Dumping syndrome is a complex of gastrointestinal symptoms originally studied in peptic ulcer surgery patients. At present, it is most prevalent in patients who underwent bariatric, upper gastrointestinal cancer or anti-reflux surgery. The symptom pattern comprises early and late dumping symptoms. Several management options have been reported including nutritional, pharmacological and surgical approaches.

In this study, we aimed to review the current evidence on dumping syndrome definition, diagnosis and treatment, including preliminary data from newer pharmacological studies.

Current pathophysiological concepts and analyses of provocative tests has led to a clear definition of dumping syndrome, including both early and late dumping symptoms. The term postbariatric hypoglycemia represents a limited focus on late dumping only. The diagnosis relies on recognition of symptoms and signs in a patient with appropriate surgical history; and can be confirmed by provocative testing or registration of spontaneous hypoglycemia. The initial treatment focuses on dietary intervention, to which meal viscosity enhancers and/or the glycosidase inhibitor acarbose can be added. The most effective therapy is the use of short- or long-acting somatostatin analogues, which is however expensive and entails side effect issues. In case of refractory hypoglycemia, diazoxide or SGLT2 inhibitors can be considered, based on limited evidence. In refractory patients, continuous enteral feeding or (rarely) surgical reinterventions have been advocated, although not supported by solid evidence. Therapies under current evaluation include the broad-spectrum somatostatin analogue pasireotide, GLP-1 receptor antagonists, GLP-1 receptor agonists and administration of stable forms of glucagon are currently under study.

Dumping syndrome is a well-defined but probably under-diagnosed complication of upper gastrointestinal, especially bariatric, and surgeries. Diagnosis is confirmed by a provocative test and incremental therapies starting with diet, adding meal viscosity enhancers or glycosidase inhibitors and adding somatostatin analogues in refractory cases. A number of emerging therapies targeting intestinal propulsion, peptide hormone effects and hypoglycemic events are under evaluation.

A woman in her 40s presented with severe post-bariatric hypoglycaemia that persisted despite nutritional therapy and pharmacological therapy with acarbose and subcutaneous octreotide with meals. The nutritional limitations were difficult to sustain, and she developed adverse effects to the pharmacological therapy, and hence, doses could not be increased. She was subsequently treated with subcutaneous octreotide via an insulin pump, with a continuous basal rate and additional bolus doses with meals. This led to significant improvements in hypoglycaemia and less side effects, as well as the ability to titrate doses. This report describes the course of her treatment, illustrating continuous octreotide treatment via an insulin pump as a potential additional treatment option in post-bariatric hypoglycaemia.

Diabetes mellitus (DM) and obesity have become public issues of global concern. Bariatric surgery for the treatment of obesity combined with type 2 DM has been shown to be a safe and effective approach; however, there are limited studies that have systematically addressed the challenges of surgical treatment of obesity combined with DM. In this review, we summarize and answer the most pressing questions in the field of surgical treatment of obesity-associated DM. I believe that our insights will be of great help to clinicians in their daily practice.

Post bariatric hypoglycaemia (PBH) is typically a post-prandial hypoglycaemia occurring about 2-4 hours after eating in people who have undergone bariatric surgery. PBH develops relatively late after surgery and often after discharge from post-surgical follow-up by bariatric teams, leading to variability in diagnosis and management in non-specialist centres.

to improve and standardise clinical practice in the diagnosis and management of PBH.

(1) to undertake an up-to-date review of the current literature; (2) to formulate practical and evidence-based guidance with regards on the diagnosis and treatment of PBH; (3) to recommend future avenues for research in this condition.

A scoping review was undertaken after an extensive literature search. A consensus on the guidance and confidence in the recommendations was reached by the steering group authors prior to review by key stakeholders.

We make pragmatic recommendations for the practical diagnosis and management of PBH including criteria for diagnosis and recognition, as well as recommendations for research areas that should be explored.

