International publications

2020 Jan 25;114:104591. doi: 10.1016/j.psyneuen.2020.104591.

Maternal chronic stress correlates with serum levels of cortisol, glucose and C-peptide in the fetus, and maternal non chronic stress with fetal growth.

INTRODUCTION:During pregnancy, maternal stressors cause changes in both maternal and fetal HPA axes. We therefore investigated the impact of maternal non chronic and chronic stress on fetal glucose metabolism and growth, and serum levels of cortisol in the fetus.

MATERIALS AND METHODS:Normal weight pregnant women (n = 192; mean ± SD 27.9 ± 4.2 years old, and; 26.9 ± 2.4 kg/m²) were assessed during the 2nd and 3rd trimester with anthropometry, fetal ultrasound, blood samples for serum CRH, cortisol and IL6, and STAI trait and state stress questionnaires. We measured serum cortisol, insulin and c-peptide, and plasma glucose from cord blood. Neonates underwent anthropometry at the 3rd post-delivery day.

RESULTS:In both 2nd and 3rd trimesters, women with STAI trait scores ≥40 had significantly greater levels of fasting serum CRH and cortisol than those with STAI trait scores<40. 2nd trimester: STAI trait scores correlated positively with cord blood glucose and c-peptide. Maternal serum CRH correlated negatively with U/S fetal biparietal head diameter, while serum cortisol correlated positively with abdominal circumference. Maternal serum IL6, CRH and cortisol all correlated positively with birth waist circumference. 3rd trimester: Women with STAI state scores ≥40 had fetuses with larger U/S abdominal and smaller head circumferences compared to those of women with STAI scores <40. Women with STAI trait scores ≥40 had greater levels of cord blood cortisol, glucose, and c-peptide compared to women with STAI scores <40. STAI state scores ≥40 correlated positively with maternal CRH and U/S fetal abdominal circumference, and negatively with fetal head circumference and biparietal diameter. STAI trait scores correlated positively with cord blood c-peptide, glucose, insulin and cortisol. Maternal serum levels of CRH correlated positively with U/S fetal abdominal circumference and cord blood cortisol, and negatively with fetal head circumference and biparietal head diameter. Maternal serum levels of both CRH and cortisol correlated positively with cord blood c-peptide, glucose, and insulin. STAI trait was the best positive predictor of cord blood cortisol, glucose and c-peptide, whilst STAI state was the best positive and negative predictor, respectively of fetal abdominal circumference and fetal head circumference or biparietal diameter.

CONCLUSIONS:Increased maternal chronic stress (reflected by the STAI trait score) associates with increased fetal cortisol, glucose, c-peptide secretion and thus, insulin resistance. Maternal non chronic stress (STAI state) in the 3rd trimester associates with changes in fetal growth pattern, including increased and decreased measurements of fetal abdominal and head growth respectively.


2020 Mar 25:1-5.

Demographic, clinical and hormonal characteristics of patients with premature ovarian insufficiency and those of early menopause: data from two tertiary premature ovarian insufficiency centers in Greece.


The aim of the study was to compare demographic, hormonal and clinical parameters in patients with premature ovarian insufficiency (POI) and women with early menopause in Greece. One hundred thirty-nine women of Greek origin, aged 14-45 years, referring for oligomenorrhea and having elevated FSH concentrations were divided into three groups regarding the age of menstrual disturbances onset [POI1: </=30 years (n = 42); POI2: 31-39 years (n = 36); early menopause: 40-45 years (n = 61)]. The mean age of menstrual disturbances onset and that of diagnosis in all POI and early menopause patients were 28.7 years (28.7 ± 7.7) versus 42.1 years (42.1 ± 1.5) and 33.8 years (33.8 ± 7.2) versus 43.3 years (43.3 ± 1.4), respectively. POI patients and women with early menopause were diagnosed, respectively, five years and approximately four to six months later than the age of menstrual disturbances onset. Moreover, FSH2 (second confirmatory FSH measurement at 4-to-6-weeks interval) was greater in all POI patients than in early menopause women (55.4 ± 33.9 vs. 32.4 ± 19.4; p < .05) whereas mean age of menarche was greater in early menopause women than in POI patients (13 ± 1.3 vs. 12 ± 2.2; p < .05). Furthermore, FSH2 was increased in all POI and decreased in early menopause patients.


Mediators Inflamm. 2018 Dec 5;2018:8476217.

Association between Brain-Derived Neurotrophic Factor (BDNF) Levels in 2nd Trimester Amniotic Fluid and Fetal Development.

Antonakopoulos N, Iliodromiti Z, Mastorakos G, Iavazzo C, Valsamakis G, Salakos N, Papageorghiou A, Margeli A, Kalantaridou S, Creatsas G, Deligeoroglou E, Vrachnis N.

