Hypoglycemia after gastric bypass: An emerging complication

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As the obesity epidemic worsens, more people are opting for weight-loss surgery, including gastric bypass. Of the possible complications associated with this procedure, hypoglycemia secondary to hyperinsulinemia is becoming a more common and therefore more relevant problem.


  • The differential diagnosis for endogenous causes of hyperinsulinemic hypoglycemia after gastric bypass surgery includes insulinoma, late dumping syndrome, and post-gastric bypass hypoglycemia (PGBH).
  • The Whipple triad consists of measured low blood glucose, symptoms of low blood glucose, and reversal of symptoms when low blood glucose is corrected. If the triad is not present, then hypoglycemia is not causing the patient’s symptoms.
  • PGBH should initially be treated with a high-protein, high-fiber, low-carbohydrate diet and then, if hypoglycemia persists, by medication (initially acarbose, then a calcium channel blocker and octreotide or diazoxide or both).
  • PGBH ranges from mild, in which neuroglycopenia resolves with dietary changes with or without acarbose, to severe, in which neuroglycopenia persists despite dietary changes and multiple drugs.
  • Gastric bypass reversal and pancreatic surgery are a last resort for patients with debilitating neuroglycopenia when dietary modification and drug therapy fail.



Bariatric surgery, though beneficial, is associated with complications, one of which is post-gastric bypass hypoglycemia (PGBH).1 The mean time from gastric bypass to documented hypoglycemia is about 28 months.2

PGBH is probably more common than initially thought. In older reports, the prevalence was only 0.1% to 0.36%.1,3 In contrast, in a mail survey in 2015,4 one-third of bariatric surgery patients reported symptoms that raised the suspicion of hypoglycemia. Those with suspicious symptoms were more likely to have undergone Roux-en-Y surgery, to have had no preoperative diabetes, to have had a longer interval since surgery, and to be female. Restricting the suspicion of postprandial hypoglycemia to those who reported more serious symptoms, including needing third-party assistance, the prevalence was 11.6%.

Kefurt et al5 followed Roux-en-Y patients who wore a continuous glucose monitor for 86 months after surgery and found that 38% had hypoglycemia; however, symptoms of hypoglycemia were not discussed.

Thus, the exact prevalence is currently unknown. But as time goes by and more procedures are performed, the incidence will likely rise.


Obesity is rampant, and its prevalence continues to rise. In 2011–2012, more than two-thirds of adults in the United States were reported as obese.6 Complications of obesity such as cardiac disease, diabetes, and cancer lead to increased mortality risk.7 Obesity is difficult to reverse, as many people fail to lose weight with diet, exercise, and pharmacotherapy.

Given the difficulty of losing weight and the complications that arise from obesity, bariatric surgery has become increasingly popular. Not only do patients lose significantly more weight with bariatric surgery than with conventional measures, but surgery also reduces and often cures conditions associated with obesity.8

Nguyen et al9 reported that 671,959 patients underwent gastric bypass procedures in the United States from 2003 to 2008. In a registry maintained by the American Society for Metabolic and Bariatric Surgery10 from June 2007 to May 2009, the most common bariatric procedure in the United States was Roux-en-Y gastric bypass, followed by sleeve gastrectomy.


Differential diagnosis for hyperinsulinemic hypoglycemia

The differential diagnosis for hyperinsulinemic hypoglycemia after gastric bypass surgery includes exogenous and endogenous causes (Table 1). Exogenous causes include abuse of insulin secretagogues such as sulfonylureas or meglitinides and abuse of insulin, which may occur in patients with Munchausen syndrome, Munchausen syndrome by proxy, or malingering. Endogenous causes include insulinoma, early and late dumping syndromes, and PGBH.