Post-bariatric hypoglycaemia (PBH) is a metabolic complication of bariatric surgery (BS), consisting of low post-prandial glucose levels in patients having undergone bariatric procedures. While BS is currently the most effective and relatively safe treatment for obesity and its complications, the development of PBH can significantly impact patients' quality of life and mental health. The diagnosis of PBH is still challenging, considering the lack of definitive and reliable diagnostic tools, and the fact that this condition is frequently asymptomatic. However, PBH's prevalence is alarming, involving up to 88% of the post-bariatric population, depending on the diagnostic tool, and this may be underestimated. Given the prevalence of obesity soaring, and an increasing number of bariatric procedures being performed, it is crucial that physicians are skilled to diagnose PBH and promptly treat patients suffering from it. While the milestone of managing this condition is nutritional therapy, growing evidence suggests that old and new pharmacological approaches may be adopted as adjunct therapies for managing this complex condition.

Postbariatric hypoglycemia affects >50% of individuals who have undergone Roux-en-Y gastric bypass surgery. Despite the often debilitating nature of this complication, existing treatment options are limited and often inefficient. Dasiglucagon is a stable glucagon analog available in a ready-to-use formulation and was recently shown to mitigate postbariatric hypoglycemia in experimental settings. Here, we aimed to evaluate the hypoglycemic hindering potential of dasiglucagon in an outpatient trial.

We conducted a randomized, double-blind, placebo-controlled, crossover, proof-of-concept study at the Center for Clinical Metabolic Research at Gentofte Hospital in Denmark. The study included 24 individuals who had undergone Roux-en-Y gastric bypass surgery (n = 23 women) with continuous glucose monitor-verified postbariatric hypoglycemia (≥15 min at <3.9 mmol/L three or more times per week) randomly assigned to two treatment periods of 4 weeks of self-administered subcutaneous dasiglucagon at 120 μg or placebo. The primary and key secondary outcomes were continuous glucose monitor-captured percentage of time in level 1 and 2 hypoglycemia (<3.9 and <3.0 mmol/L), respectively.

Compared with placebo, treatment with dasiglucagon significantly reduced time in level 1 hypoglycemia by 33% (-1.2 percentage points; 95% CI -2.0 to -0.5; P = 0.002) and time in level 2 hypoglycemia by 54% (-0.4 percentage points; 95% CI -0.6 to -0.2; P < 0.0001). Furthermore, dasiglucagon corrected hypoglycemia within 15 min in 401 of 412 self-administrations, compared with 104 of 357 placebo self-administrations (97.3% vs. 29.1% correction of hypoglycemia rate; P < 0.001). Dasiglucagon was generally well tolerated, with mostly mild to moderate adverse events of nausea.

Compared with placebo, 4 weeks of self-administered dasiglucagon effectively reduced clinically relevant hypoglycemia in individuals who had undergone Roux-en-Y gastric bypass surgery.

While bariatric surgery remains the most effective treatment for obesity that allows substantial weight loss with improvement and possibly remission of obesity-associated comorbidities, some postoperative complications may occur. Managing physicians need to be familiar with the common problems to ensure timely and effective management. Of these complications, postoperative hypoglycemia is an increasingly recognized complication of bariatric surgery that remains underreported and underdiagnosed.

This article highlights the importance of identifying hypoglycemia in patients with a history of bariatric surgery, reviews pathophysiology and addresses available nutritional, pharmacological and surgical management options. Systemic evaluation including careful history taking, confirmation of hypoglycemia and biochemical assessment is essential to establish accurate diagnosis. Understanding the weight-dependent and weight-independent mechanisms of improved postoperative glycemic control can provide better insight into the causes of the exaggerated responses that lead to postoperative hypoglycemia.

Management of post-operative hypoglycemia can be challenging and requires a multidisciplinary approach. While dietary modification is the mainstay of treatment for most patients, some patients may benefit from pharmacotherapy (e.g. GLP-1 receptor antagonist); Surgery (e.g. reversal of gastric bypass) is reserved for unresponsive severe cases. Additional research is needed to understand the underlying pathophysiology with a primary aim in optimizing diagnostics and treatment options.