The development of the fetal nervous system mirrors general fetal development, comprising a combination of genetic resources and effects of the intrauterine environment. Our aim was to assess the 2nd trimester amniotic fluid levels of brain-derived neurotrophic factor (BDNF) and to investigate its association with fetal growth. In accordance with our study design, samples of amniotic fluid were collected from women who had undergone amniocentesis early in the 2nd trimester. All pregnancies were followed up until delivery and fetal growth patterns and birth weights were recorded, following which pregnancies were divided into three groups based on fetal weight: (1) AGA (appropriate for gestational age), (2) SGA (small for gestational age), and (3) LGA (large for gestational age). We focused on these three groups representing a reflection of the intrauterine growth spectrum. Our results revealed the presence of notably higher BDNF levels in the amniotic fluid of impaired growth fetuses by comparison with those of normal growth. Both SGA and macrosomic fetuses are characterized by notably higher amniotic fluid levels of BDNF (mean values of 36,300 pg/ml and 35,700 pg/ml, respectively) compared to normal-growth fetuses (mean value of 32,700 pg/ml). Though apparently small, this difference is, nevertheless, statistically significant (p value < 0.05) in SGA fetuses in the extremes of the distribution, i.e., below the 3rd centile. In conclusion, there is clear evidence that severe impairment of fetal growth induces the increased production of fetal brain growth factor as an adaptive mechanism in reaction to a hostile intrauterine environment, thereby accelerating fetal brain development and maturation.


J Diabetes Complications. 2019 Jun 27:107401.

Increased risk of non-alcoholic fatty liver disease in women with gestational diabetes mellitus: A population-based cohort study, systematic review and meta-analysis.

Lavrentaki A, Thomas T, Subramanian A, Valsamakis G, Thomas N, Toulis KA, Wang J, Daly B, Saravanan P, Sumilo D, Mastorakos G, Tahrani AA, Nirantharakumar K.

AIMS: Non-Alcoholic Fatty Liver Disease (NAFLD) is one of the leading causes of liver transplantation in the West. This study seeks to examine whether women with gestational diabetes mellitus (GDM) are at increased risk of developing NAFLD compared to women without GDM.

METHODS: We conducted a population-based retrospective matched-controlled cohort study utilising The Health Improvement Network (THIN), a large primary care database representative of the United Kingdom population, between 01/01/1990 to 31/05/2016 followed by systematic review of available literature. The study population included 9640 women with GDM and 31,296 controls without GDM, matched for age, body mass index (BMI) and time of pregnancy. All study participants were free from NAFLD diagnosis at study entry. Patients with GDM and patients developing NAFLD were identified by clinical codes.

RESULTS: The median (range) follow-up duration was similar in women with and without GDM (2.95 (1.21-6.01) vs 2.85 (1.14-5.75) years respectively). Unadjusted incidence rate ratio (IRR) for NAFLD development in women with vs without GDM was 3.28 (95% CI 2.14-5.02), which remained significant after adjustment for wide range of potential confounders (IRR 2.70; 95% CI 1.744-4.19). The risk of NAFLD in GDM remained high (IRR 2.46: 95% CI 1.51-4.00) despite women being censored after they developed type 2 diabetes. The meta-analysis of 3 studies (including the current study) showed increased NAFLD risk in women with vs without GDM (OR 2.60; 95% CI 1.90-3.57, I2=0%). As our study is based on routine clinical diagnosis of NAFLD, this study could potentially have underestimated the risk of NAFLD development.

CONCLUSIONS: Women with GDM are at increased risk of developing NAFLD in their later life compared to women without GDM regardless of the development of type 2 diabetes. Clinicians should have a low threshold to investigate women with history of GDM for the presence of NAFLD. Further studies to identify screening strategies are needed.

Sci Rep. 2018 Oct 24;8(1):15691.

Biochemistry, hormones and adipocytokines in prepubertal children born with IUGR evoke metabolic, hepatic and renal derangements.

Sidiropoulou EJ, Paltoglou G, Valsamakis G, Margeli A, Mantzou A, Papassotiriou I, Hassiakos D, Iacovidou N, Mastorakos G.

Children born with IUGR develop features of the metabolic syndrome and exhibit deranged markers of hepatorenal physiology. Metabolic and hepatorenal biochemistry and the rs9939609 FTO polymorphism were investigated in prepubertal children born with IUGR. Ninety-eight prepubertal children (46 IUGR and 52 AGA), subdivided in <5 years and >5 years old groups were included. Anthropometry; creatinine, eGFR, urea, AST, ALT, triglycerides, uric acid, total cholesterol, HDL-c, LDL-c, glucose, C-peptide, insulin and glucagon z-scores; HOMA-IR; leptin and adiponectin concentrations; rs9939609 FTO polymorphism frequency were measured. In males, weight and ALT were higher and adiponectin was lower, in IUGR < 5 years; C-peptide, insulin and leptin were higher in IUGR > 5 years; C-peptide was higher in all IUGR, than the respective AGA. In females, creatinine and triglycerides were higher in IUGR < 5 years old; creatinine was higher and eGFR was lower in all IUGR, than the respective AGA. In males and females, creatinine was higher in all IUGR, than the respective AGA; C-peptide, insulin and HOMA-IR were lower, and AST was higher in IUGR < 5 than in IUGR > 5 years old. FTO rs9939609 frequency did not differ between IUGR and AGA. In conclusion prepubertal males born with IUGR increased weight, insulin and leptin and decreased adiponectin, as compared to males born AGA, emerge as early metabolic syndrome characteristics. The concentrations of these hormones do not differ between prepubertal males and females born with IUGR. Weight control, healthy nutrition and physical exercise should be recommended to these children. The deranged renal (particularly evident in females below the age of 5) and liver biochemistry in prepubertal children born with IUGR suggests that hepatorenal derangements might commence in utero. Regular checkup of biochemical and lipid profile is recommended for all children born with IUGR.

