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Lactate, the end product of anaerobic glycolysis, is produced in high amounts by innate immune cells during inflammatory activation. Although immunomodulating effects of lactate have been reported, evidence from human studies is scarce. Here we show that expression of genes involved in lactate metabolism and transport is modulated in human immune cells during infection and upon inflammatory activation with TLR ligands , indicating an important role for lactate metabolism in inflammation. Extracellular lactate induces metabolic reprogramming in innate immune cells, as evidenced by reduced glycolytic and increased oxidative rates of monocytes immediately after exposure to lactate. A short-term infusion of lactate in humans increased glucose consumption of PBMCs, but effects on metabolic rates and cytokine production were limited. Interestingly, long-term treatment with lactate , reflecting pathophysiological conditions in local microenvironments such as tumor or adipose tissue, significantly modulated cytokine production with predominantly anti-inflammatory effects. We found time- and stimuli-dependent effects of extracellular lactate on cytokine production, further emphasizing the complex interplay between metabolism and immune cell function. Together, our findings reveal lactate as a modulator of immune cell metabolism which translates to reduced inflammation and may ultimately function as a negative feedback signal to prevent excessive inflammatory responses.

Hypoglycemia is the most frequent complication of insulin therapy in patients with type 1 diabetes. Since the brain is reliant on circulating glucose as its main source of energy, hypoglycemia poses a threat for normal brain function. Paradoxically, although hypoglycemia commonly induces immediate decline in cognitive function, long-lasting changes in brain structure and cognitive function are uncommon in patients with type 1 diabetes. In fact, recurrent hypoglycemia initiates a process of habituation that suppresses hormonal responses to and impairs awareness of subsequent hypoglycemia, which has been attributed to adaptations in the brain. These observations sparked great scientific interest into the brain’s handling of glucose during (recurrent) hypoglycemia. Various neuroimaging techniques have been employed to study brain (glucose) metabolism, including PET, fMRI, MRS and ASL. This review discusses what is currently known about cerebral metabolism during hypoglycemia, and how findings obtained by functional and metabolic neuroimaging techniques contributed to this knowledge.

Impaired awareness of hypoglycemia (IAH), resulting from habituation to recurrent hypoglycemia, can be reversed by strict avoidance of hypoglycemia. Adjunctive treatment with glucagon-like peptide-1 receptor agonists may reduce glucose variability, hence lower the risk of hypoglycemia and improve awareness. The aim of our study was to investigate the effect of exenatide on awareness of hypoglycemia in patients with type 1 diabetes and IAH. This was a randomized double-blind, placebo-controlled crossover trial. Ten patients with type 1 diabetes and IAH were included [age, 38.5 ± 4.4 years; 40% males; glycated hemoglobin 7.2% ± 0.4% (55.2 ± 4.8 mmol/mol)]. Patients were treated with exenatide 5 µg twice daily (first two weeks), followed by 10 µg twice daily (remaining four weeks) or matching placebo, with a four-week washout period. Patients wore blinded glucose sensors in the final weeks and modified hyperinsulinemic normoglycemic-hypoglycemic glucose clamps (nadir 2.5 mmol/L) were performed at the end of each treatment period. Treatment with exenatide caused body weight to decrease compared with placebo (-3.9 ± 0.9 vs 0.6 ± 1.2 kg, P = 0.047). Exenatide did not change mean 24-hour glucose levels (8.3 ± 0.4 vs 8.5 ± 0.3 mmol/L, exenatide vs placebo, P = 0.64), median (interquartile range) percentage of time spent in hypoglycemia [15.5 (4.5, 25.5) vs 7.8 (4.4, 17.1)%, P = 0.11] and frequency of hypoglycemia (15.8 ± 3.7 vs 12.1 ± 3.5, P = 0.19). Symptom scores in response to clamped hypoglycemia were similar between exenatide [median change 1.0 (-1.5, 7.0)] and placebo [4.5 (1.5, 5.8), P = 0.08]. Six weeks of treatment with exenatide did not improve awareness of hypoglycemia in patients with type 1 diabetes and IAH.

Aims/hypothesisChronic hyperglycaemia in type 1 diabetes affects the structure and functioning of the brain, but the impact of recurrent hypoglycaemia is unclear. Changes in the neurochemical profile have been linked to loss of neuronal function. We therefore aimed to investigate the impact of type 1 diabetes and burden of hypoglycaemia on brain metabolite levels, in which we assumed the burden to be high in individuals with impaired awareness of hypoglycaemia (IAH) and low in those with normal awareness of hypoglycaemia (NAH).MethodsWe investigated 13 non-diabetic control participants, 18 individuals with type 1 diabetes and NAH and 13 individuals with type 1 diabetes and IAH. Brain metabolite levels were determined by analysing previously obtained 1H magnetic resonance spectroscopy data, measured under hyperinsulinaemic–euglycaemic conditions.ResultsBrain glutamate levels were higher in participants with diabetes, both with NAH (+15%, p = 0.013) and with IAH (+19%, p = 0.003), compared with control participants. Cerebral glutamate levels correlated with HbA1c levels (r = 0.40; p = 0.03) and correlated inversely (r = −0.36; p = 0.04) with the age at diagnosis of diabetes. Other metabolite levels did not differ between groups, apart from an increase in aspartate in IAH.Conclusions/interpretationIn conclusion, brain glutamate levels are elevated in people with type 1 diabetes and correlate with glycaemic control and age of disease diagnosis, but not with burden of hypoglycaemia as reflected by IAH. This suggests a potential role for glutamate as an early marker of hyperglycaemia-induced cerebral complications of type 1 diabetes.ClinicalTrials.gov NCT03286816; NCT02146404; NCT02308293