Patients with chronic gastrointestinal disease such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease, gastroesophageal reflux disease (GERD), pancreatitis, and chronic liver disease (CLD) often suffer from obesity because of coincidence (IBD, IBS, celiac disease) or related pathophysiology (GERD, pancreatitis and CLD). It is unclear if such patients need a particular diagnostic and treatment that differs from the needs of lean gastrointestinal patients. The present guideline addresses this question according to current knowledge and evidence.

The present practical guideline is intended for clinicians and practitioners in general medicine, gastroenterology, surgery and other obesity management, including dietitians and focuses on obesity care in patients with chronic gastrointestinal diseases.

The present practical guideline is the shortened version of a previously published scientific guideline developed according to the standard operating procedure for ESPEN guidelines. The content has been re-structured and transformed into flow-charts that allow a quick navigation through the text.

In 100 recommendations (3× A, 33× B, 24 × 0, 40× GPP, all with a consensus grade of 90% or more) care of gastrointestinal patients with obesity - including sarcopenic obesity - is addressed in a multidisciplinary way. A particular emphasis is on CLD, especially metabolic associated liver disease, since such diseases are closely related to obesity, whereas liver cirrhosis is rather associated with sarcopenic obesity. A special chapter is dedicated to obesity care in patients undergoing bariatric surgery. The guideline focuses on adults, not on children, for whom data are scarce. Whether some of the recommendations apply to children must be left to the judgment of the experienced pediatrician.

The present practical guideline offers in a condensed way evidence-based advice how to care for patients with chronic gastrointestinal diseases and concomitant obesity, an increasingly frequent constellation in clinical practice.

To evaluate medical and surgical treatment of postbariatric hypoglycaemia (PBH) in daily practice.

Retrospective data were extracted from medical records from four hospitals. PBH was defined by neuroglycopenic symptoms together with a documented glucose <3.0 mmol/L in the postprandial setting after previous bariatric surgery. Data were scored semiquantitatively on efficacy and side effects by two reviewers independently. Duration of efficacy and of use were calculated.

In total, 120 patients were included with a median follow-up of 27 months with a mean baseline age of 41 years, total weight loss of 33% and glucose nadir 2.3 mmol/L. Pharmacotherapy consisted of acarbose, diazoxide, short- and long-acting octreotide and glucagon-like peptide-1 receptor agonist analogues (liraglutide and semaglutide) with an overall efficacy in 45%-75% of patients. Combination therapy with two drugs was used by 30 (25%) patients. The addition of a second drug was successful in over half of the patients. Long-acting octreotide and the glucagon-like peptide-1 receptor agonist analogues scored best in terms of efficacy and side effects with a median duration of use of 35 months for octreotide. Finally, 23 (19%) patients were referred for surgical intervention. Efficacy of the surgical procedures, pouch banding, G-tube placement in remnant stomach and Roux-en-Y gastric bypass reversal, pooled together, was 79% with a median duration of initial effect of 13 months.

In daily practice, pharmacotherapy for PBH was successful in half to three quarters of patients. Combination therapy was often of value. One in five patients finally needed a surgical procedure, with overall good results.

Although promising therapeutics are in the pipeline, bariatric surgery (also known as metabolic surgery) remains our most effective strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Of the many available options, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are currently the most widely used procedures. RYGB and VSG have very different anatomical restructuring but both surgeries are effective, to varying degrees, at inducing weight loss and T2DM remission. Both weight loss-dependent and weight loss-independent alterations in multiple tissues (such as the intestine, liver, pancreas, adipose tissue and skeletal muscle) yield net improvements in insulin resistance, insulin secretion and insulin-independent glucose metabolism. In a subset of patients, post-bariatric hypoglycaemia can develop months to years after surgery, potentially reflecting the extreme effects of potent glucose reduction after surgery. This Review addresses the effects of bariatric surgery on glucose regulation and the potential mechanisms responsible for both the resolution of T2DM and the induction of hypoglycaemia.

This manuscript provides a review of post-bariatric hypoglycemia (PBH) with a special focus on the role of the registered dietitian-nutritionist (RDN) and medical nutrition therapy (MNT) recommendations as foundational for management.