Psychoneuroendocrinology. 2018 Sep 22;100:48-57.

Stress, female reproduction and pregnancy.

Valsamakis G, Chrousos G, Mastorakos G3

Stress is one of the commonest and underappreciated causes of reproductive frailty in women. The stress system leads to adaptive responses via mobilization of hormonal systems. Adaptability and resistance to stress are fundamental to life. The response to stressors depends on the type of stressor, the timing and duration of stress, the genetic predisposition, personality characteristics, and the way of coping with stress. The hypothalamic-pituitary-adrenal (HPA) axis has a direct inhibitory action on the hypothalamic-pituitary-ovarian (HPO) axis at multiple levels. Acute and chronic stress impairs reproduction, eventually acting on varying mechanisms. Undernutrition, over-training, and psychological stress contribute to hypothalamic amenorrhea via reduced HPO activity. In utero stress exposure is a significant predictor of subsequent adult telomere length. Some of the metabolic consequences of intrauterine growth restriction can be mitigated by ensuring early appropriate catch-up growth, while avoiding excessive weight gain if relative hypercortisolism is not installed. The effect of maternal stress on fetuses regarding fetal HPA axis responsiveness (increased or decreased) remains under investigation. Maternal stress and depression are associated with structural and functional changes of brain parts such as hippocampus. In utero stress modifies epigenetically components of the HPA axis which can be transmitted transgenerationally.

Endocrine. 2018 Apr;60(1):175-184.

Metabolic phenotype of male obesity-related secondary hypogonadism pre-replacement and post-replacement therapy with intra-muscular testosterone undecanoate therapy.

Dimitriadis GK, Randeva HS, Aftab S, Ali A, Hattersley JG, Pandey S, Grammatopoulos DK, Valsamakis G, Mastorakos G, Jones TH, Barber TM

AIM: To explore the metabolic phenotype of obesity-related secondary hypogonadism (SH) in men pre-replacement and post-replacement therapy with long-acting intramuscular (IM) testosterone undecanoate (TU).
METHODS: A prospective observational pilot study on metabolic effects of TU IM in male obesity-related SH (hypogonadal [HG] group, n = 13), including baseline comparisons with controls (eugonadal [EG] group, n = 15). Half the subjects (n = 7 in each group) had type 2 diabetes mellitus (T2D). Baseline metabolic assessment on Human Metabolism Research Unit: fasting blood samples; BodPod (body composition), and; whole-body indirect calorimetry. The HG group was treated with TU IM therapy for 6-29 months (mean 14.8-months [SD 8.7]), and assessment at the Human Metabolism Research Unit repeated. T-test comparisons were performed between baseline and follow-up data (HG group), and between baseline data (HG and EG groups). Data reported as mean (SD).
RESULTS: Overall, TU IM therapy resulted in a statistically significant improvement in HbA1C (9 mmol/mol, P = 0.03), with 52% improvement in HOMA%B. Improvement in glycaemic control was driven by the HG subgroup with T2D, with 18 mmol/mol [P = 0.02] improvement in HbA1C. Following TU IM therapy, there was a statistically significant reduction in fat mass (3.5 Kg, P = 0.03) and increase in lean body mass (2.9 kg, P = 0.03). Lipid profiles and energy expenditure were unchanged following TU IM therapy. Comparisons between baseline data for HG and EG groups were equivalent apart from differences in testosterone, SHBG and basal metabolic rate (BMR).
CONCLUSION: In men with obesity-related SH (including a subgroup with T2D), TU IM therapy improved glycaemic control, beta cell function, and body composition.

Psychoneuroendocrinology. 2017 Oct;84:11-16.

In pregnancy increased maternal STAI trait stress score shows decreased insulin sensitivity and increased stress hormones.

Valsamakis G, Papatheodorou DC, Chalarakis N, Vrachnis N, Sidiropoulou EJ, Manolikaki M, Mantzou A, Margeli A, Papassotiriou I, Chrousos GP, Mastorakos G.

INTRODUCTION: Chronic or acute stressors influence maternal and fetal Hypothalamus-Pituitary-Adrenal Axes (HPA) during pregnancy. In this study, the effect of maternal stress into maternal insulin sensitivity was investigated during pregnancy.
MATERIALS AND METHODS: Eighty-two pregnant women [aged 27.1±2.5 (mean±SD) yrs; BMI=25±2.2kg/m2] had at the 2nd and 3rd trimesters anthropometry, fasting blood samples (cortisol, Corticotropin Releasing Hormone (CRH), active amylin, Interleukin (IL6)), Oral Glucose Tolerance Test (OGTT) for glucose and insulin, state-trait anxiety inventory (STAI) trait and state questionnaires (for stress assessment).
RESULTS: Maternal cortisol, CRH and STAI state score increased significantly from 2nd to 3rd trimester. At these trimesters women with STAI trait scores ≥40 had greater serum cortisol and CRH concentrations and lower insulin sensitivity index (ISI) values than those with scores <40 while STAI trait score predicted negatively ISI. At the 2nd trimester maternal CRH concentrations correlated positively with maternal STAI state, Homeostatic Model Assessment Insulin Resistance (HOMAR), 1st and 2nd phase insulin secretion and negatively with ISI. STAI trait correlated negatively with ISI. STAI state correlated positively with maternal systolic blood pressure and HOMAR. At the 3rd trimester STAI trait correlated negatively and positively with ISI and STAI state, respectively, while STAI state correlated positively with HOMAR. In women with STAI state scores ≥40, these scores correlated positively with maternal CRH.
CONCLUSIONS: In normal pregnant women, enhanced long-term stress is associated with decreased insulin sensitivity. Both long- and short- term stress are associated with enhanced maternal HPA axis and increased placental CRH secretion.

