomes at nadir, carriers had similar T2D remission rates when compared to non-carriers. Weight-independent metabolic benefits of RYGB might contribute to this observation.

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Abbreviations

LMP:

Leptin melanocortin pathway

RYGB:

Roux-en-Y gastric bypass

T2D:

Type 2 Diabetes

WR:

Weight recurrence

TBWL:

Total body weight loss

GLTs:

Glucose lowering therapies

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Acknowledgements

We thank the participants from the Mayo Clinic Biobank and Rhythm Pharmaceuticals for the genotyping studies.

Funding

Dr. Acosta is supported by NIH (NIH K23-DK114460), The Mayo Clinic Biobank, and Rhythm Pharmaceuticals for the genotyping studies. The Mayo Clinic Biobank is supported by the Mayo Clinic Center for Individualized Medicine. The funding source was not involved in the study design, in the collection, analysis, and interpretation of the data, in writing the report, or in the decision to submit the paper for publication.

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Authors and Affiliations

  1. Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, 200 First St. S.W., Rochester, MN, 55902, USA

    Diego Anazco, Wissam Ghusn, Alejandro Campos, Lizeth Cifuentes, Sima Fansa, Elif Tama, Khushboo Gala, Maria D. Hurtado & Andres Acosta

  2. Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, Mayo Clinic, Jacksonville, FL, 32224, USA

    Elif Tama & Maria D. Hurtado

  3. Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, 55902, USA

    Joshua T. Bublitz & Janet E. Olson

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  1. Diego Anazco
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Contributions

All authors had full access to all the data and statistical analyses. AA had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: AA, DA.

Acquisition, analysis, or interpretation of data: DA, WG, AC, LC, SF, ET, JTB, KG, MDH, JEO, AA.

Drafting of the manuscript: DA.

Critical revision of the manuscript for important intellectual content: AA, MDH, JEO.

Statistical analysis: DA.

Supervision: AA, MDJ, JEO.

Corresponding author

Correspondence to Andres Acosta.

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Conflict of Interest

Andres Acosta was supported by NIH (NIH K23-DK114460), The Mayo Clinic Biobank, and Rhythm Pharmaceuticals for the genotyping studies. The Mayo Clinic Biobank is supported by the Mayo Clinic Center for Individualized Medicine. The funding source was not involved in the study design, in the collection, analysis, and interpretation of the data, in writing the report, or in the decision to submit the paper for publication. Andres Acosta holds equity in Phenomix Sciences Inc. Andres Acosta served as a consultant for Rhythm Pharmaceuticals, General Mills, Currax, Nestle, Amgen, Structure, and Boehringer Ingelheim. The rest of the authors declare no conflicts of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Statement of Informed Consent

Informed consent was obtained from all individual participants included in the study and all participants provided prior written authorization for research use of their medical records and biological samples, including their use for genotyping studies.

Clinical trial registration

None.

Data Sharing and Transparency

The investigators will share deidentified data that underlies the results reported in this article after deidentification upon request by bona fide researchers who provide a methodologically appropriate proposal. Proposals should be directed to acosta.andres@mayo.edu. To gain access, data requestors will need to sign a data access agreement.

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Key Points

• Almost 10% of patients undergoing Roux-en-Y gastric bypass can have genetic variants in the leptin-melanocortin pathway.

• Carriers of heterozygous genetic variants in the leptin-melanocortin pathway can have significant weight regain in the mid- and long-term after Roux-en-Y gastric bypass.

• Despite inferior weight loss outcomes at nadir, carriers of heterozygous genetic variants in the leptin-melanocortin pathway have similar type 2 diabetes remission rates and maintenance after Roux-en-Y Gastric bypass than non-carriers.

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Anazco, D., Ghusn, W., Campos, A. et al. Type 2 Diabetes Remission in Patients with Heterozygous Variants in the Leptin-Melanocortin Pathway after Roux-en-Y Gastric Bypass: A Matched Case–Control Study. OBES SURG 33, 3502–3509 (2023). https://doi.org/10.1007/s11695-023-06859-x

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