Post-bariatric surgery hypoglycaemia is typically mediated by hyperinsulinaemia, although the exact mechanisms are incompletely understood. Two cases of non-insulin mediated, ketotic hypoglycaemia following sleeve gastrectomy are presented. After fasting for 40 and 65 h, respectively, both patients developed symptomatic hypoglycaemia, with corresponding low insulin, low c-peptide and elevated beta-hydroxybutyrate levels. Morning cortisol and IGF1 levels were normal. Potential mechanisms for ketotic hypoglycaemia following bariatric surgery include reduction in hepatic, renal and intestinal gluconeogenesis, or alternatively an underlying inborn error of metabolism such as a glycogen storage disorder unmasked by bariatric surgery. Most glycogen storage disorders present in childhood, but there have been rare case reports of glycogen storage disorders types I, III and IX diagnosed in adulthood. Neither of the above cases had other features of a glycogen storage disorder such as elevated lactate, hyperuricaemia, hypertriglyceridaemia, hepatomegaly, myopathy or an indicative family history. Both patients trialled first-line dietary management, which was inadequate in managing hypoglycaemia. Treatment with the glucagon-like peptide-1 receptor agonist semaglutide resulted in the resolution of hypoglycaemic episodes in one patient, and a significant reduction in hypoglycaemic episodes in the other patient.

Recent advances in understanding type 1 diabetes (T1D) highlight the complexity of managing hypoglycemia, a frequent and perilous complication of diabetes therapy. This letter delves into a novel study by Jin et al, which elucidates the role of intestinal glucagon-like peptide-1 (GLP-1) in the counterregulatory response to hypoglycemia in T1D models. The study employed immunofluorescence, Western blotting, and enzyme-linked immunosorbent assay to track changes in GLP-1 and its receptor expression in diabetic mice subjected to recurrent hypoglycemic episodes. Findings indicate a significant increase in intestinal GLP-1 and GLP-1 receptor expression, correlating with diminished adrenal and glucagon responses, crucial for glucose stabilization during hypoglycemic events. This letter aims to explore the implications of these findings for future therapeutic strategies and the broader understanding of T1D management.

Postprandial hypoglycemia (PPH) is a challenging and significant complication that can occur following bariatric and metabolic surgery. Symptoms of PPH are typical of hypoglycemia, such as sweating, weakness, disorientation, palpitation, etc. The complex nature of PPH is essential to achieve accurate diagnosis and effective management. This review aims to give extensive coverage of the intricate nature of PPH common with bariatric and metabolic surgery, outlining its pathogenesis, risk factors, clinical presentation, diagnostic strategies, and treatment options. The study explores various clinical forms and pathogenic mechanisms behind PPH while discussing diagnostic tools like continuous glucose monitoring or mixed meal tolerance tests. Furthermore, it considers possible interventions, including dietary changes, pharmaceutical therapies, and surgeries, to relieve symptoms and improve patient's quality of life. It aims to comprehensively understand how healthcare professionals can effectively manage this disorder for patients undergoing bariatric and metabolic surgery.

Metabolic surgery is the foremost treatment for obesity and its associated medical conditions. Nonetheless, post-bariatric hypoglycemia (PBH) emerges as a prevalent complication. PBH pathophysiology implicates heightened insulin and glucagon-like peptide 1 (GLP-1) levels, with bile acids (BA) contributing to GLP-1 release. A plausible association exists between cholecystectomy and PBH, which is attributed to alterations in BA metabolism and ensuing hormonal responses. The objective of this retrospective cohort study was to evaluate the impact of cholecystectomy on PBH pharmacological treatment, diagnostic timelines and metabolic parameters.

Patients diagnosed with PBH after bariatric surgery were evaluated based on their history of cholecystectomy. Demographic, anthropometric and clinical data were collected. Mixed meal tolerance tests (MMTT) results were compiled to assess metabolic responses.

Of the 131 patients with PBH included in the study, 29 had prior cholecystectomy. The time to PBH diagnosis was similar across groups. Patients with prior cholecystectomy required higher doses of acarbose (p = 0.046), compared to those without prior cholecystectomy. Additionally, MMTT revealed higher insulin (t = 60 min: p = 0.010 and t = 90 min: p = 0.034) and c-peptide levels (t = 60 min: p = 0.008) and greater glycemic variability in patients with prior cholecystectomy (p = 0.049), highlighting the impact of cholecystectomy on glucose metabolism.

