Brain Lactate Concentration Falls in Response to Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia

Wiegers, Evita C; Rooijackers, Hanne M; Tack, Cees J.; Heerschap, Arend; Galan, Bastiaan E. de

doi:10.2337/db16-0068

Cited by 39 publications

(39 citation statements)

References 26 publications

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“…In addition, the role of brain lactate to prevent seizures was reinforced by the fact that when seizures began, the brain levels of lactate in the Ins, Ins + Lac, or Ins + Glc groups were lower (p < 0.05) than those in the control group ( Figure 2H). In agreement with these results, Wiegers et al (2016) demonstrated that in type 1 diabetes patients, symptoms of insulin-induced hypoglycemia are related to the decreased availability of lactate in the brain.…”

Section: Discussionsupporting

confidence: 83%

Oral lactate intensifies insulin toxicity during severe insulin-induced hypoglycemia in mice

Vilela

Antunes

Godoi

et al. 2018

Braz. J. Pharm. Sci.

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We investigated whether oral lactate could prevent seizures and deaths in mice with severe hypoglycemia induced by a high dose of insulin. For this purpose, mice were fasted for 15 h and then given an intraperitoneal injection of regular insulin (5.0 U/kg or 10.0 U/kg). Immediately after insulin injection, the mice received an oral dose of saline (control), glucose (5.5 mmol/kg), or lactate (18.0 mmol/kg). Glucose and lactate levels were measured in the blood and brain before and after the seizures began. Glucose and lactate delayed (p < 0.05) the onset of seizures associated with severe insulin-induced hypoglycemia. Elevated (p < 0.05) brain levels of lactate were associated with an absence of seizures in mice that received glucose or lactate, suggesting that lactate could prevent convulsions associated with severe insulin-induced hypoglycemia. However, the same oral dose of lactate that delayed the onset of convulsions also increased the mortality rate. In contrast, diazepam (3.0 mg/kg) prevented seizures and markedly decreased the frequency of death during severe insulin-induced hypoglycemia. The results demonstrated that in contrast to oral glucose, oral lactate intensifies insulin toxicity.

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Section: Discussionsupporting

confidence: 83%

Oral lactate intensifies insulin toxicity during severe insulin-induced hypoglycemia in mice

Vilela

Antunes

Godoi

et al. 2018

Braz. J. Pharm. Sci.

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“…A study by Wiegers et al found a decline in brain lactate concentrations in response to hypoglycemia in patients with type 1 diabetes and impaired awareness of hypoglycemia, but not in type 1 diabetic patients with normal awareness of hypoglycemia or in healthy control subjects. 14 Upon lactate infusion, Wiegers et al found only small increases in cerebral lactate concentrations during experimental hypoglycemia in patients with type 1 diabetes. 15 By contrast, data by De Feyter et al did not reveal increased lactate oxidation during hypoglycemia in type 1 diabetic subjects despite increased levels of brain lactate.…”

Section: Introductionmentioning

confidence: 99%

Lactate infusion increases brain energy content during euglycemia but not hypoglycemia in healthy men