As the number of bariatric surgeries rises yearly, with 256,000 performed in 2019, PBH is an increasingly encountered late complication. Following Roux-en-Y (RYGB) or vertical sleeve gastrectomy (VSG), about 1/3 of patients report symptoms suggestive of at least mild postprandial hypoglycemia, with severe and/or medically confirmed hypoglycemia in 1-10%. Anatomical alterations, changes in GLP1 and other intestinally derived hormones, excessive insulin response, reduced insulin clearance, impaired counterregulatory hormone response to hypoglycemia, and other factors contribute to PBH. MNT is the cornerstone of multidisciplinary treatment, with utilization of personal continuous glucose monitoring to improve safety when possible. While many individuals require pharmacotherapy, there are no currently approved medications for PBH. Increasing awareness and identification of individuals at risk for or with PBH is critical given the potential impact on safety, nutrition, and quality of life. A team-based approach involving the individual, the RDN, and other clinicians is essential in providing ongoing assessment and individualization of MNT in the long-term management of PBH.

Postprandial hyperinsulinaemic hypoglycaemia is a common complication of bariatric surgery. Although in general its evolution is mild and self-limited, it can lead to neuroglycopaenia and compromise the patient's safety and quality of life. The aim of this document is to offer some recommendations to facilitate the clinical care of these complex patients, reviewing the aetiopathogenesis, its diagnosis and treatment that, sequentially, will include dietary and pharmacological measures and surgery in refractory cases. In the absence of high-quality studies, the diagnostic and therapeutic approach proposed is based on the consensus of experts of the Grupo de Obesidad de la Sociedad Española de Endocrinología y Nutrición [Obesity Group of the Spanish Society of Endocrinology and Nutrition], GOSEEN. Those undergoing bariatric surgery should be informed of the possibility of developing this complication.

Patients with chronic gastrointestinal (GI) disease such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease, gastroesophageal reflux disease (GERD), pancreatitis, and chronic liver disease (CLD) often suffer from obesity because of coincidence (IBD, IBS, celiac disease) or related pathophysiology (GERD, pancreatitis and CLD). It is unclear if such patients need a particular diagnostic and treatment that differs from the needs of lean GI patients. The present guideline addresses this question according to current knowledge and evidence.

The objective of the guideline is to give advice to all professionals working in the field of gastroenterology care including physicians, surgeons, dietitians and others how to handle patients with GI disease and obesity.

The present guideline was developed according to the standard operating procedure for European Society for Clinical Nutrition and Metabolism guidelines, following the Scottish Intercollegiate Guidelines Network grading system (A, B, 0, and good practice point [GPP]). The procedure included an online voting (Delphi) and a final consensus conference.

In 100 recommendations (3x A, 33x B, 24x 0, 40x GPP, all with a consensus grade of 90% or more) care of GI patients with obesity - including sarcopenic obesity - is addressed in a multidisciplinary way. A particular emphasis is on CLD, especially fatty liver disease, since such diseases are closely related to obesity, whereas liver cirrhosis is rather associated with sarcopenic obesity. A special chapter is dedicated to obesity care in patients undergoing bariatric surgery. The guideline focuses on adults, not on children, for whom data are scarce. Whether some of the recommendations apply to children must be left to the judgment of the experienced pediatrician.

The present guideline offers for the first time evidence-based advice how to care for patients with chronic GI diseases and concomitant obesity, an increasingly frequent constellation in clinical practice.

Patients with chronic gastrointestinal (GI) disease such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease, gastroesophageal reflux disease (GERD), pancreatitis, and chronic liver disease (CLD) often suffer from obesity because of coincidence (IBD, IBS, celiac disease) or related pathophysiology (GERD, pancreatitis and CLD). It is unclear if such patients need a particular diagnostic and treatment that differs from the needs of lean GI patients. The present guideline addresses this question according to current knowledge and evidence.

The objective of the guideline is to give advice to all professionals working in the field of gastroenterology care including physicians, surgeons, dietitians and others how to handle patients with GI disease and obesity.

The present guideline was developed according to the standard operating procedure for ESPEN guidelines, following the Scottish Intercollegiate Guidelines Network (SIGN) grading system (A, B, 0, and good practice point (GPP)). The procedure included an online voting (Delphi) and a final consensus conference.