Our study offers novel insights into PBH pharmacotherapy, indicating that PBH patients with a history of cholecystectomy require elevated doses of acarbose for symptom control than PBH patients without such surgical history. Furthermore, our findings underscore the pivotal role of hyperinsulinism in PBH aetiology, emphasizing the significance of the BA-GLP-1-insulin axis.

Obesity surgery (OS) and diet-induced weight loss rapidly improve insulin resistance. We aim to investigate the impact of either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery compared with a diet low in energy (low-calorie diet; LCD) on body composition, glucose control and insulin sensitivity, assessed both at the global and tissue-specific level in individuals with obesity but not diabetes.

In this parallel group randomised controlled trial, patients on a waiting list for OS were randomised (no blinding, sealed envelopes) to either undergo surgery directly or undergo an LCD before surgery. At baseline and 4 weeks after surgery (n=15, 11 RYGB and 4 SG) or 4 weeks after the start of LCD (n=9), investigations were carried out, including an OGTT and hyperinsulinaemic-euglycaemic clamps during which concomitant simultaneous whole-body [18F]fluorodeoxyglucose-positron emission tomography (PET)/MRI was performed. The primary outcome was HOMA-IR change.

One month after bariatric surgery and initiation of LCD, both treatments induced similar reductions in body weight (mean ± SD: -7.7±1.4 kg and -7.4±2.2 kg, respectively), adipose tissue volume (7%) and liver fat content (2% units). HOMA-IR, a main endpoint, was significantly reduced following OS (-26.3% [95% CI -49.5, -3.0], p=0.009) and non-significantly following LCD (-20.9% [95% CI -58.2, 16.5). For both groups, there were similar reductions in triglycerides and LDL-cholesterol. Fasting plasma glucose and insulin were also significantly reduced only following OS. There was an increase in glucose AUC in response to an OGTT in the OS group (by 20%) but not in the LCD group. During hyperinsulinaemia, only the OS group showed a significantly increased PET-derived glucose uptake rate in skeletal muscle but a reduced uptake in the heart and abdominal adipose tissue. Both liver and brain glucose uptake rates were unchanged after surgery or LCD. Whole-body glucose disposal and endogenous glucose production were not significantly affected.

The short-term metabolic effects seen 4 weeks after OS are not explained by loss of body fat alone. Thus OS, but not LCD, led to reductions in fasting plasma glucose and insulin resistance as well as to distinct changes in insulin-stimulated glucose fluxes to different tissues. Such effects may contribute to the prevention or reversal of type 2 diabetes following OS. Moreover, the full effects on whole-body insulin resistance and plasma glucose require a longer time than 4 weeks.

ClinicalTrials.gov NCT02988011 FUNDING: This work was supported by AstraZeneca R&D, the Swedish Diabetes Foundation, the European Union's Horizon Europe Research project PAS GRAS, the European Commission via the Marie Sklodowska Curie Innovative Training Network TREATMENT, EXODIAB, the Family Ernfors Foundation, the P.O. Zetterling Foundation, Novo Nordisk Foundation, the Agnes and Mac Rudberg Foundation and the Uppsala University Hospital ALF grants.

We have previously shown that prandial endogenous glucose production (EGP) during insulin-induced hypoglycemia is smaller in non-diabetic subjects with gastric bypass (GB), where prandial glucagon-like peptide 1 (GLP-1) concentrations are 5-10 times higher than those in non-operated controls. Here, we sought to determine the effect of endogenous GLP-1 on prandial counterregulatory response to hypoglycemia after GB. Glucose fluxes, and islet-cell and gut hormone responses before and after mixed-meal ingestion were compared during a hyperinsulinemic hypoglycemic (~3.2 mmol/l) clamp with and without a GLP-1 receptor (GLP-1R) antagonist exendin-(9-39) (Ex-9) in non-diabetic subjects with prior GB compared to matched subjects with SG and non-surgical controls. In this setting, GLP-1R blockade had no effect on insulin secretion or insulin action, whereas prandial glucagon was enhanced in all 3 groups. Ex-9 infusion raised prandial EGP response to hypoglycemia in every GB subject but had no consistent effects on EGP among subjects with SG or non-operated controls (P < 0.05 for interaction). These results indicate that impaired post-meal glucose counterregulatory response to hypoglycemia after GB is partly mediated by endogenous GLP-1, highlighting a novel mechanism of action of GLP-1R antagonists for the treatment of prandial hypoglycemia in this population.

