Research ArticleDiabetes

Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator

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Science Translational Medicine  16 Jan 2019:
Vol. 11, Issue 475, eaau3441
DOI: 10.1126/scitranslmed.aau3441
  • Fig. 1 Insulin secretory response to glucose and TTP399 in perfused mouse islets.

    TTP399 was tested in the presence of 3 mM glucose. The horizontal gray bar indicates when islets were exposed to experimental treatments. Data are means ± SEM (n = 6).

  • Fig. 2 GK nuclear translocation.

    (A) GK translocation at 5 mM glucose in the presence or absence of TTP399 (green, GK; blue, Hoechst nuclear stain). Scale bars, 50 μm. (B) Changes in nuclear/cell intensity ratio of GK staining in the presence of 5, 15, and 25 mM glucose. ns, not significant. Data are presented as median (midline), 25th and 75th quartiles (box), and 1.5× interquartile range (upper and lower whiskers) of observations of 250 to 300 nuclei per well (n = 8).

  • Fig. 3 Effect of TTP399 and NNC80-3281 on plasma glucose and insulin in fasted rats.

    (A) Plasma glucose and (B) plasma insulin concentrations in rats. Data are means ± SEM (n = 7 per group).

  • Fig. 5 Changes in HbA

    1c and body weight at month 6 and over time. (A) Changes in HbA1c at month 6 (top) and over time (bottom) (n = 171). QD, once daily; FAS, full analysis set; sita, sitagliptin. (B) Placebo-subtracted change in HbA1c at month 6. (C) Changes in body weight at month 6 (top) and over time (bottom) (n = 174). Data are presented as least squares (LS) means ± SEM. P values based on analysis of covariance (ANCOVA) model with treatment group as a factor and baseline value as a covariate.

  • Table 1 Patient demographics and baseline characteristics.

    Patient demographics and baseline characteristics.. FPG, fasting plasma glucose.

    CharacteristicTTP399 (400 mg) (n = 50)TTP399 (800 mg)
    (n = 42)
    Sitagliptin
    (n = 49)
    Placebo
    (n = 48)
    Mean age, y (±SD)52.8 ± 10.757.0 ± 8.555.1 ± 9.655.7 ± 11.7
    Male, n (%)23 (46.0)22 (52.4)29 (59.2)27 (56.3)
    White, n (%)42 (84.0)32 (76.2)41 (85.4)39 (81.3)
    Mean weight, kg (±SD)94.1 ± 19.492.3 ± 24.295.8 ± 19.091. 6 ± 19.8
    Mean body mass index, kg/m2 (±SD)33.3 ± 5.432.1 ± 5.833.1 ± 5.732.4 ± 5.6
    Mean HbA1c, % (±SD)7.9 ± 0.78.1 ± 0.78.1 ± 0.77.9 ± 0.7
    Mean metformin dose, mg (±SD)1652 ± 4511625 ± 5181647 ± 4451693 ± 513
    Mean years since diagnosis (±SD)7.3 ± 6.27.7 ± 5.48.3 ± 6.88.2 ± 6.0
    FPG, mg/dl (±SD)163.9 ± 39.0162.8 ± 44.0163.4 ± 41.1167.4 ± 36.3
    Glucagon, ng/liter (±SD)40.6 ± 33.442.5 ± 34.253.1 ± 55.444.6 ± 26.5
    GLP-1, ng/liter (±SD)4.5 ± 5.94.3 ± 6.98.3 ± 16.46.5 ± 9.9
    LDL-C, mg/dl (±SD)97.7 ± 34.085.5 ± 24.495.6 ± 37.484.0 ± 30.9
    HDL-C, mg/dl (±SD)48.8 ± 13.652.9 ± 13.846.4 ± 11.648.8 ± 14.8
    TG, mg/dl (±SD)185.4 ± 111.0157.5 ± 104.9195.8 ± 143.6163.8 ± 96.8
    Non–HDL-C, mg/dl (±SD)134.7 ± 37.3116.4 ± 31.7134.1 ± 48.8117.0 ± 36.1
  • Table 2 Placebo-subtracted changes from baseline at 6 months.

    Placebo-subtracted changes from baseline at 6 months.. Data are presented as LSM (least squares mean) changes (95% CI).

    TTP399 (400 mg)
    (n = 50)
    TTP399 (800 mg)
    (n = 42)
    Sitagliptin
    (n = 49)
    HbA1c, %−0.2 (−0.8 to 0.5)−0.9 (−1.5 to −0.3)**−1.0 (−1.5 to −0.5)
    FPG, mg/dl5.5 (−19.6 to 30.5)−4.8 (−31.0 to 21.5)−16.6 (−41.8 to 8.6)
    Weight, kg−0.11 (−1.6 to 1.4)−1.2 (−2.7 to 0.3)0.5 (−1.0 to 1.9)
      Weight in patients ≥100 kg−0.2 (−2.7 to 2.4)−3.4 (−6.2 to −0.6)*−0.6 (−3.1 to 2.0)
    Insulin, μIU/ml0.67 (−4.3 to 5.6)1.22 (−4.4 to 6.9)−1.3 (−7.3 to 4.7)
    Glucagon, ng/liter−8.1 (−24.2 to 8.0)−19.6 (−34.8 to −4.4)*−2.0 (−17.0 to 13.0)
    GLP-1, ng/liter10.6 (−12.7 to 33.8)0.4 (−15.1 to 15.9)18.2 (3.3 to 33.0)
    C-peptide, μg/liter0.05 (−0.60 to 0.70)−0.19 (−0.82 to 0.44)0.23 (−0.38 to 0.85)
    Lipids
      HDL-C, mg/dl−0.4 (−3.4 to 2.6)3.2 (0.2 to 6.1)*0.9 (−1.9 to 3.7)
      Non–HDL-C, mg/dl7.9 (−8.2 to 23.9)2.9 (−13.1 to 18.8)−2.0 (−17.0 to 13.0)
      TG, mg/dl1.5 (−50.0 to 53.1)−13.3 (−59.6 to 33.0)−27.4 (−73.5 to 18.7)
      Total cholesterol, mg/dl5.5 (−11.4 to 22.4)6.9 (−9.8 to 23.6)−2.4 (−17.9 to 13.1)
    Lactate, mg/dl0.71 (−2.5 to 3.9)0.93 (−2.3 to 4.1)0.68 (−2.4 to 3.8)

    *P < 0.05.

