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1Post-Bariatric Hypoglycemia: Recognition, Mechanisms, and Management Approaches

Post-Bariatric Hypoglycemia: Recognition, Mechanisms, and Management Approaches

This activity is supported by an independent educational grant from Eiger BioPharmaceuticals.

This activity is jointly provided by Postgraduate Institute for Medicine and AccreditEd.

Release date: December 28, 2017.

Expiration date: December 28, 2018.

Estimated time to complete activity: 1 hour and 15 minutes


Target Audience

This activity is intended for endocrinologists and other post-bariatric surgery team members who are responsible for caring for post-bariatric surgery patients (nutritionists, bariatric surgeons, and gastroenterologists) and who are interested in the management of patients with post-bariatric hypoglycemia (PBH).

Educational Objectives

Upon completion of this activity, participants should be better able to

• Review the definition, clinical scope, consequences, and frequency of hypoglycemia following bariatric surgery

• Explain the possible mechanisms mediating PBH • Review approaches to identify patients at risk, and

optimize treatment decisions if warranted • Compare and contrast the efficacy and safety of current

therapeutic options used to treat PBH and discuss new therapeutic options in development

Physician Continuing Medical Education

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and AccreditEd. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

The Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Disclosure of Conflicts of Interest

Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflicts of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

The authors reported the following financial relationships or relationships they or their spouse/life partner have with commercial interests related to the content of this continuing education activity:

Name of Faculty or AuthorsReported Financial Relationship

Marzieh Salehi, MD, MS No real or apparent conflicts of interest to report

Sten Madsbad, MD No real or apparent conflicts of interest to report

The PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz, MSN, RN, CHCP, have nothing to disclose.

The AccreditEd team has nothing to disclose.

Faculty

Marzieh Salehi, MD, MSAssociate Professor, Department of Biomedical Science, Department of Medicine

Director of Clinical Research, Diabetes & Obesity Research Institute

Cedars Sinai Medical Center Los Angeles, California

Sten Madsbad, MDProfessor, Chief Physician, MD, Dr.Med.SciDepartment of Endocrinology (afs. 541)Hvidovre University HospitalUniversity of CopenhagenCopenhagen, Denmark


IntroductionObesity is an increasing health problem worldwide, with a prevalence that has more than doubled during the period between 1980 and 2014.1 By World Health Organization estimates for 2014, 600 million adults over 18 years of age were considered obese, having a body mass index (BMI) ≥30 kg/m2.1 In the same year in the United States, more than one-third (36.5%) of adults aged 20 years and over, and 17% of youths aged 2 to 19 years, were considered obese.2 The obesity pandemic is especially noteworthy considering its association with multiple related conditions and diseases. In addition to type 2 diabetes, ischemic heart disease, and stroke, obesity contributes to hypertension, dyslipidemia, obstructive sleep apnea, non-alcoholic steatohepatitis, polycystic ovary syndrome, osteoarthritis, cardiovascular disease, gallbladder conditions, skin disease, and several forms of cancer.3,4 Furthermore, obese persons frequently have psychological impairments such as low self-esteem, and they encounter social issues such as prejudice and discrimination.5 Therefore, it is not surprising that obesity is linked to increased mortality risk, decreased quality of life, and enormous direct and indirect health care costs.3,6

Bariatric surgery is recognized as the most effective treatment for morbid obesity, as it improves multiple obesity-related comorbidities.7 Depending on the surgical approach, substantial weight loss, averaging 30 to 40 kg (or about 60% of excess body weight), can be achieved.8 Compared with nonsurgical approaches, bariatric surgery is more effective in achieving sustained weight reductions, improving glycemic control, reducing or eliminating the need for glucose-lowering medications, and improving quality of life in patients with type 2 diabetes.9-13 In over three-quarters of cases, surgical approaches to weight loss lead to an improvement or resolution of type 2 diabetes,8,14 achieving good control of hyperglycemia while reducing cardiovascular risk factors.15 Consequently, bariatric surgery has recently been recommended in a joint statement by international diabetes organizations as a treatment for type 2 diabetes in patients with BMI ≥35 kg/m2, and as a consideration for patients with BMI ≥30 kg/m2 when hyperglycemia is inadequately controlled by lifestyle and optimal medical therapy.15

Globally, the most commonly performed bariatric surgery is the Roux-en-Y gastric bypass (RYGB). In a 2013 survey of worldwide bariatric societies, RYGB was performed in 45% of reported cases, followed by vertical sleeve gastrectomy (VSG, 37%) and laparoscopic adjustable gastric banding (LAGB, 10%) (Figure 1).7,15 Based on studies comparing bariatric surgical procedures vs lifestyle interventions, the efficacy in terms of weight loss and glycemic control corresponds with the popularity of the procedure: RYGB > VSG > LAGB > medical therapy.10,13,15-17 A noteworthy outcome is that the improvement in glycemic control, which occurs rapidly following RYGB and VSG, occurs well in advance of major weight loss.18-21 A randomized controlled trial comparing RYGB with VSG showed that, despite similar weight loss, RYGB achieved more durable glycemic control, and it uniquely restored β-cell function.20

Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Method of Participation and Request for Credit

There are no fees for participating and receiving CME credit for this activity. During the period October 16, 2017, through October 16, 2018, participants must read the educational objectives and faculty disclosures and study the educational activity.

If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation on www.cmeuniversity.com. On the navigation menu, click on “Find Post-test/Evaluation by Course” and search by course ID 12289. Upon registering and successfully completing the post-test with a score of 75% or better and the activity evaluation, your certificate will be made available immediately.


Post-Bariatric Hypoglycemia (PBH): A Bariatric Surgery Complication

As the number of bariatric surgery procedures being performed has steadily increased, an uncommon, but dangerous, complication of these surgeries has been recognized: post-bariatric hypoglycemia (PBH).22,23 Initially reported as a case series of 6 patients in 2005,24 PBH has been most commonly observed following RYGB procedures.23,25 Although the exact prevalence of PBH is unclear, due in part to variation in the definition used for hypoglycemia, one study found that the relative risk for PBH symptoms requiring hospital evaluation was 2- to 7-fold higher in gastric bypass patients than in the reference group who did not have an operation.25 Hypoglycemic symptoms that accompany PBH range from autonomic perturbations to life-threatening neuroglycopenic outcomes such as seizure or loss of consciousness, which could lead to falls or motor vehicle accidents.26 Interestingly, one large retrospective study determined that, although the RYGB procedure was associated with significant reductions in long-term mortality from disease-specific causes, the rates of death not related to disease (eg, accidents) were higher in RYGB patients than in a control group.27

Definition of PBH

PBH is defined by the presence of Whipple’s triad (ie, symptoms of hypoglycemia associated with low glucose, with immediate relief of symptoms following carbohydrate administration) that occurs within 3-5 hours from meal ingestion in a post-bariatric surgery patient. PBH, which seems to represent an extreme phenotype of the glucose-

lowering effects of RYGB, is exclusively postprandial, associated with inappropriately elevated insulin at the time of hypoglycemia, and it generally develops at 1 or more years after gastric bypass surgery. As compared with patients without symptomatic postprandial hypoglycemia after RYGB, those with PBH symptoms experience larger excursions of meal-induced insulin and increased secretion of gut hormones, mainly glucagon-like peptide-1 (GLP-1).28

Importance of Understanding PBH

Despite the serious nature of this condition, therapeutic options for PBH are limited, and the ones that are used are often lacking in efficacy. No Food and Drug Administration (FDA)–approved treatments currently exist.29-31 Given the combination of rising obesity rates and the recent use of bariatric surgery as the most effective treatment for this condition and its comorbidities, such as type 2 diabetes,15 the number of individuals treated with this surgical intervention is already significant and will likely continue to increase. It is therefore important for health care professionals to become aware of the potential for PBH in their post-bariatric surgery patients. This CME activity provides information on how to recognize PBH, its possible mechanisms, and the approach to diagnosis. Existing and emerging treatment options for PBH are also discussed.

Recognition of PBH SymptomsRecognition of PBH is often delayed because the clinical features of hypoglycemia emerge gradually over time and are frequently nonspecific, overlapping with those of other conditions occurring after gastric bypass surgery such as “dumping syndrome” (described on page 8).26 Furthermore, except for a few published recommendations based on anecdotal observations, there have not been any evidence-based, comprehensive guidelines available for clinicians to use.30,32 Although symptoms of hypoglycemia are broad, they can generally be categorized as either autonomic symptoms (resulting from autonomic nervous system activation) or neuroglycopenic symptoms (resulting from glucose deprivation in the central nervous system).26,29 The Edinburgh Hypoglycemia Symptom Scale (EHSS), a validated survey used in insulin-treated diabetes patients to identify symptoms of hypoglycemia, has been used in many studies to assess the presence and severity of hypoglycemic symptoms in patients with PBH.33,34

Autonomic Symptoms

Autonomic symptoms, which include perspiration, shaking, palpitations, anxiety, paresthesia, and hunger,33,34 begin when plasma glucose levels fall below 60 mg/dL (3.2 mmol/L).35 The occurrence of these symptoms can be relatively common after RYGB, but they are nonspecific to PBH, given the overlap with dumping symptoms, and therefore are not reliable for diagnostic purposes.31

Figure 1. Bariatric surgeries associated with PBH.