Endocrine. 2017 Mar;55(3):925-933.

Interrelations among the adipocytokines leptin and adiponectin, oxidative stress and aseptic inflammation markers in pre- and early-pubertal normal-weight and obese boys.

Paltoglou G, Schoina M, Valsamakis G, Salakos N, Avloniti A, Chatzinikolaou A, Margeli A, Skevaki C, Papagianni M, Kanaka-Gantenbein C, Papassotiriou I, Chrousos GP, Fatouros IG, Mastorakos G.

PURPOSE: Presumed interrelationships among deleterious aspects of adipose tissue metabolism, inflammation, and cellular oxidative stress could be influenced by pubertal hormonal changes. They were investigated in pre- and early pubertal normal-weight and obese boys before and after an exercise bout employed as an energy demanding stimulator.
METHODS: Cross-sectional study. Seventy-six healthy pre- (mean ± SD, 10.6 ± 0.2 years old, 28 normal-weight, and 11 obese) and early-(11.4 ± 0.2 years old, 25 normal-weight, and 12 obese) pubertal boys, were blood-sampled before and after a bout of exercise at 70% VO2 max. Leptin, adiponectin, markers of inflammation (high-sensitivity C-reactive protein, high sensitivity IL-6), pro- (thiobarbitouric acid reactive substances, protein carbonyls) and anti- (glutathione, oxidized glutathione, glutathione peroxidase, catalase, total antioxidant capacity) oxidation were measured.
RESULTS: Baseline and post-exercise adiponectin was greater and leptin and high-sensitivity C-reactive protein were lower in normal-weight than in obese pre- and early pubertal boys, while high sensitivity IL-6 was greater in obese than in normal-weight pre-pubertal boys. In pre-pubertal obese boys: at baseline, high-sensitivity C-reactive protein correlated negatively with catalase; high sensitivity IL-6 correlated positively with protein carbonyls; Δ (difference during exercise) adiponectin correlated positively with Δcatalase. In all boys: at baseline, high sensitivity IL-6 correlated positively with leptin and was the best negative and the second best positive predictor for post-exercise glutathione/oxidized glutathione and protein carbonyls, respectively; leptin was the best negative predictor for post-exercise glutathione; waist to height ratio was the best positive predictor for post-exercise thiobarbitouric acid reactive substances; body mass index z-score and adiponectin were, respectively, the best positive predictor for post-exercise protein carbonyls and catalase.
CONCLUSIONS: In all subjects, leptin and adiponectin predict negatively and positively anti-oxidation, respectively, while high sensitivity IL-6 predicts positively and negatively pro- and anti-oxidation, respectively. High-sensitivity C-reactive protein is increased and negatively associated with anti-oxidation in pre-pubertal obese boys, suggesting that childhood obesity is associated with aseptic inflammation and oxidative stress.

Annu Rev Pharmacol Toxicol. 2017 Jan 6;57:585-605.

New Targets for Drug Treatment of Obesity.

Valsamakis G, Konstantakou P, Mastorakos G.

Antiobesity medical management has shown unsatisfactory results to date in terms of efficacy, safety, and long-term maintenance of weight loss. This poor performance could be attributed to the complexity of appetite regulation mechanisms; the serious drug side effects; and, crucially, the lack of profile-matching treatment strategies and individualized, multidisciplinary follow-up. Nevertheless, antiobesity pharmacotherapy remains a challenging, exciting field of intensive scientific interest. According to the latest studies, the future of bariatric medicine lies in developing drugs acting at multiple levels of the brain-gut axis. Currently, research is focused on the generation of combination treatments based on gut hormones in a way that mimics changes underlying surgically induced weight loss, in addition to centrally acting agents; these aim to restore energy balance disruptions and enhance energy expenditure. Collectively, the pharmacological resolution of obesity could potentially be achieved with combination regimens targeting different molecules and levels of the energy homeostasis system, in parallel with matching patients’ needs, resulting in a favorable metabolic profile.

J Matern Fetal Neonatal Med. 2016 Apr 19:1-10.

Dysregulation of 11beta-hydroxysteroid dehydrogenases: implications during pregnancy and beyond.

Konstantakou P, Mastorakos G, Vrachnis N, Tomlinson JW, Valsamakis G.

