title: Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia.
abstract: Hypoglycemia occurs frequently during intensive insulin therapy in patients with both type 1 and type 2 diabetes and remains the single most important obstacle in achieving tight glycemic control. Using a rodent model of hypoglycemia, we demonstrated that exposure to antecedent recurrent hypoglycemia leads to adaptations of brain metabolism so that modest increments in circulating lactate allow the brain to function normally under acute hypoglycemic conditions. We characterized 3 major factors underlying this effect. First, we measured enhanced transport of lactate both into as well as out of the brain that resulted in only a small increase of its contribution to total brain oxidative capacity, suggesting that it was not the major fuel. Second, we observed a doubling of the glucose contribution to brain metabolism under hypoglycemic conditions that restored metabolic activity to levels otherwise only observed at euglycemia. Third, we determined that elevated lactate is critical for maintaining glucose metabolism under hypoglycemia, which preserves neuronal function. These unexpected findings suggest that while lactate uptake was enhanced, it is insufficient to support metabolism as an alternate substrate to replace glucose. Lactate is, however, able to modulate metabolic and neuronal activity, serving as a "metabolic regulator" instead.
authors.affiliation: Department of Internal Medicine, Section of Endocrinology, Yale School of Medicine, New Haven, Connecticut 06520-8040, USA. raimund.herzog@yale.edu
authors.forename: Raimund I
authors.initials: RI
authors.lastname: Herzog
authors.forename: Lihong
authors.initials: L
authors.lastname: Jiang
authors.forename: Peter
authors.initials: P
authors.lastname: Herman
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Basavaraju G
authors.initials: BG
authors.lastname: Sanganahalli
authors.forename: Graeme F
authors.initials: GF
authors.lastname: Mason
authors.forename: Fahmeed
authors.initials: F
authors.lastname: Hyder
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Rothman
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sherwin
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Behar
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000196:embryology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism* / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009474:Neurons / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence
chemical_list: D001786:Blood Glucose; D007328:Insulin; D019344:Lactic Acid; D005947:Glucose; D010100:Oxygen
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