Evaluation of the Neuro-endocrine Response to Post-prandial Hyperinsulinaemic Hypoglycaemia.

NCT ID: NCT04334161

Last Updated: 2021-08-10

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 32 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2020-10-02
• Study Completion Date: 2021-07-13

Brief Summary

The primary objective of this study is to assess the neuro-endocrine response to hypoglycaemia in PHH vs. non-PHH post-gastric bypass individuals.

Detailed Description

Obesity is a major global public health concern, for which the most effective therapy is bariatric surgery. Beyond weight loss, bariatric surgery exerts powerful effects on glucose metabolism, achieving complete type 2 diabetes remission in up to 70% of cases. An exaggeration of these effects, however, can result in an increasingly recognized metabolic complication known as postprandial hyperinsulinaemic hypoglycaemia (PHH). The condition manifests 1-3 years after surgery with hypoglycaemic episodes after meals. Emerging data suggest that PHH is more frequent than previously thought and affects approximately 30% of postoperative patients, more commonly after gastric bypass than sleeve gastrectomy . Despite such frequency, the underlying pathophysiology of PHH remains incompletely understood.

A striking finding in PHH patients is the observed lack of insulin suppression and inadequate glucagon response to the sharply falling glucose levels. The blunted glucagon response to hypoglycaemia may result from altered alpha-cell function (acute or chronic) and an interaction with gut hormones (e.g. glucagon-like peptide 1 (GLP-1) that is known to exert glucagon-inhibitory effects) or altered brain signalling. It is conceivable that, both, lack of endogenous insulin suppression in response to falling postprandial blood glucose levels and impaired glucagon secretion contribute to PHH.

Further neuroendocrine regulatory processes to counteract hypoglycaemia involve catecholamines, cortisol, growth hormone and autonomic nervous system activity. Two previous studies examined counter-regulatory hormones during experimentally induced hypoglycaemia in patients after gastric bypass surgery and found lower levels than before surgery, suggesting that bariatric surgery per se influences counter-regulation to hypoglycaemia. Underlying mechanisms remain speculative. Of note, impaired neuroendocrine counter-regulation to hypoglycaemia is further supported by the high proportion of asymptomatic patients, which may be reflective of impaired hypoglycaemia awareness. The role of counter-regulatory hormones in PHH patients remains not fully understood.

Apart from the neuroendocrine milieu, effectiveness of hypoglycaemia counter-regulation depends on the capacity to provide glucose from the liver, also known as endogenous glucose production. In healthy humans, approximately 85% of the glucose produced by the liver during the initial 60-90min of hypoglycaemia is derived from liver glycogen. Postprandial hepatic glycogen stores, in turn, depend heavily on the hepatic glucose uptake following a meal. Postprandial hepatic glucose disposal and mobilization of hepatic glucose during hypoglycaemia in PHH patients remain unexplored to date.

There is currently no evidence, that increased insulin sensitivity is implicated in the pathophysiology of PHH. Conversely, previous studies suggested increased non-insulin dependent whole body glucose uptake in PHH compared to non-PHH in the light of similar or even decreased insulin sensitivity.

The primary objective of this study is to assess the neuro-endocrine response to hypoglycaemia in PHH vs. non-PHH post-gastric bypass individuals. The investigators hypothesize that the glucagon response to standardized and controlled hypoglycaemia is significantly diminished in PHH vs. non-PHH post-gastric bypass individuals. Involvement of non-surgical non-PHH controls and sleeve-gastrectomy non-PHH controls will allow to explore effects of bariatric surgery on counter-regulatory mechanisms to hypoglycaemia, including differences between procedures (gastric bypass vs. sleeve gastrectomy).

Conditions

Roux-en-y Gastric Bypass; Post Prandial Hypoglycemia

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

PHH patients

Patients with Roux-en-Y gastric bypass ≥1 year ago and confirmed postprandial hyperglycaemic hypoglycaemia (PHH). PHH is defined as postprandial plasma or sensor glucose\<3.0mmol/l according to the International Hypoglycaemia Study Group and exclusion of other causes of hypoglycaemia

Administration of glucose and controlled induction of hypoglycaemia.