In 100 recommendations (3x A, 33x B, 24x 0, 40x GPP, all with a consensus grade of 90% or more) care of GI patients with obesity - including sarcopenic obesity - is addressed in a multidisciplinary way. A particular emphasis is on CLD, especially fatty liver disease, since such diseases are closely related to obesity, whereas liver cirrhosis is rather associated with sarcopenic obesity. A special chapter is dedicated to obesity care in patients undergoing bariatric surgery. The guideline focuses on adults, not on children, for whom data are scarce. Whether some of the recommendations apply to children must be left to the judgment of the experienced pediatrician.

The present guideline offers for the first time evidence-based advice how to care for patients with chronic GI diseases and concomitant obesity, an increasingly frequent constellation in clinical practice.

Glucagon is essential for endogenous glucose regulation along with the paired hormone, insulin. Unlike insulin, pharmaceutical use of glucagon has been limited due to the unstable nature of the peptide. Glucagon has the potential to address hypoglycemia as a major limiting factor in the treatment of diabetes, which remains very common in the type 1 and type 2 diabetes. Recent developments are poised to change this paradigm and expand the use of glucagon for people with diabetes. Glucagon emergency kits have major limitations for their use in treating severe hypoglycemia. A complicated reconstitution and injection process often results in incomplete or aborted administration. New preparations include intranasal glucagon with an easy-to-use and needle-free nasal applicator as well as two stable liquid formulations in pre-filled injection devices. These may ease the burden of severe hypoglycemia treatment. The liquid preparations may also have a role in the treatment of non-severe hypoglycemia. Despite potential benefits of expanded use of glucagon, undesirable side effects (nausea, vomiting), cost, and complexity of adding another medication may limit real-world use. Additionally, more long-term safety and outcome data are needed before widespread, frequent use of glucagon is recommended by providers.

To investigate the efficacy and safety of dasiglucagon, a novel stable glucagon analog in a liquid formulation, in Roux-en-Y gastric bypass (RYGB)-operated individuals suffering from postbariatric hypoglycemia (PBH).

In a randomized, double-blind, placebo-controlled, crossover trial, 10 RYGB-operated participants with continuous glucose monitoring-verified PBH were randomly assigned to 3 trial days, each consisting of a 240-min standardized liquid mixed-meal test with the subcutaneous injection of placebo or 80 μg or 200 μg dasiglucagon.

Compared with placebo, treatment with both 80 and 200 μg dasiglucagon raised nadir plasma glucose (PG) (placebo: 3.0 ± 0.2 mmol/L [mean ± SEM]; 80 μg dasiglucagon: 3.9 ± 0.3 mmol/L, P = 0.002; 200 μg dasiglucagon: 4.5 ± 0.2 mmol/L, P = 0.0002) and reduced time in hypoglycemia (PG <3.9 mmol/L) by 70.0 min (P = 0.030 and P = 0.008).

Single-dose administration of dasiglucagon effectively mitigated postprandial hypoglycemia.

Severe hypoglycemia with neuroglycopenia, termed post-bariatric hypoglycemia (PBH). typically occurs postprandially, but it is also reported after activity or mid-nocturnally.

To quantify glycemia, glycemic variability, and magnitude/duration of low sensor glucose (SG) values in patients with PBH after Roux-en-Y gastric bypass (PBH-RYGB).

This retrospective analysis of data from an academic medical center included individuals with PBH-RYGB (n = 40), reactive hypoglycemia without gastrointestinal surgery (Non-Surg Hypo, n = 20), prediabetes (Pre-DM, n = 14), newly diagnosed T2D (n = 5), and healthy controls (HC, n = 38). Masked continuous glucose monitoring (Dexcom G4) was used to assess patterns over 24 hours, daytime (6 am-midnight) and nighttime (midnight-6 am). Prespecified measures included mean and median SG, variability, and percent time at thresholds of sensor glucose.