Glucococorticoids play a critical role in the developmental programing and fetal growth. Key molecules mediating and regulating tissue-specific glucocorticoid actions are 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 and 2 isozymes, both of which are expressed in the placenta and the fetal membranes. 11beta-HSD1 is implicated in the pathogenesis of metabolic syndrome and its dysregulation has been observed in pregnancy-related complications (pre-eclampsia, intrauterine growth restriction). Interestingly, preliminary clinical data have associated certain 11beta-HSD1 gene polymorphisms with hypertensive disorders in pregnancy, suggesting, if confirmed by further targeted studies, it’s potential as a putative prognostic marker. Animal studies and observations in humans have confirmed that 11beta-HSD2 insufficiency is related with pregnancy adversity (pre-eclampsia, intrauterine growth restriction, preterm birth). Importantly, down-regulation or deficiency of placental 11beta-HSD2 is associated with significant restriction in fetal growth and low-birth weight, and unfavorable cardio-metabolic profile in adulthood. The potential association of 11beta-HSD1 tissue-specific dysregulation with gestational diabetes, as well as the plausible utility of 11beta-HSD2, as a biomarker of pregnancy adversity and later life morbidity, are emerging areas of intense scientific interest and future investigation.

Hormones (Athens). 2015 Jul-Sep;14(3):345-57.

Effect of maternal obesity on pregnancy outcomes and long-term metabolic consequences.

Valsamakis G, Kyriazi EL, Mouslech Z, Siristatidis C, Mastorakos G.


Endocrinology. 2015 Aug;156(8):2863-71.

5α-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic Phenotype in Human Hepatocytes.

Nasiri M, Nikolaou N, Parajes S, Krone NP, Valsamakis G, Mastorakos G, Hughes B, Taylor A, Bujalska IJ, Gathercole LL, Tomlinson JW.

Glucocorticoids and androgens have both been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); androgen deficiency in males, androgen excess in females, and glucocorticoid excess in both sexes are associated with NAFLD. Glucocorticoid and androgen action are regulated at a prereceptor level by the enzyme 5α-reductase type 2 (SRD5A2), which inactivates glucocorticoids to their dihydrometabolites and converts T to DHT. We have therefore explored the role of androgens and glucocorticoids and their metabolism by SRD5A2 upon lipid homeostasis in human hepatocytes. In both primary human hepatocytes and human hepatoma cell lines, glucocorticoids decreased de novo lipogenesis in a dose-dependent manner. Whereas androgen treatment (T and DHT) increased lipogenesis in cell lines and in primary cultures of human hepatocytes from female donors, it was without effect in primary hepatocyte cultures from men. SRD5A2 overexpression reduced the effects of cortisol to suppress lipogenesis and this effect was lost following transfection with an inactive mutant construct. Conversely, pharmacological inhibition using the 5α-reductase inhibitors finasteride and dutasteride augmented cortisol action. We have demonstrated that manipulation of SRD5A2 activity can regulate lipogenesis in human hepatocytes in vitro. This may have significant clinical implications for those patients prescribed 5α-reductase inhibitors, in particular augmenting the actions of glucocorticoids to modulate hepatic lipid flux.

Pediatr Res. 2015 Aug;78(2):158-64.

Antioxidation improves in puberty in normal weight and obese boys, in positive association with exercise-stimulated growth hormone secretion.

Paltoglou G, Fatouros IG, Valsamakis G, Schoina M, Avloniti A, Chatzinikolaou A, Kambas A, Draganidis D, Mantzou A, Papagianni M, Kanaka-Gantenbein C, Chrousos GP, Mastorakos G.

BACKGROUND: Oxidative stress is associated with obesity while the evidence for the role of GH in pro- and antioxidation is inconclusive. This study investigates the relationships between growth hormone (GH), pro- and antioxidation in relation to obesity and puberty before and after an acute bout of exercise.

METHODS: In this case-control study, 76 healthy normal-weight and obese, prepubertal and pubertal boys underwent a blood sampling before and immediately after an aerobic exercise bout until exhaustion at 70% maximal oxygen consumption. Markers of prooxidation (thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PCs)) and antioxidation (glutathione (GSH), oxidized glutathione disulfide (GSSG), GSH/GSSG ratio, glutathione peroxidase (GPX), catalase, and total antioxidant capacity (TAC)) and hormones (GH, insulin-like growth factor (IGF)-1, IGF-BP-3, luteinizing hormone, follicle-stimulating hormone, and testosterone) were measured.

RESULTS: Baseline and postexercise TBARS and PCs were greater, while baseline GSH, GSH/GSSG ratio, GPX, and TAC were lower in obese than that in normal-weight participants. In all participants, waist was the best negative and positive predictor for postexercise GPX and TBARS, respectively. Baseline TAC was greater in pubertal than that in pre-pubertal participants. In all participants, baseline GH was the best negative predictor for postexercise PCs. Significant positive linear correlation exists between the exercise-associated GH, and GSSG increases in pubertal normal-weight boys.

CONCLUSIONS: Higher prooxidation and lower antioxidation were observed in obese boys, while antioxidation improves with puberty and postexercise, paralleling GH accentuated secretion.

Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000-.

2015 Apr 8.

New molecular targets for the Pharmacotherapy of Obesity.

Konstantinos L, Karavis M, Mastorakos G, Valsamakis G.


In: De Groot LJ, Beck-Peccoz P, Chrousos G, Dungan K, Grossman A, Hershman JM, Koch C, McLachlan R, New M, Rebar R, Singer F, Vinik A, Weickert MO, editors.

