Research ArticleBasic Science Investigations

Brain Glucose Transport and Phosphorylation Under Acute Insulin-Induced Hypoglycemia in Mice: An 18F-FDG PET Study

Malte F. Alf, João M.N. Duarte, Roger Schibli, Rolf Gruetter and Stefanie D. Krämer
Journal of Nuclear Medicine December 2013, 54 (12) 2153-2160; DOI: https://doi.org/10.2967/jnumed.113.122812

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Brain time–activity curves and arterial input functions in representative normoglycemic mouse (norm, Gp 6.7 mmol/L) and hypoglycemic mouse (hypo, Gp 2.1 mmol/L).

  • FIGURE 2.
    FIGURE 2.

    (A) Glucose clearance K1,glc from plasma to brain increases with decreasing Gp. K1,glc at Gp of less than 2 mmol/L was normalized for CBF. (B) 18F-FDG partitioning at BBB (K1,FDG/k2,FDG) with sharp increase below G′p 2 mmol/L (dashed line). (C) k3,glc sharply increased at G′p of less than 2 mmol/L. (D) Intracellular balance between 18F-FDG phosphorylation and efflux (k3,FDG/k2,FDG). Open symbols = insulin-treated; closed symbols = untreated; squares = 57BL/6 mice; circles = CD1 mice; crosses = not corrected for CBF increase (Supplemental Fig. 3); solid black line = fit with Equation 6 (fit parameters in graph); dashed blue lines = 95% confidence band; dashed red lines = 95% prediction band. R2 = 0.553 (A), 0.616 (C).

  • FIGURE 3.
    FIGURE 3.

    KFDG shows clear dependence on Gp.

  • FIGURE 4.
    FIGURE 4.

    (A) LC determined with different methods: constant value of 0.6 (LC1) (26,27); estimated from rat data (LC2) (13); and estimated from L1, L2, and L3 (LC3) (28). (B) CMRglc estimated with constant LC 0.6. (C) CMRglc dependence on Gp if calculated with Gp-dependent LC (LC2, LC3).

  • FIGURE 5.
    FIGURE 5.

    Influence of Gp on K1,glc in cortex (A), striatum (B), cerebellum (C), and hypothalamus (D). Lines as in Figure 2A. Values at Gp of less than 2.0 mmol/L were corrected for expected increase in CBF by 57%. Hippocampus and thalamus, as well as Tglc vs. G′p, are presented in Supplemental Figures 12 and 13. R2 = 0.524 (A), 0.589 (B), 0.399 (C), and 0.289 (D). Solid black line = fit with Equation 6 (fit parameters in graph); dashed blue lines = 95% confidence band; dashed red lines = 95% prediction band.

  • FIGURE 6.
    FIGURE 6.

    Intracellular glucose concentrations of cerebrum (solid line) and hypothalamus (dashed line) simulated as functions of Gp from fit parameters for transport and phosphorylation. Inset shows extended Gp range.

Tables

  • TABLE 1.

    CMRglc (μmol/min/100 g) Grouped by Gp, Estimated with Different LC

    LCCTXSTRHIPTHAHYPCBCER
    LC1 = 0.6 (26)
    Gp > 2.5 mmol/L56 ± 2962 ± 2565 ± 2766 ± 2955 ± 1971 ± 2866 ± 27
    Gp < 2.5 mmol/L48 ± 1656 ± 2054 ± 1755 ± 2243 ± 1655 ± 1655 ± 21
    LC2 (13)
    Gp > 2.5 mmol/L56 ± 3462 ± 3065 ± 3265 ± 3554 ± 2371 ± 3366 ± 32
    Gp < 2.5 mmol/L20 ± 7*23 ± 9*23 ± 9*23 ± 9*18 ± 7*23 ± 9*26 ± 17*
    LC3 (28)
    Gp > 2.5 mmol/L58 ± 2861 ± 2463 ± 2466 ± 2957 ± 2370 ± 3067 ± 23
    Gp < 2.5 mmol/L33 ± 7*37 ± 9*37 ± 9*38 ± 10*30 ± 8*37 ± 9*38 ± 11*

    • ↵* P < 0.003, all t > 3.34 compared with situation with Gp < 2.5 mmol/L.

    • CTX = cortex; STR = striatum; HIP = hippocampus; THA = thalamus; HYP = hypothalamus; CB = cerebellum; CER = cerebrum.

  • TABLE 2.

    Post Hoc Tests of Repeated-Measures Variance Analysis

    HYP minus averageCTX minus average
    GpK1,FDGKFDGK1,FDGKFDG
    >2.5 mmol/L−0.017 ± 0.046−0.007 ± 0.008−0.007 ± 0.017−0.009 ± 0.008
    <2.5 mmol/L−0.063 ± 0.060*−0.035 ± 0.015†−0.047 ± 0.067*−0.028 ± 0.015†

    • ↵* P < 0.05.

    • ↵† P < 0.0002.

    • Data are mL/min/cm3. Interaction of region × Gp was further explored with post hoc t tests. Compared with average of other brain structures, hypoglycemia led to significantly smaller increase in K1,FDG and KFDG in hypothalamus (HYP) and cortex (CTX).

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