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Endocrine Care: A. B. Goldfine, E. C. Mun, E. Devine, R. Bernier, M. Baz-Hecht, D. B. Jones, B. E. Schneider, J. J. Holst, and M. E. Patti Patients with Neuroglycopenia after Gastric Bypass Surgery Have Exaggerated Incretin and Insulin Secretory Responses to a Mixed Meal J Clin Endocrinol Metab 2007; 92: 4678-4685 [Abstract] [Full text] [PDF]

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Letter to the Editor

Ted Okerson (MD), Thomas Carpenter (PhD), Gary Bloomgren (MD)   (26 February 2008)

Letter to the Editor 26 February 2008
Ted Okerson (MD), Sr Dir Medical Affairs Amylin Pharmaceuticals, Inc, Thomas Carpenter (PhD), Gary Bloomgren (MD) Send letter to journal: Re: Letter to the Editor ted.okerson{at}amylin.com Ted Okerson (MD), et al.	We note with interest the recent publication by Goldfine et al. (1), in which a subset of patients who had undergone Roux-en-Y surgery for morbid obesity later presented with refractory postprandial hypoglycemia. These patients were observed to have a hyperinsulinemic response to a mixed meal test and exhibited elevated postprandial levels of both GLP-1 and GIP relative to overweight or morbid obese controls who had not undergone surgery. The authors speculate on a number of possible explanations for the refractory hypoglycemia observed in these patients, including the role of the seemingly exaggerated incretin response with particular attention to the role of GLP-1. To help inform this discussion, we have reviewed a substantial body of both animal and human data with the incretin mimetic exenatide, a peptide that shares a number of glucoregulatory mechanisms with GLP-1. There have been no definitive cases of severe refractory hypoglycemia reported in the exenatide clinical trials (nearly 4,000 patients with a cumulative 3,716 patient-years of exposure, and exposure lasting up to 3.5 years (2)) or in 2.5 years of post-approval pharmacovigilance surveillance. Also of note, exenatide does not elicit pathological changes in pancreatic islets after long-term (up to two years) exposure at high circulating concentrations in animals (roughly 100-400 fold higher than that used in patients treated with exenatide). It is important to note there are clear differences in these two clinical settings: patients with type 2 diabetes who have been treated with exenatide in contrast to a subset of morbidly obese subjects who have undergone Roux-en-Y bypass surgery and have experienced refractory hypoglycemia. Although the importance of the augmented mealtime GLP-1 response in the patients that Dr. Goldfine and colleagues report remains to be investigated, it is reassuring nevertheless that animal and human experience with exenatide does not raise concern in this regard. The phenomenon Dr. Goldfine and colleagues describe is likely a manifestation of multiple physiologic, hormonal, and metabolic changes that occur after bariatric surgery (3-5), and clearly warrants further investigation. References 1. Goldfine AB, Mun EC, Devine E, Bernier R, Baz-Hecht M, Jones DB, Schneider BE , Holst JJ, Patti ME 2007 Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal. J Clin Endocrinol Metab 92:4678-4685 2. Klonoff DC, Buse JB, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, Wintle ME, Maggs DG 2008 Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin 24:275-286 3. Korner J, Bessler M, Cirilo LJ, Conwell IM, Daud A, Restuccia NL, Wardlaw SL 2005 Effects of Roux-en-Y gastric bypass surgery on fasting and postprandial concentrations of plasma ghrelin, peptide yy, and insulin. J Clin Endocrinol Metab 90:359-365 4. Borg CM, le Roux CW, Ghatei MA, Bloom SR, Patel AG, Aylwin SJB 2006 Progressive rise in gut hormone levels after Roux-en-Y gastric bypass suggest gut adaptation and explains altered satiety. Br J Surg 93:210-215 5. Kellum JM , Kuemmerle JF, O'Dorisio TM, Rayford P, Martin D, Engle K, Wolf L, Sugerman HJ 1990 Gastrointestinal hormone responses to meals before and after gastric bypass and vertical banded gastroplasty. Ann Surg 211:763-770