Obesity is a complex medical problem with to date poor pharmacotherapy-based management. Phentermine, benzphetamine, phendimetrazine, and diethylpropion, which are approved only for short-term use in the USA, and orlistat, which reduces fat absorption, have failed to combat the obesity epidemic. However, current insights provided by the new biology are leading to the development of novel anti-obesity drugs with central/anorexigenic effects. As such, combined phentermine and topiramate (Qsymia) and lorcaserin (Belviq) were both approved in 2012 by the FDA for the body weight management of adults who are obese as well as overweight, with risk factors such as high blood pressure, high cholesterol or diabetes. In late 2014 two more anti-obesity drugs also won approval for usage in clinical practice: the diabetes drug liraglutide (Saxenda), and combined bupropion and naltrexone (Contrave). Given that current drug therapy does not cure obesity but only achieves moderate reduction in weight loss, moreover with authority for use time-limited, and that when drug therapy is discontinued weight is expected to rise, the aim of current research is to develop more potent anti-obesity drugs while substantially improving the above parameters. This chapter provides information concerning potential molecular targets of the homeostatic system and new anti-obesity drugs at present in development. For compete coverage of related areas, visit

Clin Obes. 2014 Aug;4(4):209-19.

New molecular targets in the pathophysiology of obesity and available treatment options under investigation.


Valsamakis G, Lois K, Kumar S, Mastorakos G.


The pharmacotherapy of obesity has historically recorded an overall poor safety and efficacy profile largely because of the complex mechanisms involved in the pathophysiology of obesity. It is hoped that a better understanding of the regulation of body weight will lead us to the development of effective and safer drugs. Recent advances in our understanding of the regulation of energy homeostasis has allowed the design of novel anti-obesity drugs targeting specific molecules crucial for the modulation of energy balance, including drugs that induce satiety, modulate nutrient absorption or influence metabolism or lipogenesis. Almost a decade after the Food and Drug Administration approved the first weight loss medication, it recently approved two novel anti-obesity drugs Belviq (lorcaserin) and Qsymia (topiramate and phentermine), thus signalling the beginning of a new era in the pharmacotherapy of obesity. It is believed that the next generation of weight-loss drugs will be based on combination treatments with gut hormones in a manner that mimics the changes underlying surgically induced weight loss thus introducing the so called ‘bariatric pharmacotherapy’. An in-depth understanding of the interrelated physiological and behavioural effects of these new molecules together with the development of new treatment paradigms is needed so that future disappointments in the field of obesity pharmacotherapy may be avoided.

Early Hum Dev. 2014 Sep;90(9):487-92. doi: 10.1016/j.earlhumdev.2014.07.001.

Neonatal birth waist is positively predicted by second trimester maternal active ghrelin, a pro-appetite hormone, and negatively associated with third trimester maternal leptin, a pro-satiety hormone.

Valsamakis G, Papatheodorou DC, Naoum A, Margeli A Papassotiriou I, Kapantais E, Creatsas G, Kumar S, Mastorakos G


In pregnancy physiological mechanisms activated by maternal appetite contribute to adequate energy intake for the mother and for the fetus. The role of maternal appetite-related peptides and their possible association with neonatal energy stores and glucose metabolism have not been investigated as yet. The aim was to investigate, during pregnancy, the association of fasting maternal appetite-related hormones levels [ghrelin (active), GLP1 (active), total PYY and leptin] with neonatal waist, percent total body fat and insulin levels at birth.


Forty-two normal and thirty eight overweight women (mean±SD; age: 26.9±2.5years; pre-pregnancy BMI 26±2.2kg/m(2)) were seen during each of the three trimesters, had blood sampling and a 75g oral glucose tolerance test. At birth, neonates underwent anthropometry and cord blood sampling for c-peptide, glucose, insulin.


During all three trimesters maternal weight correlated positively with percent total neonatal body fat while during the second and third trimesters it correlated positively with birth weight. The second trimester maternal active ghrelin levels correlated positively with neonatal waist and were its best positive predictor. The third trimester maternal active ghrelin levels correlated positively with neonatal waist and negatively with percent total neonatal body fat, fetal cord blood insulin levels and were the best negative predictor of the latter. The third trimester maternal leptin levels correlated negatively with neonatal waist.


During pregnancy circulating maternal active ghrelin, a pro-appetite hormone, is associated with neonatal visceral energy storage (as expressed by neonatal waist). By inhibiting glucose-driven maternal insulin secretion, ghrelin might ensure adequate fasting glucose and nutrient supplies to the fetus while limiting overall fetal adipose tissue deposition.

Vrachnis N, Zygouris D, Iliodromiti Z, Daniilidis A, Valsamakis G, Kalantaridou S.

Probing the impact of sex steroids and menopause-related sex steroid deprivation on modulation of immune senescence.

Maturitas. 2014 Jul;78(3):174-178. doi: 10.1016/j.maturitas.2014.04.014. Epub 2014 May 1.


