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Erschienen in: Wiener klinische Wochenschrift 11-12/2012

01.06.2012 | original article

Hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with type 2 diabetes and relations with insulin resistance and chronic complications

verfasst von: Ivana Prpić-Križevac, MD, PhD, Silvija Canecki-Varžić, MD, Ines Bilić-Ćurčić, M.D, PhD

Erschienen in: Wiener klinische Wochenschrift | Ausgabe 11-12/2012

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Summary

Objective

Connection between abdominal obesity, type 2 diabetes, and the hypothalamic-pituitary-adrenal (HPA) axis activity remains unclear. The aim of this study was to measure HPA axis activity in 121 type 2 diabetics, in 29 obese subjects, and 19 control subjects.

Research design and methods

Physical examination, anthropometric measures, psychological questionnaire, psychiatric interview, neurological and ophthalmologic examination were performed. Biochemical parameters, urinary free cortisol levels (UFC), cortisol and ACTH levels at 8 and 16 h, cortisol levels after overnight suppression with 1 mg dexamethasone followed by ACTH test in 30 and 60 min were measured. Groups were stratified in relation to obesity, body fat distribution, and chronic complications.

Results

UFC and postdexamethasone cortisol were significantly increased in diabetic patients compared with both obese subjects (p < 0.01) and control group (p < 0.05), regardless to diabetic complications and obesity. Postdexamethasone cortisol was correlated with waist circumference. ACTH-induced cortisol levels were significantly higher in all type 2 diabetic patients. An independent association was found between AUC cortisol in ACTH test and insulin resistance. Multiple regression analysis showed that waist circumference was independently associated with sex, fasting plasma insulin, morning cortisol, and AUC of cortisol in ACTH test (R 2 = 0.334,p < 0.0000).