From Rubino F, et al.15 Used with permission.

Roux-en-Y Gastric Bypass Vertical Sleeve Gastrectomy

A B


Moreover, patients who have experienced repeated episodes of hypoglycemia, as occurs in PBH, may develop hypoglycemic unawareness resulting from an impairment in the release of stress hormones in response to hypoglycemia.36 In fact, gastric bypass surgery has been reported to reduce the triggering of autonomic symptoms in response to induced hypoglycemia as early as 6 months after surgery.28 This was observed among individuals who had normal glucose tolerance at baseline.37 Consequently, hypoglycemia can occur without warning, putting patients with PBH at risk for dangerous, prolonged episodes of hypoglycemia with neuroglycopenia.

Neuroglycopenic Symptoms

Neuroglycopenic symptoms of PBH include blurred vision, confusion, drowsiness, odd behavior, speech difficulty, incoordination, dizziness, and inability to concentrate.33,34 The occurrence of postprandial neuroglycopenic symptoms associated with low glucose values are a hallmark of PBH, and they are more closely related to the degree of hypoglycemia than are other symptoms.31,38 Neuroglycopenic symptoms occur when plasma glucose concentrations fall below 50 mg/dL (2.8 mmol/L).35 Although several underlying causes have been proposed,31 neuroglycopenic symptoms are considered to be a direct result of brain glucose deprivation,26,29 which can cause cognitive impairment, behavioral changes, psychomotor abnormalities, seizures, and loss of consciousness.26,39 Such serious consequences underscore the importance of recognition and diagnosis of PBH.

PBH: Post-Bariatric Hypoglycemia

• An uncommon complication of bariatric surgery

• Generally occurs 1 or more years after surgery

• Characterized by postprandial hypoglycemia, usually 1 to 3 hours after meals

• Diagnosis requires the presence of hypoglycemic symptoms (mainly neuroglycopenia) associated with low blood glucose and the relief of symptoms with carbohydrate administration

• Prominent postprandial neuroglycopenic symptoms are a hallmark of PBH

• PBH is associated with excessive postprandial insulin and GLP-1 secretion

• First-line therapy for mild hypoglycemia involves use of nutritional modifications with carbohydrate restriction

• For more severe hypoglycemia, therapy with pharmacologic agents (eg, acarbose, calcium channel blockers, diazoxide, and somatostatin analogs) may be considered

• Investigational drugs for PBH are in development, but currently, no FDA-approved treatments for PBH exist

Risk Factors and Predictive Markers Certain risk factors and predictive markers have been proposed as playing a possible role in PBH, but published reports have often conflicted, and have been based on very small sample sizes. Therefore, additional research is necessary.

A retrospective, questionnaire-based study done in the United States found that patients who underwent RYGB or VSG and subsequently reported symptoms of PBH were more likely to report preoperative symptoms of hypoglycemia.40 Another study by the same group, which excluded patients with diabetes or preoperative hypoglycemia, found that PBH was associated with lower preoperative HbA1c levels and greater weight loss at 6 months.22 Similarly, in a small study of post-bariatric surgery patients reporting symptoms of PBH, high presurgical insulin sensitivity and better β-cell glucose sensitivity were predictors of PBH following either RYGB or VSG.41

The role of gender, age, race, and presurgical or postsurgical body weight or BMI as risk factors for PBH is less clear. The BOLD study (Bariatric Outcomes Longitudinal Database) followed 275,618 patients, among whom RYGB was the most commonly performed procedure (145,582).42 For the RYGB patients, there was no statistically significant association between post-RYGB hypoglycemia and age, race, or gender.42 There was also no statistically significant association between preoperative BMI or weight and the risk of developing subsequent hypoglycemia.42 Other studies, however, have reported a difference in the risk for hypoglycemia favoring women. A poll of more than 800 post-bariatric surgery patients found women to be at higher risk for self-reported hypoglycemia, especially those who had lost most of their weight after the gastric bypass.43 The risk persisted long after the surgery was performed. In another questionnaire-based study, by Nielsen et al., younger age and a lower postsurgical BMI were predictors for PBH in post-RYGB patients.44 A major limitation of these studies is the lack of documented low glucose at the time of symptoms.

Prevalence of PBHThe true prevalence of PBH is unknown, but PBH is believed to be an uncommon or rare complication of bariatric surgery. Many published studies addressing the prevalence of PBH are limited to patient self-reported postprandial symptoms and do not include any plasma glucose measurements. Conversely, some studies use variable thresholds for defining low plasma glucose while neglecting the presence or absence of symptoms. Ideally, the incidence of PBH would be based on demonstration


of Whipple’s triad, or minimally, the combination of postprandial hypoglycemia verified by blood glucose measurements together with hypoglycemic symptoms.

The prevalence of PBH following RYGB surgery has been variously reported as ranging from 0.1% to 75%,39,45 depending on the diagnostic criteria and the method of data collection used in the study. Table 1 summarizes several of

these studies, and includes potential limitations that may have influenced the accuracy of the reported prevalence. Future studies that base estimates of PBH prevalence on validated glucose measurements in both symptomatic and asymptomatic patients who are followed for many years after surgery will permit a more precise characterization of the true prevalence of PBH.

Study PopulationMethod of

PBH Assessment Incidence Limitations

Swedish studyMarsk, et al.25

• 5040 RYGB patients

• Hospitalization rates for hypoglycemia-related conditions

• <1% (hypoglycemia leading to hospitalization)

• Inpatient care for hypoglycemia was more common after RYGB surgery than in the general population

• No specific information regarding glucose values or fasting vs fed conditions

Prospective CGM + symptoms following MMTTHalperin, et al.32


• 10 with neuroglycopenia symptoms (9 on treatment)

• 6 asymptomatic

• CGM following MMTT • Hypoglycemia = glucose <70 mg/dL (3.9 mmol/L)

CGM results • 9 of the 10 patients with neuroglycopenia had hypoglycemia by CGM

• 3 of the 6 asymptomatic patients had hypoglycemia by CGM

MMTT results (less precise than CGM) • 3 of 9 neuroglycopenia patients

• 3 of 5 asymptomatic patients

• Small sample size • Previous medical management of neuroglycopenia could have modified the glycemic variable and therefore affected the study outcomes and conclusions

BOLD42 • 275,000 patients

• RYGB (n=145,582)

• VSG (n=29,930)

• LAGB (n=100,106)

• Self-report of hypoglycemia

0.1% • Patient-reported rate of hypoglycemia was not verified by glucose monitoring

• Influence of concomitant medications was unknown

Prospective, longitudinal study Itariu, et al.50

• 36 nondiabetic patients at ~1 yr after gastric bypass

• Post-load glucose <60 mg/mL at 2 hr during OGTT

• 50%Majority reported no symptoms, including 1 patient with glucose 14 mg/dL (0.78 mmol/L)

• Low glucose following OGTT, in the absence of any symptoms, reflects a high incidence of asymptomatic low glucose values in background non-operated population during OGTT

• Small sample size

Table 1. Studies reporting PBH incidence.

CGM=continuous glucose monitoring; EMR=electronic medical records; MMTT=mixed meal tolerance test; OGTT=oral glucose tolerance test.


Study PopulationMethod of

PBH Assessment Incidence Limitations

Johns Hopkins Lee, et al.40

• 450 patients

• RYGB (78.9%)

• VSG (21.1%)

• Questionnaire

• PBH based on postprandial symptoms alone

• PBH based on neuroglycopenic symptoms, with or without the need for assistance, or medically confirmed hypoglycemia

• 34.2% with postprandial symptoms alone

• 11.6% with more severe symptoms only

• Bias of response and recall

• Lack of confirmation of hypoglycemia, potentially including patients with dumping syndrome

Prospective CGM following MMTT Kefurt, et al.47


• With or without dumping syndrome

• 86 mo postsurgery (median)

• 5-day CGM with normal eating habits, compared with MMTT

• Hypoglycemia = glucose ≤55 mg/dL (3.1 mmol/L)

CGM results

• Any hypoglycemic episode in 30 of 40 patients (75%) over 5 days

• Duration: 71 ± 25 min (mean)

• 3±1 episodes/patient (mean) over 5 days

• Nocturnal: 38%

• Duration: 94 ± 60 min

MMTT results

• Hypoglycemia in 15 of 51 patients (29%)

• Not longitudinal

• Relationship between symptoms and episodes of hypoglycemia (part of Whipple’s triad) was not examined

• OGTT or MMTT may provide false-negative results because they do not reflect real-life conditions

3-day CGM study

Abrahamsson, et al.16


• 15 non-operated controls (15 duodenal switch patients not included here)

• CGM during normal daily activity

• Hypoglycemia = glucose 60 mg/dL (3.3 mmol/L)

• High glycemic variability

• 2.9% of time spent in hypoglycemia

• Relationship between symptoms and episodes of hypoglycemia (part of Whipple’s triad) was not examined

Denmark study

Gribsholt109


• Self-report of hypoglycemia symptoms that led to health care contact

6.6% • Patient-reported rate of hypoglycemia was not verified by glucose monitoring

• Influence of concomitant medications was unknown

Single-center cohort

Lee, et al.22


• No pre-existing diabetes or preoperative diagnosis of hypoglycemia

• EMR

• PBH = any glucose <60 mg/dL (3.3 mmol/L) in the EMR, any clinical diagnosis of hypoglycemia, or use of any medication to treat hypoglycemia for ≥1 mo after surgery

• Severe hypoglycemia = any glucose <40 mg/dL (<2.22 mmol/L), or any visit to the emergency room or hospitalization because of hypoglycemia using ICD-9 code

• Mean follow-up: 4.8 yr

For PBH

• 3% at 1 yr, 10% at 3 yr, and 13% at 5 yr after surgery

For severe hypoglycemia

• 0.1%, 0.3%, and 0.7%, respectively

• Failure to correlate biochemical hypoglycemia with symptoms

• Medications for hypoglycemia may have been used to treat dumping syndrome, and thus inclusion of these cases may have slightly underestimated the PBH incidence

Table 1 (cont.)


