Exercise in the insulin-deficient diabetic state is characterized by a further increase in elevated circulating glucose and NEFA levels and by excessive counterregulatory hormone levels. The aim of this study was to distinguish the direct glucoregulatory effects of insulinopenia during exercise from the indirect effects that result from the metabolic and hormonal environment that accompanies insulin deficiency. For this purpose, dogs underwent 90 min of treadmill exercise during SRIF infusion with (SRIF+INS, n = 8) or without (SRIF-INS, n = 6) intraportal insulin replacement. Glucagon was not replaced, thus allowing assessment of the direct effect of insulinopenia at the liver independent of the potentiation of glucagon action. Glucose was infused to maintain euglycemia. Hepatic glucose production (Ra); glucose utilization (Rd); and LGIcU, LGIcE, and LGIcO were assessed with tracers ([3H]glucose, [14C]glucose) and arteriovenous differences. With exercise, insulin fell from 66 ± 6 to 42 ± 6 pM in the SRIF+INS group, and was undetectable in the SRIF-INS group. Plasma glucose was 6.33 ± 0.38 and 6.26 ± 0.30 mM at rest in the SRIF+INS and SRIF-INS groups, respectively, and was unchanged with exercise. Ra rose from 7.5 ± 2.3 to 16.5 ± 2.2 μmol · kg−1 · min−1 and 9.1 ± 2.0 to 31.4 ± 3.9 μmol · kg−1 · min−1 with exercise in the SRIF+INS and SRIF-INS groups, whereas Rd rose from 19.5 ± 2.0 to 46.8 ± 3.9 μmol · kg−1 · min−1 and 15.1 ± 1.8 to 29.9 ± 3.3 μmol · kg−1 · min−1. LGIcU rose from 36 ± 9 to 112 ± 25 μmol/min and 1 5 ± 4 t o 59 ± 13 μmol/min and LGIcO rose from 5 ± 2 to 61 ± 12 μmol/min and 5 ± 3 to 32 ± 9 μmol/min with exercise in the SRIF+INS and SRIF-INS groups, respectively. Arterial levels and limb balances of NEFAs and glycerol were similar in the two groups. In summary, during exercise: 1) marked insulinopenia attenuates the increases in muscle glucose uptake and oxidation by ∼50%, independent of changes in circulating metabolic substrate levels; 2) substantial increases in muscle glucose uptake and oxidation are, however, still present even in the absence of detectable insulin levels; and 3) insulinopenia facilitates the increase in Ra, independent of the potentiation of basal glucagon action. In conclusion, marked insulinopenia contributes directly to the exacerbation of glucoregulation during exercise in the diabetic state by limiting the rises in glucose uptake and metabolism and by enhancing hepatic glucose production.

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