SALIVARY CORTISOL FLUCTUATIONS AND HYPERGLICEMIC STRESS IN PATIENTS WITH ABDOMINAL OBESITY

Transcription

1 SALIVARY CORTISOL FLUCTUATIONS AND HYPERGLICEMIC STRESS IN PATIENTS WITH ABDOMINAL OBESITY Corina Dima-Cozma 1, Andreea Szalontay 2, Cristina Ghiciuc 3, Sebastian Cozma 4, Francesca Romana Patacchioli 5 1 Department of Internal Medicine, Cardiovascular Rehabilitation Clinic, Faculty of Medicine 2 6 th Psychiatric Clinic, Faculty of Dental Medicine 3 Department of Pharmacology, Faculty of Medicine 4 E.N.T. Clinic, Rehabilitation Hospital, Faculty of Dental Medicine University of Medicine and Pharmacy "Grigore T. Popa" - Iasi, Romania 5 Department of Physiology and Pharmacology, 2nd Medical School, Sapienza University of Rome, Italy *Corresponding author: Corina Dima-Cozma, PhD, Department of Internal Medicine Cardiovascular Rehabilitation Clinic cdimacozma@yahoo.com ABSTRACT Objectives We investigated a possible relationship between the onset of hyperglycaemia in prediabetes and the perturbations of hypothalamo-pituitary-adrenocortical axis. Material and methods The study included 20 risk factors for diabetes mellitus like abdominal obesity or positive family history. All patients underwent oral glucose tolerance test (OGTT) and 4 concomitant determinations of salivary cortisol levels, in basal condition, at wakening, and at 1, 2, and respectively 3 hours after oral administration of 75 grams of glucose. Results The evolution of salivary cortisol levels in the morning ) it Conclusion The simple method of salivary cortisol measurement could become a useful tool for the HPA axis functionality screening. Key words: obesity, hyperglycaemia, salivary cortisol INTRODUCTION Glucocorticoids are stress hormones with complex metabolism and actions. They have numerous physiological actions that have been involved in metabolic, inflammatory, cardiovascular and behavioural processes. In addition, clinical findings suggest that the levels of cortisol are elevated in primary or metabolic syndrome, pathologic situations that cumulates many cardiovascular risk factors like central obesity, hypertension, hyperlipidaemia, insulin resistance and glucose intolerance (1). Recently, much attention has focused on the role of cortisol metabolism in the pathogenesis of obesity. A study in the general population indicates that even modestly increased cortisol levels contribute to obesity and weight loss led to lower plasma cortisol and reduced insulin resistance (1, 2, 3). Tissue-specific glucocorticoid metabolism is also very important in the determinism of obesity, diabetes and insul - hydroxy- - 17