Immune senescence denotes the general decline in immune system function, characterized by a reduced immune response and an increased inflammatory state. Menopause is a natural change in a women’s life, the menopause-related low estrogen levels affecting many body functions, among them the immune system. Numerous human studies with menopausal women and animal models with surgically induced menopause show a clear impact of sex steroids in immune responses. Female superiority in vaccination response and predisposition to infections are eliminated after menopause, while during menopause inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α), Interleukins-1β, 6, 8 and 13 (IL-1β, IL-6, IL-8, IL-13) and Monocyte Chemoattractant Protein-1 (MCP-1) are increased, implying a molecular connection of sex steroid loss with immune senescence. Moreover, immune cells modify their number and function after the menopausal transition, this offering another explanation for immune senescence. Until now most of the existing studies have concluded that menopause plays an additional role to aging in immune senescence. While it is clear that we are as yet far from thoroughly understanding the molecular pathways connecting sex steroids and menopause with immune senescence, such knowledge is highly likely to enable future targeted interventions in treatment and prevention of age-related diseases in women.

Valsamakis G, Papatheodorou DC, Margeli A3, Bakoulas V, Kapantais E, Papassotiriou I, Creatsas G, Kumar S, Mastorakos G.

First trimester maternal BMI is a positive predictor of cord blood c-peptide levels while maternal visfatin levels is a negative predictor of birth weight.

Hormones (Athens). 2014 Jan;13(1):87-94.

OBJECTIVE: The role of first trimester maternal body mass index (BMI) and adipocytokines in cord blood c-peptide and birth weight in pregnancy was investigated.

DESIGN: Seventy non-diabetic pregnant Caucasian women were recruited. Anthropometry and measurements of fasting adipocytokines (visfatin, leptin, adiponectin), insulin and glucose were performed in each of the three trimesters. At birth, birth weight and cord blood c-peptide, glucose, insulin, visfatin, leptin, adiponectin and IL6 in each neonate were measured.

RESULTS: First trimester maternal BMI correlated positively with cord blood c-peptide (p=0.035, r=0.74) and negatively with cord blood visfatin (p=0.049, r=-0.67). First trimester HOMAR was negatively correlated with cord blood visfatin (p=0.037, r=-0.90) and negatively with cord blood leptin (p=0.031, r=0.90). First trimester maternal BMI was a positive predictor of cord blood c-peptide (p=0.007). First trimester maternal visfatin levels were negative predictors of birth weight (p=0.017).

CONCLUSIONS: We conclude that first trimester maternal BMI and serum visfatin seem to be strongly associated with fetal insulin secretion and final birth weight, respectively, suggesting a role of early-pregnancy maternal adipose tissue in the pregnancy metabolic environment.

Papatheodorou DC, Karagiannidis LK, Paltoglou G, Margeli A, Kaparos G, Valsamakis G, Chrousos GP, Creatsas G, Mastorakos G.

Pulsatile Interleukin-6 Leads CRH Secretion and Is Associated With Myometrial Contractility During the Active Phase of Term Human Labor.

J Clin Endocrinol Metab. 2013 Oct;98(10):4105-12. doi: 10.1210/jc.2012-4023. Epub 2013 Aug 8.

Conclusion: IL-6 and CRH are both secreted in a pulsatile fashion during the active phase of human labor. The time-integrated concentrations of the two hormones are positively correlated, with IL-6 leading CRH secretion. It appears, thus, that proinflammatory mediators may be direct and/or indirect promoters of placental CRH release. Furthermore, the secretion of IL-6, which is a myokine, seems to be associated positively with uterine contractility. Additional studies are needed to elucidate the combined effect of inflammation, placental CRH release, and/or the receptors of the latter in parturition.

Valsamakis G, Lois K, Kumar S, Mastorakos G.

Metabolic and other effects of pioglitazone as an add-on therapy to metformin in the treatment of polycystic ovary syndrome (PCOS).

Hormones (Athens). 2012 Jul;12(3):363-378.

Insulin resistance is a key pathogenic defect of the clustered metabolic disturbances seen in polycystic ovary syndrome (PCOS). Metformin is an insulin sensitizer acting in the liver and the peripheral tissues that ameliorates the metabolic and reproductive defects in PCOS. In addition, pioglitazone is an insulin sensitizer used in diabetes mellitus type 2 (T2DM), improving insulin resistance (IR) in adipose tissue and muscles. In T2DM, these drugs are also used as a combined treatment due to their “add-on effect” on insulin resistance. Although the beneficial role of troglitazone (a member of the thiazolidinediones (TZDs) family) in PCOS has been shown in the past, currently only pioglitazone is available in the market. A few small randomized controlled trials have directly compared the effectiveness of pioglitazone in women with PCOS, while there are a limited number of small studies that support the beneficial metabolic add-on effect of pioglitazone on metformin-treated PCOS women as compared to metformin or pioglitazone monotherapy. These findings suggest a potentially promising role for combined pioglitazone/metformin treatment in the management of PCOS in metformin-resistant patients. In view of recent concerns regarding pioglitazone usage and its associated health risk, we aim to compare the pros and cons of each drug regarding their metabolic and other hormonal effects in women with PCOS and to explore the possible beneficial effect of combined therapy in certain cases, taking into consideration the teratogenic effect of pioglitazone. Finally, we discuss the need for a randomized controlled trial that will evaluate the metabolic and other hormonal effects of combined metformin/pioglitazone treatment in PCOS with selective treatment targets.

Markopoulos MC, Valsamakis G, Kouskouni E, Boutsiadis A, Papassotiriou I, Creatsas G, Mastorakos G

Study of carbohydrate metabolism indices and adipocytokine profile and their relationship with androgens in polycystic ovary syndrome after menopause.

