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TABLE 2

Arterial levels and net hepatic balances of plasma NEFAs, 3-hydroxybutyrate, glycerol, lactate, and alanine before and after oral administration of BAY R 3401 in the presence of non-insulin-induced hypoglycemia with and without mild hyperinsulinemia and in the presence of the maintenance of euglycemia with and without mild hyperinsulinemia in 18-h-fasted conscious dogs

GroupControl periodBAY R 3401 with or without peripheral glucose infusion (min)
1020306090120180
NEFA         
 Hypoglycemia         
  Plasma level (mmol/l) 0.67 ± 0.04 0.68 ± 0.07 0.80 ± 0.07* 0.92 ± 0.14* 1.29 ± 0.23* 1.39 ± 0.20* 1.49 ± 0.15* 1.52 ± 0.09* 
  NHB (μmol · kg−1 · min−1−2.51 ± 0.32 −2.51 ± 0.26 −2.85 ± 0.26 −3.22 ± 0.37* −4.43 ± 0.90* −5.32 ± 0.71* −6.12 ± 0.74* −6.69 ± 1.05* 
 Hypoglycemia + insulin         
  Plasma level (mmol/l) 0.82 ± 0.08 0.72 ± 0.09 0.53 ± 0.09 0.64 ± 0.10 0.73 ± 0.14 0.73 ± 0.14 0.79 ± 0.10 0.77 ± 0.164 
  NHB (μmol · kg−1 · min−1−3.18 ± 0.56 −3.27 ± 0.40 −1.95 ± 0.40 −2.39 ± 0.20 −3.20 ± 1.02 −3.47 ± 0.54 −2.90 ± 0.19 −2.06 ± 0.61 
 Euglycemia         
  Plasma level (mmol/l) 0.79 ± 0.09 0.73 ± 0.08 0.81 ± 0.08 0.80 ± 0.10 0.84 ± 0.13 0.78 ± 0.12 0.82 ± 0.06 0.91 ± 0.06 
  NHB (μmol · kg−1 · min−1−1.83 ± 0.29 −1.51 ± 0.35 −1.43 ± 0.33 −1.96 ± 0.33 −2.06 ± 0.51 −2.18 ± 0.39 −2.32 ± 0.25 −2.39 ± 0.24 
 Euglycemia + insulin         
  Plasma level (mmol/l) 0.65 ± 0.09 0.68 ± 0.09 0.56 ± 0.09 0.48 ± 0.08 0.34 ± 0.06* 0.31 ± 0.05* 0.33 ± 0.06* 0.29 ± 0.06* 
  NHB (μmol · kg−1 · min−1−1.65 ± 0.22 −1.92 ± 0.27 −1.44 ± 0.30 −0.86 ± 0.24 −0.71 ± 0.19* −0.48 ± 0.18* −0.73 ± 0.23* −0.58 ± 0.17* 
3-Hydroxybutyrate         
 Hypoglycemia         
  Blood level (μmol/l) 20 ± 3 19 ± 2 15 ± 2 16 ± 3 28 ± 4 49 ± 4* 65 ± 7* 111 ± 20* 
  NHB (μmol · kg−1 · min−10.72 ± 0.14 0.64 ± 0.12 0.76 ± 0.12 0.66 ± 0.11 1.17 ± 0.17 1.93 ± 0.21* 2.52 ± 0.47* 3.91 ± 1.25* 
 Hypoglycemia + insulin         
  Blood level (μmol/l) 29 ± 8 21 ± 3 19 ± 3 14 ± 3 32 ± 15 32 ± 15 25 ± 9 24 ± 8 
  NHB (μmol · kg−1 · min−11.41 ± 0.45 0.75 ± 0.17 0.82 ± 0.17 0.87 ± 0.19 2.02 ± 0.89 1.69 ± 0.83 1.30 ± 0.62 1.86 ± 1.04 
 Euglycemia         
  Blood level (μmol/l) 33 ± 11 24 ± 6 27 ± 6 32 ± 3 24 ± 3 14 ± 1* 17 ± 4 31 ± 15 