Intervention Type: COMBINATION_PRODUCT

Functional metabolic test involving a 15g oral glucose load (enriched with 1.5% U-13C glucose) and subsequent controlled 20min hypoglycaemic clamp period. Neuroendocrine response will be assessed using frequent blood samples for hormones and metabolites, continuous heart rate monitoring and evaluation for hypoglycaemic symptoms.

non-PHH gastric bypass patients

Patients with Roux-en-Y gastric bypass ≥1 year ago without evidence of PHH.

Administration of glucose and controlled induction of hypoglycaemia.

Intervention Type: COMBINATION_PRODUCT

Functional metabolic test involving a 15g oral glucose load (enriched with 1.5% U-13C glucose) and subsequent controlled 20min hypoglycaemic clamp period. Neuroendocrine response will be assessed using frequent blood samples for hormones and metabolites, continuous heart rate monitoring and evaluation for hypoglycaemic symptoms.

non-PHH sleeve gastrectomy patients

Patients with sleeve gastrectomy ≥1 year ago without evidence PHH.

Administration of glucose and controlled induction of hypoglycaemia.

Intervention Type: COMBINATION_PRODUCT

Functional metabolic test involving a 15g oral glucose load (enriched with 1.5% U-13C glucose) and subsequent controlled 20min hypoglycaemic clamp period. Neuroendocrine response will be assessed using frequent blood samples for hormones and metabolites, continuous heart rate monitoring and evaluation for hypoglycaemic symptoms.

non-PHH non-surgical controls

Absence of any conditions or previous surgery known to affect gastro-intestinal integrity and food absorption.

Administration of glucose and controlled induction of hypoglycaemia.

Intervention Type: COMBINATION_PRODUCT

Functional metabolic test involving a 15g oral glucose load (enriched with 1.5% U-13C glucose) and subsequent controlled 20min hypoglycaemic clamp period. Neuroendocrine response will be assessed using frequent blood samples for hormones and metabolites, continuous heart rate monitoring and evaluation for hypoglycaemic symptoms.

Interventions

Administration of glucose and controlled induction of hypoglycaemia.

Functional metabolic test involving a 15g oral glucose load (enriched with 1.5% U-13C glucose) and subsequent controlled 20min hypoglycaemic clamp period. Neuroendocrine response will be assessed using frequent blood samples for hormones and metabolites, continuous heart rate monitoring and evaluation for hypoglycaemic symptoms.

Intervention Type: COMBINATION_PRODUCT

Eligibility Criteria

Inclusion Criteria

• Aged ≥18 years
• Roux-en-Y gastric bypass ≥1 year ago
• PHH defined as postprandial plasma or sensor glucose<3.0mmol/l according to the International Hypoglycaemia Study Group (1) and exclusion of other causes of hypoglycaemia

• Aged ≥18 years
• Roux-en-Y gastric bypass (Group 2) or sleeve gastrectomy (Group 3) ≥1 year ago
• No evidence of PHH

• Aged ≥18 years
• Absence of any condition or previous surgery known to affect gastro-intestinal integrity and food absorption

Exclusion Criteria

• Clinically relevant weight changes (≥5%) within the past 3 months
• Incapacity to give informant consent
• Historical or current diabetes based on HbA1c ≥6.5% without glucose-lowering treatment
• Haemoglobin level below 13.5 g/l
• Ongoing treatment with glucose-lowering drugs, anorectic drugs, steroids or any medications known to affect gastric motility
• Active heart, lung, liver, gastrointestinal, renal or neurological disease
• Inability to follow study procedures
• Pregnancy or breast-feeding

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Lia Bally

OTHER

Sponsor Role: lead

Responsible Party

Lia Bally

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Lia Bally, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University Hospital Bern & University of Bern

Locations

Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism

Bern, , Switzerland

Countries

Switzerland

References

Tripyla A, Herzig D, Reverter-Branchat G, Pavan J, Schiavon M, Eugster PJ, Grouzmann E, Nakas CT, Sauvinet V, Meiller L, Zehetner J, Giachino D, Nett P, Gawinecka J, Del Favero S, Thomas A, Thevis M, Dalla Man C, Bally L. Counter-regulatory responses to postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia vs surgical and non-surgical control individuals. Diabetologia. 2023 Apr;66(4):741-753. doi: 10.1007/s00125-022-05861-9. Epub 2023 Jan 17.

Reference Type: DERIVED

PMID: 36648553 (View on PubMed)

Other Identifiers

DEEP1B

Identifier Type: -

Identifier Source: org_study_id