The Effect Lactate Administration on Cerebral Blood Flow During Hypoglycemia

Study Overview
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Brief Summary
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It is thought that altered brain lactate handling is involved in the development of impaired awareness of hypoglycemia (IAH), i.e. the inability to timely detect hypoglycemia in people with type 1 diabetes (T1DM). Infusion of lactate diminishes symptomatic and hormonal responses to hypoglycemia in patients with normal awareness of hypoglycemia (NAH), resembling the situation of patients with IAH. It is unknown whether this attenuating effect is due to brain lactate oxidation or the result of lactate-induced alterations of global and regional cerebral blood flow (CBF). Normally, hypoglycemia causes a redistribution of CBF towards the thalamus, from where the sympathetic response to hypoglycemia is coordinated, but in IAH this effect is absent and global CBF is increased. We hypothesize that lactate infusion in patients with NAH will result in blunting of thalamic activation and/or enhanced global CBF. If so, these results may help delineating the pathogenesis of IAH which eventually creates new avenues to protect against the morbidity associated with hypoglycemia and IAH. Study design: Single-blind placebo controlled, randomized cross-over intervention study Study population: T1DM patients with NAH (n=10) Intervention: On two separate occasions, patients with T1DM and NAH will undergo a hyperinsulinemic euglycemic-hypoglycemic glucose clamp with or without the infusion of exogenous lactate. ASL-MRI will be applied to measure global and regional changes in CBF. Main study parameters/endpoints: The change in regional thalamic CBF in response to intravenous lactate infusion compared to placebo, during hypoglycemia

Official Title
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The Effect of Lactate Administration on Cerebral Blood Flow During Hypoglycemia; Are the Suppressive Effects of Lactate on Counterregulatory Responses to Hypoglycemia Reflected in an Altered CBF Response?

Conditions
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Type1diabetes, Hypoglycemia Unawareness

Intervention / Treatment
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* Drug: Sodium Lactate
* Drug: Sodium chloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diabetes duration ≥ 1 year Age: 18-50 years Body-Mass Index: 18-30 kg/m2 HbA1c: 42-75 mmol/mol (6-9%) Outcome Clarke questionnaire: 0-1 Blood pressure: <160/90 mmHg Exclusion Criteria: Inability to provide informed consent Use medication other than insulin, except for oral contraceptives or stable thyroxin supplementation therapy Presence of any other medical condition that might interfere with the study protocol, such as brain injuries, epilepsy, a major cardiovascular disease event or cardiac failure, known liver disease, anxiety disorders or a history of panic attacks. Microvascular complications of T1DM: Proliferative retinopathy, symptomatic diabetic neuropathy (including autonomic neuropathy) or Nephropathy; clinical/overt albuminuria or an estimated glomerular filtration rate <60ml/min/1.73m2. MRI contraindications (pregnancy, severe claustrophobia, metal parts in body)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lactate infusion<br>Subjects will receive an intravenous lactate infusion to elevate plasma lactate levels | Drug: Sodium Lactate<br>* IV infusion<br>|
| Placebo Comparator: NaCl infusion<br>As a control condition, subjects will receive intravenous NaCl infusion | Drug: Sodium chloride<br>* IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Regional CBF in ml/100g/min measured with ASL-MRI | The change in regional thalamic CBF in response to intravenous lactate infusion compared to placebo, during hypoglycemia | during stable euglycemia (40 minutes) and hypoglycemia (45 minutes) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global CBF in ml/100g/min measured with ASL-MRI | The change in global CBF in response to intravenous lactate infusion | during stable euglycemia (40 minutes) and hypoglycemia (45 minutes) | 
| Counterregulatory hormone responses to hypoglycemia | The difference in adrenaline (pmol/L) responses to hypoglycemia during lactate infusion compared to placebo | during stable euglycemia (40 minutes) and hypoglycemia (45 minutes) | 
| Symptom responses to hypoglycemia | The difference in symptom responses to hypoglycemia (meausured with a validated questionnaire) during lactate infusion compared to placebo | during stable euglycemia (40 minutes) and hypoglycemia (45 minutes) | 
| Measurements of metabolites in cell lysates or supernatants of the cultured immune cells | The effect of lactate administration on immune cell function and metabolism | during stable euglycemia (40 minutes) and hypoglycemia (45 minutes) |