  NHB (μmol · kg−1 · min−11.06 ± 0.38 0.60 ± 0.1 0.94 ± 0.1 1.01 ± 0.08 1.10 ± 0.06 0.61 ± 0.05 0.90 ± 0.15 1.00 ± 0.33 
 Euglycemia + insulin         
  Blood level (μmol/l) 19 ± 3 21 ± 3 14 ± 3 13 ± 3 5 ± 1* 4 ± 1* 6 ± 1* 4 ± 2* 
  NHB (μmol · kg−1 · min−10.60 ± 0.08 0.49 ± 0.04 0.54 ± 0.06 0.40 ± 0.03 0.27 ± 0.07* 0.24 ± 0.03* 0.23 ± 0.08* 0.15 ± 0.07* 
Glycerol         
 Hypoglycemia         
  Blood level (μmol/l) 63 ± 4 66 ± 5 77 ± 5* 98 ± 12* 107 ± 15* 107 ± 12* 119 ± 5* 124 ± 11* 
  NHB (μmol · kg−1 · min−1−1.12 ± 0.11 −1.11 ± 0.11 −1.63 ± 0.11* −2.34 ± 0.56* −2.39 ± 0.51* −2.31 ± 0.43* −2.68 ± 0.27* −2.91 ± 0.50* 
 Hypoglycemia + insulin         
  Blood level (μmol/l) 88 ± 10 68 ± 9 57 ± 9 78 ± 6 92 ± 18 88 ± 6 105 ± 10 108 ± 9 
  NHB (μmol · kg−1 · min−1−2.20 ± 0.28 −1.42 ± 0.21 −1.49 ± 0.21 −2.06 ± 0.34 −2.60 ± 0.65 −2.36 ± 0.28 −2.88 ± 0.46 −3.34 ± 0.61 
 Euglycemia         
  Blood level (μmol/l) 85 ± 5 74 ± 7 98 ± 7 73 ± 10 96 ± 7 92 ± 12 70 ± 8 78 ± 13 
  NHB (μmol · kg−1 · min−1−1.41 ± 0.14 −1.29 ± 0.15 −1.26 ± 0.15 −1.35 ± 0.17 −1.68 ± 0.10 −1.63 ± 0.16 −1.49 ± 0.19 −1.45 ± 0.21 
 Euglycemia + insulin         
  Blood level (μmol/l) 68 ± 7 51 ± 7 49 ± 8 45 ± 6* 38 ± 7* 36 ± 7* 43 ± 7* 53 ± 9* 
  NHB (μmol · kg−1 · min−1−1.08 ± 0.20 −0.78 ± 0.20 −0.79 ± 0.19 −0.61 ± 0.10 −0.56 ± 0.04* −0.52 ± 0.07* −0.59 ± 0.13* −0.78 ± 0.18* 
Lactate         
 Hypoglycemia         
  Blood level (μmol/l) 632 ± 113 595 ± 65 522 ± 65 573 ± 53 479 ± 56 461 ± 44* 467 ± 54* 452 ± 42* 
  NHB (μmol · kg−1 · min−1−1.18 ± 2.76 −2.08 ± 2.67 −2.44 ± 2.67 −4.21 ± 1.78 −4.37 ± 0.83* −5.80 ± 1.39* −7.62 ± 1.24* −8.73 ± 1.36* 
 Hypoglycemia + insulin         
  Blood level (μmol/l) 716 ± 147 630 ± 129 616 ± 129 542 ± 109 464 ± 112 506 ± 129 619 ± 136 548 ± 52 
  NHB (μmol · kg−1 · min−1−2.09 ± 1.71 −2.23 ± 1.19 −3.84 ± 1.19 −5.82 ± 2.76* −5.45 ± 2.44* −4.80 ± 1.32* −6.56 ± 1.97* −8.48 ± 2.22* 
 Euglycemia         
  Blood level (μmol/l) 636 ± 81 647 ± 124 615 ± 124 536 ± 98 564 ± 91 548 ± 69 469 ± 71* 430 ± 73* 
  NHB (μmol · kg−1 · min−1−3.05 ± 2.69 −1.27 ± 4.15 −3.71 ± 4.15 −3.40 ± 3.56 −1.02 ± 2.23 −2.44 ± 0.89 −4.20 ± 0.27 −5.47 ± 0.42 
 Euglycemia + insulin         
  Blood level (μmol/l) 775 ± 120 700 ± 120 650 ± 80 560 ± 60 450 ± 40* 370 ± 20* 370 ± 30* 420 ± 40* 