PBH DiagnosisEstablishing a diagnosis of PBH begins with recognition of the specific constellation of indicators known as Whipple’s triad: postprandial neuroglycopenic symptoms which are associated with a low blood glucose concentration (see below) in the absence of treatment with insulin or insulin secretagogues, and which are relieved by correcting the low glucose.23,31,39 Autonomic symptoms suggestive of hypoglycemia from other conditions such as dumping syndrome may overlap with those of PBH. Because some patients fail to demonstrate pronounced autonomic symptoms of hypoglycemia,32,46,47 neuroglycopenic symptoms may be more reliable for identifying patients likely to have recurrent hypoglycemia.38 Some investigators have used circulatory levels of insulin and C-peptide associated with low glucose—ie, insulin ≥3 μU/mL (18 pmol/L) and C-peptide ≥0.6 ng/mL (199 pmol/L)—as part of the diagnostic criteria.23,24 However, measuring insulin secretion in the context of low glucose is only warranted if fasting hypoglycemia is suspected (eg, by nocturnal symptoms or early onset after surgery). Furthermore, it is difficult to compare cut-off levels between insulin and C-peptide assays.

Hypoglycemic Thresholds for PBH

There is currently no consensus on the definition of biochemical hypoglycemia in patients with PBH.32,38 Substantial heterogeneity has been reported in the literature for plasma glucose levels that define hypoglycemia associated with PBH.26,30,45,48 Some reports have used a threshold of <50 mg/dL (2.8 mmol/L),43,48,49 while others have used <60 mg/dL (3.3 mmol/L).49,50 In the earliest report of PBH by Service et al., a serum glucose level of <55 mg/dL (3.1 mmol/L) was used to define hypoglycemia.24 The definitions for hypoglycemia in nondiabetic patients by The Endocrine Society (<55 mg/dL, 3.1 mmol/L)51 and the International Hypoglycemia Study Group of the American Diabetes Association (<54 mg/dL, 3.0 mmol/L)52 represent a reasonable threshold when diagnosing PBH as part of Whipple’s triad.29 In healthy individuals, hypoglycemic symptoms may become evident at a mean plasma glucose concentration of approximately 55 mg/dL (3.0 mmol/L), but this may shift to lower concentrations in patients with recurrent hypoglycemia.28,32,38,49,51

Provocative Testing

Important clues to support the diagnosis can be gained by reviewing the patient’s medical history, conducting a comprehensive interview with the patient and family members who witnessed the episodes, and obtaining information regarding glucose levels measured at the time of symptoms. Ambulatory, blinded, continuous monitoring of interstitial fluid glucose levels over 3 to 7 days can be

used to identify the peak and nadir glucose levels under real-world conditions. Used in conjunction with a food and symptom log, continuous glucose monitoring (CGM) provides information regarding glucose excursions after meals and the relationship between low glucose levels and symptomatic episodes, as well as on the frequency of this condition. Clinicians should be aware, however, that the accuracy of CGM in the hypoglycemic range is not optimal.31,53 Thus, in most cases, the diagnosis should be confirmed using provocative testing.

Some investigators have measured hypoglycemia following an oral glucose tolerance test (OGTT),49,54-56 but the OGTT may also induce hypoglycemia even in patients who have had no bariatric surgery.51 Therefore, the OGTT is not recommended for this purpose.48,57 Ideally, if a post-bariatric surgery patient has postprandial neuroglycopenic symptoms of hypoglycemia and no documented low glucose levels at home, fulfilling Whipple’s triad, a mixed-meal tolerance test (MMTT) should be performed. Although lacking standardization, the MMTT has the advantage of being more physiologically relevant.57 Variable test meals, from a liquid mixed meal to a combined solid and liquid mixed meal, have been tried across different referral centers for this purpose. During the meal test, blood is drawn for estimation of plasma glucose during the fasting state and every 5 to 30 minutes after the mixed meal.48 The presence of hypoglycemic symptoms when the blood glucose level is below 50-55 mg/dL (2.8-3.0 mmol/L) and the absence of symptoms when glucose levels are corrected confirms the diagnosis.

Differential Diagnosis

PBH is exclusively postprandial.39,40 Therefore, any hypoglycemia that occurs under fasting conditions (beyond 5 hours from eating), or hypoglycemia which occurs within the first year from surgery, should prompt a 3-day fasting test to rule out insulinoma or other etiologies causing fasting hypoglycemia.26,40,48 Patients who have undergone bariatric surgery can also experience postprandial gastrointestinal symptoms (abdominal pain, bloating, nausea, and diarrhea) as well as vasomotor symptoms (fatigue, flushing, palpitations, perspiration, tachycardia, and syncope), collectively termed “dumping syndrome.”26,58 Dumping syndrome is thought to result from undigested food reaching the jejunum too rapidly due to anatomic alterations made during the bariatric surgery; it generally occurs within 1 hour of ingesting calorie-dense foods (eg, refined sugars and fats).23,48,58 Dumping syndrome often occurs early in the postoperative period, from a few days to 1 year after the surgery, when the patient reinstates eating very energy-dense food, especially with fast-absorbing carbohydrate. Dumping syndrome generally responds to nutritional modification (frequent, small, low-carbohydrates meals) or pharmacologic therapy.26,31


The presence of more prominent neuroglycopenic symptoms in PBH, which may include cognitive dysfunction and a hypoglycemia that is less responsive to dietary modifications, help to differentiate PBH from dumping syndrome.30,31,39 Additionally, the timing of onset of PBH, at 1 or more years after surgery, is a key differentiator. Therefore, hypoglycemia which manifests within the first year of surgery should prompt a work-up for non-PBH etiologies.48 Alternative explanations for postprandial hypoglycemia, such as alcohol intake, liver and renal disease, adrenal insufficiency, or concomitant use of medications to treat diabetes, should be excluded.

In summary, diagnosis of PBH requires a detailed medical and dietary history in combination with documentation of low plasma glucose concentrations, optimally fulfilling the criteria of Whipple’s triad.48 Understanding of the definition of PBH, the timing of symptoms relative to meals, and the presumed pathophysiology all aid in the diagnosis of PBH.

Pathophysiology of PBHThe precise mechanisms underlying postprandial hypoglycemia in patients who have undergone gastric bypass surgery are emerging but remain incompletely understood.38 Most likely, the pathophysiology of PBH is multifactorial. PBH appears to be procedure-specific, occurring particularly in association with RYGB.59,60 PBH is unlikely related to weight loss per se, because other restrictive procedures, such as vertical banded gastroplasty or gastric banding, do not lead to a higher incidence of postprandial hypoglycemia than in the general population.25 Moreover, the maximum weight loss after RYGB is generally achieved within 6 to 12 months after surgery, whereas PBH manifests at 1 year or more, and sometimes several years, after surgery.

Several hypotheses have been proposed to explain both the resolution of diabetes in the majority of patients and the development of PBH in a subgroup of individuals with possible susceptibility to glucose abnormalities following RYGB.

β-Cell Hyperplasia and Hyperfunction

PBH is characterized by inappropriate secretion of insulin from pancreatic β cells in the presence of low blood glucose.24,61 Early investigators reported hyperplastic β cells in the small number of patients with PBH who had undergone partial pancreatectomy.24,62 These findings were subsequently challenged by Meier et al., who compared histology samples from these same patients with those from obese or weight-matched controls.63 They found that β-cell area was not increased in PBH patients, nor was there any increase in β-cell formation or decrease in β-cell loss, when compared with obese, or even lean, control patients. However, this group noted that β-cell nuclear diameter was increased, suggesting increased insulin secretory activity.

Increased Nutrient Transit Following Gastric Bypass Surgery

Recent evidence17,29,64 indicates that the exaggerated β-cell response to meal ingestion after RYGB is associated with faster nutrient transit and enhanced gut-islet axis activity as a result of the rerouted gastrointestinal tract. Following RYGB, the rapid transit of food from the gastric pouch into the small intestine produces a higher, and more rapid, rise in glucose levels as compared with the response in nonsurgical controls.38 The evidence suggests that the systemic appearance of nutrients after meal ingestion is higher in persons with PBH than in those without.61 Along with this, secretion of postprandial insulin and insulinotropic hormone (mainly GLP-1) is also exaggerated in patients with hypoglycemia vs those without hypoglycemia (Figure 2).17,26,65,66

Figure 2. Potential mechanisms involved in PBH.

CNS=central nervous system.

Patti ME, Goldfine AB.26 Used with permission.


