Effect of lactate administration on cerebral blood flow during hypoglycemia in people with type 1 diabetes

Lian A van Meijel, Jack J A van Asten, Joanes Grandjean, Arend Heerschap, Cornelis J Tack, Marinette van der Graaf, Evita C Wiegers, Bastiaan E de Galan, Lian A van Meijel, Jack J A van Asten, Joanes Grandjean, Arend Heerschap, Cornelis J Tack, Marinette van der Graaf, Evita C Wiegers, Bastiaan E de Galan

Abstract

Introduction: Impaired awareness of hypoglycemia, clinically reflected by the inability to timely detect hypoglycemia, affects approximately 25% of the people with type 1 diabetes. Both altered brain lactate handling and increased cerebral blood flow (CBF) during hypoglycemia appear to be involved in the pathogenesis of impaired awareness of hypoglycemia. Here we examine the effect of lactate on CBF during hypoglycemia.

Research design and methods: Nine people with type 1 diabetes and normal awareness of hypoglycemia underwent two hyperinsulinemic euglycemic-hypoglycemic (3.0 mmol/L) glucose clamps in a 3T MR system, once with sodium lactate infusion and once with sodium chloride infusion. Global and regional changes in CBF were determined using pseudocontinuous arterial spin labeling.

Results: Lactate (3.3±0.6 vs 0.9±0.2 mmol/L during lactate infusion vs placebo infusion, respectively) suppressed the counter-regulatory hormone responses to hypoglycemia. Global CBF increased considerably in response to intravenous lactate infusion but did not further increase during hypoglycemia. Lactate also blunted the hypoglycemia-induced regional redistribution of CBF towards the thalamus.

Conclusions: Elevated lactate levels enhance global CBF and blunt the thalamic CBF response during hypoglycemia in patients with type 1 diabetes, mimicking observations of impaired awareness of hypoglycemia. These findings suggest that alteration of CBF associated with lactate may play a role in some aspects of the development of impaired awareness of hypoglycemia.

Trial registration number: NCT03730909.

Keywords: awareness; clinical study; diabetes mellitus, type 1; hypoglycemia.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
(A) Schematic overview of the study protocol, (B) Arterial glucose levels during lactate infusion (red circles) and placebo infusion (black circles) and (C) arterial lactate levels during lactate infusion (red circles) and placebo infusion (black circles). CBF, cerebral blood flow.
Figure 2
Figure 2
Counter-regulatory hormone levels at baseline (Bsl), during euglycemia (Eu) and during hypoglycemia, with lactate infusion (red) and placebo infusion (black), *p

Figure 3

(A) Change in global cerebral…

Figure 3

(A) Change in global cerebral blood flow (CBF) from baseline during lactate infusion…

Figure 3
(A) Change in global cerebral blood flow (CBF) from baseline during lactate infusion (red circles) and placebo infusion (black circles). Bsl=baseline measurement; mean CBF value of three euglycemic CBF measurements without lactate/placebo infusion. (B) Quantitative CBF maps averaged over all subjects with type 1 diabetes mellitus and normal awareness of hypoglycemia during euglycemic and hypoglycemic state and during infusion of lactate and placebo. CBF values are color coded with the Flow(Brain colors) (iso) lookup table and range from 1 to 100 mL/100 g tissue/min.

Figure 4

Redistribution of cerebral blood flow…

Figure 4

Redistribution of cerebral blood flow (CBF) in response to hypoglycemia by type of…

Figure 4
Redistribution of cerebral blood flow (CBF) in response to hypoglycemia by type of infusion in subjects with type 1 diabetes mellitus and normal awareness of hypoglycemia. Z-scores of infusion-induced significant changes (p
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References
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Figure 3
Figure 3
(A) Change in global cerebral blood flow (CBF) from baseline during lactate infusion (red circles) and placebo infusion (black circles). Bsl=baseline measurement; mean CBF value of three euglycemic CBF measurements without lactate/placebo infusion. (B) Quantitative CBF maps averaged over all subjects with type 1 diabetes mellitus and normal awareness of hypoglycemia during euglycemic and hypoglycemic state and during infusion of lactate and placebo. CBF values are color coded with the Flow(Brain colors) (iso) lookup table and range from 1 to 100 mL/100 g tissue/min.
Figure 4
Figure 4
Redistribution of cerebral blood flow (CBF) in response to hypoglycemia by type of infusion in subjects with type 1 diabetes mellitus and normal awareness of hypoglycemia. Z-scores of infusion-induced significant changes (p

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