  NHB (μmol · kg−1 · min−17.73 ± 4.55 2.51 ± 5.10 0.29 ± 3.24 1.99 ± 2.09 0.32 ± 1.09* −0.96 ± 0.92* −0.91 ± 0.56* −1.87 ± 0.57* 
Alanine         
 Hypoglycemia         
  Blood level (μmol/l) 317 ± 21 312 ± 21 301 ± 21 292 ± 13 270 ± 29 227 ± 27* 206 ± 26* 161 ± 26* 
  NHB (μmol · kg−1 · min−1−1.99 ± 0.21 −1.67 ± 0.23 −2.37 ± 0.23 −2.71 ± 0.22* −2.97 ± 0.52* −2.73 ± 0.36* −2.97 ± 0.47* −2.74 ± 0.54* 
 Hypoglycemia + insulin         
  Blood level (μmol/l) 340 ± 29 325 ± 33 312 ± 33 310 ± 40 254 ± 36* 217 ± 30* 198 ± 27* 172 ± 17* 
  NHB (μmol · kg−1 · min−1−2.75 ± 0.37 −2.98 ± 0.58 −2.79 ± 0.59 −3.38 ± 0.70 −3.23 ± 0.88 −3.05 ± 0.73 −2.87 ± 0.60 −2.90 ± 0.52 
 Euglycemia         
  Blood level (μmol/l) 299 ± 25 290 ± 25 257 ± 25 253 ± 28 246 ± 25 245 ± 27 232 ± 35* 204 ± 34* 
  NHB (μmol · kg−1 · min−1−2.31 ± 0.32 −2.12 ± 0.46 −1.94 ± 0.46 −2.33 ± 0.34 −1.85 ± 0.27 −2.02 ± 0.51 −2.20 ± 0.37 −1.99 ± 0.63 
 Euglycemia + insulin         
  Blood level (μmol/l) 390 ± 45 370 ± 50 370 ± 50 330 ± 40 290 ± 30* 210 ± 20* 190 ± 20* 170 ± 20* 
  NHB (μmol · kg−1 · min−1−1.93 ± 0.39 −2.23 ± 0.39 −2.22 ± 0.41 −2.04 ± 0.25 −2.29 ± 0.43 −1.73 ± 0.26 −1.67 ± 0.20 −1.65 ± 0.24 
GroupControl periodBAY R 3401 with or without peripheral glucose infusion (min)
1020306090120180
NEFA         
 Hypoglycemia         
  Plasma level (mmol/l) 0.67 ± 0.04 0.68 ± 0.07 0.80 ± 0.07* 0.92 ± 0.14* 1.29 ± 0.23* 1.39 ± 0.20* 1.49 ± 0.15* 1.52 ± 0.09* 
  NHB (μmol · kg−1 · min−1−2.51 ± 0.32 −2.51 ± 0.26 −2.85 ± 0.26 −3.22 ± 0.37* −4.43 ± 0.90* −5.32 ± 0.71* −6.12 ± 0.74* −6.69 ± 1.05* 
 Hypoglycemia + insulin         
  Plasma level (mmol/l) 0.82 ± 0.08 0.72 ± 0.09 0.53 ± 0.09 0.64 ± 0.10 0.73 ± 0.14 0.73 ± 0.14 0.79 ± 0.10 0.77 ± 0.164 
  NHB (μmol · kg−1 · min−1−3.18 ± 0.56 −3.27 ± 0.40 −1.95 ± 0.40 −2.39 ± 0.20 −3.20 ± 1.02 −3.47 ± 0.54 −2.90 ± 0.19 −2.06 ± 0.61 
 Euglycemia         
  Plasma level (mmol/l) 0.79 ± 0.09 0.73 ± 0.08 0.81 ± 0.08 0.80 ± 0.10 0.84 ± 0.13 0.78 ± 0.12 0.82 ± 0.06 0.91 ± 0.06 
  NHB (μmol · kg−1 · min−1−1.83 ± 0.29 −1.51 ± 0.35 −1.43 ± 0.33 −1.96 ± 0.33 −2.06 ± 0.51 −2.18 ± 0.39 −2.32 ± 0.25 −2.39 ± 0.24 
 Euglycemia + insulin         
  Plasma level (mmol/l) 0.65 ± 0.09 0.68 ± 0.09 0.56 ± 0.09 0.48 ± 0.08 0.34 ± 0.06* 0.31 ± 0.05* 0.33 ± 0.06* 0.29 ± 0.06* 