With a rise in obesity and more patients opting for bariatric surgery, it becomes crucial to understand associated complications like postprandial hypoglycemia (PPH). After bariatric surgery, significant changes are seen in insulin sensitivity, beta cell function, glucagon-like peptide 1 (GLP-1) levels, the gut microbiome, and bile acid metabolism. And in a small subset of patients, exaggerated imbalances in these functional and metabolic processes lead to insulin-glucose mismatch and hypoglycemia. The main treatment for PPH involves dietary modifications. For those that do not respond, medications or surgical interventions are considered to reverse some of the imbalances. We present a few case reports of patients that safely tolerated GLP-1 agonists. However, larger randomized control trials are needed to further characterize PPH and understand its treatment.

Growth hormone (GH) is an essential regulator of growth, body composition and fuel metabolism and, consequently, GH secretion is under the feedback control of numerous nutritional and endocrine mediators. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to exert pleiotropic effects, including stimulation of the activity of the hypothalamic-pituitary-adrenal axis. As GLP-1RAs exert multiple metabolic effects, we hypothesised that they may also affect the secretion of GH and examined the effect of a short-acting and a long-acting GLP-1 RA on GH secretion.

This is a post hoc analysis of data from clinical trials. Two separate single-group open-label clinical trials were carried out in the ambulatory care setting with a duration of 1 and 21 days, respectively. Healthy adult male and female volunteers with no chronic illnesses or use of daily medicines were recruited for the study. The two interventions were: study 1, single dose of 10 µg exenatide administered subcutaneously (s.c.); study 2, 0.6 mg liraglutide administered s.c. once daily for 21 days.

Administration of a single dose of exenatide (study 1) caused a clear increase in GH levels, peaking between 60 and 120 min post-administration. There was also a small but statistically significant decrease in luteinising hormone and testosterone levels 120 min after exenatide dosing. Administration of the long-acting GLP-1RA liraglutide daily for 21 days (study 2) elicited an increase in GH levels with no change in insulin-like growth factor-1 (IGF-1) concentrations after 3 weeks of treatment.

The results show that the administration of GLP-1RAs may elicit an increase in growth hormone levels. GLP-1 signalling may be a novel mechanism of regulation of GH secretion. This finding needs to be replicated in the placebo-controlled trial.

NCT02089256 and NCT03160261.

Postprandial hyperinsulinemic hypoglycemia with neuroglycopenia is an increasingly recognized complication of Roux-en-Y gastric bypass and gastric sleeve surgery that may detrimentally affect patient quality of life. One likely causal factor is glucagon-like peptide-1 (GLP-1), which has an exaggerated rise following ingestion of carbohydrates after bariatric surgery. This paper sought to assess the role of GLP-1 receptor agonists (GLP-1RAs) in managing postprandial hypoglycemia following bariatric surgery.

MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and Scopus were systematically and critically appraised for all peer-reviewed publications that suitably fulfilled the inclusion criteria established a priori. This systematic review was developed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols (PRISMA-P). It followed methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions and is registered with PROSPERO (International Prospective Register of Systematic Reviews; identifier CRD420212716429).

Postprandial hyperinsulinemic hypoglycemia remains a notoriously difficult to manage metabolic complication of bariatric surgery. This first, to the authors' knowledge, systematic review presents evidence suggesting that use of GLP-1RAs does not lead to an increase of hypoglycemic episodes, and, although this approach may appear counterintuitive, the findings suggest that GLP-1RAs could reduce the number of postprandial hypoglycemic episodes and improve glycemic variability.

Accumulating evidence supports the early use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose transporter-2 inhibitors (SGLT-2is) for the treatment of type 2 diabetes. Indeed, these compounds exert numerous pleiotropic actions that favorably affect metabolism and diabetes comorbidities, showing an additional effect beyond glucose control. Although a substantial amount of knowledge has been generated regarding the mechanism of action of both drug classes, much remains to be understood. Growth hormone (GH) is an important driver for multiple endocrine responses involving changes in glucose and lipid metabolism, and affects several tissues and organs (e.g., bone, heart). It acts directly on several target tissues, including skeletal muscle and bone, but several effects are mediated indirectly by circulating (liver-derived) or locally produced IGF-1. In consideration of the multiple metabolic and cardiovascular effects seen in subjects treated with GLP-1RAs and SGLT-2is (e.g., reduction of hyperglycemia, weight loss, free/fat mass and bone remodeling, anti-atherosclerosis, natriuresis), it is reasonable to speculate that GH and IGF-1 may play a about a relevant role in this context. This narrative mini-review aims to describe the involvement of the GH/IGF-1/IGF-1R axis in either mediating or responding to the effects of each of the two drug classes.

