Generalized decrease in brain glucose metabolism during fasting in humans studied by PET

Abstract

In prolonged fasting, the brain derives a large portion of its oxidative energy from the ketone bodies, beta-hydroxybutyrate and acetoacetate, thereby reducing whole body glucose consumption. Energy substrate utilization differs regionally in the brain of fasting rat, but comparable information has hitherto been unavailable in humans. We used positron emission tomography (PET) to study regional brain glucose and oxygen metabolism, blood flow, and blood volume in four obese subjects before and after a 3-wk total fast. Whole brain glucose utilization fell to 54% of control (postabsorptive) values (P less than 0.002). The whole brain rate constant for glucose tracer phosphorylation fell to 51% of control values (P less than 0.002). Both parameters decreased uniformly throughout the brain. The 2-fluoro-2-deoxy-D-glucose lumped constant decreased from a control value of 0.57 to 0.43 (P less than 0.01). Regional blood-brain barrier transfer coefficients for glucose tracer, regional oxygen utilization, blood flow, and blood volume were unchanged.

Human Cerebral Blood Flow and Metabolism in Acute Insulin-Induced Hypoglycemia

“…However, in this context, it is also worthwhile to consider the physiology of glucose transport. At B17%, the extraction fraction of glucose E g is neither extremely small nor large (Hasselbalch et al, 1995;Redies et al, 1989), but is close to values where perfusion may become relevant, particularly when plasma glucose is low. Thus, the inward flux rate of glucose K i may best be described as including both flow and transport components, that is, K i ¼ Flow E g ¼ -Flow(1Àexp(PS/Flow)), where PS is the permeability-surface area product for glucose.…”

Ketosis Proportionately Spares Glucose Utilization in Brain

“…A summary of these data collected from the various studies measuring CMR glc and blood ketone concentrations include (see Figure 2 legend for details): PET-FDG studies conducted in fasted humans showing a 27% decrease in CMR glc after 3.5 days of fasting, 7 in humans that were fasted for 3 weeks, the authors reported a 46% decrease in CMR glc relative to the nonfasted baseline conditions. 2 Other studies using different methodologies for assessing glucose utilization in ketotic rats also showed similar decreases. In one study where [6-14 C]glucose and autoradiography were applied, glucose utilization decreased 12% in conscious 2-day fasted rats with mild ketosis.…”

“…Data were normalized (%) against control state (non-fasted, non-diabetic conditions) and graphed as a function of total blood ketone bodies level (mmol/L). The study, method, and reported outcome is noted for each point: (a) data from Al-Mudallal et al, 21 ketosis by KG diet in rat, 2-DG method; no significant cortical change in CMR glc , (b) data from Corddry et al, 22 3 days fasted rats, 2-DG method; frontal cortical change, not significant, (c) and (d) data from Dalquist et al, 27 3 days fasted rats, A-V uptake method; no significant change, (e) data from Hasselbach et al, 5 3.5 days fasted humans, PET-FDG imaging; significant reduction, (f ) data from Owen et al, 1 5 to 6 weeks fasted obese human subjects, A-V uptake method, CMR glc , was indirectly calculated by O 2 consumption; significant change, (g) data from Redies et al, 2 20 to 24 days fasted obese human subjects, PET-FDG and A-V uptake method; significant CMR glc reduction, (h) data from Ruderman et al, 7 1-2 days fasted rats, A-V uptake method; trended significant, (i) Data from Mans et al, 6 2 days fasted rats, compartmental modeling with non-trapping tracer (autoradiography); significant reduction, (j) data from Issad et al, 28 2 days fasted rats, (autoradiography), no significant change, (k) data from Cherel et al, 3 6 days fasted rats, modified 2-DG method, no significant change. The meta-analysis plot shows a linear relationship between CMR glc and level of ketosis in human or rat subjects.…”

“…1,2 The conviction was founded on the rationale that under glucose-sparing conditions, a large portion of oxidative energy must be derived from ketone bodies and thus resulting in reduced glucose consumption. [1][2][3] Historically, there has been controversy among researchers whether there is a causal relationship between changes in CMR glc with degree and duration of ketosis. The inconsistencies across studies were revealed when the effects of short-term fasting (or acute ketosis) on changes in CMR glc were further explored.…”

“…9,20 In the last few decades, the 2-deoxy-D-glucose or positron emission tomography (PET) approaches have been applied to ketotic studies, in both animal, 18,[21][22][23] and humans. 2,5,24,25 Reports of altered CMR glc as a result of short-term fasting [3][4][5][6][7] or acute infusions of ketone bodies 25,26 had generated discrepancies. What remained to be clarified was (i) whether oxidation of ketone bodies can replace glucose proportionately during acute/mild ketosis under normoglycemia and (ii) the percent of glucose sparing with degree of ketosis.…”