Mean and median SG were similar for PBH-RYGB and HC (mean: 99.8 ± 18.6 vs 96.9 ± 10.2 mg/dL; median: 93.0 ± 14.8 vs 94.5 ± 7.4 mg/dL). PBH-RYGB had a higher coefficient of variation (27.3 ± 6.8 vs 17.9 ± 2.4%, P < 0.0001) and range (154.5 ± 50.4 vs 112.0 ± 26.7 mg/dL, P < 0.0001). Nadir was lowest in PBH-RYGB (42.5 ± 3.7 vs HC 49.0 ± 11.9 mg/dL, P = 0.0046), with >2-fold greater time with SG < 70 mg/dL vs HC (7.7 ± 8.4 vs 3.2 ± 4.1%, P = 0.0013); these differences were greater at night (12.6 ± 16.9 vs 1.0 ± 1.5%, P < 0.0001). Non-Surg Hypo also had 4-fold greater time with SG < 70 at night vs HC (SG < 70: 4.0 ± 5.9% vs 1.0 ± 1.5%), but glycemic variability was not increased.

Patients with PBH-RYGB experience higher glycemic variability and frequency of SG < 70 compared to HC, especially at night. These data suggest that additional pathophysiologic mechanisms beyond prandial changes contribute to PBH.

Roux-en-Y gastric bypass (RYGB) is an established treatment for type 2 diabetes and obesity. The study objective was to establish RYGB's effects on glycemic variability (GV) and hypoglycemia.

This was a prospective observational study of 10 participants with obesity and prediabetes or type 2 diabetes who underwent RYGB. Patients were studied before RYGB (Pre) and 1 month, 1 year, and 2 years postsurgery with continuous glucose measurement (CGM). A mixed-meal test (MMT) was conducted at Pre, 1 month, and 1 year.

After RYGB, mean CGM decreased (at 1 month, 1 year, and 2 years), and GV increased (at 1 year and 2 years). Five of the 10 participants had a percent time in range (%TIR) <3.0 mmol/L (54 mg/dL) greater than the international consensus target of 1% at 1 or 2 years. Peak glucagon-like peptide-1 (GLP-1) and glucagon area under the curve during MMT were positively and negatively associated, respectively, with contemporaneous %TIR <3.0 mmol/L.

Patients undergoing RYGB are at risk for development of postbariatric hypoglycemia due to a combination of reduced mean glucose, increased GV, and increased GLP-1 response.

Postbariatric hypoglycemia (PBH) is a potentially serious complication after Roux-en-Y gastric bypass (RYGB), and impaired counterregulatory hormone responses have been suggested to contribute to the condition.

We evaluated counterregulatory responses during postprandial hypoglycemia in individuals with PBH who underwent RYGB.

University hospital.

Eleven women with documented PBH who had RYGB underwent a baseline liquid mixed meal test (MMT) followed by 5 MMTs preceded by treatment with (1) acarbose 50 mg, (2) sitagliptin 100 mg, (3) verapamil 120 mg, (4) liraglutide 1.2 mg, and (5) pasireotide 300 μg. Blood was collected at fixed time intervals. Plasma and serum were analyzed for glucose, insulin, glucagon, epinephrine, norepinephrine, pancreatic polypeptide (PP), and cortisol.

During the baseline MMT, participants had nadir blood glucose concentrations of 3.3 ± .2 mmol/L. At the time of nadir glucose, there was a small but significant increase in plasma glucagon. Plasma epinephrine concentrations were not increased at nadir glucose but were significantly elevated by the end of the MMT. There were no changes in norepinephrine, PP, and cortisol concentrations in response to hypoglycemia. After treatment with sitagliptin, 8 individuals had glucose nadirs <3.2 mmol/L (versus 4 individuals at baseline), and significant increases in glucagon, PP, and cortisol responses were observed.

In response to postprandial hypoglycemia, individuals with PBH who underwent RYGB only had minor increases in counterregulatory hormones, while larger hormone responses occurred when glucose levels were lowered during treatment with sitagliptin. The glycemic threshold for counterregulatory activation could be altered in individuals with PBH, possibly explained by recurrent hypoglycemia.