Richter¹,

Rabe²,

Duysen³

et al. 2019

NMR in Biomedicine

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A special characteristic of the brain is the usage of lactate as alternative fuel instead of glucose to preserve its energy homeostasis. This physiological function is valid for sufficient cerebral glucose supply, as well as presumably during hypoglycemia, given that exogenous lactate infusion suppresses hormonal counterregulation. However, it is not yet clarified whether this effect is mediated by the use of lactate as an alternative cerebral energy substrate or any other mechanism. We hypothesized that under conditions of limited access to glucose (ie, during experimental hypoglycemia) lactate infusion would prevent hypoglycemia‐induced neuroenergetic deficits in a neuroprotective way. In a randomized, double‐blind, crossover study, lactate vs placebo infusion was compared during hyperinsulinemic‐hypoglycemic clamps in 16 healthy young men. We measured the cerebral high‐energy phosphate content — ie, adenosine triphosphate (ATP), phosphocreatine (PCr) and inorganic phosphate (Pi) levels — by 31P‐magnetic resonance spectroscopy as well as the neuroendocrine stress response. During euglycemia, lactate infusion increased ATP/Pi as well as PCr/Pi ratios compared with baseline values and placebo infusion. During hypoglycemia, there were no differences between the lactate and the placebo condition in both ratios. Hormonal counterregulation was significantly diminished upon lactate infusion. Our data demonstrate an elevated cerebral high‐energy phosphate content upon lactate infusion during euglycemia, whereas there was no such effect during experimental hypoglycemia. Nevertheless, lactate infusion suppressed hypoglycemic hormonal counterregulation. Lactate thus adds to cerebral energy provision during euglycemia and may contribute to an increase in ATP reserves, which in turn protects the brain against neuroglucopenia under recurrent hypopglycemic conditions, eg, in diabetic patients.

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“…Interestingly, an earlier study investigated the frontal and parietal cortex, and reported no differences in metabolite levels (namely NAA/creatine and choline/creatine) between of type 1 diabetes patients with and without recurrent hypoglycaemia [32]. Recent studies reported no difference in baseline concentrations of neurochemicals in the brain of type 1 diabetes patients relative to healthy control subjects, while the brain metabolic response to hypoglycaemia may be impaired in diabetes [33,34]. In healthy subjects a hypoglycaemia insult leads to a reduction of brain glutamate levels, a response that is blunted in diabetes patients depending on their degree of hypoglycaemia-associate autonomic failure, a syndrome that includes hypoglycaemia unawareness [33,34].…”

Section: Mrs In Diabetes Patients Type 1 Diabetesmentioning

confidence: 99%

“…Recent studies reported no difference in baseline concentrations of neurochemicals in the brain of type 1 diabetes patients relative to healthy control subjects, while the brain metabolic response to hypoglycaemia may be impaired in diabetes [33,34]. In healthy subjects a hypoglycaemia insult leads to a reduction of brain glutamate levels, a response that is blunted in diabetes patients depending on their degree of hypoglycaemia-associate autonomic failure, a syndrome that includes hypoglycaemia unawareness [33,34]. In addition, brain lactate levels drop during hypoglycaemia in diabetes patients (depending on whether awareness of hypoglycaemia is impaired or not), suggesting stimulated utilisation of lactate as metabolic substrate [33,34].…”

Section: Mrs In Diabetes Patients Type 1 Diabetesmentioning

confidence: 99%

Metabolism in the Diabetic Brain: Neurochemical Profiling by 1H Magnetic Resonance Spectroscopy

Duarte¹

2016

DMD

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Diabetes is associated with decrements in cognitive function and with abnormalities in brain morphology. In addition, alterations of metabolism have been reported in the diabetic brain. Magnetic Resonance Spectroscopy (MRS) is a non-invasive technique that can be employed to determine the concentration of metabolites in a fully non-invasive manner under normal physiological conditions. The present article reviews major findings from 1 H MRS studies in the brain of diabetes patients, and of pre-clinical models of both insulin-dependent and insulin-resistant diabetes. Metabolic alterations measured in vivo by MRS are closely associated to events of the neurodegenerative process at cellular level, and thus allow understanding the pathophysiology of diabetes-associated brain complications. Moreover, MRS constitutes an excellent tool for tracking outcomes of therapeutic interventions. However, further studies are required to clearly establish the links between diabetes-induced alterations of metabolism, structure and function in the brain.

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Brain Lactate Concentration Falls in Response to Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia

Cited by 39 publications

References 26 publications

Oral lactate intensifies insulin toxicity during severe insulin-induced hypoglycemia in mice

Oral lactate intensifies insulin toxicity during severe insulin-induced hypoglycemia in mice

Lactate infusion increases brain energy content during euglycemia but not hypoglycemia in healthy men

Metabolism in the Diabetic Brain: Neurochemical Profiling by 1H Magnetic Resonance Spectroscopy

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