Clinical trial NCT03286816: The Effect of Intravenous Lactate on Brain Lactate Concentrations During Hypoglycemia
Official title: The Effect of Intravenous Lactate Administration on Brain Lactate Concentrations and pH During Euglycemia and Hypoglycemia in Patients With Type 1 Diabetes With and Without Impaired Awareness of Hypoglycemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type 1 Diabetes Mellitus With Hypoglycemia
Keywords: type 1 diabetes mellitus
impaired awareness of hypoglycemia
lactate
MR spectroscopy
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Dutch Diabetes Research Foundation
name: European Foundation for the Study of Diabetes
First posted: 2017-09-19
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Patients with type 1 diabetes (T1DM) who are unable to perceive symptoms of hypoglycemia, referred to as impaired awareness of hypoglycemia (IAH), are at very high risk of severe hypoglycemia. IAH affects approximately 25% of patients with T1DM. Brain lactate may be involved in the development of IAH. A recent study indicated increased brain lactate utilization during hypoglycemia in T1DM patients with IAH, which did not occur in patients with normal awareness of hypoglycemia (NAH). Conversely, administration of lactate to patients with NAH has been shown to attenuate counterregulatory hormone responses to and symptomatic awareness of hypoglycemia, thus causing a situation that resembles IAH. It has, however, not been demonstrated whether the excess of lactate is actually taken up or metabolized by the brain, and if so whether this occurs under euglycemic or hypoglycemic conditions or both.

This project consists of two related studies. The objective of part 1 is to investigate the effect of elevated plasma lactate levels that are sufficient to impair awareness of hypoglycemia on brain lactate concentrations during euglycemia and hypoglycemia in T1DM patients with NAH. The objective of part 2 is to compare the effect of exogenous lactate on brain lactate concentrations between T1DM patients with NAH and T1DM patients with IAH.

Furthermore, this study aims to determine the effect of acute hypoglycemia on the inflammatory function and composition of peripheral blood mononuclear cells.


Eligibility criteria: 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 or \>=3
* 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, known liver disease, anxiety disorders or a history of panic attacks.
* Microvascular complications of T1DM: Proliferative retinopathy, Symptomatic diabetic neuropathy (including autonomic neuropathy), Nephropathy; clinical/overt albuminuria or an estimated glomerular filtration rate \<60ml/min/1.73m2
* MR(I) contraindications (pregnancy, severe claustrophobia, metal parts in body)

Primary outcomes:
measure: the effect of intravenous lactate administration, compared to placebo, on brain lactate concentrations during euglycemia and hypoglycemia in patients with T1DM and normal awareness of hypoglycemia
timeFrame: during stable euglycemia (40 min) and hypoglycemia (45 min)
measure: the effect of exogenous lactate on brain lactate concentrations during euglycemia and hypoglycemia between T1DM patients with normal awareness of hypoglycemia and T1DM patients with impaired awareness of hypoglycemia
timeFrame: during stable euglycemia (40 min) and hypoglycemia (45 min)
Secondary outcomes:
measure: The changes in counterregulatory hormone and to hypoglycemia in response to lactate infusion, compared to placebo, in patients with normal awareness of hypoglycemia
timeFrame: during stable euglycemia (40 min) and hypoglycemia (45 min)
measure: The changes in and symptoms to hypoglycemia in response to lactate infusion, compared to placebo, in patients with normal awareness of hypoglycemia
timeFrame: during stable euglycemia (40 min) and hypoglycemia (45 min)
measure: The changes in brain pH in response to intravenous lactate administration, compared to placebo
timeFrame: during stable euglycemia (40 min) and hypoglycemia (45 min)
measure: Changes in immune cell composition capacity in response to hypoglycemia compared to euglycemia and in response to lactate infusion compared to placebo
timeFrame: during stable euglycemia (40 min) and hypoglycemia (45 min)
measure: Changes in immune cell cytokine production capacity in response to hypoglycemia compared to euglycemia and in response to lactate infusion compared to placebo
timeFrame: during stable euglycemia (40 min) and hypoglycemia (45 min)
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud umc
Study officials:
References:
citation: De Feyter HM, Mason GF, Shulman GI, Rothman DL, Petersen KF. Increased brain lactate concentrations without increased lactate oxidation during hypoglycemia in type 1 diabetic individuals. Diabetes. 2013 Sep;62(9):3075-80. doi: 10.2337/db13-0313. Epub 2013 May 28.
citation: Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J. Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans. Diabetes. 1994 Nov;43(11):1311-7. doi: 10.2337/diab.43.11.1311.
citation: Maran A, Crepaldi C, Trupiani S, Lucca T, Jori E, Macdonald IA, Tiengo A, Avogaro A, Del Prato S. Brain function rescue effect of lactate following hypoglycaemia is not an adaptation process in both normal and type I diabetic subjects. Diabetologia. 2000 Jun;43(6):733-41. doi: 10.1007/s001250051371.
citation: Wiegers EC, Rooijackers HM, Tack CJ, Heerschap A, de Galan BE, van der Graaf M. Brain Lactate Concentration Falls in Response to Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia. Diabetes. 2016 Jun;65(6):1601-5. doi: 10.2337/db16-0068. Epub 2016 Mar 18.
citation: Wiegers EC, Rooijackers HM, van Asten JJA, Tack CJ, Heerschap A, de Galan BE, van der Graaf M. Elevated brain glutamate levels in type 1 diabetes: correlations with glycaemic control and age of disease onset but not with hypoglycaemia awareness status. Diabetologia. 2019 Jun;62(6):1065-1073. doi: 10.1007/s00125-019-4862-9. Epub 2019 Apr 19.