The Effect Lactate Administration on Cerebral Blood Flow During Hypoglycemia

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?

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

Study Overview

• Status: Unknown
• Conditions: Type1diabetes; Hypoglycemia Unawareness
• Intervention / Treatment: Drug: Sodium Lactate; Drug: Sodium chloride

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Bastiaan de Galan, PhD; Phone Number: 0243613286; Email: bastiaan.degalan@radboud.nl

Study Locations

• Netherlands
  • Nijmegen, Netherlands
    • Recruiting
    • Radoud university medical center
    • Contact: Bastiaan de Galan, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Radboud University Medical Center

Publications and helpful links

General Publications

• van Meijel LA, van Asten JJA, Grandjean J, Heerschap A, Tack CJ, van der Graaf M, Wiegers EC, de Galan BE. Effect of lactate administration on cerebral blood flow during hypoglycemia in people with type 1 diabetes. BMJ Open Diabetes Res Care. 2022 Mar;10(2):e002401. doi: 10.1136/bmjdrc-2021-002401.

Study record dates

Study Major Dates

• Study Start (Actual): June 11, 2018
• Primary Completion (Anticipated): April 11, 2019
• Study Completion (Anticipated): June 11, 2019

Study Registration Dates

• First Submitted: October 22, 2018
• First Submitted That Met QC Criteria: November 1, 2018
• First Posted (Actual): November 5, 2018

Study Record Updates

• Last Update Posted (Actual): November 5, 2018
• Last Update Submitted That Met QC Criteria: November 1, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hypoglycemia
• Other Study ID Numbers: Lactate_CBF

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No