The Effect Lactate Administration on Cerebral Blood Flow During Hypoglycemia

Not Applicable

• Conditions: Type1diabetes; Hypoglycemia Unawareness
• Interventions: Drug: Sodium Lactate; Drug: Sodium chloride

• Registration Number: NCT03730909
• Lead Sponsor: Radboud University Medical Center

Brief Summary

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

Detailed Description

Not available

Study Timeline

• Study Start: 2018-06-11
• Status Verified: 2018-10
• Study First Submitted: 2018-10-22
• Study First Submitted QC: 2018-11-01
• Last Update Submitted: 2018-11-01
• Study First Posted: 2018-11-05
• Last Update Posted: 2018-11-05
• Primary Completion: 2019-04-11
• Study Completion: 2019-06-11

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 10

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Lactate infusion	Sodium Lactate	Subjects will receive an intravenous lactate infusion to elevate plasma lactate levels
NaCl infusion	Sodium chloride	As a control condition, subjects will receive intravenous NaCl infusion

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Radoud university medical center; 🇳🇱 Nijmegen, Netherlands