McLaughlin et al. noted significant improvements in neuroglycopenic symptoms in a post-RYGB patient who had a gastrostomy tube placed during hospitalization for a small-bowel obstruction.66 Subsequent testing demonstrated complete reversal of metabolic abnormalities, including hypersecretion of insulin and GLP-1, when a standardized liquid meal was administered via the gastrostomy tube into the remnant stomach, but not by the oral route. This study supports a mechanism for PBH related to altered nutrient delivery leading to increased β-cell response.

Enhanced Gut-Pancreatic Axis Activity: Emerging Role of GLP-1

Postprandial glucose metabolism is tightly regulated by factors derived from the gastrointestinal system affecting β-cell response to meal ingestion in proportion to the ingested nutrient. The difference in insulin secretion after oral administration of glucose vs an equivalent dose of intravenous glucose is termed the “incretin effect.” The incretin effect is partly attributed to 2 gastrointestinal hormones, gastric inhibitory peptide (GIP) and GLP-1, secreted from K cells and L cells, respectively, after eating.64,67 These 2 incretins together are responsible for approximately 50% of postprandial insulin secretion in healthy individuals.17,67

In patients with diabetes, weight loss–independent glycemic improvement has been partly linked to an enhanced incretin effect associated with increased GLP-1 secretion.64 In post-RYGB patients with PBH, meal-induced insulin and GLP-1 secretion is exaggerated as compared with that in asymptomatic patients.28 Augmented postprandial hyperinsulinemia in symptomatic patients seems to be caused by increased insulin secretion due to an exaggerated GLP-1 action,61 as well as by reduced insulin clearance.38,68 Elimination of GLP-1 action by continuous intravenous infusion of a GLP-1 receptor antagonist corrects the hypoglycemia along with suppressing insulin secretion.61,69 Despite the exaggerated GLP-1 release and action, β-cell sensitivity to GLP-1 and GIP remains unchanged as compared with the preoperative state, indicating that intrinsic β-cell function remains unchanged in glucose-tolerant patients even years after RYGB.46,70 Furthermore, GLP-1 receptors were not overexpressed in pancreatic specimens from PBH patients vs controls.71 Therefore, altered gut-islet regulation resulting in inappropriate insulin secretion appears to drive the risk of postprandial hyperinsulinemic hypoglycemia in PBH.46,61,69,70,72-74

Impaired Counter-regulatory Response to Hypoglycemia

Defects in counter-regulatory hormones such as cortisol and glucagon may also be involved.28,37,75 Post-RYGB patients have increased glucagon secretion after eating,28 although patients with PBH have no further increase in

glucagon response during hypoglycemia as compared with those without hypoglycemia. A cross-sectional analysis conducted in 65 patients who had undergone gastric bypass surgery and 11 controls (matched by BMI) assessed insulin secretion rates and islet cell and gastrointestinal hormone responses to liquid mixed meals.38 Although glucagon levels were elevated in the patients with PBH, there were no differences between those who developed hypoglycemia and those who did not, suggesting an impaired α-cell response to low glucose following RYGB surgery. Two separate subsequent studies conducted using a hyperinsulinemic hypoglycemic clamp showed that the α-cell response to hypoglycemia was impaired after this surgery,37,76 which, in turn, could interfere with recovery from hypoglycemia.

Summary of Pathophysiology of PBH

PBH is an extreme phenotype of the post-meal glycemic profile present after RYGB and is caused by multiple factors. The rapid emptying of nutrients from the gastric pouch into the gut after RYGB leads to an altered postprandial glucose pattern exhibiting earlier and higher peak glucose levels and lower nadir glucose levels. This pattern is exaggerated in patients with PBH. In addition, meal-induced insulin secretion is enhanced, partly due to increased GLP-1 secretion and action. Patients with PBH have larger postprandial insulin excursions (hyperinsulinemia), mediated by augmented GLP-1 action. In fact, blocking GLP-1 signaling corrects hypoglycemia in affected individuals via suppression of the insulin response to meal ingestion.

Altered glucose patterns, in addition to dysregulated islet cell function involving both β cells and α cells, predispose susceptible individuals to glucose abnormalities.61 Coupled with the greater β-cell secretory response to meal ingestion, impaired circulatory clearance of insulin in post-RYGB patients with PBH contributes to their post-meal hyperinsulinemia.

Current Approaches to Treatment Management of hypoglycemia after gastric bypass surgery must be tailored to the severity of the condition.29,77-79 The initial aim of treatment is to lower the postprandial glucose surges, thereby reducing insulin responses, by slowing nutrient transit. Therapeutic options are limited, and their effectiveness is not well investigated. Dietary modifications are the cornerstone of treatment, followed by stepped medical interventions, generally beginning with acarbose. For persistent hypoglycemia, surgical approaches may need to be considered.39,58,80


Medical Nutritional Therapy

First-line therapy for mild hypoglycemia involves the use of nutritional modifications. These typically involve getting the patient to reduce the intake of carbohydrates during a single meal, avoid high-glycemic-index carbohydrates, split the food intake into 5 to 6 small meals per day, and combine carbohydrate with protein and fat for each meal and snack consumed.26,29 The efficacy of these measures has been shown in various studies.

Bantle et al. demonstrated that a low-carbohydrate test meal effectively prevented hyperinsulinemia and hypoglycemia in 3 patients with neuroglycopenic symptoms of PBH.78 Subsequently, Kellogg et al. studied 14 patients with postprandial symptoms suggestive of hypoglycemia without any documented low glucose levels who were 1 to 10 years post-RYGB.77 After a mixed meal high in carbohydrates (80 g carbohydrates), 9 of 14 patients experienced hypoglycemia (glucose <50 mg/dL) within 120 minutes. When an isocaloric low-carbohydrate meal (2 g carbohydrates) was consumed, the patients showed no changes in plasma glucose levels, as would be expected given the amount of carbohydrates consumed.

More recently, Botros et al. evaluated the effects of reducing meal carbohydrate content and the glycemic index on glycemic responses.79 In their study, 14 patients with post-RYGB hypoglycemia received 2 meal tests: a solid mixed meal containing 30 g carbohydrate, and an isocaloric liquid mixed meal containing 28 g low-glycemic-index carbohydrates. Neither test meal caused hypoglycemia, regardless of glycemic-index. As a dietary strategy for post-RYGB PBH, these investigators thus recommended carbohydrate restriction at each meal, a minimum protein intake of 1.0 to 1.5 g/kg ideal body weight, and a total of 5 to 6 small meals per day.79 Manipulation of carbohydrate composition has also been shown to narrow postprandial glucose excursions and increase glucose nadirs in patients with PBH.81 Additionally, the use of uncooked starch as a snack or in addition to a meal has been used for treatment of this condition based on studies of nonsurgical insulin-induced hypoglycemia in patients with diabetes.82

The carbohydrate-restricted diets discussed above are generally effective in the treatment of mild to moderate hypoglycemia and dumping syndrome. However, their efficacy appears to be limited in patients with more severe hypoglycemia. For patients with more severe forms of hypoglycemia, escalation of therapy to pharmacologic agents is often necessary.26,48,58

Pharmacologic Options

In the absence of FDA-approved treatments for PBH, several types of pharmacologic agents used to treat dumping syndrome or insulinoma have been examined in PBH. Unfortunately, the evidence for their efficacy is generally limited to smaller studies and case reports.42,48,58,83,84

Pharmacologic agents that have been used to manage PBH include acarbose, diazoxide, calcium channel blockers, and somatostatin analogs.26,83

Acarbose is an α-glucosidase inhibitor that prevents hypoglycemia by delaying glucose absorption from the intestine, thereby reducing blood sugar levels, plasma insulin levels, and GLP-1 secretion.29 Premeal acarbose treatment has been shown to slow the digestion of carbohydrates, and it is considered a first-line therapy for dumping syndrome and hypoglycemia.26,85 Valderas et al. conducted a study of 8 post-RYGB patients with neuroglycopenic symptoms, measuring variables before and after treatment with 100 mg acarbose.86 Prior to acarbose treatment, 5 of the 8 patients developed asymptomatic hypoglycemia (glucose <50 mg/dL, 2.8 mmol/L), hyperinsulinemia, and an exaggerated GLP-1 response. Acarbose treatment decreased GLP-1 and hyperinsulinemia, and avoided postprandial hypoglycemia. Gastrointestinal side effects from acarbose include excessive flatulence, bloating, and diarrhea.85

Diazoxide, a potassium channel agonist that inhibits the secretion of insulin by β cells, has been used to treat hypoglycemia due to insulinoma. A case report on the use of diazoxide to treat post-RYGB PBH described a 52-year-old woman with a past medical history of obesity, type 2 diabetes, and dyslipidemia.84 Her postprandial blood glucose levels were as low as 29, 48, and 55 mg/dL when measured during episodes of hypoglycemia, which occurred at 2 hours after a meal, along with symptoms of sweating, hunger, nervousness, and discomfort. Despite dietary modifications, symptoms persisted. Use of diazoxide 50 mg twice a day, however, eliminated the symptoms, and the resolution was sustained, provided the diazoxide was not discontinued.

Hyperglycemia and edema are major limiting factors for the use of this agent.29,87

Calcium channel blockers, such as nifedipine and verapamil, have also been used to reduce the secretion of insulin in bariatric surgery patients with hypoglycemia.26,48,83 In one case study, the patient achieved a reduction in the frequency and intensity of symptoms after 1 month of verapamil therapy.83 Although the dose of verapamil was increased in an attempt to control persistent symptoms, this was not tolerated by the patient due to severe drowsiness. The addition of acarbose (50 mg 3 times daily) to the verapamil, however, helped to significantly improve the hypoglycemic episodes.