  NHB (μmol · kg−1 · min−1−1.65 ± 0.22 −1.92 ± 0.27 −1.44 ± 0.30 −0.86 ± 0.24 −0.71 ± 0.19* −0.48 ± 0.18* −0.73 ± 0.23* −0.58 ± 0.17* 
3-Hydroxybutyrate         
 Hypoglycemia         
  Blood level (μmol/l) 20 ± 3 19 ± 2 15 ± 2 16 ± 3 28 ± 4 49 ± 4* 65 ± 7* 111 ± 20* 
  NHB (μmol · kg−1 · min−10.72 ± 0.14 0.64 ± 0.12 0.76 ± 0.12 0.66 ± 0.11 1.17 ± 0.17 1.93 ± 0.21* 2.52 ± 0.47* 3.91 ± 1.25* 
 Hypoglycemia + insulin         
  Blood level (μmol/l) 29 ± 8 21 ± 3 19 ± 3 14 ± 3 32 ± 15 32 ± 15 25 ± 9 24 ± 8 
  NHB (μmol · kg−1 · min−11.41 ± 0.45 0.75 ± 0.17 0.82 ± 0.17 0.87 ± 0.19 2.02 ± 0.89 1.69 ± 0.83 1.30 ± 0.62 1.86 ± 1.04 
 Euglycemia         
  Blood level (μmol/l) 33 ± 11 24 ± 6 27 ± 6 32 ± 3 24 ± 3 14 ± 1* 17 ± 4 31 ± 15 
  NHB (μmol · kg−1 · min−11.06 ± 0.38 0.60 ± 0.1 0.94 ± 0.1 1.01 ± 0.08 1.10 ± 0.06 0.61 ± 0.05 0.90 ± 0.15 1.00 ± 0.33 
 Euglycemia + insulin         
  Blood level (μmol/l) 19 ± 3 21 ± 3 14 ± 3 13 ± 3 5 ± 1* 4 ± 1* 6 ± 1* 4 ± 2* 
  NHB (μmol · kg−1 · min−10.60 ± 0.08 0.49 ± 0.04 0.54 ± 0.06 0.40 ± 0.03 0.27 ± 0.07* 0.24 ± 0.03* 0.23 ± 0.08* 0.15 ± 0.07* 
Glycerol         
 Hypoglycemia         
  Blood level (μmol/l) 63 ± 4 66 ± 5 77 ± 5* 98 ± 12* 107 ± 15* 107 ± 12* 119 ± 5* 124 ± 11* 
  NHB (μmol · kg−1 · min−1−1.12 ± 0.11 −1.11 ± 0.11 −1.63 ± 0.11* −2.34 ± 0.56* −2.39 ± 0.51* −2.31 ± 0.43* −2.68 ± 0.27* −2.91 ± 0.50* 
 Hypoglycemia + insulin         
  Blood level (μmol/l) 88 ± 10 68 ± 9 57 ± 9 78 ± 6 92 ± 18 88 ± 6 105 ± 10 108 ± 9 
  NHB (μmol · kg−1 · min−1−2.20 ± 0.28 −1.42 ± 0.21 −1.49 ± 0.21 −2.06 ± 0.34 −2.60 ± 0.65 −2.36 ± 0.28 −2.88 ± 0.46 −3.34 ± 0.61 
 Euglycemia         
  Blood level (μmol/l) 85 ± 5 74 ± 7 98 ± 7 73 ± 10 96 ± 7 92 ± 12 70 ± 8 78 ± 13 
  NHB (μmol · kg−1 · min−1−1.41 ± 0.14 −1.29 ± 0.15 −1.26 ± 0.15 −1.35 ± 0.17 −1.68 ± 0.10 −1.63 ± 0.16 −1.49 ± 0.19 −1.45 ± 0.21 
 Euglycemia + insulin         
  Blood level (μmol/l) 68 ± 7 51 ± 7 49 ± 8 45 ± 6* 38 ± 7* 36 ± 7* 43 ± 7* 53 ± 9* 
  NHB (μmol · kg−1 · min−1−1.08 ± 0.20 −0.78 ± 0.20 −0.79 ± 0.19 −0.61 ± 0.10 −0.56 ± 0.04* −0.52 ± 0.07* −0.59 ± 0.13* −0.78 ± 0.18* 
Lactate         
 Hypoglycemia         
  Blood level (μmol/l) 632 ± 113 595 ± 65 522 ± 65 573 ± 53 479 ± 56 461 ± 44* 467 ± 54* 452 ± 42* 
