Assessing Insulin Turnover Using an In-vivo Deuterated Water Experiment.

Study Overview
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Brief Summary
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The primary objective of this study is to observe the kinetics of pre-stored and de-novo synthesized insulin that is secreted into the circulation using an in-vivo heavy water (D2O) labelling experiment in patients with postprandial hyperinsulinaemic hypoglycaemia (PHH) and non-surgical non-PHH controls.

Detailed Description
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Despite an increased prevalence, the underlying pathophysiology of PHH remains incompletely understood. It is generally assumed that PHH is caused by excess insulin secretion, either due to an intrinsic beta-cell abnormality (histology showing increased beta-cell mass or signs of hyperfunction) and/or increased postprandial insulinotropic signals (also known as the incretin-effect) as a consequence of the re-arranged gastrointestinal tract and accelerated nutrient transit and absorption. Either of the two explanations would imply an altered insulin turnover in these patients with higher amounts of pre-stored insulin and/or accelerated de-novo insulin synthesis in response to stimulus-depletion of the available insulin pool. A non-invasive in vivo technique to study insulin turnover has not been established yet and data related to PHH are consequently lacking. The primary objective of this study is to observe the kinetics of pre-stored and de-novo synthesized insulin that is secreted into the circulation using an in-vivo heavy water (D2O) labelling experiment in patients with postprandial hyperinsulinaemic hypoglycaemia (PHH) and non-surgical non-PHH controls. The investigators hypothesize that the suggested methodological approach is feasible to assess insulin turnover and provides the foundation for further studies in different target groups.

Official Title
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Deciphering the Enigma of Postprandial Hyperinsulinaemic Hypoglycaemia After Bariatric Surgery, Part 1 A: Assessing Insulin Turnover Using an In-vivo Deuterated Water Experiment. A Proof-of-concept Study.

Conditions
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Bariatric Surgery, Hypoglycemia, Gastric Bypass

Intervention / Treatment
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* Other: Heavy water experiment


Participation Criteria
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Eligibility Criteria
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Inclusion criteria for PHH patients: 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 and exclusion of other causes of hypoglycaemia Inclusion criteria for non-PHH non-surgical controls: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| PHH patients<br>Patients following Roux-en-Y gastric bypass surgery (≥1 year ago) with confirmed post-prandial hyperinsulinemic hypoglycemia | Other: Heavy water experiment<br>* 3 times daily heavy water (deuterated-water) and mixed meal administration for one week<br>|
| Healthy controls<br>Non-PHH, non-surgical healthy individuals | Other: Heavy water experiment<br>* 3 times daily heavy water (deuterated-water) and mixed meal administration for one week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total amount of pre-stored insulin secreted | Measured using deuterium (2H)-labelled insulin in the plasma | During the 7 days of the heavy water administration period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time course of the increase in 2H-labelled insulin in plasma |  | During the 7 days of the heavy water administration period | 
| Time course of the increase in 2H-labelled insulin in urine |  | During the 7 days of the heavy water administration period | 
| Time course of the increase in 2H-labelled c-peptide in plasma |  | During the 7 days of the heavy water administration period | 
| Time course of the increase in 2H-labelled c-peptide in urine |  | During the 7 days of the heavy water administration period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin turnover, Insulin secretion, Deuterated Water, De-novo insulin synthesis