Somatostatin analogs are frequently used for insulinoma, and they act by blocking somatostatin receptors throughout the body. Therefore, they block the secretion of many hormones involved in glucose homeostasis, leading to lower insulin, GLP-1, growth hormone, and glucagon levels.26,88 The use of somatostatin analogs is suggested for patients with PBH who do not respond to dietary modifications or who cannot tolerate acarbose treatment.58 Several case reports describe the successful use of somatostatin analogs for


PBH.88-90 In one patient, after 6 months of treatment with octreotide, GLP1-levels and insulin response were reduced, as compared with levels measured after the same meal administered 6 months previously. The patient remained asymptomatic for 4 years after being switched to lanreotide, a longer-acting analog.88

Surgical Therapies

Surgical options for PBH include reducing the size of the gastrojejunal anastomosis or reversing the gastric bypass.26,40 Reversal of gastric bypass is not always successful in correcting the hypoglycemia,62 and revision surgery may be accompanied by weight regain, reappearance of diabetes, and the risks inherent with any surgical procedure.91 As discussed previously, providing nutrition solely through a gastrostomy tube placed into the gastric remnant (original stomach) has also been utilized for treatment in severe cases26,66,80 or as a potential predictor of positive outcome after RYGB reversal. In a recent case report, GLP-1 and insulin responses were attenuated, and plasma glucose and symptoms improved, following gastric tube feeding. Further improvement was noted after reversal of the RYGB procedure.87 The patient in this case report remained free of hypoglycemic symptoms for over 10 months of follow-up.

A review of 17 cases of RYGB reversal found resolution of symptoms in 13 cases (76%).91 However, other reports suggest that the reversal of gastric bypass is not universally successful for resolving PBH.62,92 Similarly, another report of 2 individuals undergoing reversal after RYGB described marked reduction in GLP-1, but persistent hyperinsulinemia and hypoglycemia.92 In these patients, GIP levels were substantially elevated after the reversal.87 One explanation for the opposing findings for RYGB reversal might be the use of slightly different surgical techniques in relation to whether the Roux-limb is resected or retained, and the effects on secretion of incretin hormones and insulin.92,93

Pancreatic resection (Whipple procedure) has been used in the past to correct moderate to severe hypoglycemia, but it is no longer recommended due to its variable effectiveness and its invasiveness.26,42 Laparoscopic restoration of gastric restriction prior to a pancreatectomy has been investigated. In a study involving 12 patients who developed severe postprandial hypoglycemia after RYGB, several options were compared: gastric restriction by placement of a silastic ring (n=8), simultaneous distal pancreatectomy (n=2), and placement of an adjustable gastric band around the pouch (n=4).94 At follow-up after 3 to 12 months, all but one of the patients was either asymptomatic or significantly improved with respect to postprandial hypoglycemia and dumping symptoms. The one patient who had recurrent hypoglycemia required a distal pancreatectomy and was then free of hypoglycemic symptoms at 4 months postsurgery. Despite relief of symptoms in the short term, the long-term effectiveness of partial pancreatectomy beyond 2 years is poor.95

To summarize, reversal of RYGB has been described as a therapy of last resort.48,93 Pancreatectomy is not effective over the long term, and it is associated with an increased rate of morbidity and can lead to insulin-dependent diabetes; thus, full or partial pancreatectomy is no longer recommended.29,48 The benefit of relief of symptoms achieved by surgical options must be carefully weighed against the relative risks of regaining the weight, reestablishing diabetes, and complications of surgery.29

Emerging TherapyExendin 9-39, a GLP-1 Receptor Antagonist

GLP-1 plays an important role in glucose tolerance after RYGB via increased insulin secretion and suppression of glucagon secretion in the postprandial state.96 The role of endogenous GLP-1 has been elucidated through studies using a GLP-1 receptor antagonist called exendin 9-39.73,97-99 Exendin 9-39 is a truncated version of exendin-4, a high-potency agonist. Exendin 9-39 is an antagonist at the GLP-1 receptor of insulin-secreting β cells.100 Blockade of the GLP-1 receptor with exendin 9-39 following RYGB surgery has been used as a tool to investigate the role of endogenous GLP-1 in improving glucose tolerance in patients with type 2 diabetes,73 and also in the pathophysiology and treatment of PBH.38

Role of GLP-1 in improving glucose tolerance after RYGB

Several studies have employed exendin 9-39 to examine the role of endogenous GLP-1 in postprandial insulin secretion in patients without diabetes.19,61,72,96 The findings from these studies reveal a greater effect of GLP-1 on glucose tolerance and meal-induced insulin secretion after RYGB. In patients with diabetes, however, the findings are not consistent.

Jorgensen et al. used the GLP-1 receptor antagonist to study 9 patients with type 2 diabetes before, and 3 months after, RYGB surgery.97 Exendin 9-39 did not affect β cell function or glucagon release prior to surgery, but it did impair glucose tolerance. Following RYGB, exendin 9-39 decreased glucose sensitivity, increased glucagon secretion, and impaired glucose tolerance. These results were not observed by Vetter et al., who compared GLP-1-induced insulin secretion among patients with similar weight loss after RYGB or life style intervention.101 Similarly, Jimenez et al. reported only a limited deterioration of postprandial glucose tolerance using exendin 9-39 in 8 patients with type 2 diabetes remission following RYGB as compared with nonsurgical controls.98 Both of these studies reported a larger effect of GLP-1 on insulin secretion after RYGB but a trivial effect on the glucose profile. This suggests that the dramatic increase in secretion of GLP-1 long after RYGB surgery may not be the key determinant of the resolution of type 2 diabetes.


Role of GLP-1 in PBH

Despite a questionable role of GLP-1 in restoring glucose tolerance after RYGB, as just discussed, enhanced GLP-1 secretion and action have been shown to play a major role in the pathogenesis of PBH.

Salehi et al. used exendin 9-39 to further elucidate the role of GLP-1 in PBH.61 The study involved 24 individuals: 9 patients with recurrent documented hypoglycemia based on Whipple’s triad after gastric bypass surgery, 7 patients who were asymptomatic after gastric bypass, and 8 healthy control subjects. Exendin 9-39 eliminated postprandial hypoglycemia in all patients with symptomatic PBH. This was associated with reducing total insulin secretion as well as β-cell glucose sensitivity during MMTT. As observed in other studies, glucagon levels were higher in gastric bypass patients than in controls who had not undergone surgery. Exendin 9-39 increased glucagon levels in both the symptomatic and asymptomatic gastric bypass groups, indicating that while α-cell function differs between these and control subjects, it is regulated by GLP-1 in both groups.

These results were consistent with findings from a previous study by the same investigators that used a glucose clamp, precluding any assessment of glycemia.73 The more recent study represented an advance over the older one because it infused exendin 9-39 during an MMTT (to replicate the meal-time setting in which PBH patients experience hypoglycemia) and assessed changes in blood glucose levels as the primary outcome.61 Limitations of this study include limited study size and a highly selected study population. Together, these studies demonstrated that GLP-1 activity contributes to the pathogenicity of PBH and that GLP-1 antagonists may have an important therapeutic role in treating the condition.

The ability of exendin 9-39 to correct hypoglycemia in symptomatic PBH patients was confirmed in a cross-over study by Craig et al.69 In this study of 8 patients with confirmed PBH, the effects of intravenous infusion of exendin 9-39 were compared with placebo following OGTT. Study participants satisfied Whipple’s triad, and demonstrated a plasma glucose level ≤55 mg/dL (3.1 mmol/L) during OGTT in association with plasma insulin ≥21 pmol/L or C-peptide >0.1 nmol/L. Infusion of exendin 9-39 during OGTT prevented hypoglycemia in all 8 participants, ameliorating hyperinsulinemia and raising the postprandial glucose nadir by more than 70%. In addition to effects on GLP-1, exendin 9-39 infusion reduced GIP levels by 15%, but it only mildly increased glucagon levels. The authors concluded that the bulk of insulin secretion in these symptomatic PBH patients was mediated through GLP-1 receptor signalling, supporting a critical role for GLP-1 in mediating PBH.

The use of exendin 9-39 for the treatment of PBH has been evaluated in a single ascending-dose study using a subcutaneous formulation of the GLP-1 antagonist.74 In the first part of the study, the bioavailability of exendin

9-39 after subcutaneous vs intravenous administration was examined in a single participant. In the second phase, involving single ascending doses in 8 participants, subcutaneous administration of exendin 9-39 after OGTT decreased peak insulin levels by 57%, increased postprandial glucose nadir by 66%, and reduced neuroglycopenic symptoms by 80% on average.

