The Role of Endogenous Lactate in Brain Preservation and Counterregulatory Defenses Against Hypoglycemia

Not Applicable

Completed

• Conditions: Type 1 Diabetes Mellitus; Hypoglycemia Unawareness
• Interventions: Behavioral: Lay down comfortably; Behavioral: High intensity exercise

• Registration Number: NCT02308293
• Lead Sponsor: Radboud University Medical Center

Brief Summary

Iatrogenic hypoglycemia is the most frequent acute complication of insulin therapy in people with type 1 diabetes (T1DM). Recurrent hypoglycemic events initiate a process of habituation, characterized by suppression of hypoglycemic symptoms, eventually leading to hypoglycemia unawareness, which creates a particularly high risk of severe hypoglycemia. Recent evidence suggest a pivotal role for (brain) lactate in the pathogenesis of hypoglycemia unawareness. Indeed, exogenous lactate administration may preserve brain function and attenuate counterregulatory responses to and symptomatic awareness of hypoglycemia. It is unknown whether endogenous elevation of plasma lactate produces the same effects and whether such effects differ between patients with T1DM with and without hypoglycemia unawareness and healthy controls.

Objective: To investigate the effect of elevated levels of endogenous lactate on brain lactate accumulation and on counterregulatory responses to, symptomatic awareness of and cognitive function during hypoglycemia in patients with T1DM with and without hypoglycemia unawareness and normal controls.

Hypothesis: The investigators hypothesize first that endogenous lactate, when raised through high intensity exercise, preserves neuronal metabolism during subsequent hypoglycemia, which in turn will attenuate counterregulatory hormone responses, appearance of symptoms and deterioration of cognitive function. Second, the investigators posit that these effects will be augmented in patients with hypoglycemia unawareness compared to healthy subjects and T1DM patients with normal awareness as a consequence of greater transport capacity of lactate into the brain.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-11-14
• Study First Submitted QC: 2014-12-03
• Study First Posted: 2014-12-04
• Study Start: 2015-01
• Status Verified: 2016-04
• Primary Completion: 2016-05
• Study Completion: 2016-07
• Last Update Submitted: 2016-11-23
• Last Update Posted: 2016-11-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Lay down comfortably	Lay down comfortably	As a control conditions, subjects wil lay down comfortably and rest
High intensity exercise	High intensity exercise	Subjects will preform a high intensity training exercise (3\* 30 seconds all out sprint on a cycle ergometer) to raise plasma lactate levels

Primary Outcome Measures

Name	Time	Method
Plasma level of adrenaline in response to hypoglycemia (Adrenaline, measured in arterial plasma)	during 60 m of hypoglycemia

Secondary Outcome Measures

Name	Time	Method
Plasma lactate levels (Lactate levels measured in arterial plasma)	During 60 min hypoglycemia	Lactate levels measured in arterial plasma
Glucose infusion rate (Amount of glucose 20% necessary to maintain plasma glucose at steady state values)	During 60 min hypoglycemia	Amount of glucose 20% necessary to maintain plasma glucose at steady state values
Plasma levels of inflammatory markers (levels of cytokines)	During 60 min hypoglycemia	levels of cytokines
Brain perfusion measured with ASL-MRI	During 60 min hypoglycemia	Brain perfusion measured with ASL-MRI
Plasma levels of other counter-regulatory hormones (Levels of counter-regulatory hormones measured in arterial plasma)	During 60 min hypoglycemia	Levels of counter-regulatory hormones measured in arterial plasma
Cognitive functioning, as measured by cognitive tests	During 60 min hypoglycemia	Cognitive test will be: Dutch State Trait Anxiety Inventory, Digit Span, Stroop color word test, word fluency test, trail making test and Pasat
Brain lactate accumulation measured with 1H-MRS	During 60 min of hypoglycemia	Brain lactate levels measured with 1H-MRS

Trial Locations

Locations (1)

Radboud umc; 🇳🇱 Nijmegen, Netherlands