Biochemical patterns and timing of hypoglycemia

When differentiating endogenous from exogenous hypoglycemia, insulin and C-peptide levels are useful (Table 2). The pancreas produces proinsulin, which is broken down into insulin and C-peptide. Since exogenous insulin does not have a C-peptide component, people abusing insulin have elevated insulin levels with a low C-peptide level.11 Insulin secretagogues cause endogenous insulin secretion, resulting in elevated levels of both insulin and C-peptide. Thus, a screen for these medications is necessary to determine this as the cause.

Differentiating endogenous causes of hypoglycemia

Differentiating the endogenous causes (insulinoma, early or late dumping syndrome, and PGBH) can be challenging, as all 3 have similar biochemical profiles (Table 2).

Insulinoma is a tumor of pancreatic beta cells that produces excessive amounts of insulin. Unlike dumping syndrome, which only occurs postprandially, insulinoma primarily causes fasting hypoglycemia, although postprandial hypoglycemia can occur less commonly. Insulinoma after Roux-en-Y is rare. Only 7 cases have been reported.12

Dumping syndrome is classified as either early or late.

Early dumping syndrome usually occurs within 20 minutes of eating. The rapid transit of carbohydrates into the small intestine results in a fluid shift and a sympathetic response characterized by tachycardia, nausea, and diarrhea. Hypoglycemia is not present. Early dumping syndrome usually arises during the first few months after surgery.13

Late dumping syndrome usually occurs 1 to 4 hours after ingestion of a carbohydrate load, with symptoms of diaphoresis, dizziness, and fatigue caused by hypoglycemia from an excessive insulin release in response to the carbohydrates.13 It does not tend to cause neuroglycopenic symptoms.14 We define late dumping syndrome as postprandial hypoglycemic symptoms that occur after eating simple sugars and that resolve with dietary changes alone.

Differentiating late dumping syndrome from PGBH is difficult, as the line between the 2 processes is blurred.13

Dietary advice for patients after bariatric surgery

PGBH is defined as postprandial hypoglycemia (although it can be fasting in severe cases), often with neuroglycopenic symptoms, that occurs despite adherence to an acceptable bariatric diet (outlined in Table 3). We categorize PGBH as mild, moderate, or severe. Mild PGBH resolves with dietary changes with or without an alpha-glucosidase inhibitor. Moderate PGBH does not respond to an alpha-glucosidase inhibitor and dietary changes, and alternative or additional medication or medications are needed for resolution. Severe PGBH does not respond to dietary or medical interventions, and patients experience persistent episodes of neuroglycopenia.


Patients with PGBH have a significant postprandial rise in glucose (often with levels > 200 mg/dL), leading to a robust insulin response and a subsequent drop in blood glucose.15

The exact mechanisms causing hypoglycemia are unknown, but excessive release of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are thought to contribute. GLP-1 is primarily secreted in the gut in response to nutrients, causing a glucose-dependent release of insulin and suppression of glucagon, as well as a delay in gastric emptying and motility. Salehi et al16 demonstrated excessive GLP-1 and insulin release after glucose administration in postbypass patients, with a more exaggerated response in those experiencing postprandial hypoglycemia.

Excessive incretin hormones may also contribute to pancreatic islet cell hyperplasia, leading to hyperinsulinism.17 Other proposed mechanisms of PGBH are the lack of a decrease in beta cell mass after gastric bypass, a postoperative increase in insulin sensitivity, a decrease in ghrelin (an insulin counterregulatory hormone), and an abnormal glucagon response.13,17

Pathologic changes vary widely

PGBH is a challenging diagnosis to make pathologically. On review of pancreatic tissue from 36 patients undergoing partial pancreatectomy for PGBH, the pancreatic islet cells of the PGBH group were larger and more irregular compared with controls.18,19 This histologic condition with islet-cell hypertrophy, hyperplasia, and other changes has been termed nesidioblastosis.11,14,20 However, the pancreatic tissue appears grossly normal. The histopathologic findings can vary greatly in individual cases and in one-third of cases the pancreatic changes can be minimal, so that “normal” and PGBH cells can be nearly impossible to distinguish from each other.21

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