The Effect of Epinephrine on Glucose-Mediated and Insulin-Mediated Disposal in Insulin-Dependent Diabetes
Glucose
J.M. Walters, G.M. Ward, A. Kalfas, J.D. Best, and F.P. Alford The aim of this study was to determine the relative roles of changes in glucose-mediated glucose disposal (SG) and insulin sensitivity (SI) on the impairment of glucose disposal caused by epinephrine (EPI) infusion in type I (insulin-dependent) diabetes mellitus (IDDM). Seven non-obese young adult diabetics with minimal endogenous insulin secretion had EPI infusions at 25 ng/kg/min for 5.5 hours, after a basal overnight insulin infusion (12 mu/kg/h), and glucose infusion as required to maintain euglycemia. The EPI infusion produced approximately an eightfold increase in plasma EPI. At 2.5 hours, an intravenous glucose tolerance test (IVGlT) was performed with supplemental exogenous insulin infusion to achieve an approximation of normal endogenous insulin secretion. In random order, each subject also had a control (CTR) infusion of basal insulin before the IVGTT. The results were analyzed according to a modification of the minimal model of Bergman et al. EPI infusion was associated with (1) elevated basal plasma glucose (EPI v CTR, 9.8 2 0.3 SE v 7.7 + 0.7 mmoll L, P < .05); (2) elevated plasma nonesterified fatty acids (NEFA, 0.9 2 0.1 Y 0.3 f 0.1 mmol/L, P < .05); and (3) profoundly reduced glucose disposal (KG 0.59 f 0.1 Y 1.91 + 0.33 min-l x 102, P < .02). Further analysis showed that the reduced glucose disposal was attributable to a marked decrease in SI (EPI 0.9 + 0.5 v CTR 7.03 f 3.2 min-’ . mu-’ . L x 104, P c .05) with no significant change in SG (EPI 2.5 f 0.2 v CTR 3.1 2 0.5 but not glucosemin-l x 102, NS). These results show that physiological EPI elevation in IDDM impairs insulin-mediated, mediated, Copyright
glucose disposal. 0 1992 by W.B. Saunders Company
C multifactorial and is dependent on the amount insulin secreted by the pancreatic l3 cells in response ONTROL
is of to glucose, and on the effectiveness of secreted insulin in promoting glucose disposal (SI or insulin sensitivity).’ In addition, glucose disposal is promoted by the mass-action effect of glucose, independent of insulin. This effect, known as glucose-mediated glucose disposal (SG), is of physiological importance, as SG represents 75% to 85% of glucose uptake in the postabsorptive state.2 Moreover, when hyperglycemia (in the absence of hyperinsulinemia), hypoinsulinemia, or insulin resistance are also present, the proportion of non-insulin-mediated glucose uptake (NIMGU) is further increased.2 In a recent study, we have shown that both SI and SG are impaired in patients with insulin-dependent diabetes mellitus (IDDM) with satisfactory glycemic control.3 However, patients with IDDM are well aware of the added problems of maintaining good glycemic control during stress situations, when increased levels of stress hormones adversely affect glucose utilization. It has been shown that elevation of serum epinephrine (EPI) levels, as found during moderate stress, is associated with increased fasting blood glucose and impaired glucose utilization in patients with established IDDM.4 The mechanisms involved include increased hepatic glucose production that is more marked than in normal subjects,5 decreased hepatic and peripheral glucose uptake,6 and, theoretically, inhibition of impaired residual p-cell secretion. The first two mechanisms could be mediated by reduced suppression of hepatic glucose production and reduced stimulation of peripheral glucose uptake by insulin (related to SI) or by glucose itself (related to SG). In previous reports,5,6 studies have mainly focused on the postabsorptive state. However, the effects of EPI on SI and SG in the postprandial state have not yet been fully evaluated in IDDM patients. Therefore, the aim of the present study was to determine the relative contribution of altered SG and SI (following a glucose load) to the impairment of glucose disposal caused by infusion of EPI at Metabolism,
OF TOTAL
body glucose utilization
Vol41, No 6 (June), 1992: pp 671-677
a rate appropriate IDDM.
