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The melanocortin system and insulin resistance in humans: insights from a patient with complete POMC deficiency and type 1 diabetes mellitus

International Journal of Obesity volume 38, pages 148–151 (2014)Cite this article

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Abstract

The central melanocortin system is essential for the regulation of long-term energy homeostasis in humans. Rodent experiments suggest that this system also affects glucose metabolism, in particular by modulating peripheral insulin sensitivity independently of its effect on adiposity. Rare patients with complete genetic defects in the central melanocortin system can provide insight into the role of this system in glucose homeostasis in humans. We here describe the eighth individual with complete proopiomelanocortin (POMC) deficiency and the first with coincidental concomitant type 1 diabetes, which provides a unique opportunity to determine the role of melanocortins in glucose homeostasis in human. Direct sequencing of the POMC gene in this severely obese patient with isolated adrenocorticotropic hormone deficiency identified a homozygous 5′ untranslated region mutation −11C>A, which we find to abolish normal POMC protein synthesis, as assessed in vitro. The patient’s insulin requirements were as expected for his age and pubertal development. This unique patient suggests that in humans the central melanocortin system does not seem to affect peripheral insulin sensitivity, independently of its effect on adiposity.

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References

  1. Farooqi S, O'Rahilly S . Genetics of obesity in humans. Endocr Rev 2006; 27: 710–718.

    Article  CAS  PubMed  Google Scholar 

  2. Coll AP, Challis BG, Lopez M, Piper S, Yeo GS, O'Rahilly S . Proopiomelanocortin-deficient mice are hypersensitive to the adverse metabolic effects of glucocorticoids. Diabetes 2005; 54: 2269–2276.

    Article  CAS  PubMed  Google Scholar 

  3. Coll AP, Loraine YCTung . Pro-opiomelanocortin (POMC)-derived peptides and the regulation of energy homeostasis. Mol Cell Endocrinol 2009; 300: 147–151.

    Article  CAS  PubMed  Google Scholar 

  4. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A . Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19: 155–157.

    Article  CAS  PubMed  Google Scholar 

  5. Krude H, Biebermann H, Schnabel D, Tansek MZ, Theunissen P, Mullis PE et al. Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10. J Clin Endocrinol Metab 2003; 88: 4633–4640.

    Article  CAS  PubMed  Google Scholar 

  6. Farooqi IS, Drop S, Clements A, Keogh JM, Biernacka J, Lowenbein S et al. Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes 2006; 55: 2549–2553.

    Article  CAS  PubMed  Google Scholar 

  7. Clement K, Dubern B, Mencarelli M, Czernichow P, Ito S, Wakamatsu K et al. Unexpected endocrine features and normal pigmentation in a young adult patient carrying a novel homozygous mutation in the POMC gene. J Clin Endocrinol Metab 2008; 93: 4955–4962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Erlich H, Valdes AM, Noble J, Carlson JA, Varney M, Concannon P et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 2008; 57: 1084–1092.

    Article  CAS  PubMed  Google Scholar 

  9. Kaufman FR . Type 1 diabetes mellitus. Pediatr Rev. 2003; 24: 291–300.

    Article  PubMed  Google Scholar 

  10. Coppari R, Bjorbaek C . Leptin revisited: its mechanism of action and potential for treating diabetes. Nat Rev Drug Discov 2012; 11: 692–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Xu Y, Elmquist JK, Fukuda M . Central nervous control of energy and glucose balance: focus on the central melanocortin system. Ann N Y Acad Sci 2011; 1243: 1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Morton GJ, Schwartz MW . Leptin and the central nervous system control of glucose metabolism. Physiol Rev 2011; 91: 389–411.

    Article  CAS  PubMed  Google Scholar 

  13. Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, Zhang CY et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 2007; 449: 228–232.

    Article  CAS  PubMed  Google Scholar 

  14. Mergen M, Mergen H, Ozata M, Oner R, Oner C . A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity. J Clin Endocrinol Metab 2001; 86: 3448.

    Article  CAS  PubMed  Google Scholar 

  15. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392: 398–401.

    Article  CAS  PubMed  Google Scholar 

  16. Lubrano-Berthelier C, Le Stunff C, Bougneres P, Vaisse C . A homozygous null mutation delineates the role of the melanocortin-4 receptor in humans. J Clin Endocrinol Metab 2004; 89: 2028–2032.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was performed with support from NIH RO1 DK068152IA and established investigator award from the American Heart Association (AHA#0740041N). IRA was supported by a Genentech Clinical Fellowship and an ADA Mentored fellowship award. SAR was supported by a Pediatric Endocrinology Training Grant T32-DK07161.

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Authors and Affiliations

  1. Children’s Hospital Oakland & Research Center Institute, San Francisco, CA, USA

    I R Aslan & J A Noble

  2. Palo Alto Medical Foundation, San Francisco, CA, USA

    S A Ranadive

  3. Department of Medicine and Diabetes Center, University of California San Francisco, San Francisco, CA, USA

    I Valle & C Vaisse

  4. Keiser Permanente, Roseville, San Francisco, CA, USA,

    S Kollipara

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  1. I R Aslan
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  2. S A Ranadive
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  3. I Valle
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  4. S Kollipara
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  5. J A Noble
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  6. C Vaisse
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Correspondence to C Vaisse.

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Aslan, I., Ranadive, S., Valle, I. et al. The melanocortin system and insulin resistance in humans: insights from a patient with complete POMC deficiency and type 1 diabetes mellitus. Int J Obes 38, 148–151 (2014). https://doi.org/10.1038/ijo.2013.53

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