Roux-en-Y gastric bypass surgery (RYGB) markedly improves glycemia in patients with type 2 diabetes (T2D), but underlying mechanisms and changes over time are incompletely understood.

Integrated assessment of neuroendocrine and metabolic changes over time in T2D patients undergoing RYGB.

Follow-up of single-center randomized study.

Thirteen patients with obesity and T2D compared to 22 healthy subjects.

Blood chemistry, adipose biopsies, and heart rate variability were obtained before and 4, 24, and 104 weeks post-RYGB.

After RYGB, glucose-lowering drugs were discontinued and hemoglobin A1c fell from mean 55 to 41 mmol/mol by 104 weeks (P < 0.001). At 4 weeks, morning cortisol (P < 0.05) and adrenocorticotropin (P = 0.09) were reduced by 20%. Parasympathetic nerve activity (heart rate variability derived) increased at 4 weeks (P < 0.05) and peaked at 24 weeks (P < 0.01). C-reactive protein (CRP) and white blood cells were rapidly reduced (P < 0.01). At 104 weeks, basal and insulin-stimulated adipocyte glucose uptake increased by 3-fold vs baseline and expression of genes involved in glucose transport, fatty acid oxidation, and adipogenesis was upregulated (P < 0.01). Adipocyte volume was reduced by 4 weeks and more markedly at 104 weeks, by about 40% vs baseline (P < 0.01).

We propose this order of events: (1) rapid glucose lowering (days); (2) attenuated cortisol axis activity and inflammation and increased parasympathetic tone (weeks); and (3) body fat and weight loss, increased adipose glucose uptake, and whole-body insulin sensitivity (months-years; similar to healthy controls). Thus, neuroendocrine pathways can partly mediate early glycemic improvement after RYGB, and adipose factors may promote long-term insulin sensitivity and normoglycemia.

While Roux-en-Y gastric bypass (RYGB) surgery in obese individuals typically improves glycemic control and prevents diabetes, it also frequently causes asymptomatic hypoglycemia. Previous work showed attenuated counterregulatory responses following RYGB. The underlying mechanisms as well as the clinical consequences are unclear. In this study, 11 subjects without diabetes with severe obesity were investigated pre- and post-RYGB during hyperinsulinemic normo-hypoglycemic clamps. Assessments were made of hormones, cognitive function, cerebral blood flow by arterial spin labeling, brain glucose metabolism by ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography, and activation of brain networks by functional MRI. Post- versus presurgery, we found a general increase of cerebral blood flow but a decrease of total brain FDG uptake during normoglycemia. During hypoglycemia, there was a marked increase in total brain FDG uptake, and this was similar for post- and presurgery, whereas hypothalamic FDG uptake was reduced during hypoglycemia. During hypoglycemia, attenuated responses of counterregulatory hormones and improvements in cognitive function were seen postsurgery. In early hypoglycemia, there was increased activation post- versus presurgery of neural networks in brain regions implicated in glucose regulation, such as the thalamus and hypothalamus. The results suggest adaptive responses of the brain that contribute to lowering of glycemia following RYGB, and the underlying mechanisms should be further elucidated.

Postprandial hypoglycemia is a disabling complication of the treatment of obesity by gastric bypass surgery. So far, no therapy exists, and the underlying mechanisms remain unclear. Here, we hypothesized that glucose-induced IL-1β leads to an exaggerated insulin response in this condition. Therefore, we conducted a placebo-controlled, randomized, double-blind, crossover study with the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra (clinicaltrials.govNCT03200782; n = 12). Both drugs reduced postprandial insulin release and prevented hypoglycemia (symptomatic events requiring rescue glucose: placebo = 7/12, empagliflozin = 2/12, and anakinra = 2/12, pval_{likelihood ratio test (LRT)} = 0.013; nadir blood glucose for placebo = 2.4 mmol/L, 95% CI 2.18-2.62, empagliflozin = 2.69 mmol/L, 95% CI 2.31-3.08, and anakinra = 2.99 mmol/L, 95% CI 2.43-3.55, pval_LRT = 0.048). Moreover, analysis of monocytes ex vivo revealed a hyper-reactive inflammatory state that has features of an exaggerated response to a meal. Our study proposes a role for glucose-induced IL-1β in postprandial hypoglycemia after gastric bypass surgery and suggests that SGLT2-inhibitors and IL-1 antagonism may improve this condition.