To achieve strict glycaemic control and avoid chronic diabetes complications, individuals with type 1 diabetes (T1D) are recommended to follow an intensive insulin regimen. However, the risk and fear of hypoglycaemia often prevent individuals from achieving the treatment goals. Apart from early insulin suspension in insulin pump users, carbohydrate ingestion is the only option for preventing and treating non-severe hypoglycaemic events. These rescue treatments may give extra calories and cause overweight. As an alternative, the use of low-dose glucagon to counter hypoglycaemia has been proposed as a tool to raise glucose concentrations without adding extra calories. Previously, the commercially available glucagon formulations required reconstitution from powder to a solution before being injected subcutaneously or intramuscularly-making it practical only for treating severe hypoglycaemia. Several companies have developed more stable formulations that do not require the time-consuming reconstitution process before use. As well as treating severe hypoglycaemia, non-severe and impending hypoglycaemia can also be treated with lower doses of glucagon. Once available, low-dose glucagon can be either delivered manually, as an injection, or automatically, by an infusion pump. This review focuses on the role and perspectives of using glucagon to treat and prevent hypoglycaemia in T1D.

To evaluate the safety, efficacy and pharmacokinetics of repeat dosing of two formulations of subcutaneous (SC) avexitide (exendin 9-39) in patients with post-bariatric hypoglycaemia (PBH).

In this phase 2, multiple-ascending-dose study conducted at Stanford University, 19 women with PBH underwent a baseline oral glucose tolerance test (OGTT), with metabolic and symptomatic assessments. Fourteen were then sequentially assigned to receive one of four ascending-dose levels of twice-daily lyophilized (Lyo) avexitide by SC injection for 3 days. On the basis of safety, efficacy and tolerability, five additional participants then received a novel liquid formulation (Liq) of avexitide by SC injection at a fixed dose of 30 mg twice daily for 3 days. All 19 participants underwent a repeat OGTT on day 3 of dosing to quantify metabolic, symptomatic and pharmacokinetic responses.

Treatment with Lyo avexitide reduced the magnitude of symptomatic hyperinsulinaemic hypoglycaemia at all dose levels, with dose-dependent improvements in glucose nadir, insulin peak and symptom score; doses ≥20 mg twice daily did not require glycaemic rescue (administered at glucose <2.8 mmol/L). Participants receiving Liq avexitide 30 mg twice daily did not require any glycaemic rescue, and on average achieved a 47% increase in glucose nadir, a 67% reduction in peak insulin, and a 47% reduction in overall symptom score. Equivalent doses of Liq versus Lyo avexitide yielded higher and more sustained plasma concentrations. Both formulations were well tolerated.

In patients with PBH, twice-daily administration of SC avexitide effectively raised the glucose nadir and prevented severe hypoglycaemia requiring rescue intervention. Avexitide may represent a viable therapy for PBH.

Postbariatric hypoglycemia (PBH) can threaten safety and reduce quality of life. Current therapies are incompletely effective.

Patients with PBH were enrolled in a double-blind, placebo-controlled, crossover trial to evaluate a closed-loop glucose-responsive automated glucagon delivery system designed to reduce severe hypoglycemia. A hypoglycemia detection and mitigation algorithm was embedded in the artificial pancreas system connected to a continuous glucose monitor (CGM, Dexcom) driving a patch infusion pump (Insulet) filled with liquid investigational glucagon (Xeris) or placebo (vehicle). Sensor/plasma glucose responses to mixed meal were assessed during 2 study visits. The system delivered up to 2 doses of study drug (300/150 μg glucagon or equal-volume vehicle) if triggered by the algorithm. Rescue dextrose was given for plasma glucose <55 mg/dL or neuroglycopenia.

Twelve participants (11 females/1 male, age 52 ± 2, 8 ± 1 years postsurgery, mean ± SEM) completed all visits. Predictive hypoglycemia alerts prompted automated drug delivery postmeal, when sensor glucose was 114 ± 7 vs 121 ± 5 mg/dL (P = .39). Seven participants required rescue glucose after vehicle but not glucagon (P = .008). Five participants had severe hypoglycemia (<55 mg/dL) after vehicle but not glucagon (P = .03). Nadir plasma glucose was higher with glucagon vs vehicle (67 ± 3 vs 59 ± 2 mg/dL, P = .004). Plasma glucagon rose after glucagon delivery (1231 ± 187 vs 16 ± 1 pg/mL at 30 minutes, P = .001). No rebound hyperglycemia occurred. Transient infusion site discomfort was reported with both glucagon (n = 11/12) and vehicle (n = 10/12). No other adverse events were observed.

