Research ArticleDiabetes

Striatal dopamine regulates systemic glucose metabolism in humans and mice

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Science Translational Medicine  23 May 2018:
Vol. 10, Issue 442, eaar3752
DOI: 10.1126/scitranslmed.aar3752
  • Fig. 1 Effect of vALIC-DBS on insulin sensitivity in nondiabetic OCD patients.

    (A to F) Bar graphs showing the effect of vALIC-DBS on basal rate of EGP assessed after an overnight fast (A), insulin-mediated suppression of basal EGP (B), insulin-stimulated Rd of glucose (C), striatal dopamine release in lean and overweight/obese subjects (P = 0.018 for Δ D2/3R BP in lean versus overweight/obese subjects) (D), peripheral insulin sensitivity in lean and obese subjects (E), and hepatic insulin sensitivity in lean and obese subjects (F). n = 13 to 14. Data are means ± SEM. *P < 0.05 by two-sided paired t tests (A to C) or Wilcoxon signed-rank test (D and E); **P < 0.01 by two-sided paired t test.

  • Fig. 2 Effect of dopamine reduction on insulin sensitivity in healthy subjects.

    (A) Effect of AMPT administration on plasma homovanillic acid. (B) Effect of AMPT administration on plasma prolactin. The arrows indicate the times of AMPT administration. (C to E) Bar graphs showing basal EGP (C), insulin-mediated suppression of basal EGP (D), and insulin-stimulated Rd of glucose (E). n = 10. Data are means ± SEM. *P < 0.05 by two-sided paired t test; **P < 0.01 by Wilcoxon signed-rank test; ***P < 0.001 by two-sided paired t tests.

  • Fig. 3 Effect of optogenetic activation of NAc D1R+ neurons on glucose tolerance in transgenic mice.

    (A) Effect of optical stimulation of NAc D1R+ neurons on glucose concentrations during IPGTT. (B) Plasma insulin concentrations during IPGTT. n = 9. Data are means ± SEM. *P < 0.01 for laser on versus laser off by two-way analysis of variance (ANOVA) (stimulation-time interaction F = 4.31, P = 0.004; main effect stimulation F = 14.42, P = 0.002).

  • Table 1 Metabolic parameters of a 55-year-old diabetes patient with vALIC-DBS.

    Indicators of improved insulin sensitivity are highlighted in bold.

    Unstimulated
    (DBS off)
    Stimulated (DBS on)
    Height (cm)171
    Weight (kg)123
    BMI (kg/m2)42
    Body fat content (%)41
    Glucose (mM)*6.96.9
    Insulin (pM)*265206
    FFAs (mM)*0.470.38
    EGP (μmol kg−1 min−1)*9.849.96
    Glucose (mM)5.35.0
    Insulin (pM)340378
    Glucagon (ng/liter)9699
    Suppression of
    EGP (%)
    3747
    Suppression of
    FFAs (%)
    1118
    Glucose Rd
    (μmol kg−1 min−1)
    6.87.3
    Glucose (mM)4.85.0
    Insulin (pM)540529
    Glucagon (ng/liter)9090
    Suppression of
    EGP (%)
    6875
    Suppression of
    FFAs (%)
    5566
    Glucose Rd
    (μmol kg−1 min−1)
    9.110.9
    Resting energy
    expenditure
    (kcal/day)
    22582418

    *In the basal state, after an overnight fast.

    During step 1 of the clamp (insulin infusion dose, 20 mIU m−2 min−1).

    During step 2 of the clamp (insulin infusion dose, 40 mIU m−2 min−1).

    • Table 2 Characteristics of OCD patients with vALIC-DBS.

      Data are count, means ± SD, or median (interquartile range), depending on type and distribution. Overweight/obesity was defined as BMI ≥25 kg/m2. HDL, high-density lipoprotein; LDL, low-density lipoprotein; AST, aspartate aminotransferase; ALT, alanine aminotransferase.