Conclusions

In type 2 diabetic patients, the HPA axis is clearly hyperactive as evident in increased urinary free cortisol, diminished cortisol suppression after dexamethasone and increased ACTH-induced cortisol levels. Abdominal obesity and the presence of chronic complications increased the HPA axis hyperactivity in type 2 diabetes. Augmentation of positive feedback is associated with insulin resistance and negative feedback with abdominal obesity.
Literatur
1.
Zurück zum Zitat DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14:173–94.PubMedCrossRef DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14:173–94.PubMedCrossRef
2.
3.
Zurück zum Zitat Connell JMC, Whitworth JA, Davies DL, Lever AF, Richards AM, Fraser R. Effects of ACTH and cortisol administrations on blood pressure, electrolyte metabolism, atrial natriuretic peptide and renal function in normal man. J Hypertens. 1986;5:425–33. Connell JMC, Whitworth JA, Davies DL, Lever AF, Richards AM, Fraser R. Effects of ACTH and cortisol administrations on blood pressure, electrolyte metabolism, atrial natriuretic peptide and renal function in normal man. J Hypertens. 1986;5:425–33.
4.
Zurück zum Zitat Bjorntorp P, Holm G, Rosmond R. Hypothalamic arousal, insulin resistance and type 2 diabetes mellitus. Diabetic Med. 1999;16:373–81.PubMedCrossRef Bjorntorp P, Holm G, Rosmond R. Hypothalamic arousal, insulin resistance and type 2 diabetes mellitus. Diabetic Med. 1999;16:373–81.PubMedCrossRef
5.
Zurück zum Zitat Hüther KJ, Scholz HR. The plasma concentrations and rate of plasma clearance and plasma production of cortisol and corticosterone in healthy persons and in subjects with asymptomatic and clinical diabetes mellitus. Horm Metab Res. 1969;1:253.PubMedCrossRef Hüther KJ, Scholz HR. The plasma concentrations and rate of plasma clearance and plasma production of cortisol and corticosterone in healthy persons and in subjects with asymptomatic and clinical diabetes mellitus. Horm Metab Res. 1969;1:253.PubMedCrossRef
6.
Zurück zum Zitat Cameron OG, Kronfol Z, Greden JF, Carroll BJ. Hypothalamic-pituitary-adrenocortical activity in patients with diabetes mellitus. Arch Gen Psychiatry. 1984;41:1090–5.PubMedCrossRef Cameron OG, Kronfol Z, Greden JF, Carroll BJ. Hypothalamic-pituitary-adrenocortical activity in patients with diabetes mellitus. Arch Gen Psychiatry. 1984;41:1090–5.PubMedCrossRef
7.
Zurück zum Zitat Hudson JI, Hudson MS, Rotschils AJ, Vignati L, Schatzberg AF, Melby JC. Abnormal results of dexamethasone suppression tests in nondepressed patients with diabetes mellitus. Arch Gen Psychiatry. 1984;41:1086–9.PubMedCrossRef Hudson JI, Hudson MS, Rotschils AJ, Vignati L, Schatzberg AF, Melby JC. Abnormal results of dexamethasone suppression tests in nondepressed patients with diabetes mellitus. Arch Gen Psychiatry. 1984;41:1086–9.PubMedCrossRef
8.
Zurück zum Zitat Tsigos C, Young RJ, White A. Diabetic neuropathy is associated with increased activity of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab. 1993;76:554–8.PubMedCrossRef Tsigos C, Young RJ, White A. Diabetic neuropathy is associated with increased activity of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab. 1993;76:554–8.PubMedCrossRef
9.
Zurück zum Zitat Liu H, Bravata DM, Cabaccan J, Raffa H, Ryzen E. Elevated late-night salivary cortisol levels in elderly male type 2 diabetic veterans. Clin Endocrinol (Oxf). 2005;63:642–9.CrossRef Liu H, Bravata DM, Cabaccan J, Raffa H, Ryzen E. Elevated late-night salivary cortisol levels in elderly male type 2 diabetic veterans. Clin Endocrinol (Oxf). 2005;63:642–9.CrossRef
10.
Zurück zum Zitat Roy MS, Roy A, Brown S. Increased urinary free cortisol outputs in diabetic patients. J Diabetes Complicat. 1998;12:24–7.PubMedCrossRef Roy MS, Roy A, Brown S. Increased urinary free cortisol outputs in diabetic patients. J Diabetes Complicat. 1998;12:24–7.PubMedCrossRef
11.
Zurück zum Zitat Dacou-Voutetakis C, Peppa-Patrikiou M, Dracopoulou M. Urinary free cortisol and its nyctohemeral variations in adolescent and young adults with IDDM: relation to endothelin 1 and indices of diabetic angiopathy. J Pediatr Endocrinol. 1998;11:437–45.CrossRef Dacou-Voutetakis C, Peppa-Patrikiou M, Dracopoulou M. Urinary free cortisol and its nyctohemeral variations in adolescent and young adults with IDDM: relation to endothelin 1 and indices of diabetic angiopathy. J Pediatr Endocrinol. 1998;11:437–45.CrossRef
12.
