American Diabetes Association

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

Group	Control period	BAY R 3401 with or without peripheral glucose infusion (min)
Group	Control period			10	20	30	60	90	120	180
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⁻¹)	0.72 ± 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⁻¹)	1.41 ± 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⁻¹)	1.06 ± 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⁻¹)	0.60 ± 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⁻¹)	7.73 ± 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

Group	Control period	BAY R 3401 with or without peripheral glucose infusion (min)
Group	Control period			10	20	30	60	90	120	180
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⁻¹)	0.72 ± 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⁻¹)	1.41 ± 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⁻¹)	1.06 ± 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⁻¹)	0.60 ± 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⁻¹)	7.73 ± 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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