Research Article| Volume 47, ISSUE 10, P1252-1257, October 1998

Recurrent hypoglycemia does not impair the cortisol response to adrenocorticotropin infusion in healthy humans

  • Corrine K. Welt
    Address reprint requests to Corrine K. Welt, MD, Reproductive Endocrinology, Massachusetts General Hospital, Bartlett Hall Extension, 511 Fruit St, Boston, MA 02114.
    Department of Medicine, Joslin Diabetes Center, and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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  • Brendan T. Kinsley
    Department of Medicine, Joslin Diabetes Center, and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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  • Donald C. Simonson
    Department of Medicine, Joslin Diabetes Center, and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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      Previous studies have shown that hypoglycemia may reduce counterregulatory responses to subsequent hypoglycemia in healthy subjects and in patients with diabetes. The effect of hypoglycemia on the hormonal response to a nonhypoglycemic stimulus is uncertain. To test the hypothesis that the cortisol response to corticotropin (ACTH) infusion is independent of antecedent hypoglycemia, 10 healthy subjects received a standard ACTH infusion (0.25 mg Cosyntropin [Organon, West Orange, NJ] intravenously over 240 minutes) at 8:00 am on day 1 and day 3 and a hypoglycemic insulin clamp study (1 mU/kg/min) at 8:00 am on day 2. During the hypoglycemic clamp, plasma glucose decreased from 5.0 mmol/L to 2.8 mmol/L for two periods of 120 minutes (mean glucose, 2.9 ± 0.03 and 2.8 ± 0.02 mmol/L, respectively) separated by a 60-minute interval of euglycemia (mean glucose, 4.7 ± 0.01 mmol/L). Seven subjects also had paired control studies in random order during which a 330-minute euglycemic clamp (mean glucose, 5.0 ± 0.11 mmol/L) instead of a hypoglycemic clamp was performed on day 2. Basal ACTH (4.6 ± 0.7 v 2.6 ± 0.4 pmol/L, P < .02) and basal cortisol (435 ± 46 v 317 ± 40 nmol/L, P < .02) both decreased from day 1 to day 3 following intervening hypoglycemia. In contrast, with intervening euglycemia, neither basal ACTH (5.9 ± 1.5 v 4.5 ± 1.0 pmol/L) nor basal cortisol (340 ± 38 v 318 ± 60 nmol/L) were reduced significantly on day 3 compared with day 1. Following interval hypoglycemia, the area under the curve (AUC) for the cortisol response to successive ACTH infusions was increased (4,734 ± 428 nmol/L over 240 minutes [day 3] v 3,526 ± 434 nmol/L over 240 minutes [day 1], P < .01). The maximum incremental cortisol response was also significantly increased (805 ± 63 nmol/L (day 3) v 583 ± 58 nmol/L (day 1), P < .05). In contrast, the AUC for the cortisol response to successive ACTH infusions with interval euglycemia (3,402 ± 345 nmol/L over 240 minutes [day 3] v 3,709 ± 391 nmol/L over 240 minutes [day 1] and the incremental cortisol response (702 ± 62 nmol/L [day 3] v 592 ± 85 nmol/L [day 1] were unchanged. Following exposure to intermittent hypoglycemia in healthy humans, fasting morning ACTH and cortisol levels are reduced and the incremental cortisol response to an infusion of ACTH is enhanced. The enhanced cortisol response to exogenous ACTH infusion after intervening hypoglycemia (but not intervening euglycemia) may reflect priming of the adrenal gland by endogenous ACTH produced during the hypoglycemia. These data suggest that adrenal function testing by exogenous ACTH administration is not impaired by prior exposure to hypoglycemia. Moreover, the reduced cortisol response to recurrent hypoglycemia in patients with well-controlled diabetes is not likely the result of impaired adrenal responsiveness.
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        • Rizza RA
        • Cryer PE
        • Gerich JE
        Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation.
        J Clin Invest. 1979; 64: 62-74
        • DeFeo P
        • Perriello G
        • Torlone E
        • et al.
        Contribution of cortisol to glucose counterregulation in humans.
        Am J Physiol. 1989; 257: E35-E42
        • DeFeo P
        • Perriello G
        • Torlone E
        • et al.
        Demonstration of a role for growth hormone in glucose counterregulation.
        Am J Physiol. 1989; 256: E835-E843
        • Gerich JE
        • Langlois M
        • Noacco C
        • et al.
        Lack of glucagon response to hypoglycemia in diabetes: Evidence for an intrinsic pancreatic alpha cell defect.
        Science. 1973; 182: 171-173
        • White NH
        • Skor DA
        • Cryer PE
        • et al.
        Identification of type 1 diabetic patients at increased risk for hypoglycemia during intensive therapy.