Zurück zum Zitat Oltmanns KM, Dodt B, Raspe HH, Schweiger U, Born J, Fehm H, et al. Cortisol correlates with metabolic disturbances in a population study of type 2 diabetic patients. Eur J Endocrinol. 2006;154:325–31.PubMedCrossRef Oltmanns KM, Dodt B, Raspe HH, Schweiger U, Born J, Fehm H, et al. Cortisol correlates with metabolic disturbances in a population study of type 2 diabetic patients. Eur J Endocrinol. 2006;154:325–31.PubMedCrossRef
13.
Zurück zum Zitat Lee ZSK, Chan JCN, Yeung VTF, Chow CC, Lau MSW, Ko GTC, et al. Plasma insulin, growth hormone, cortisol, and central obesity among young Chinese type 2 diabetic patients. Diabetes Care. 1999;22:1450–7.PubMedCrossRef Lee ZSK, Chan JCN, Yeung VTF, Chow CC, Lau MSW, Ko GTC, et al. Plasma insulin, growth hormone, cortisol, and central obesity among young Chinese type 2 diabetic patients. Diabetes Care. 1999;22:1450–7.PubMedCrossRef
14.
Zurück zum Zitat Chiodini I, Adda G, Scillitani A, Coletti F, Morelli V, Di Lembo S, et al. Cortisol secretion in patients with type 2 diabetes: relationship with chronic complications. Diabetes Care. 2007;30:83–8.PubMedCrossRef Chiodini I, Adda G, Scillitani A, Coletti F, Morelli V, Di Lembo S, et al. Cortisol secretion in patients with type 2 diabetes: relationship with chronic complications. Diabetes Care. 2007;30:83–8.PubMedCrossRef
15.
Zurück zum Zitat Putigano P, Duini A, Toja P, Inviti C, Bonfanti S, Raedelli G, et al. Salivatory cortisol measurement in normal-weight, obese and anorectic women: comparison with plasma cortisol. Eur J Endocrinol. 2001;145:165–71.CrossRef Putigano P, Duini A, Toja P, Inviti C, Bonfanti S, Raedelli G, et al. Salivatory cortisol measurement in normal-weight, obese and anorectic women: comparison with plasma cortisol. Eur J Endocrinol. 2001;145:165–71.CrossRef
16.
Zurück zum Zitat Haffner SM, Gonzales C, Mietinen H, Kennedy E, Stern MP. A prospective analysis of the HOMA model. The Mexico city diabetes study. Diabetes Care. 1996;19:1138–41.PubMedCrossRef Haffner SM, Gonzales C, Mietinen H, Kennedy E, Stern MP. A prospective analysis of the HOMA model. The Mexico city diabetes study. Diabetes Care. 1996;19:1138–41.PubMedCrossRef
17.
Zurück zum Zitat Ewing DJ, Clarke BF. Diagnosis and management of diabetic autonomic neuropathy. Br Med J. 1985;285:916–8.CrossRef Ewing DJ, Clarke BF. Diagnosis and management of diabetic autonomic neuropathy. Br Med J. 1985;285:916–8.CrossRef
18.
Zurück zum Zitat Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Green DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care. 1994;17:1281–9.PubMedCrossRef Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Green DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care. 1994;17:1281–9.PubMedCrossRef
19.
Zurück zum Zitat Chiodera P. Low-dose ovine corticotropin-releasing hormone stimulation test in diabetes mellitus with or without neuropathy. Metabolism. 1995;44:538–42.CrossRef Chiodera P. Low-dose ovine corticotropin-releasing hormone stimulation test in diabetes mellitus with or without neuropathy. Metabolism. 1995;44:538–42.CrossRef
20.
Zurück zum Zitat Akama SF, Cascio CS, Du JZ, Levin N, Dallman MF. Reset of feedback in the adrenocortical system: an apparent shift in sensitivity of adrenocorticotropin to inhibition by corticosterone between morning and evening. Endocrinology. 1986;119:2325–32.CrossRef Akama SF, Cascio CS, Du JZ, Levin N, Dallman MF. Reset of feedback in the adrenocortical system: an apparent shift in sensitivity of adrenocorticotropin to inhibition by corticosterone between morning and evening. Endocrinology. 1986;119:2325–32.CrossRef
21.
Zurück zum Zitat Pavlovcik RA, Phillips MI, Kappy MS, Raiyada MK. Insulin inhibits pyramidal neurons in hypocampal slices. Brain Res. 1984;309:187–91.CrossRef Pavlovcik RA, Phillips MI, Kappy MS, Raiyada MK. Insulin inhibits pyramidal neurons in hypocampal slices. Brain Res. 1984;309:187–91.CrossRef
22.
Zurück zum Zitat Jacobsen L, Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev. 1991;12:118–34.CrossRef Jacobsen L, Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev. 1991;12:118–34.CrossRef
23.
Zurück zum Zitat Fruehwald-Schuletes B, Kern W, Bong W, Wellhoener P, Kerner W, Born J, et al. Supraphysiological hyperinsulinemia acutely increases hypothalamic-pituitary-adrenal secretory activity in humans. J Clin Endocrinol Metab. 1999;84:3041–6.CrossRef Fruehwald-Schuletes B, Kern W, Bong W, Wellhoener P, Kerner W, Born J, et al. Supraphysiological hyperinsulinemia acutely increases hypothalamic-pituitary-adrenal secretory activity in humans. J Clin Endocrinol Metab. 1999;84:3041–6.CrossRef