Repeat dosing of subcutaneous exendin 9-39 has been studied by Tan et al.,102 who conducted a 2-part study involving 19 participants with PBH. In the first part, 14 patients underwent a baseline OGTT, followed by 3 consecutive days of up to twice-daily administration of a lyophilized formulation of exendin 9-39 in doses ranging from 2.5 to 32 mg. In the second part, 5 participants underwent a baseline OGTT, followed by up to 3 consecutive days of twice-daily dosing of 30 mg of a novel liquid formulation of exendin 9-39. In both parts, a repeat OGTT was conducted on day 3 to evaluate metabolic, clinical, and pharmacokinetic responses. Interim results demonstrated dose-dependent improvements in postprandial hypoglycemia and substantial reductions in symptoms. Neuroglycopenic symptoms were prevented, and doses were identified (≥18 mg) which prevented hypoglycemia. The liquid formulation provided equivalent or greater protection against PBH while providing potentially greater pharmacokinetic exposure and longer duration of action. Final results of the study, including pharmacokinetic profiles, have not yet been published.

Overall, the results of these studies portray exendin 9-39 as a promising candidate for improving glycemic control in PBH. Additional data from late Phase 2 and Phase 3 studies will be informative.

Insulin Monoclonal Antibody

The insulin receptor has emerged as a new therapeutic target for mitigating insulin-induced hypoglycemia in post-bariatric surgery patients. XOMA 358 (originally described as XMetD, for “deactivate”) is a fully human immunoglobulin G2 (IgG2), allosteric modulating monoclonal antibody that targets the human insulin receptor. It has been shown to antagonize insulin receptor activation and signaling both in vitro and in vivo.103,104

A Phase 1, double-blind, placebo-controlled study investigated the pharmacokinetics of XOMA 358 in healthy volunteers.105 Dose-related increases in postprandial glucose levels during MMTTs were observed through day 6 of administration of XOMA 358, as well as marked reductions in insulin sensitivity. XOMA 358 appeared to be well tolerated, with no serious or severe adverse events reported.105

In a recent Phase 2 study, 12 gastric bypass patients with established postprandial hypoglycemia were treated with a single intravenous infusion of XOMA 358 at varying doses.106 In these patients, peak glucose levels following the meal test were higher after treatment with XOMA 358


than at baseline, and the duration of bedside glucose levels above 60 mg/dL was prolonged over 3 to 5 days following treatment.106 Longer time until glucose nadir and higher glucose nadirs were observed with a higher dose (9 mg/kg) as compared with lower doses (3 or 6 mg/kg).106

Glucagon Infusion

Glucagon, which functions to increase glucose levels by breaking down hepatic glycogen, has emerged as another investigational target. Secretion of glucagon may be impaired in hypoglycemia. Several clinical studies have assessed the safety and efficacy of the closed-loop combined insulin and glucagon delivery system in preventing or treating hypoglycemia in patients with type 1 diabetes.

A recent study tested the hypothesis that glucagon delivered via a subcutaneous infusion pump could prevent severe hypoglycemia without rebound hyperglycemia. Release of the investigational stable liquid glucagon used in this study was guided by alerts of low glucose, triggered by CGM, using a prediction algorithm. This proof-of-concept study predicted severe hypoglycemic episodes and showed that glucagon could help to prevent them, in 2 out 5 patients.107

Another recent proof-of-concept study involved automatic administration of micro-dose glucagon via a closed-loop bionic pancreas.108 The study involved 10 patients who had persistent PBH despite treatment (including acarbose and/or octreotide). Patients were randomized to placebo or glucagon infusion, guided by CGM, for 7 days. There was a significant reduction in the amount of time spent with blood glucose <70 mg/dL during glucagon treatment days as opposed to the placebo days, although there was no increase in mean glucose levels. The microdose of glucagon was well tolerated.

Further studies will be needed to better understand the role of glucagon both during a PBH episode and as a candidate for improved glycemic control. Several stable liquid glucagon formulations are in development, which may be used for treatment of hypoglycemia in open-loop and closed-loop settings.

SummaryThe use of bariatric surgery is likely to continue to increase as evidence of its positive impact on the comorbidities of obesity accumulates, and as clinicians adopt its guideline-recommended use in diabetes management. A corresponding increase in the number of cases of PBH is expected. Given the potentially dangerous neuroglycopenic symptoms that can accompany PBH, greater clinical awareness is warranted.

The presentation of PBH is delayed, usually beginning at 1 or more years after bariatric surgery. Episodes of PBH are related to meal consumption, which, in susceptible individuals, leads to postprandial hypoglycemia at 1 to 3

hours after a meal. Why some patients experience chronic, severe hypoglycemia episodes as a long-term complication of their bariatric surgery is not clear. Identifying patients with PBH is hindered by the lack of uniform criteria for defining PBH itself as well as the hypoglycemia associated with it. In addition, screening protocols for PBH vary, particularly with regard to the use of CGM, which is often the only means for detecting hypoglycemia in patients with reduced awareness. The Endocrine Society has published very clear guidelines and criteria for evaluating and managing hypoglycemia in diabetic and nondiabetic patients,51 but these are not specifically focused on PBH. Some recommendations specific to PBH have recently been issued by the American Society for Metabolic and Bariatric Surgery (ASMBS), although most of them are not evidence-based, due to the lack of research in this area.48

Based on some studies, it is possible that patients who report a clinical history of postprandial symptoms suggestive of hypoglycemia before surgery are more likely to experience postprandial hypoglycemia following RYGB. Further studies are needed to identify reliable risk factors and biomarkers, along with clear diagnostic criteria, to improve the identification of persons with PBH, some of whom may require aggressive treatment.

The glucose dysregulation in PBH is characterized by exaggerated GLP-1 secretion and β-cell secretory response to a meal, together with potentially reduced insulin clearance.

In the absence of specific FDA-approved therapies, current practices rely on medical nutritional therapy as the main first step in treating this condition. For severe hypoglycemia, a stepped therapeutic regimen in addition to nutritional manipulation is generally recommended. This approach involves sequential introduction of acarbose and certain drugs (including off-label use of agents such as diazoxide, calcium-channel blockers, or somatostatin analogs). Many of these drugs are poorly tolerated, however, and the hypoglycemia may be refractory to such interventions in some cases. Clearly, new therapies are needed.

Among emerging therapies, incretin-based therapies such as exendin 9-39, which seek to address the enhanced GLP-1–induced insulin secretion after surgical procedures, may hold the most potential for patients with severe cases of PBH. Long-term effectiveness, tolerability, patient adherence to the regimen, and individual patient sensitivities to this treatment remain to be studied.

Gastrostomy tube placement or gastric revision surgery with or without prior gastrostomy tube placement are other invasive options to treat this condition when nutritional and medical treatments fail. Partial or full pancreatectomy is no longer recommended.48

An improved understanding of the pathophysiology and better characterization of the hormone dysregulation underlying PBH may lead to safe and effective treatments for this serious condition.


References

1. Mancini MC, de Melo ME. The burden of obesity in the current world and the new treatments available: focus on liraglutide 3.0 mg. Diabetol Metab Syndr. 2017;9:44.

2. Ogden CL, Carroll MD, Fryar CD, Flegal KM. Prevalence of obesity among adults and youth: United States, 2011-2014. NCHS data brief, no. 219. Hyattsville, MD: National Center for Health Statistics 2015:1-8.

3. O’Brien PE. Bariatric surgery: mechanisms, indications and outcomes. J Gastroenterol Hepatol. 2010;25: 1358-1365.

4. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129:S102-S138.

5. Kolotkin RL, Meter K, Williams GR. Quality of life and obesity. Obes Rev. 2001;2:219-229.

6. Mokdad AH, Marks JS, Stroup DF, Gerberding JL. Actual causes of death in the United States, 2000. JAMA. 2004;291:1238-1245.

7. Angrisani L, Santonicola A, Iovino P, Formisano G, Buchwald H, Scopinaro N. Bariatric surgery worldwide 2013. Obes Surg. 2015;25:1822-1832.

8. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA. 2004;292:1724-1737.

9. Colquitt JL, Pickett K, Loveman E, Frampton GK. Surgery for weight loss in adults. Cochrane Database Syst Rev. 2014:CD003641.

10. Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357:741-752.

11. Crookes PF. Surgical treatment of morbid obesity. Annu Rev Med. 2006;57:243-264.

12. DeMaria EJ. Bariatric surgery for morbid obesity. N Engl J Med. 2007;356:2176-2183.

13. Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes--3-year outcomes. N Engl J Med. 2014;370:2002-2013.

14. Dixon JB, O’Brien PE, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299:316-323.

15. Rubino F, Nathan DM, Eckel RH, et al. Metabolic surgery in the treatment algorithm for type 2 diabetes: a joint statement by international diabetes organizations. Diabetes Care. 2016;39:861-877.

16. Abrahamsson N, Eden Engstrom B, Sundbom M, Karlsson FA. Hypoglycemia in everyday life after gastric bypass and duodenal switch. Eur J Endocrinol. 2015;173:91-100.

17. Madsbad S, Dirksen C, Holst JJ. Mechanisms of changes in glucose metabolism and bodyweight after bariatric surgery. Lancet Diabetes Endocrinol. 2014;2:152-164.

18. Thomas F, Smith GC, Lu J, et al. Differential acute impacts of sleeve gastrectomy, Roux-en-Y gastric bypass surgery and matched caloric restriction diet on insulin secretion, insulin effectiveness and non-esterified fatty acid levels among patients with type 2 diabetes. Obes Surg. 2016;26:1924-1931.

19. Schauer PR, Burguera B, Ikramuddin S, et al. Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus. Ann Surg. 2003;238:467-484; discussion 484-465.