  NHB (μmol · kg−1 · min−1−1.18 ± 2.76 −2.08 ± 2.67 −2.44 ± 2.67 −4.21 ± 1.78 −4.37 ± 0.83* −5.80 ± 1.39* −7.62 ± 1.24* −8.73 ± 1.36* 
 Hypoglycemia + insulin         
  Blood level (μmol/l) 716 ± 147 630 ± 129 616 ± 129 542 ± 109 464 ± 112 506 ± 129 619 ± 136 548 ± 52 
  NHB (μmol · kg−1 · min−1−2.09 ± 1.71 −2.23 ± 1.19 −3.84 ± 1.19 −5.82 ± 2.76* −5.45 ± 2.44* −4.80 ± 1.32* −6.56 ± 1.97* −8.48 ± 2.22* 
 Euglycemia         
  Blood level (μmol/l) 636 ± 81 647 ± 124 615 ± 124 536 ± 98 564 ± 91 548 ± 69 469 ± 71* 430 ± 73* 
  NHB (μmol · kg−1 · min−1−3.05 ± 2.69 −1.27 ± 4.15 −3.71 ± 4.15 −3.40 ± 3.56 −1.02 ± 2.23 −2.44 ± 0.89 −4.20 ± 0.27 −5.47 ± 0.42 
 Euglycemia + insulin         
  Blood level (μmol/l) 775 ± 120 700 ± 120 650 ± 80 560 ± 60 450 ± 40* 370 ± 20* 370 ± 30* 420 ± 40* 
  NHB (μmol · kg−1 · min−17.73 ± 4.55 2.51 ± 5.10 0.29 ± 3.24 1.99 ± 2.09 0.32 ± 1.09* −0.96 ± 0.92* −0.91 ± 0.56* −1.87 ± 0.57* 
Alanine         
 Hypoglycemia         
  Blood level (μmol/l) 317 ± 21 312 ± 21 301 ± 21 292 ± 13 270 ± 29 227 ± 27* 206 ± 26* 161 ± 26* 
  NHB (μmol · kg−1 · min−1−1.99 ± 0.21 −1.67 ± 0.23 −2.37 ± 0.23 −2.71 ± 0.22* −2.97 ± 0.52* −2.73 ± 0.36* −2.97 ± 0.47* −2.74 ± 0.54* 
 Hypoglycemia + insulin         
  Blood level (μmol/l) 340 ± 29 325 ± 33 312 ± 33 310 ± 40 254 ± 36* 217 ± 30* 198 ± 27* 172 ± 17* 
  NHB (μmol · kg−1 · min−1−2.75 ± 0.37 −2.98 ± 0.58 −2.79 ± 0.59 −3.38 ± 0.70 −3.23 ± 0.88 −3.05 ± 0.73 −2.87 ± 0.60 −2.90 ± 0.52 
 Euglycemia         
  Blood level (μmol/l) 299 ± 25 290 ± 25 257 ± 25 253 ± 28 246 ± 25 245 ± 27 232 ± 35* 204 ± 34* 
  NHB (μmol · kg−1 · min−1−2.31 ± 0.32 −2.12 ± 0.46 −1.94 ± 0.46 −2.33 ± 0.34 −1.85 ± 0.27 −2.02 ± 0.51 −2.20 ± 0.37 −1.99 ± 0.63 
 Euglycemia + insulin         
  Blood level (μmol/l) 390 ± 45 370 ± 50 370 ± 50 330 ± 40 290 ± 30* 210 ± 20* 190 ± 20* 170 ± 20* 
  NHB (μmol · kg−1 · min−1−1.93 ± 0.39 −2.23 ± 0.39 −2.22 ± 0.41 −2.04 ± 0.25 −2.29 ± 0.43 −1.73 ± 0.26 −1.67 ± 0.20 −1.65 ± 0.24 

Data for each group are means ± SE from five dogs.

*

Significantly changed from the values during the control period in the same group. Positive and negative values in net hepatic balance (NHB) represent output and uptake rates, respectively.

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