to physiological stress in patients with
PATIENTS AND METHODS
Seven male IDDM patients were studied. Mean age was 31 years (range, 2.5 to 36 years) and mean weight was 77 kg (range, 65 to 85 kg), with a body mass index of 20 to 26 kg/m2. No patients had other disorders or complications (although two had a history of mildly increased blood pressure [135/90, 140/88 mm Hg] without microalbuminuria [ < 15, < 17 ug/min] or proteinuria, and had been treated with enalapril 10 mg/d, with the treatment being the same for each study period). Apart from this, no patients were taking medications known to affect carbohydrate metabolism. Liver and renal function tests were normal, and hemoglobin Ate (HbAlc) values were 7.1% 2 1.3% (normal range,
Glucose
J.M. Walters, G.M. Ward, A. Kalfas, J.D. Best, and F.P. Alford The aim of this study was to determine the relative roles of changes in glucose-mediated glucose disposal (SG) and insulin sensitivity (SI) on the impairment of glucose disposal caused by epinephrine (EPI) infusion in type I (insulin-dependent) diabetes mellitus (IDDM). Seven non-obese young adult diabetics with minimal endogenous insulin secretion had EPI infusions at 25 ng/kg/min for 5.5 hours, after a basal overnight insulin infusion (12 mu/kg/h), and glucose infusion as required to maintain euglycemia. The EPI infusion produced approximately an eightfold increase in plasma EPI. At 2.5 hours, an intravenous glucose tolerance test (IVGlT) was performed with supplemental exogenous insulin infusion to achieve an approximation of normal endogenous insulin secretion. In random order, each subject also had a control (CTR) infusion of basal insulin before the IVGTT. The results were analyzed according to a modification of the minimal model of Bergman et al. EPI infusion was associated with (1) elevated basal plasma glucose (EPI v CTR, 9.8 2 0.3 SE v 7.7 + 0.7 mmoll L, P < .05); (2) elevated plasma nonesterified fatty acids (NEFA, 0.9 2 0.1 Y 0.3 f 0.1 mmol/L, P < .05); and (3) profoundly reduced glucose disposal (KG 0.59 f 0.1 Y 1.91 + 0.33 min-l x 102, P < .02). Further analysis showed that the reduced glucose disposal was attributable to a marked decrease in SI (EPI 0.9 + 0.5 v CTR 7.03 f 3.2 min-’ . mu-’ . L x 104, P c .05) with no significant change in SG (EPI 2.5 f 0.2 v CTR 3.1 2 0.5 but not glucosemin-l x 102, NS). These results show that physiological EPI elevation in IDDM impairs insulin-mediated, mediated, Copyright
glucose disposal. 0 1992 by W.B. Saunders Company
C multifactorial and is dependent on the amount insulin secreted by the pancreatic l3 cells in response ONTROL
is of to glucose, and on the effectiveness of secreted insulin in promoting glucose disposal (SI or insulin sensitivity).’ In addition, glucose disposal is promoted by the mass-action effect of glucose, independent of insulin. This effect, known as glucose-mediated glucose disposal (SG), is of physiological importance, as SG represents 75% to 85% of glucose uptake in the postabsorptive state.2 Moreover, when hyperglycemia (in the absence of hyperinsulinemia), hypoinsulinemia, or insulin resistance are also present, the proportion of non-insulin-mediated glucose uptake (NIMGU) is further increased.2 In a recent study, we have shown that both SI and SG are impaired in patients with insulin-dependent diabetes mellitus (IDDM) with satisfactory glycemic control.3 However, patients with IDDM are well aware of the added problems of maintaining good glycemic control during stress situations, when increased levels of stress hormones adversely affect glucose utilization. It has been shown that elevation of serum epinephrine (EPI) levels, as found during moderate stress, is associated with increased fasting blood glucose and impaired glucose utilization in patients with established IDDM.4 The mechanisms involved include increased hepatic glucose production that is more marked than in normal subjects,5 decreased hepatic and peripheral glucose uptake,6 and, theoretically, inhibition of impaired residual p-cell secretion. The first two mechanisms could be mediated by reduced suppression of hepatic glucose production and reduced stimulation of peripheral glucose uptake by insulin (related to SI) or by glucose itself (related to SG). In previous reports,5,6 studies have mainly focused on the postabsorptive state. However, the effects of EPI on SI and SG in the postprandial state have not yet been fully evaluated in IDDM patients. Therefore, the aim of the present study was to determine the relative contribution of altered SG and SI (following a glucose load) to the impairment of glucose disposal caused by infusion of EPI at Metabolism,
OF TOTAL
body glucose utilization
Vol41, No 6 (June), 1992: pp 671-677
a rate appropriate IDDM.
to physiological stress in patients with
PATIENTS AND METHODS
Seven male IDDM patients were studied. Mean age was 31 years (range, 2.5 to 36 years) and mean weight was 77 kg (range, 65 to 85 kg), with a body mass index of 20 to 26 kg/m2. No patients had other disorders or complications (although two had a history of mildly increased blood pressure [135/90, 140/88 mm Hg] without microalbuminuria [ < 15, < 17 ug/min] or proteinuria, and had been treated with enalapril 10 mg/d, with the treatment being the same for each study period). Apart from this, no patients were taking medications known to affect carbohydrate metabolism. Liver and renal function tests were normal, and hemoglobin Ate (HbAlc) values were 7.1% 2 1.3% (normal range,