2 HSD1) is a bidirectional enzyme, highly expressed in liver, adipose tissue, and muscle, who can generate the active glucocorticoid cortisol from inactive cortisone or inactivating cortisol to cor - HSD1 inhibitors administered to rodents and primates decrease local glucocorticoid generation improve glucose tolerance, increase insulin sensitivity and may promote weight loss (4). Basal hypothalamo-pituitary-adrenal (HPA) function is up regulated in uncontrolled or poorly controlled diabetes, and also in stress exposure (5). Our study measured the fluctuations of salivary cortisol in the situations of oral glucose tolerance test induced hyperglycaemia, knowing that salivary cortisol level exhibits a similar trend with circulating cortisol level (6). MATERIAL AND METHODS The study included 20 patients (10 We recruited patients who agree to participate in the study by informed consent, younger than 65 years, and we excluded patients with a long history of diabetes and those with anxiety or depression (Hamilton score for anxiety and depression was < 17). Clinical examination revealed the presence of cardiovascular and metabolic risk factors: positive family history for diabetes and than 4000 grams, obesity, and dyslipidaemia. Body mass index (BMI) was calculated as weight divided by the height squared (kg/m 2 ) and the abdominal circumference was measured midway between the lower costal and the iliac crest. For all the patients the hyperglycaemia was induced by a standard OGTT, performed in the day after clinical assessment, and glycaemia was measured on fasting and 3 times every one hour, after a standardised lunch of 75 grams of glucose. The assessment of cortisol was done in the same time with glucose measurements, using a sampling device called Salivette, that consist of a small cotton-wool tampon inside a centrifugation tube, produced by Sarstedt, Germany. The collection of saliva. For a correct saliva collection the cotton tampon is keep in the mouth for about 2 minutes, moving it without chewing. The tampon must be put away in the test tube with the attention to close it very well. The tubes were centrifuged 15 minutes at 2000 r.p.m. The cortisol was measured for the rest of 8 patients, by a competitive immunoassay technique, performed in the Laboratory of the Physiology and Pharmacology from University Sapienza of Rome. Medium values and standard deviation were calculated for all numerical parameters. RESULTS The analysis of anthropometric parameters showed that 6 patients were supraponderals, 7 with grade I of obesity and 7 with grade II of obesity (mean value of BMI kg/m 2 ), most of the patients with abdominal obesity (abdominal circumference - AC cm). Between the patients with hyperglycaemia, at 12 patients the levels of glycaemia exceeded 200 after 2 hours being characterized as diabetes mellitus. The descriptive data of the patients and the medium values of the glycaemia (BG) and salivary cortisol (SC) fasting and in the next 3 hours after administration of 75 grams of glucose are presented below (table 1 and 2). Central obesity is a major pathogenic factor in the metabolic syndrome and it is encouraging that only a modest loss of 5-10% of body weight in obese patients is associated with preferential mobilization of visceral adipose tissue (VAT) (7). We represented the age (Fig. 1), BMI (Fig. 2) and the predisposition of central obesity (Fig. 3). Several papers have suggested many 18

3 correlations of increased glucocorticoid metabolism with hyperinsulinism, hyperglycaemia and hypertension. The adrenalectomy resulted in significantly reduced plasma insulin, glucose and triglyceride levels (8). In our study, most of the patients had abnormal OGTT, 12 with diabetes mellitus. Usually the trend of cortisol concentrations is decreasing after the peak registered in the first hours of the morning. In patients with disglycaemic risk and obesity, the administration of high dose of glucose was followed by a new ascendant trend of salivary concentrations of cortisol for almost all patients and for medium values (Fig. 4, 5, 6, 7). Parameter (Patients = 20) Age (years) BMI (kg/m 2 ) AC (cm) Table 1. The descriptive data of the patients Fig. 1. Age distribution in studied patients Fig. 2. BMI distribution in studied patients Fig. 3. AC distribution in studied patients Parameter (Patients = 20) BG1 (7:30) BG2 (8:30) BG3 (9:30) BG4 (10:30) SC1 (7:30) SC2 (8:30) Table 2. Medium values of glycaemia and cortisol SC3 (9:30) SC4 (10:30) Fig. 4. The values of glycaemia at the OGTT DISCUSSIONS In the last years, saliva collection is an accepted non-invasive alternative to plasma determinations of cortisol. In a normal diurnal cortisol pattern, cortisol levels are high in the morning and decrease at 75% or less after Fig. 5. The salivary cortisol levels 16:00 hour to midnight (9). Other studies showed a good correlation between total urinary glucocorticoids metabolites and the number of features of the metabolic syndrome. Stress-induced cortisol response is consistently correlated with obesity (1, 10). 19

