The Effect of Intravenous Lactate on Brain Lactate Concentrations During Hypoglycemia

Type 1 Diabetes Mellitus With Hypoglycemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03286816
• Other study ID #: Lac_iv
• Status: Completed
• Phase: N/A
• First received: November 23, 2016
• Last updated: September 14, 2017
• Start date: November 2016
• Est. completion date: August 2017

Study information

• Verified date: November 2016
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: August 2017
• Est. primary completion date: May 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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)

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Hypoglycemia
• Type 1 Diabetes Mellitus With Hypoglycemia

Intervention

Drug:
• SodiumChloride

• Sodium Lactate

Locations

Country	Name	City	State
Netherlands	Radboud umc	Nijmegen

Sponsors (3)

Lead Sponsor	Collaborator
Radboud University	Dutch Diabetes Research Foundation, European Foundation for the Study of Diabetes

Country where clinical trial is conducted

Netherlands, 

References & Publications (4)

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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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		during stable euglycemia (40 min) and hypoglycemia (45 min)
Primary	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		during stable euglycemia (40 min) and hypoglycemia (45 min)
Secondary	The changes in counterregulatory hormone and to hypoglycemia in response to lactate infusion, compared to placebo, in patients with normal awareness of hypoglycemia		during stable euglycemia (40 min) and hypoglycemia (45 min)
Secondary	The changes in and symptoms to hypoglycemia in response to lactate infusion, compared to placebo, in patients with normal awareness of hypoglycemia		during stable euglycemia (40 min) and hypoglycemia (45 min)
Secondary	The changes in brain pH in response to intravenous lactate administration, compared to placebo		during stable euglycemia (40 min) and hypoglycemia (45 min)
Secondary	Changes in immune cell composition capacity in response to hypoglycemia compared to euglycemia and in response to lactate infusion compared to placebo		during stable euglycemia (40 min) and hypoglycemia (45 min)
Secondary	Changes in immune cell cytokine production capacity in response to hypoglycemia compared to euglycemia and in response to lactate infusion compared to placebo		during stable euglycemia (40 min) and hypoglycemia (45 min)