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      Effects of caloric restriction and low glycemic index diets associated with metformin on glucose metabolism and cortisol response in overweight/obese subjects: a case series study

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          Abstract

          Background

          To determine whether cortisol secretion and glucocorticoid receptors in lymphocytes and monocytes are altered in patients with impaired glucose tolerance, and whether treatment with a hypocaloric diet and metformin could interfere with these aspects.

          Methods

          This is an analytical, interventional, case series study. Patients with impaired glucose tolerance were included. They received 500 mg of metformin twice daily and followed a low glycemic index diet for 16 weeks. Cortisol levels were assessed at 8:00 A.M. before and after use of 0.25 mg of dexamethasone at 11:00 P.M. the day before.

          Results

          Sixteen subjects (9 men) were included. Normal basal levels of cortisol and adequate responses to the low dose of dexamethasone were observed before and after treatment. There was no significant correlation between the parameters evaluated and cortisol levels. Nevertheless, there was a strong correlation between the number of glucocorticoid receptors, BMI (r = 0.88; p = 0.02), and insulin AUC (r = 0.94; p = 0.005) before treatment; after treatment, all these associations ceased to exist.

          Conclusion

          The cortisol secretion remained normal in the group of patients with impaired glucose tolerance. Treatment with metformin and diet did not change this condition. However, glucocorticoid receptor number had a strong correlation with insulin, due to insulin resistance, but this characteristic was lost after treatment.

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          Most cited references39

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          Molecular mechanism of action of metformin: old or new insights?

          Metformin is the first-line drug treatment for type 2 diabetes. Globally, over 100 million patients are prescribed this drug annually. Metformin was discovered before the era of target-based drug discovery and its molecular mechanism of action remains an area of vigorous diabetes research. An improvement in our understanding of metformin’s molecular targets is likely to enable target-based identification of second-generation drugs with similar properties, a development that has been impossible up to now. The notion that 5' AMP-activated protein kinase (AMPK) mediates the anti-hyperglycaemic action of metformin has recently been challenged by genetic loss-of-function studies, thrusting the AMPK-independent effects of the drug into the spotlight for the first time in more than a decade. Key AMPK-independent effects of the drug include the mitochondrial actions that have been known for many years and which are still thought to be the primary site of action of metformin. Coupled with recent evidence of AMPK-independent effects on the counter-regulatory hormone glucagon, new paradigms of AMPK-independent drug action are beginning to take shape. In this review we summarise the recent research developments on the molecular action of metformin.
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            Obesity: preventing and managing the global epidemic

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              Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities.

              Abdominal obesity has been suggested to be associated with perturbations of the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. In a population of 51-yr-old men (n = 284) salivary cortisol concentrations were determined on repeated (n = 7) occasions over a random working day, and perceived stress was reported in parallel. Cortisol values were then related to reported stress (stress-related cortisol). A standardized lunch was used as a physiological challenge. A low dose (0.5 mg) dexamethasone suppression test was also performed as well as determinations of testosterone and insulin-like growth factor I (IGF-I). Body mass index [weight (kilograms)/height (meters)2]; waist/hip circumference ratio (WHR); sagittal trunk recumbent diameter (D); fasting insulin; blood glucose; triglycerides; and total, low density (LDL), and high density (HDL) lipoprotein cholesterol were also determined. Cortisol concentrations were highest in the morning, and lunch was followed by a peak (P = 0.044). Two types of diurnal cortisol curves were identified, one characterized by a high variability with high morning values, and another with low variability and low morning values. Both correlated strongly with suppression of salivary cortisol by dexamethasone (P < 0.001). Stress-related cortisol secretion was associated with D (P = 0.051), low IGF-I (P = 0.006), and diastolic blood pressure (P = 0.078). When the type of diurnal cortisol curve was taken into consideration by statistical weighting, stress-related cortisol secretion in subjects with high variability showed associations with testosterone (P < 0.001), D, total and LDL cholesterol, diastolic blood pressure (P < 0.001), fasting insulin (P = 0.039), and glucose (P = 0.030) as well as, negatively, triglycerides (P < 0.001). When weighted for a low variability of diurnal cortisol secretion, stress-related cortisol secretion showed strong negative relationships with IGF-I, testosterone, and HDL. Furthermore, strong, consistent relationships (all P < 0.001) were found with obesity factors (body mass index, WHR, and D), and with metabolic (insulin, glucose, triglycerides, and total and LDL cholesterol) as well as hemodynamic variables (systolic and diastolic blood pressure and heart rate). These results clearly show interactions between diurnal cortisol secretion related to perceived stress and anthropometric, endocrine, metabolic, and hemodynamic variables. This seems to occur with apparently normal regulation of the HPA axis (high morning peaks and variability as well as dexamethasone suppression of cortisol), where other endocrine variables are not affected. With a low diurnal cortisol variation and blunted dexamethasone suppression, indicating abnormal regulation of the HPA axis, perceived stress-dependent cortisol values were strongly related to perturbations of other endocrine axes as well as abdominal obesity with metabolic and hemodynamic abnormalities. Perturbations of the regulations of the HPA axis such as those described in combination with low dexamethasone suppressibility are known to follow long term overactivation of the axis by factors such as environmental stress.
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                Author and article information

                Contributors
                lacasulari@unb.br
                roxomotta@ambr.org.br
                fabio.celotti@unimi.it
                vinicius.fabio@gmail.com
                caioedureis@gmail.com
                thmdacosta@gmail.com
                Journal
                Diabetol Metab Syndr
                Diabetol Metab Syndr
                Diabetology & Metabolic Syndrome
                BioMed Central (London )
                1758-5996
                22 July 2015
                22 July 2015
                2015
                : 7
                : 65
                Affiliations
                [ ]Unit of Endocrinology, University Hospital Brasilia, University of Brasilia, Brasilia, Brazil
                [ ]Dipartimento di Scienze Farmacologiche e Biomolecolari, Sezione di Biomedicina ed Endocrinologia, Università di Milano, Milan, Italy
                [ ]Postgraduate course in Health Sciences, University of Brasilia, Brasilia, Brazil
                [ ]Department of Nutrition, School of Health Sciences, University of Brasilia, Brasilia, Brazil
                [ ]CLINEN – Clínica de Neurologia e Endocrinologia. SCN quadra 1, bloco F, Ed. America Office Tower, sala 1111, Brasília, DF 70711-905 Brazil
                Article
                57
                10.1186/s13098-015-0057-9
                4533768
                3488dec9-9b81-4ba2-9382-01fb8a8fa2ad
                © Casulari et al. 2015

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 14 January 2015
                : 23 June 2015
                Categories
                Research
                Custom metadata
                © The Author(s) 2015

                Nutrition & Dietetics
                diabetes,glucose intolerance,calorie-restricted diet,metformin,cortisol,receptor
                Nutrition & Dietetics
                diabetes, glucose intolerance, calorie-restricted diet, metformin, cortisol, receptor

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