        N Engl J Med. 1983; 308: 485-491
        • Bolli GB
        • De Feo P
        • De Cosmo S
        • et al.
        A reliable and reproducible test for adequate glucose counterregulation in type 1 diabetes mellitus.
        Diabetes. 1984; 33: 732-737
        • Heller SR
        • Herbert M
        • Macdonald IA
        • et al.
        Influence of sympathetic nervous system on hypoglycaemic warning symptoms.
        Lancet. 1987; 2: 359-363
        • Simonson DC
        • Tamborlane WV
        • DeFronzo RA
        • et al.
        Intensive insulin therapy reduces counterregulatory hormone responses to hypoglycemia in patients with type I diabetes.
        Ann Intern Med. 1985; 103: 184-190
        • Amiel SA
        • Tamborlane WV
        • Simonson DC
        • et al.
        Defective glucose counterregulation after strict glycemic control of insulin-dependent diabetes mellitus.
        N Engl J Med. 1987; 22: 1376-1383
        • Amiel SA
        • Sherwin RS
        • Simonson DC
        • et al.
        Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release.
        Diabetes. 1988; 37: 901-907
        • Widom B
        • Simonson DC
        Glycemic control and neuropsychologic function during hypoglycemia in patients with insulin-dependent diabetes mellitus.
        Ann Intern Med. 1990; 112: 904-912
        • Heller SR
        • Cryer PE
        Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans.
        Diabetes. 1991; 40: 223-226
        • Davis MR
        • Shamoon H
        Counterregulatory adaptation on hypoglycemia in normal humans.
        J Clin Endocrinol Metab. 1991; 73: 995-1001
        • Widom B
        • Simonson DC
        Intermittent hypoglycemia impairs glucose counterregulation.
        Diabetes. 1992; 41: 1597-1602
        • Veneman T
        • Mitrakou A
        • Mokan M
        • et al.
        Induction of hypoglycemia unawareness by asymptomatic nocturnal hypoglycemia.
        Diabetes. 1993; 42: 1233-1237
        • Davis MR
        • Mellman M
        • Shamoon H
        Further defects in counter-regulatory responses induced by recurrent hypoglycemia in IDDM.
        Diabetes. 1992; 41: 1335-1340
        • Lingenfelser T
        • Renn W
        • Sommerwerck U
        • et al.
        Compromised hormonal counterregulation, symptom awareness, and neurophysiological function after recurrent short-term episodes of insulin-induced hypoglycemia in IDDM patients.
        Diabetes. 1993; 42: 610-618
        • Moriarty KT
        • Simpson EI
        • Brown NS
        • et al.
        Effect of mild hypoglycemia on counterregulatory responses to moderate hypoglycemia induced immediately afterwards in healthy men.
        Clin Sci. 1993; 85: 537-542
        • Peters A
        • Rohloff F
        • Kerner W
        Preserved counterregulatory hormone release and symptoms after short term hypoglycemic episodes in normal men.
        J Clin Endocrinol Metab. 1995; 80: 2894-2898
        • George E
        • Harris N
        • Bedford C
        • et al.
        Prolonged but partial impairment of the hypoglycemic physiological responses following short term hypoglycemia in normal subjects.
        Diabetologia. 1995; 38: 1183-1190
        • Boyle PJ
        • Nagy RJ
        • O'Connor A
        • et al.
        Adaptation in brain glucose uptake following recurrent hypoglycemia.
        in: ed 3. Proc Natl Acad Sci USA. 91. 1994: 9352-9356
        • Boyle PJ
        • Kempers SF
        • O'Connor AM
        • et al.
        Brain glucose uptake and unawareness of hypoglycemia in patients with insulin dependent diabetes mellitus.
        N Engl J Med. 1996; 333: 1726-1731
        • Davis SN
        • Shavers C
        • Costa F
        • et al.
        Role of cortisol in the pathogenesis of deficient counterregulation after antecedent hypoglycemia in normal humans.
        J Clin Invest. 1996; 98: 680-691
        • Kinsley BT
        • Simonson DC
        Evidence for a hypothalamic-pituitary versus adrenal cortical effect of glycemic control on counter-regulatory hormone responses to hypoglycemia in insulin-dependent diabetes mellitus.
        J Clin Endocrinol Metab. 1996; 81: 684-691
        • Hirsch BR
        • Shamoon H
        Defective epinephrine and growth hormone responses in type I diabetes are stimulus specific.
        Diabetes. 1987; 36: 20-26
        • Kinsley BT
        • O'Donnell C
        • Levy C
        • et al.
        Counterregulatory hormone response to exercise is independent of glycemic control in IDDM.