    **P < 0.01.

    • Table 3 Adverse events.

      Adverse events.. Data are provided as n (%).

      TTP399 (400 mg)
      (n = 50)
      TTP399 (800 mg)
      (n = 42)
      Sitagliptin
      (n = 49)
      Placebo
      (n = 48)
      Patients with ≥1 TEAE26 (52.0)21 (50.0)30 (61.2)29 (60.4)
      Serious AEs0 (0)0 (0)0 (0)0 (0)
      Patients with ≥1 treatment-
      related AEs
      3 (6.0)8 (19.0)8 (16.3)4 (8.3)
      AE leading to withdrawal0 (0)4 (9.5)3 (6.1)1 (2.1)
      AEs occurring in ≥5%
        Headache6 (12.0)2 (4.8)4 (8.2)2 (4.2)
        Upper respiratory tract
      infection
      6 (12.0)1 (2.4)2 (4.1)2 (4.2)
        Diarrhea2 (4.0)3 (7.1)3 (6.1)2 (4.2)
        Nausea2 (4.0)3 (7.1)3 (6.1)1 (2.1)
        Hypoglycemia0 (0)3 (7.1)2 (4.1)2 (4.2)
        Urinary tract infection4 (8.0)1 (2.4)1 (2.0)1 (2.1)
        Cough2 (4.0)1 (2.4)3 (6.1)0 (0)
        Nasopharyngitis0 (0)0 (0)2 (4.1)3 (6.3)
      Hypoglycemia AEs
        Number of hypoglycemic
      events
      0 (0)327
        Patients with ≥1
      hypoglycemic event
      0 (0)3 (7.1)2 (4.1)3 (6.30)
        Severe hypoglycemia0 (0)0 (0)0 (0)0 (0)
        Documented symptomatic
      hypoglycemia
      0 (0)1 (2.4)1 (2.0)1 (2.1)
        Probable symptomatic
      hypoglycemia
      0 (0)2 (4.8)1 (2.0)1 (2.1)
        Relative hypoglycemia0 (0)0 (0)0 (0)1 (2.1)

    Supplementary Materials

    • www.sciencetranslationalmedicine.org/cgi/content/full/11/475/eaau3441/DC1

      Materials and Methods

      Fig. S1. The effect of TTP399 on GK activity.

      Fig. S2. TTP399 stimulation of glucose metabolism in isolated rat hepatocytes.

      Fig. S3. Differential uptake of TTP399 into rat hepatocytes and β cells.

      Fig. S4. The effect of TTP399 on HbA1c concentrations in diabetic Umeå ob/ob mice.

      Fig. S5. Liver TG content in diabetic Umeå ob/ob mice after 4 weeks of treatment with TTP399.

      Fig. S6. Effect of 4 weeks of treatment with TTP399 on body weight and food intake in diabetic Umeå ob/ob mice.

      Fig. S7. The effect of metformin alone or metformin + TTP399 on blood glucose and insulin levels in Gottingen minipigs.

      Fig. S8. Metabolic changes at month 6 and over time.

      Table S1. Area under the plasma glucose concentration-time curve after doses of TTP399 on days 1 and 22 in diabetic Umeå ob/ob mice.

      Table S2. Plasma insulin concentration before treatment and after 22 days of treatment in diabetic Umeå ob/ob mice.

      Table S3. Plasma concentrations of TGs and lactic acid during treatment with TTP399 in Gottingen minipigs.

      Table S4. Hepatic-free glycerol, TGs, and glycogen content after 3 months of treatment with TTP399 (50 mg/kg per day) in Gottingen minipigs.

      Reference (50)

    • This PDF file includes:

      • Materials and Methods
      • Fig. S1. The effect of TTP399 on GK activity.
      • Fig. S2. TTP399 stimulation of glucose metabolism in isolated rat hepatocytes.
      • Fig. S3. Differential uptake of TTP399 into rat hepatocytes and β cells.
      • Fig. S4. The effect of TTP399 on HbA1c concentrations in diabetic Umeå ob/ob mice.
      • Fig. S5. Liver TG content in diabetic Umeå ob/ob mice after 4 weeks of treatment with TTP399.
      • Fig. S6. Effect of 4 weeks of treatment with TTP399 on body weight and food intake in diabetic Umeå ob/ob mice.
      • Fig. S7. The effect of metformin alone or metformin + TTP399 on blood glucose and insulin levels in Gottingen minipigs.
      • Fig. S8. Metabolic changes at month 6 and over time.
      • Table S1. Area under the plasma glucose concentration-time curve after doses of TTP399 on days 1 and 22 in diabetic Umeå ob/ob mice.
      • Table S2. Plasma insulin concentration before treatment and after 22 days of treatment in diabetic Umeå ob/ob mice.
      • Table S3. Plasma concentrations of TGs and lactic acid during treatment with TTP399 in Gottingen minipigs.
      • Table S4. Hepatic-free glycerol, TGs, and glycogen content after 3 months of treatment with TTP399 (50 mg/kg per day) in Gottingen minipigs.
      • Reference (50)

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