Roles of increased glycemic variability, GLP-1 and glucagon in hypoglycaemia after Roux-en-Y gastric bypass

ObjectiveRoux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment for diabetes and obesity. An increasingly recognized and highly disabling complication of RYGB is postprandial hypoglycaemia (PPH). The pathophysiology of PPH remains unclear with multiple mechanisms suggested including nesidioblastosis, altered insulin clearance and increased glucagon-like peptide-1 (GLP-1) secretion. Whilst many PPH patients respond to dietary modification, some have severely disabling symptoms. Multiple treatments are proposed, including dietary modification, GLP-1 antagonism, GLP-1 analogues and even surgical reversal, with none showing a more decided advantage over the others. A greater understanding of the pathophysiology of PPH could guide the development of new therapeutic strategies.MethodsWe studied a cohort of PPH patients at the Imperial Weight Center. We performed continuous glucose monitoring to characterize their altered glycaemic variability. We also performed a mixed meal test (MMT) and measured gut hormone concentrations.ResultsWe found increased glycaemic variability in our cohort of PPH patients, specifically a higher mean amplitude glucose excursion (MAGE) score of 4.9. We observed significantly greater and earlier increases in insulin, GLP-1 and glucagon in patients who had hypoglycaemia in response to an MMT (MMT Hypo) relative to those that did not (MMT Non-Hypo). No significant differences in oxyntomodulin, GIP or peptide YY secretion were seen between these two groups.ConclusionAn early peak in GLP-1 and glucagon may together trigger an exaggerated insulinotropic response to eating and consequent hypoglycaemia in patients with PPH.</jats:sec

The metabolomic effects of tripeptide gut hormone infusion compared to Roux-en-Y gastric bypass and caloric restriction

Context: The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) are regulators of energy intake and glucose homeostasis, and are thought to contribute to the glucose-lowering effects of bariatric surgery. Objective: To establish the metabolomic effects of a combined infusion of GLP-1, OXM and PYY (tripeptide “GOP”) in comparison to a placebo infusion, Roux-en-Y gastric bypass (RYGB) surgery, and a very low-calorie diet (VLCD). Design and setting: Sub-analysis of a single-blind, randomised, placebo-controlled study of GOP infusion (ClinicalTrials.gov NCT01945840), including VLCD and RYGB comparator groups. Patients and interventions: 25 obese patients with type 2 diabetes or prediabetes were randomly allocated to receive a 4-week subcutaneous infusion of GOP (n=14) or 0.9% saline control (SAL; n=11). An additional 22 patients followed a VLCD, and 21 underwent RYGB surgery. Main outcome measures: Plasma and urine samples collected at baseline and 4 weeks into each intervention were subjected to cross-platform metabolomic analysis, followed by unsupervised and supervised modelling approaches to identify similarities and differences between the effects of each intervention. Results: Aside from glucose, very few metabolites were affected by GOP, contrasting with major metabolomic changes seen with VLCD and RYGB. Conclusions: Treatment with GOP provides a powerful glucose-lowering effect but does not replicate the broader metabolomic changes seen with VLCD and RYGB. The contribution of these metabolomic changes to the clinical benefits of RYGB remains to be elucidated

The role of gut hormones in mediating the beneficial effects of RYGB on glycaemia and energy balance

Obesity and type 2 diabetes are both on the rise. Bariatric surgery is currently the most efficient treatment for obesity. Early weight-loss-independent improvement in glycaemia and longer-term ‘remission’ of type 2 diabetes are typically observed post-RYGB. The Gut hormones, GLP-1, OXM and PYY (GOP), are augmented post-prandially after RYGB. They are anorectic and have the potential to enhance beta cell function and increase energy expenditure. We hypothesized that the elevation in GOP levels, mediate the beneficial metabolic effects of RYGB. GOP infused subcutaneously at combined doses of 4/4/0.4 pmol/kg/min, successfully, replicated the peak post-prandial circulating levels of the individual hormone post-RYGB. Subsequently, GOP at 4/4/0.4 pmol/kg/min was infused chronically for 28 days in obese volunteers with type 2 diabetes, in a randomised single-blinded placebo-controlled study. Effects of GOP on Energy Intake (EI), Appetite ratings, Energy Expenditure, Anthropometrics and Glycaemia were assessed and compared to the effects of RYGB on similar parameters. Both an acute and chronic GOP infusion led to a significant reduction in EI, comparable to the effect of RYGB. A similar enhancement in satiety and decrease in ‘prospective food intake’ were observed following GOP and RYGB. However, only RYGB volunteers displayed a significant increase in Diet-induced-Thermogenesis. Weight loss was superior following RYGB compared to GOP at a similar time-frame. Nonetheless, a comparable and significant improvement in Fructosamine, HbA1c, Fasting and Post-prandial Glucose, was generated following both interventions at 4 weeks. Enhancement in beta cell function and insulin sensitivity appeared to be important. In summary, the gut hormones - GOP, are the likely candidates mediating 1) the reduction in EI post-RYGB by promoting satiety and contributing to weight loss 2) the improvement in glycaemia, early after surgery, irrespective of weight loss. Other mechanisms appear to be responsible for the increase in EE and the majority of weight loss, post-RYGB.Open Acces

Bone Perspectives in Functional Hypothalamic Amenorrhoea: An Update and Future Avenues

One of the most important and potentially long-lasting detrimental consequences of Functional Hypothalamic Amenorrhoea (FHA) is on skeletal homeostasis. Beyond oestrogen deficiency, FHA is associated with a cascade of additional neuro-endocrine and metabolic alterations, some adaptive, but which combine to disrupt skeletal homeostasis. Ultimately, this leads to a two-fold increased risk of fractures in women with FHA compared to healthy eumenorrhoeic women. Although the cornerstone of management of FHA-related bone loss remains recovery of menses via restoration of metabolic/psychological balance, there is rapidly developing evidence for hormonal manipulations (with a particular emphasis on route of administration) and other pharmacological treatments that can protect or improve skeletal homeostasis in FHA. In this mini-review, we provide an update on the pathophysiology, clinical management and future avenues in the field from a bone perspective.</jats:p

Bone Perspectives in Functional Hypothalamic Amenorrhoea: An Update and Future Avenues

One of the most important and potentially long-lasting detrimental consequences of Functional Hypothalamic Amenorrhoea (FHA) is on skeletal homeostasis. Beyond oestrogen deficiency, FHA is associated with a cascade of additional neuro-endocrine and metabolic alterations, some adaptive, but which combine to disrupt skeletal homeostasis. Ultimately, this leads to a two-fold increased risk of fractures in women with FHA compared to healthy eumenorrhoeic women. Although the cornerstone of management of FHA-related bone loss remains recovery of menses via restoration of metabolic/psychological balance, there is rapidly developing evidence for hormonal manipulations (with a particular emphasis on route of administration) and other pharmacological treatments that can protect or improve skeletal homeostasis in FHA. In this mini-review, we provide an update on the pathophysiology, clinical management and future avenues in the field from a bone perspective