4 Fig 6. The average values of glycaemia The metabolic effects of glucocorticoids are mediated by several mechanisms: - in liver increase the activities of enzymes involved in fatty acid synthesis and promotes the secretion of lipoproteins; - induce hepatic gluconeogenic pathway; - hepatic glucose output is increased; - in adipose tissue promote the differentiation of pre-adipocytes to adipocytes, which could lead to increased body fat mass; - mediate reduced insulin sensitivity in liver and muscle (11, 12). Prolonged elevated cortisol levels lead to a redistribution of body fat with truncal and abdominal obesity which promote hyperinsulinemia and high cardiovascular risk (7, 13). Our determinations showed that the peak of hyperglycaemia at the third moment of the OGTT was related to a mild elevation of salivary cortisol, but not in all patients. The abnormalities of cortisol secretion that are Fig. 7. The average values of salivary cortisol described in the onset of diabetes and prediabetes are most likely associated with abdominal obesity and insulin resistance and abdominal obesity may be an indicator of a perturbation of the HPA axis (7, 9). CONCLUSION Hyperglycaemia is one of the metabolic disturbances induced by glucocorticoid but it is also a metabolic stress possibility in the patients with obesity and metabolic syndrome. Nowadays is more evident that stressful work, with circadian misalignment, is associated with increased risk of obesity, diabetes and cardiovascular disease. Some authors reported decrease in leptin, increase in glucose and insulin, increase in mean arterial blood pressure and reduced sleep efficiency (14). This simple method could become a useful tool screening about HPA axis functionality. REFERENCES 1. Wang M., The role of glucocorticoid action in the pathophysiology of the metabolic syndrome. Nutrition Metabolism 2005; 2:3, doi: / Reinehr T., Andler W., Cortisol and its relation to insulin resistance before and after weight loss in obese children. Horm Res 2004; 62(3): Fraser R., Ingram M.C., Anderson N.H., Morrison C., Davies E., Connell J.M., Cortisol effects on body mass, blood pressure, and cholesterol in the general population. Hypertension 1999; 33(6): Tomlinson J.W., Finney J., Gay C., Hughes B.A., Hughes S.V., Stewart P.M., Impaired glucose tolerance and insulin resistance are associated with increased -hydroxysteroid -reductase activity. Diabetes 2008; 57: Chan O., Inouye K., Akirav E.M., Park E., Riddell M.C., Matthews S.G., Vranic M., Hyperglycemia does not increase basal hypothalamo-pituitary-adrenal activity in diabetes but it does impair the HPA 20

5 response to insulin-induced hypoglycemia. Am J Physiol Regul Integr Comp Physiol 2005; 289: R235-R Laudat M.H., Cerdas S., Fournier C., Guiban D., Guilhame B., Luton J.P., Salivary cortisol measurement: a practical approach to assess pituitary-adrenal function. J Clin Endocrinol Metab 1998; 66: Freedland E.S., Role of a critical visceral adipose tissue threshold (CVATT) in metabolic syndrome: implications for controlling dietary carbohydrates: a review. Nutrition Metabolism 2004; 1:12 doi: / Freedman M.R., Horwitz B.A., Stern J.S., Effect of adrenalectomy and glucocorticoid replacement on development of obesity., Am J Physiol 1986; 250 (4 Pt 2): R595-R pituitary-adrenal axis activity as a predictor of cardiovascular disease, type 2 diabetes and stroke. J Intern Med 2000; 247: Reynolds R.M., Walker B.R., Sydall H.E., Whorwood C.B., Wood P.J., Phillips D.I., Elevated plasma cortisol in glucose-intolerant men: differences in responses to glucose and habituation to venepuncture. J Clin Endocrinol Metab 2001; 86(3): Samuel V.T., Liu Z.X., Qu X., Elder B.D., Bilz S., Befroy D., Romanelli A.J., Shulman G.I., Mechanism of hepatic insulin resistance in nonalcoholic fatty liver disease. J Biol Chem 2004; 279(31): Hollingdal M., Juhl C.B., Dall R., Sturis J., Veldhuis J.D., Schmitz O., Porksen N., Glucocorticoid induced insulin resistance impairs basal but not glucose entrained high-frequency insulin pulsatility in humans. Diabetologia 2002; 45(1). 13. secretion by dexamethasone in relation to body fat distribution: a dose-response study. Obes Res 1996; 4: Scheer F.A., Hilton M.F., Mantzoros C.S., Shea S.A., Adverse metabolic and cardiovascular consequences of circadian misalignement. PNAS 2009; 106(11):