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.

Inclusion criteria for healthy subjects

• Age: 18-40 years
• Body-Mass Index: 18-30 kg/m2
• Blood pressure: <160/90 mmHg
• Recreationally active: i.e. taking part in competitive sport or regular exercise training, of a non-professional nature, once or more a week.

Inclusion criteria T1DM patients with normal hypoglycemic awareness

• Diabetes duration ≥ 1 year
• Age: 18-40 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
• Recreationally active: i.e. taking part in competitive sport or regular exercise training, of a non-professional nature, once or more a week

Inclusion criteria T1DM patients with hypoglycemia unawareness

• Diabetes duration ≥ 1 year
• Age: 18-40 years
• Body-Mass Index: 18-30 kg/m2
• HbA1c: 42-75 mmol/mol (6-9%)
• Outcome Clarke questionnaire: =>3
• Blood pressure: <160/90 mmHg
• Recreationally active

Exclusion criteria:

• Inability to provide informed consent
• Presence of any medical condition that might interfere with the study protocol, such as brain injuries, epilepsy, a major cardiovascular disease event or anxiety disorders
• Use of any medication, except for oral contraceptives
• MR(I) contraindications (pregnancy, severe claustrophobia, metal parts in body)
• Orthopedic and/or neurological diseases that impair exercise
• Cardiopulmonary disease as stated in the 2001 American heart association and 2002 American college of cardiology/American heart association guidelines

Additional exclusion criteria for all T1DM patients:

• Use of any other medication than insulin, except for oral contraceptives or stable thyroxine supplementation therapy
• complications of T1DM, including proliferative retinopathy, neuropathy or nephropathy