24.
Zurück zum Zitat Chan O, Inouye K, Vranic M, Matthew SG. Hyperactivation of the hypothalamo-pituitary-adrenocortical axis in streptozotocin-diabetes is associated with reduced stress responsiveness and decreased pituitary and adrenal sensitivity. Endocrinology. 2002;143:1761–8.PubMedCrossRef Chan O, Inouye K, Vranic M, Matthew SG. Hyperactivation of the hypothalamo-pituitary-adrenocortical axis in streptozotocin-diabetes is associated with reduced stress responsiveness and decreased pituitary and adrenal sensitivity. Endocrinology. 2002;143:1761–8.PubMedCrossRef
25.
Zurück zum Zitat Chan O, Chan S, Inouye K, Shum K, Matthew SG, Vranic M. Diabetes impairs hypothalamo-pituitary-adrenal (HPA) response to hypoglycemia, and insulin treatment normalizes HPA but not epinephrine response. Diabetes. 2002;51:1681–9.PubMedCrossRef Chan O, Chan S, Inouye K, Shum K, Matthew SG, Vranic M. Diabetes impairs hypothalamo-pituitary-adrenal (HPA) response to hypoglycemia, and insulin treatment normalizes HPA but not epinephrine response. Diabetes. 2002;51:1681–9.PubMedCrossRef
26.
Zurück zum Zitat Kaye TB, Rubin RA, Goldfine AB, Rajamani K, Kinsley BT, Vischer UM, et al. Effect of glycemic control on the overnight dexamethasone suppression test in patients with diabetes mellitus. J Clin Endocrinol Metab. 1992;74:640–4.PubMedCrossRef Kaye TB, Rubin RA, Goldfine AB, Rajamani K, Kinsley BT, Vischer UM, et al. Effect of glycemic control on the overnight dexamethasone suppression test in patients with diabetes mellitus. J Clin Endocrinol Metab. 1992;74:640–4.PubMedCrossRef
27.
Zurück zum Zitat Fraser R, Ingram MC, Anderson NH, Morrison C, Davies E, Connell JMC. Cortisol effects on body mass, blood pressure, and cholesterol in the general population. Hypertension. 1999;33:1364–8.PubMedCrossRef Fraser R, Ingram MC, Anderson NH, Morrison C, Davies E, Connell JMC. Cortisol effects on body mass, blood pressure, and cholesterol in the general population. Hypertension. 1999;33:1364–8.PubMedCrossRef
28.
Zurück zum Zitat Reynolds RM, Labad J, Strachan MW, Braun A, Fowkes FG, Lee AJ, et al. Elevated fasting plasma cortisol is associated with ischemic heart disease and its risk factors in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. J Clin Endocrinol Metab. 2010;95:1602–8.PubMedCrossRef Reynolds RM, Labad J, Strachan MW, Braun A, Fowkes FG, Lee AJ, et al. Elevated fasting plasma cortisol is associated with ischemic heart disease and its risk factors in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. J Clin Endocrinol Metab. 2010;95:1602–8.PubMedCrossRef
29.
Zurück zum Zitat Convit A. Links between cognitive impairment in insulin resistance: an explanatory model. Neurobiol Aging. 2005;26(Suppl 1):31–5.PubMedCrossRef Convit A. Links between cognitive impairment in insulin resistance: an explanatory model. Neurobiol Aging. 2005;26(Suppl 1):31–5.PubMedCrossRef
30.
Zurück zum Zitat Bruehl H, Rueger M, Dziobek I, Sweat V, Tirsi A, Javier E, et al. Hypothalamic-pituitary-adrenal axis dysregulation and memory impairments in type 2 diabetes. J Clin Endocrinol Metab. 2007;92:2439–45.PubMedCrossRef Bruehl H, Rueger M, Dziobek I, Sweat V, Tirsi A, Javier E, et al. Hypothalamic-pituitary-adrenal axis dysregulation and memory impairments in type 2 diabetes. J Clin Endocrinol Metab. 2007;92:2439–45.PubMedCrossRef
31.
Zurück zum Zitat Bruehl H, Wolf OT, Sweat V, Tirsi A, Richardson S, Convit A. Modifiers of cognitive function and brain structure in middle-aged and elderly individuals with type 2 diabetes mellitus. Brain Res. 2009;1280:186–94.PubMedCrossRef Bruehl H, Wolf OT, Sweat V, Tirsi A, Richardson S, Convit A. Modifiers of cognitive function and brain structure in middle-aged and elderly individuals with type 2 diabetes mellitus. Brain Res. 2009;1280:186–94.PubMedCrossRef
Metadaten
Titel
Hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with type 2 diabetes and relations with insulin resistance and chronic complications
verfasst von
Ivana Prpić-Križevac, MD, PhD
Silvija Canecki-Varžić, MD
Ines Bilić-Ćurčić, M.D, PhD
Publikationsdatum
01.06.2012
Verlag
Springer Vienna
Erschienen in
Wiener klinische Wochenschrift / Ausgabe 11-12/2012
Print ISSN: 0043-5325
Elektronische ISSN: 1613-7671
DOI
https://doi.org/10.1007/s00508-012-0191-4

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