        Diabetes. 1994; 43 (abstr): 543A
        • Rattarasarn C
        • Dagogo-Jack S
        • Zachwieja JJ
        • et al.
        Hypoglycemia-induced autonomic failure in IDDM is specific for stimulus of hypoglycemia and is not attributable to prior autonomic activation.
        Diabetes. 1994; 43: 809-818
        • Kinsley BT
        • Widom B
        • Utzschneider K
        • et al.
        Stimulus specificity of defects in counterregulatory hormone secretion in insulin-dependent diabetes mellitus: Effect of glycemic control.
        J Clin Endocrinol Metab. 1994; 79: 1383-1389
        • McGuire EA
        • Helderman JH
        • Tobin JD
        • et al.
        Effects of arterial versus venous sampling on analysis of glucose kinetics in man.
        J Appl Physiol. 1976; 41: 565-573
        • DeFronzo FA
        • Tobin JD
        • Andres R
        Glucose clamp technique: A method for quantifying insulin secretion and resistance.
        Am J Physiol. 1979; 237: E214-E223
        • Souldner JS
        • Slone D
        Critical variables in the radioimmunoassay of serum insulin using the double antibody technique.
        Diabetologia. 1965; 14: 771-779
        • Tasseron SJ
        • Fiolet JW
        • Wilebrands AF
        Evaluation of radioenzymatic kit for determination of plasma catecholamines.
        Clin Chem. 1980; 26: 120-122
        • Boden G
        • Soeldner JS
        A sensitive double antibody radioimmunoassay for growth hormone.
        Diabetologia. 1967; 3: 413-421
        • Weir GC
        • Turner RC
        • Martin DB
        Glucagon radioimmunoassay using antiserum 30K: Interference by plasma.
        Horm Metab Res. 1973; 5: 241-244
        • Foster LB
        • Dunn RT
        Single-antibody technique for radioimmunoassay of cortisol in unextracted serum or plasma.
        Clin Chem. 1974; 20: 365-368
        • Zahradnik R
        • Brennan G
        • Hutchison JS
        • et al.
        Immunoradiometric assay of corticotropin with use of avidin-biotin separation.
        Clin Chem. 1989; 35: 804-807
        • Cole RA
        • Soeldner JS
        • Dunn PJ
        • et al.
        A rapid method for the determination of glycosylated hemoglobins using high pressure liquid chromatography.
        Metabolism. 1978; 27: 289-301
        • McCall AL
        • Fixman LB
        • Fleming N
        • et al.
        Chronic hypoglycemia increases brain glucose transport.
        Am J Physiol. 1986; 251: E442-E447
        • Pelligrino DA
        • Segil LJ
        • Albrecht RF
        Brain glucose utilization and transport and cortical function in chronic vs. acute hypoglycemia.
        Am J Physiol. 1990; 259: E729-E735
        • Blomquist G
        • Gjedde A
        • Gutniak M
        • et al.
        Facilitated transport of glucose from blood to brain in man and the effect of moderate hypoglycemia on cerebral glucose utilization.
        Eur J Nucl Med. 1991; 18: 834-837
        • Kumagi AK
        • Kang YS
        • Pardridge WM
        Upregulation of blood-brain-barrier GLUT1 glucose transporter protein and mRNA in experimental chronic hypoglycemia.
        Diabetes. 1995; 44: 1399-1404
        • Nelson JC
        • Tindall DJ
        A comparison of the adrenal responses to hypoglycemia, metyrapone and ACTH.
        Am J Med Sci. 1978; 275: 165-172
        • May ME
        • Carey RM
        Rapid adrenocorticotropic hormone test in practice: Retrospective review.
        Am J Med. 1985; 79: 679-684
        • Dickstein G
        • Shechner C
        • Nicholson WE
        • et al.
        Adrenocorticotropin stimulation test: Effects of basal cortisol level, time of day, and suggested new sensitive low dose test.
        J Clin Endocrinol Metab. 1991; 72: 773-778
        • Dickstein G
        • Spigel D
        • Arad E
        • et al.
        One microgram is the lowest ACTH dose to cause a maximal cortisol response.
        in: There is no diurnal variation of cortisol response to submaximal ACTH stimulation. ed 3. Eur J Endocrinol. 137. 1993: 172-175
      1. Crowley S, Hindmarsh PC, Honour JW et al: Reproducibility of the cortisol response to stimulation with a low dose of ACTH(1–24): The effect of basal cortisol levels and comparison of low-dose with high-dose secretory dynamics. J Endocrinol 136:167–172,

        • Kolanowski J
        • Pizarro MA
        • Crabbe J
        Potentiation of adrenocortical response upon intermittent stimulation with corticotropin in normal subjects.
        J Clin Endocrinol Metab. 1975; 41: 453-465