20. Kashyap SR, Bhatt DL, Wolski K, et al. Metabolic effects of bariatric surgery in patients with moderate obesity and type 2 diabetes: analysis of a randomized control trial comparing surgery with intensive medical treatment. Diabetes Care. 2013;36:2175-2182.

21. Laferrere B, Teixeira J, McGinty J, et al. Effect of weight loss by gastric bypass surgery versus hypocaloric diet on glucose and incretin levels in patients with type 2 diabetes. J Clin Endocrinol Metab. 2008;93:2479-2485.

22. Lee CJ, Wood GC, Lazo M, et al. Risk of post-gastric bypass surgery hypoglycemia in nondiabetic individuals: a single center experience. Obesity (Silver Spring). 2016;24:1342-1348.


23. Foster-Schubert KE. Hypoglycemia complicating bariatric surgery: incidence and mechanisms. Curr Opin Endocrinol Diabetes Obes. 2011;18:129-133.

24. Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005;353:249-254.

25. Marsk R, Jonas E, Rasmussen F, Naslund E. Nationwide cohort study of post-gastric bypass hypoglycaemia including 5,040 patients undergoing surgery for obesity in 1986-2006 in Sweden. Diabetologia. 2010;53: 2307-2311.

26. Patti ME, Goldfine AB. Hypoglycemia after gastric bypass: the dark side of GLP-1. Gastroenterology. 2014;146:605-608.

27. Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery. N Engl J Med. 2007;357:753-761.

28. Goldfine AB, Mun EC, Devine E, et al. 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.

29. Ritz P, Vaurs C, Barigou M, Hanaire H. Hypoglycaemia after gastric bypass: mechanisms and treatment. Diabetes Obes Metab. 2016;18:217-223.

30. Vilarrasa N, Goday A, Rubio MA, et al. Hyperinsulinemic hypoglycemia after bariatric surgery: diagnosis and management experience from a Spanish multicenter registry. Obes Facts. 2016;9:41-51.

31. Singh E, Vella A. Hypoglycemia after gastric bypass surgery. Diabetes Spectrum. 2012;25:217-221.

32. Halperin F, Patti ME, Skow M, Bajwa M, Goldfine AB. Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass. J Obes. 2011;2011:869536.

33. Deary IJ, Hepburn DA, MacLeod KM, Frier BM. Partitioning the symptoms of hypoglycaemia using multi-sample confirmatory factor analysis. Diabetologia. 1993;36:771-777.

34. Hepburn DA, Deary IJ, Frier BM, Patrick AW, Quinn JD, Fisher BM. Symptoms of acute insulin-induced hypoglycemia in humans with and without IDDM. Factor-analysis approach. Diabetes Care. 1991;14:949-957.

35. Mitrakou A, Ryan C, Veneman T, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol. 1991;260:E67-E74.

36. Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2013;369: 362-372.

37. Abrahamsson N, Borjesson JL, Sundbom M, Wiklund U, Karlsson FA, Eriksson JW. Gastric bypass reduces symptoms and hormonal responses in hypoglycemia. Diabetes. 2016;65:2667-2675.

38. Salehi M, Gastaldelli A, D’Alessio DA. Altered islet function and insulin clearance cause hyperinsulinemia in gastric bypass patients with symptoms of postprandial hypoglycemia. J Clin Endocrinol Metab. 2014;99:2008-2017.

39. Patti ME, Goldfine AB. The rollercoaster of post-bariatric hypoglycaemia. Lancet Diabetes Endocrinol. 2016;4: 94-96.

40. Lee CJ, Clark JM, Schweitzer M, et al. Prevalence of and risk factors for hypoglycemic symptoms after gastric bypass and sleeve gastrectomy. Obesity (Silver Spring). 2015;23:1079-1084.

41. Nannipieri M, Belligoli A, Guarino D, et al. Risk factors for spontaneously self-reported postprandial hypoglycemia after bariatric surgery. J Clin Endocrinol Metab. 2016;101:3600-3607.

42. Sarwar H, Chapman WH, 3rd, Pender JR, et al. Hypoglycemia after Roux-en-Y gastric bypass: the BOLD experience. Obes Surg. 2014;24:1120-1124.

43. Pigeyre M, Vaurs C, Raverdy V, Hanaire H, Ritz P, Pattou F. Increased risk of OGTT-induced hypoglycemia after gastric bypass in severely obese patients with normal glucose tolerance. Surg Obes Relat Dis. 2015;11:573-577.


44. Nielsen JB, Pedersen AM, Gribsholt SB, Svensson E, Richelsen B. Prevalence, severity, and predictors of symptoms of dumping and hypoglycemia after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2016;12: 1562-1568.

45. Goldfine AB, Patti ME. How common is hypoglycemia after gastric bypass? Obesity (Silver Spring). 2016;24:1210-1211.

46. Dirksen C, Eiken A, Bojsen-Moller KN, et al. No islet cell hyperfunction, but altered gut-islet regulation and postprandial hypoglycemia in glucose-tolerant patients 3 years after gastric bypass surgery. Obes Surg. 2016;26:2263-2267.

47. Kefurt R, Langer FB, Schindler K, Shakeri-Leidenmuhler S, Ludvik B, Prager G. Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test. Surg Obes Relat Dis. 2015;11:564-569.

48. Eisenberg D, Azagury DE, Ghiassi S, Grover BT, Kim JJ. ASMBS position statement on postprandial hyperinsulinemic hypoglycemia after bariatric surgery. Surg Obes Relat Dis. 2017;13:371-378.

49. Roslin M, Damani T, Oren J, Andrews R, Yatco E, Shah P. Abnormal glucose tolerance testing following gastric bypass demonstrates reactive hypoglycemia. Surg Endosc. 2011;25:1926-1932.

50. Itariu BK, Zeyda M, Prager G, Stulnig TM. Insulin-like growth factor 1 predicts post-load hypoglycemia following bariatric surgery: a prospective cohort study. PLoS One. 2014;9:e94613.

51. Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009;94:709-728.

52. International Hypoglycaemia Study G. Glucose concentrations of less than 3.0 mmol/l (54 mg/dl) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2017;60:3-6.

53. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36:1384-1395.

54. Lev-Ran A, Anderson RW. The diagnosis of postprandial hypoglycemia. Diabetes. 1981;30:996-999.

55. Hogan MJ, Service FJ, Sharbrough FW, Gerich JE. Oral glucose tolerance test compared with a mixed meal in the diagnosis of reactive hypoglycemia. A caveat on stimulation. Mayo Clin Proc. 1983;58:491-496.

56. Charles MA, Hofeldt F, Shackelford A, et al. Comparison of oral glucose tolerance tests and mixed meals in patients with apparent idiopathic postabsorptive hypoglycemia: absence of hypoglycemia after meals. Diabetes. 1981;30:465-470.

57. Emous M, Ubels FL, van Beek AP. Diagnostic tools for post-gastric bypass hypoglycaemia. Obes Rev. 2015;16:843-856.

58. van Beek AP, Emous M, Laville M, Tack J. Dumping syndrome after esophageal, gastric or bariatric surgery: pathophysiology, diagnosis, and management. Obes Rev. 2017;18:68-85.

59. Cui Y, Elahi D, Andersen DK. Advances in the etiology and management of hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass. J Gastrointest Surg. 2011;15:1879-1888.

60. Svane MS, Madsbad S. Bariatric surgery–effects on obesity and related co-morbidities. Curr Diabetes Rev. 2014;10:208-214.

61. Salehi M, Gastaldelli A, D’Alessio DA. Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass. Gastroenterology. 2014;146:669-680.

62. Patti ME, McMahon G, Mun EC, et al. Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia. 2005;48:2236-2240.

63. Meier JJ, Butler AE, Galasso R, Butler PC. Hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet hyperplasia or increased beta-cell turnover. Diabetes Care. 2006;29:1554-1559.

64. Laferrere B, Heshka S, Wang K, et al. Incretin levels and effect are markedly enhanced 1 month after Roux-en-Y gastric bypass surgery in obese patients with type 2 diabetes. Diabetes Care. 2007;30:1709-1716.


65. Falken Y, Hellstrom PM, Holst JJ, Naslund E. Changes in glucose homeostasis after Roux-en-Y gastric bypass surgery for obesity at day three, two months, and one year after surgery: role of gut peptides. J Clin Endocrinol Metab. 2011;96:2227-2235.

66. McLaughlin T, Peck M, Holst J, Deacon C. Reversible hyperinsulinemic hypoglycemia after gastric bypass: a consequence of altered nutrient delivery. J Clin Endocrinol Metab. 2010;95:1851-1855.

67. Laferrere B. Diabetes remission after bariatric surgery: is it just the incretins? Int J Obes (Lond). 2011;35 (Suppl 3):S22-S25.

68. Patti ME, Li P, Goldfine AB. Insulin response to oral stimuli and glucose effectiveness increased in neuroglycopenia following gastric bypass. Obesity (Silver Spring). 2015;23:798-807.

69. Craig CM, Liu LF, Deacon CF, Holst JJ, McLaughlin TL. Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia. Diabetologia. 2017;60:531-540.

70. Dirksen C, Bojsen-Moller KN, Jorgensen NB, et al. Exaggerated release and preserved insulinotropic action of glucagon-like peptide-1 underlie insulin hypersecretion in glucose-tolerant individuals after Roux-en-Y gastric bypass. Diabetologia. 2013;56:2679-2687.

