Beta-blockade, but not normoglycemia or hyperinsulinemia, markedly diminishes stress-induced hyperglycemia in diabetic dogs.

Abstract

Stress-induced hyperglycemia can lead to significant deterioration in glycemic control in individuals with diabetes. Previously, we have shown in normal dogs that, after intracerebroventricular (ICV) administration of carbachol (a model of moderate stress), increases in both the metabolic clearance rate (MCR) of glucose and endogenous glucose production (GP) occur. Howe v e r, in hyperglycemic diabetic dogs subjected to the same stress, the MCR of glucose does not increase and glycemia therefore markedly deteriorates because of stimulation of GP. Our aims were to determine the following: 1) whether insulin-induced acute normalization of glycemia, with or without -blockade, would correct glucose clearance and prevent the hyperglycemic eff e c t of stress, and 2) whether hyperinsulinemia per se could correct these abnormalities. Stress was induced by ICV carbachol in 27 experiments in five alloxan-administered diabetic dogs subjected to the following protocols in random order: 1) basal insulin infusion (BI) to restore normoglycemia; 2) basal insulin infusion with -blockade (BI+block); 3) normoglycemic-hyperinsulinemic clamp with threefold elevation of insulin above basal (3 BI); and 4) normoglycemic-hyperinsulinemic clamp with fivefold elevation of insulin above basal ( 5 BI). The BI+block protocol fully prevented stressinduced hyperglycemia, both by increasing MCR ( MCR at peak: 0.72 ± 0.25 m l · k g -1 · min -1 vs. no change in BI, P < 0.05) and by diminishing the stressinduced increment in GP observed in BI ( GP at peak: 3.72 ± 0.09 µmol · k g -1 · min -1 for BI+block vs. 14.10 ± 0.31 µmol · k g -1 · min -1 for BI, P < 0.0001). In contrast, 3 BI and 5 BI treatments with normoglycemichyperinsulinemic clamps proportionately increased basal MCR at baseline, but paradoxically were not associated with an increase in MCR in response to stress, which induced a twofold increase in GP. Thus, in alloxan-administered diabetic dogs, stress increased GP but not MCR, despite normalization of glycemia with basal or high insulin. In contrast, -a d r e n e r g i c blockade almost completely restored the metabolic response to stress to normal and prevented marked hyperglycemia, both by limiting the rise in GP and by increasing glucose MCR. We conclude that acute normalization of glycemia with basal insulin or hyperinsulinemia does not prevent hyperglycemic effects of stress unless accompanied by -blockade, and we speculate that short-term -blockade may be a useful treatment modality under some stress conditions in patients with diabetes. Diabetes 4 9 :2 5 3-262, 2000 T he increased demand for glucose by the brain, heart, and other tissues during stress necessitates adaptive alterations in glucose metabolism. In many forms of stress, the rate of glucose production rises above the rate of glucose clearance, resulting in hyperglycemia. It is well recognized that stress induces a greater derangement in glucose regulation in patients with diabetes than in nondiabetic individuals. Consequently, in diabetes there can be an exaggerated ...

Intense Exercise Has Unique Effects on Both Insulin Release and Its Roles in Glucoregulation

“…9A) and is due to a marked increase of glucose metabolic clearance. We made a similar observation in diabetic dogs, where stress (intracerebroventricular injection of carbachol) caused hyperglycemia in normal but not in diabetic dogs; this response was prevented by infusion of propranolol (54). The potential role of ␤-blockade in preventing hyperglycemia following stress or intense exercise remains to be explored.…”

Hyperglycemia does not increase basal hypothalamo-pituitary-adrenal activity in diabetes but it does impair the HPA response to insulin-induced hypoglycemia

“…The fact that insulin treatment raised basal epinephrine levels in STZ animals suggested that low epinephrine levels in diabetes may be a direct effect of hypoinsulinemia on adrenomedullary function and/or prolonged exposure to elevated glucocorticoid levels. Unchanged insulin values during the fed and fasted state could be the cause of elevated epinephrine levels during insulin treatment (44). With phloridzin treatment, we saw epinephrine levels that were The lower basal plasma glucagon levels in insulin-treated diabetic animals may stem from suppressed glucagon release by the high plasma insulin levels resulting from the insulin implant.…”

Model predictive glycaemic regulation in critical illness using insulin and nutrition input: A pilot study

“…However, endogenous insulin production is suppressed with significant exogenous insulin administration [32,35,41]. In addition, endogenous glucose production is known to be unsuppressed by insulin or glycaemia under conditions of stress [19,20]. Hence, in this study, an unknown glucose supply is assumed and its effect is lumped in the time-varying parameter, p G while endogenous insulin production is assumed to be suppressed to a steady constant value under significant exogenous insulin input.…”

“…More specifically, high effective insulin resistance due to stress of condition and increased counter-regulatory dynamics can result in hyperglycaemia regardless of hyperinsulinaemia [17,18]. Metabolic clearance rate is not stimulated with hyperinsulinaemia under conditions of stress, as endogenous glucose production is, which compounds hyperglycaemia [19,20]. Insulin effect can also saturate at the supraphysiological insulin concentrations that exist under aggressive insulin therapy [18,[21][22][23][24][25], limiting the achievable glycaemic reduction using insulin alone if effective insulin resistance is high.…”