      Overall (n = 14)Lean (n = 7)Overweight/obese (n = 7)P*
      Men/women8/64/34/31.000
      Age (years)45 (40–51)43 (38–49)45 (41–53)0.535
      Length (cm)175 ± 10175 ± 8175 ± 131.000
      Weight (kg)82 ± 1773 (67–78)93 (82–102)0.011
      BMI (kg/m2)27.0 ± 5.424.0 (22.3–24.7)30.4 (26.7–30.6)0.001
      Body fat content (%)30.8 ± 9.125.0 (21.5–28.3)33.7 (32.7–35.8)0.004
      Glucose (mM)4.9 ± 0.74.7 ± 0.75.2 ± 0.70.150
      Insulin (pM)59 (31–86)45 (8–81)79 (44–144)0.209
      Triglycerides (mM)1.2 (0.6–2.2)0.9 (0.5–1.3)2.2 (1.1–2.4)0.053
      Cholesterol (mM)4.6 ± 1.15.0 ± 1.14.3 ± 1.10.271
      HDL (mM)1.2 ± 0.41.4 ± 0.41.0 ± 0.20.054
      LDL (mM)2.8 ± 1.13.2 ± 1.22.5 ± 0.90.275
      AST (U/liter)24 ± 825 ± 723 ± 100.687
      ALT (U/liter)23 (13–33)24 (18–39)18 (13–28)0.456

      *Lean versus overweight/obese.

      †By study design.

      ‡In the basal state, after an overnight fast.

      • Table 3 Characteristics of healthy men in dopamine depletion experiments (n = 10).

        Data are means ± SD.

        Age (years)23 ± 3
        Length (cm)183 ± 5
        Weight (kg)74 ± 8
        BMI (kg/m2)22.0 ± 1.9
        Body fat content (%)15.4 ± 4.3

      Supplementary Materials

      • www.sciencetranslationalmedicine.org/cgi/content/full/10/442/eaar3752/DC1

        Fig. S1. Summary of fiber-optic cannula targeting sites and ChR2-EYFP expression.

        Table S1. Metabolic parameters in OCD patients with vALIC-DBS.

        Table S2. Psychiatric symptom severity in OCD patients with vALIC-DBS.

        Table S3. Metabolic parameters during control conditions or dopamine depletion.

        Table S4. Blood pressure and heart rate variability during control conditions or dopamine depletion.

        Data file S1. Raw data for Fig. 1.

        Data file S2. Raw data for Fig. 2.

        Data file S3. Raw data for Fig. 3.

      • Supplementary Material for:

        Striatal dopamine regulates systemic glucose metabolism in humans and mice

        Kasper W. ter Horst, Nicolette M. Lammers, Richard Trinko, Darren M. Opland, Martijn Figee, Mariette T. Ackermans, Jan Booij, Pepijn van den Munckhof, P. Richard Schuurman, Eric Fliers, Damiaan Denys, Ralph J. DiLeone, Susanne E. la Fleur, Mireille J. Serlie*

        *Corresponding author. Email: m.j.serlie{at}amc.nl

        Published 23 May 2018, Sci. Transl. Med. 10, eaar3752 (2018)
        DOI: 10.1126/scitranslmed.aar3752

        This PDF file includes:

        • Fig. S1. Summary of fiber-optic cannula targeting sites and ChR2-EYFP expression.
        • Table S1. Metabolic parameters in OCD patients with vALIC-DBS.
        • Table S2. Psychiatric symptom severity in OCD patients with vALIC-DBS.
        • Table S3. Metabolic parameters during control conditions or dopamine depletion.
        • Table S4. Blood pressure and heart rate variability during control conditions or dopamine depletion.

        [Download PDF]

        Other Supplementary Material for this manuscript includes the following:

        • Data file S1 (Microsoft Excel format). Raw data for Fig. 1.
        • Data file S2 (Microsoft Excel format). Raw data for Fig. 2.
        • Data file S3 (Microsoft Excel format). Raw data for Fig. 3.

        [Download Data files S1 to S3]

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