71. Reubi JC, Perren A, Rehmann R, et al. Glucagon-like peptide-1 (GLP-1) receptors are not overexpressed in pancreatic islets from patients with severe hyperinsulinaemic hypoglycaemia following gastric bypass. Diabetologia. 2010;53:2641-2645.

72. Shah M, Law JH, Micheletto F, et al. Contribution of endogenous glucagon-like peptide 1 to glucose metabolism after Roux-en-Y gastric bypass. Diabetes. 2014;63:483-493.

73. Salehi M, Prigeon RL, D’Alessio DA. Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans. Diabetes. 2011;60:2308-2314.

74. Craig CM, Liu LF, Nguyen T, Price C, Bingham J, McLaughlin TL. Efficacy and pharmacokinetics of subcutaneous exendin (9-39) in patients with post-bariatric hypoglycemia. Diabetes Obes Metab. 2017.

75. Nessa A, Rahman SA, Hussain K. Hyperinsulinemic hypoglycemia–the molecular mechanisms. Front Endocrinol (Lausanne). 2016;7:29.

76. Salehi M, Woods SC, D’Alessio DA. Gastric bypass alters both glucose-dependent and glucose-independent regulation of islet hormone secretion. Obesity (Silver Spring). 2015;23:2046-2052.

77. Kellogg TA, Bantle JP, Leslie DB, et al. Postgastric bypass hyperinsulinemic hypoglycemia syndrome: characterization and response to a modified diet. Surg Obes Relat Dis. 2008;4:492-499.

78. Bantle JP, Ikramuddin S, Kellogg TA, Buchwald H. Hyperinsulinemic hypoglycemia developing late after gastric bypass. Obes Surg. 2007;17:592-594.

79. Botros N, Rijnaarts I, Brandts H, Bleumink G, Janssen I, de Boer H. Effect of carbohydrate restriction in patients with hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass. Obes Surg. 2014;24:1850-1855.

80. Craig CM, Lamendola C, Holst JJ, Deacon CF, McLaughlin TL. The use of gastrostomy tube for the long-term remission of hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass: a case report. AACE Clinical Case Rep. 2015;1:e84-e87.

81. Bantle AE, Wang Q, Bantle JP. Post-gastric bypass hyperinsulinemic hypoglycemia: fructose is a carbohydrate which can be safely consumed. J Clin Endocrinol Metab. 2015;100:3097-3102.

82. Axelsen M, Wesslau C, Lonnroth P, Arvidsson Lenner R, Smith U. Bedtime uncooked cornstarch supplement prevents nocturnal hypoglycaemia in intensively treated type 1 diabetes subjects. J Intern Med. 1999;245: 229-236.

83. Moreira RO, Moreira RB, Machado NA, Goncalves TB, Coutinho WF. Post-prandial hypoglycemia after bariatric surgery: pharmacological treatment with verapamil and acarbose. Obes Surg. 2008;18:1618-1621.

84. Spanakis E, Gragnoli C. Successful medical management of status post-Roux-en-Y-gastric-bypass hyperinsulinemic hypoglycemia. Obes Surg. 2009;19:1333-1334.


85. Cadegiani FA, Silva OS. Acarbose promotes remission of both early and late dumping syndromes in post-bariatric patients. Diabetes Metab Syndr Obes. 2016;9:443-446.

86. Valderas JP, Ahuad J, Rubio L, Escalona M, Pollak F, Maiz A. Acarbose improves hypoglycaemia following gastric bypass surgery without increasing glucagon-like peptide 1 levels. Obes Surg. 2012;22:582-586.

87. Qvigstad E, Gulseth HL, Risstad H, et al. A novel technique of Roux-en-Y gastric bypass reversal for postprandial hyperinsulinemic hypoglycaemia: a case report. Int J Surg Case Rep. 2016;21:91-94.

88. Myint KS, Greenfield JR, Farooqi IS, Henning E, Holst JJ, Finer N. Prolonged successful therapy for hyperinsulinaemic hypoglycaemia after gastric bypass: the pathophysiological role of GLP1 and its response to a somatostatin analogue. Eur J Endocrinol. 2012;166:951-955.

89. Deloose E, Bisschops R, Holvoet L, et al. A pilot study of the effects of the somatostatin analog pasireotide in postoperative dumping syndrome. Neurogastroenterol Motil. 2014;26:803-809.

90. Tack J, Arts J, Caenepeel P, De Wulf D, Bisschops R. Pathophysiology, diagnosis and management of postoperative dumping syndrome. Nat Rev Gastroenterol Hepatol. 2009;6:583-590.

91. Mala T. Postprandial hyperinsulinemic hypoglycemia after gastric bypass surgical treatment. Surg Obes Relat Dis. 2014;10:1220-1225.

92. Lee CJ, Brown T, Magnuson TH, Egan JM, Carlson O, Elahi D. Hormonal response to a mixed-meal challenge after reversal of gastric bypass for hypoglycemia. J Clin Endocrinol Metab. 2013;98:E1208-E1212.

93. Svane MS, Toft-Nielsen MB, Kristiansen VB, et al. Nutrient re-routing and altered gut-islet cell crosstalk may explain early relief of severe postprandial hypoglycaemia after reversal of Roux-en-Y gastric bypass. Diabet Med. 2017.

94. Z’Graggen K, Guweidhi A, Steffen R, et al. Severe recurrent hypoglycemia after gastric bypass surgery. Obes Surg. 2008;18:981-988.

95. Vanderveen KA, Grant CS, Thompson GB, et al. Outcomes and quality of life after partial pancreatectomy for noninsulinoma pancreatogenous hypoglycemia from diffuse islet cell disease. Surgery. 2010;148:1237-1245; discussion 1245-1236.

96. Svane MS, Bojsen-Moller KN, Nielsen S, et al. Effects of endogenous GLP-1 and GIP on glucose tolerance after Roux-en-Y gastric bypass surgery. Am J Physiol Endocrinol Metab. 2016;310:E505-E514.

97. Jorgensen NB, Dirksen C, Bojsen-Moller KN, et al. Exaggerated glucagon-like peptide 1 response is important for improved beta-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes. Diabetes. 2013;62:3044-3052.

98. Jimenez A, Casamitjana R, Viaplana-Masclans J, Lacy A, Vidal J. GLP-1 action and glucose tolerance in subjects with remission of type 2 diabetes after gastric bypass surgery. Diabetes Care. 2013;36:2062-2069.

99. Jimenez A, Mari A, Casamitjana R, Lacy A, Ferrannini E, Vidal J. GLP-1 and glucose tolerance after sleeve gastrectomy in morbidly obese subjects with type 2 diabetes. Diabetes. 2014;63:3372-3377.

100. Goke R, Fehmann HC, Linn T, et al. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. J Biol Chem. 1993;268:19650-19655.

101. Vetter ML, Wadden TA, Teff KL, et al. GLP-1 plays a limited role in improved glycemia shortly after Roux-en-Y gastric bypass: a comparison with intensive lifestyle modification. Diabetes. 2015;64:434-446.

102. Tan M, Luong R, Lamendola C, Liu L-F, Craig CM. 4-LB / 4 - Repeat subcutaneous dosing of exendin 9-39 reduces hyperinsulinemic hypoglycemia and neuroglycopenic symptoms in patients with post-bariatric hypoglycemia. Paper presented at: American Diabetes Association 77th Scientific Sessions; June 9-13, 2017; San Diego, CA.

103. Issafras H, Bedinger DH, Corbin JA, et al. Selective allosteric antibodies to the insulin receptor for the treatment of hyperglycemic and hypoglycemic disorders. J Diabetes Sci Technol. 2014;8:865-873.


104. Corbin JA, Bhaskar V, Goldfine ID, et al. Inhibition of insulin receptor function by a human, allosteric monoclonal antibody: a potential new approach for the treatment of hyperinsulinemic hypoglycemia. MAbs. 2014;6:262-272.

105. Nath R, Johnson K, Roessig JM, et al. LB-104: Xoma 358, a novel treatment for hyperinsulinemic hypoglycemia: safety and clinical pharmacology from the first in human trial. The Endocrine Society’s 97th Annual Meeting and Expo; March 5-8, 2015; San Diego, CA.

106. Johnson KW, Gordon A, Neale AC, et al. OR14-6: Single administration of Xoma 358, an insulin receptor attenuator, improves post-meal and nighttime hypoglycemia profiles in post gastric bypass hypoglycemia (PGBH) patients. The Endocrine Society’s 99th Annual Meeting & Expo; April 1-4, 2017; Orlando, FL.

107. Mulla CM, Laguna A, Fowler KM, et al. OR14-5: Automated event-based system for the prevention of post-bariatric hypoglycemia using a mini-dose of a stable glucagon formulation. The Endocrine Society’s 99th Annual Meeting & Expo; April 1-4, 2017; Orlando, FL.

108. Jafri RZ, Maheno M, Balliro CA, et al. LB3: Automated glucagon administration for treatment of postbariatric hypoglycemia. Diabetes. 2017;66.

109. Gribsholt SB, Pedersen AM, Svensson E, Thomsen RW, Richelsen B. Prevalence of self-reported symptoms after gastric bypass surgery for obesity. JAMA Surg. 2016;151:504-511.

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