A CGM-guided closed-loop rescue system can detect imminent hypoglycemia and deliver glucagon, reducing severe hypoglycemia in PBH.

NCT03255629.

Obesity and obesity-related diseases are major public health concerns that have been exponentially growing in the last decades. Bariatric surgery is an effective long-term treatment to achieve weight loss and obesity comorbidity remission. Post-bariatric hypoglycemia (PBH) is a late complication of bariatric surgery most commonly reported after Roux-en-Y gastric bypass (RYGB). PBH is the end result of postprandial hyperinsulinemia but additional endocrine mechanisms involved are still under debate. Our aim was to characterize entero-pancreatic hormone dynamics associated with postprandial hypoglycemia after RYGB. Individuals previously submitted to RYGB (N=23) in a single tertiary hospital presenting PBH symptoms (Sym, n=14) and asymptomatic weight-matched controls (Asy, n=9) were enrolled. Participants underwent a mixed-meal tolerance test (MMTT) to assess glucose, total amino acids (total AA), insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and neurotensin (NT). We found that hypoglycemia during the MMTT was equally frequent in Sym and Asy groups (p=1.000). Re-grouped according to glucose nadir during the MMTT (Hypo n=11 vs NoHypo n=12; nadir <3.05 mmol/l vs ≥3.05 mmol/l), subjects presented no differences in anthropometric (BMI: p=0.527) or metabolic features (HbA_1c: p=0.358), yet distinct meal-elicited hormone dynamics were identified. Postprandial glucose excursion and peak glucose levels were similar (p>0.05), despite distinct late glycemic outcomes (t=60 min and t=90 min: p<0.01), with overall greater glycemic variability in Hypo group (minimum-to-maximum glucose ratio: p<0.001). Hypo group meal-triggered hormone profile was characterized by lower early glucagon (t=15 min: p<0.01) and higher insulin (t=30 min: p<0.05, t=45 min: p<0.001), C-peptide (t=30 min: p<0.01, t=45 min: p<0.001, t=60 min: p<0.05), and GLP-1 (t=45 min: p<0.05) levels. Hyperinsulinemia was an independent risk factor for hypoglycemia (p<0.05). After adjusting for hyperinsulinemia, early glucagon correlated with glycemic nadir (p<0.01), and prevented postprandial hypoglycemia (p<0.05). A higher insulin to glucagon balance in Hypo was observed (p<0.05). No differences were observed in total AA, GIP or NT excursions (p>0.05). In sum, after RYGB, postprandial hyperinsulinemia is key in triggering PBH, but a parallel and earlier rise in endogenous glucagon might sustain the inter-individual variability in glycemic outcome beyond the effect of hyperinsulinism, advocating a potential pivotal role for glucagon in preventing hyperinsulinemic hypoglycemia.

Post-bariatric hypoglycemia (PBH) is an increasingly encountered complication of upper gastrointestinal surgery; the prevalence of this condition is anticipated to rise given yearly increases in bariatric surgical procedures. While PBH is incompletely understood, there is a growing body of research describing the associated factors, mechanisms, and treatment approaches for this condition.

Data are integrated and summarized from studies of individuals affected by PBH and hypoglycemia following upper gastrointestinal surgery obtained from PubMed searches (1990-2020).

Information addressing etiology, incidence/prevalence, clinical characteristics, assessment, and treatment were reviewed and synthesized for the practicing physician. Literature reports were supplemented by clinical experience as indicated, when published data were not available.

PBH can be life-altering and severe for a subset of individuals. Given the chronic nature of this condition, and sequelae of both acute and recurrent episodes, increasing provider awareness of both the condition and associated risk factors is critical for assessment, prompt diagnosis, treatment, and preoperative identification of individuals at risk.