We have investigated catecholamine-glucagon-insulin interactions using three stress models: 1) hypoglycemia; 2) exercise; and 3) epinephrine infusion. Phlorizin caused mild hypoglycemia with hypoinsulinemia. Plasma glucagon increased as did hepatic glucose production. Catecholamines did not increase. Insulin caused severe hypoglycemia. Metabolic counterregulation was due mainly to the 40-fold increase in epinephrine. Glucagon played a role only in the recovery from insulin-induced hypoglycemia, which could reflect increased hepatic sensitivity to glucagon with declining plasma insulin. Glucagon suppression during exercise caused transient hypoglycemia due to an inadequate rise in glucose production. Exaggerated epinephrine release during hypoglycemic exercise prevented severe hypoglycemia by inhibiting glucose utilization and stimulating glucose production, with an associated increase in lactate and free fatty acid levels. Hypoglycemic exercise also caused increased cortisol release. Counterregulation was prevented by a euglycemic clamp. We conclude that, during exercise, glucagon is directly responsible for 80% of the increment of glucose production and controls glucose uptake by the muscle indirectly; thus glucagon spares muscle glycogen by increasing hepatic glucose production. Epinephrine infusion in normal dogs caused a transient increase in glucose production and a sustained inhibition of glucose clearance, resulting in hyperglycemia. Insulin rose transiently, followed by a relative inhibition of secretion. Glucagon suppression did not modify the metabolic effects of epinephrine. In alloxan-diabetic dogs, the glucagon response to epinephrine was augmented, whereas in depancreatized dogs, during subbasal insulin infusion, the hepatic response to glucagon was excessive. Glucagon suppression diminished hepatic responsiveness to epinephrine in both models. Stress-induced diabetic instability could relate to exaggerated glucagon release or to increased hepatic sensitivity to glucagon. Thus, during hypoglycemia, exercise, or epinephrine infusion, prevailing plasma insulin levels govern the relative metabolic roles of epinephrine and glucagon.

The plasma concentration of glucagon (IRG), catecholamines, and hepatic glucose production (Ra) were followed in insulin-induced hypoglycemia in dogs before (normal) and at 14-21 and again at 89-119 days after the injection of alloxan (diabetic). Some diabetic dogs were also tested when euglycemia was restored by phlorizin. In the normal state plasma IRG and epinephrine were raised by a factor of 3 and 15, respectively. Ra increased in two phases, an early peak (350% basal) was followed by a plataeu at about twice basal. In diabetes, irrespective of its duration, plasma IRG was decreased in hypoglycemia, and the rise in plasma epinephrine was significantly reduced. Ra remained unchanged. In phlorizin-treated euglycemic diabetic dogs plasma IRG fell, and the response in plasma epinephrine remained blunted. There was no early rise in Ra, but the same elevated plateau was reached at the same time as in normal animals. In conclusion, the following is observed in diabetic dogs. 1) The sensitivity of alpha-cells to insulin is maintained, but that to hypoglycemia is lost. The concentration of plasma catecholamines is raised less than in normals. With no increase in plasma glucagon this rise is not sufficient to increase Ra. 2) Restoration of euglycemia with phlorizin does not restore normal IRG and epinephrine responses to hypoglycemia but restores the delayed increase of Ra. Thus the restoration of euglycemia in severely diabetic dogs partially restores the responses of the liver, but not of the alpha-cell or sympathetic discharge, to hypoglycemia.

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The Canadian Council on Animal Care (CCAC) publishes data on over 25 species of animals used in science, and the US Department of Agriculture publishes data on six of those species. Between 1980 and 1999, the reduction in animal use was found to be correlated between Canada and the USA for dogs (r = 0.944, p < 0.001), cats (r = 0.839, p < 0.001), rabbits (r = 0.852, p < 0.001) and hamsters (r = 0.716, p < 0.01), with no significant correlation found for non-human primates and guinea-pigs. On the basis of the four species where correlation between the two countries was found for reduction in use, the mean ratio of the number of animals used in the USA compared to the number used in Canada was 17.0 ± 7.5. The CCAC data for these six US-regulated species were used in an analysis of regression with multiple predictors to test whether they could be used to predict the total number of animals used. No significant correlation was found. However, using the same analysis, rats, mice, fish and birds were found to be highly correlated with the total number of animals used (r2 = 0.9835, p < 0.005). The regression equation developed by using Canadian data was validated using UK animal use numbers. An almost perfect fit between the estimated values provided the evidence that total animal use in Canada and the UK decreased at about the same pace during the 1990s. Animal use data can be a useful tool to monitor the implementation of reduction measures. However, their use for the monitoring of refinement measures requires care and analysis. For example, the sustained downward trend in the number of experiments causing severe pain in unanaesthetised animals (category of invasiveness [CI] E) observed in Canada and the USA between 1996 and 1999 is indicative of effective refinement, but it would be misleading to interpret the increase in the number of animals used in Canada under CI D in 1997 as an indication of greater pain and distress. In fact, the larger number of animals in CI D resulted at least in part from the implementation of new CCAC guidelines designed to ensure better monitoring of transgenic animal care and use.

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