The study details the history of three patients, who did not have diabetes, who suffered such severe hypoglycemia following meals that they became confused and sometimes blacked out, in two cases causing automobile collisions. The immediate cause of hypoglycemia was exceptionally high levels of insulin following meals. All three patients in the collaborative study failed to respond to medication, and ultimately required partial or complete removal of the pancreas, the major source of insulin, to prevent dangerous declines in blood glucose.
"Severe hypoglycemia is a complication of gastric bypass surgery, and should be considered if the patient has symptoms such as confusion, lightheadedness, rapid heart rate, shaking, sweating, excessive hunger, bad headaches in the morning or bad nightmares," says Mary-Elizabeth Patti, M.D., Investigator in Joslin's Research Section on Cellular and Molecular Physiology and Assistant Professor of Medicine at Harvard Medical School. "If these symptoms don't respond to simple changes in diet, such as restricting intake of simple carbohydrates, patients should be evaluated hormonally, quickly," she adds. Dr. Patti and Allison B. Goldfine, M.D., also an Investigator at Joslin and Assistant Professor of Medicine at Harvard Medical School, were co-investigators of the study.
The study reported on three patients - a woman in her 20s, another in her 60s and a man in his 40s. All three lost significant amounts of weight through gastric bypass surgery, putting them in the normal Body Mass Index (BMI) range. Each, however, developed postprandial hypoglycemia (low blood glucose after meals) that failed to respond to dietary or medical intervention. As a result, all patients required removal of part or all of the pancreas. In all three cases, it was found that the insulin-producing islet cells in their pancreases had proliferated abnormally.
A potential cause of this severe hypoglycemia in these patients is "dumping syndrome," a constellation of symptoms including palpitations, lightheadedness, abdominal cramping and diarrhea, explains Dr. Patti. Dumping syndrome occurs when the small intestine fills too quickly with undigested food from the stomach, as can happen following gastric bypass surgery. But the failure to respond to dietary and medical therapy, and the conditions worsening over time suggested that additional pathology was needed to explain the symptoms' severity, Dr. Patti adds. "The magnitude of the problem was way beyond what doctors typically call dumping syndrome," she says.
Other causes of postprandial hypoglycemia can include overactive islet cells, sometimes caused by excess numbers of cells, a tumor in the pancreas that produces too much insulin, or familial hyperinsulinism (hereditary production of too much insulin), which in severe cases can necessitate removal of the pancreas.
In patients following bariatric surgery, additional mechanisms may contribute to overproduction of insulin. "First, insulin sensitivity (responsiveness to insulin) improves after weight loss of any kind, and can be quite significant after successful gastric surgery," says Dr. Patti. "Second, weight gain and obesity are associated with increased numbers of insulin producing cells in the pancreas, and so some patients may not reverse this process normally, leaving them with inappropriately high numbers of beta cells."
Finally, after gastric bypass surgery, GLP1 (glucagon-like peptide 1) and other hormones are secreted in abnormal patterns in response to food intake, since the intestinal tract has been altered. High levels of GLP1 may stimulate insulin secretion further and cause increased numbers of insulin-producing cells. "In our patients, the fact that the post-operative onset of hyperinsulinemia was not immediate suggests that active expansion of the beta cell mass contributed to the condition," Dr. Patti adds.
Other researchers participating in the study included S. Bonner-Weir, Ph.D., of Joslin; E.C. Mun, M.D., J.J. Holst, M.D., J. Goldsmith, M.D., D.W. Hanto, M.D., Ph.D., M. Callery, M.D., of Beth Israel Deaconess Medical Center. Collaborating investigators from the Brigham and Women's Hospital included R. Arky, M.D., who also is a Joslin Overseer, G.T. McMahon, M.D., M.M.Sc., A. Bitton, M.D., and V. Nose, M.D. All participants are on faculty at the Harvard Medical School. Funding for the study was provided by the National Institutes of Health, the Julie Henry Fund of BIDMC and the General Clinical Research Centers.
Besides helping afflicted gastric bypass patients, the research has hopeful implications for treating people with diabetes, says Dr. Patti. The gastric bypass patients have what many of those with diabetes lack - ample insulin - and perhaps an understanding of this phenomenon could be harnessed to help those with diabetes. "If we can understand what processes are responsible for too much insulin production and too many islet cells in these patients, we may be able to apply this information to stimulate insulin production in patients with diabetes, who lack sufficient insulin," Dr. Patti says.