Eur J Endocrinol. 2012 Dec 10;168(1):83-90. doi: 10.1530/EJE-12-0550. Print 2013 Jan.

CONCLUSIONS: Early postmenopausal PCOS women are characterized by hyperinsulinemia but attenuated insulin resistance. PCOS status and waist circumference are predictors of hyperinsulinemia while insulin sensitivity correlates negatively with FAI. The differences reported in adipocytokine levels between PCOS and non-PCOS women in reproductive years seem to disappear after menopause.

Markopoulos MC, Rizos D, Valsamakis G, Deligeoroglou E, Grigoriou O, Chrousos GP, Creatsas G, Mastorakos G.

Hyperandrogenism in women with polycystic ovary syndrome persists after menopause.

J Clin Endocrinol Metab. 2011 Mar;96(3):623-31. doi: 10.1210/jc.2010-0130. Epub 2010 Dec 22.

CONCLUSIONS: In postmenopausal PCOS women, ACTH and cortisol responses to CRH are normal. Androgen levels at baseline are higher in PCOS than control women and remain increased after ACTH stimulation. The dexamethasone suppression results in postmenopausal PCOS women suggest that DHEAS and total T are partially of adrenal origin. Although the ovarian contribution was not fully assessed, increased Δ(4)A production suggests that the ovary also contributes to hyperandrogenism in postmenopausal PCOS women. In conclusion, postmenopausal PCOS women are exposed to higher adrenal and ovarian androgen levels than non-PCOS women.

Lois K, Valsamakis G, Mastorakos G, Kumar S.

The impact of insulin resistance on woman’s health and potential treatment options.

Ann N Y Acad Sci. 2010 Sep;1205:156-65. doi: 10.1111/j.1749-6632.2010.05646.x.

Abstract: Insulin resistance (IR) is causatively related to metabolic syndrome and type 2 diabetes, both of which increase the risk of adverse cardiovascular events; in women in particular, severe IR affects the reproductive system causing subfertility and health problems to the mother and the fetus. To date lifestyle modification is the mainstay of treatment, whereas antiobesity drugs and bariatric surgery have been shown to improve insulin sensitivity and many surrogate metabolic defects, real reduction in cardiovascular endpoints has yet to be proved. Increasing attention is being directed to the role of the central nervous system in the modulation of IR, as well as to the use of recombinant adipocytokines for IR management. The scope of this article is to cast light on the detrimental effects of IR on metabolism and the body systems in women as well as to highlight the current therapeutic approach, drugs in progress, and future therapeutic perspectives.

Vitoratos N, Vrachnis N, Valsamakis G, Panoulis K, Creatsas G.

Perinatal mortality in diabetic pregnancy.

Ann N Y Acad Sci. 2010 Sep;1205:94-8. doi: 10.1111/j.1749-6632.2010.05670.x.

Abstract: Perinatal mortality rate (PMR) is one of the most important perinatal health indicators. PMR in diabetic pregnancies varies throughout the world and is higher than the background PMR. The prevalence of pregestational diabetes is increasing and is associated with an elevated risk of congenital malformations, macrosomia, preeclampsia, and preterm delivery. The incidence of PMR in preexisting diabetes mellitus ranges considerably, with congenital abnormalities and preterm labor the main factors contributing to the higher PMR. Women with gestational diabetes mellitus or impaired glucose tolerance are a mixed group that may have low to a high PMR, especially if they require insulin in their pregnancy. All the known diabetic women should plan their pregnancies and optimize glycemic control periconceptually and throughout pregnancy, as this reduces the frequency of congenital abnormalities, obstetric complications, and perinatal mortality.

Valsamakis G, Kumar S, Creatsas G, Mastorakos G.

The effects of adipose tissue and adipocytokines in human pregnancy.

Ann N Y Acad Sci. 2010 Sep;1205:76-81. doi: 10.1111/j.1749-6632.2010.05667.x.

Abstract: During pregnancy, important changes take place in maternal metabolism because of the growing fetus and placental formation. The increase in insulin resistance during pregnancy is paralleled by the progressive increase of maternal adipose tissue deposition. This review examines the topography of fat mass deposition during pregnancy in relation to factors such as parity and maternal age that might affect this deposition. We also examine adipose tissue markers, such as pregravid weight and weight gain during pregnancy, and their effect on fetal growth and pregnancy outcomes. In addition, this review studies the possible effects of cytokines that are produced by adipose tissue and the placenta on maternal metabolism and its complications. Finally, we also consider the possible role of maternal adipocytokines and fetal adipocytokines on fetal growth.

Valsamakis G, Margeli A, Vitoratos N, Boutsiadis A, Sakkas EG, Papadimitriou G, Al-Daghri NM, Botsis D, Kumar S, Papassotiriou I, Creatsas G, Mastorakos G.

The role of maternal gut hormones in normal pregnancy: fasting plasma active glucagon-like peptide 1 level is a negative predictor of fetal abdomen circumference and maternal weight change.

Eur J Endocrinol. 2010 May;162(5):897-903. doi: 10.1530/EJE-10-0047. Epub 2010 Mar 1.

CONCLUSIONS: During pregnancy, maternal GLP1 might be involved in mechanisms that compensate for the pregnancy-related increase in glycemia and insulin resistance, suggesting a role of this peptide in maternal metabolism and weight and fetal growth.

Mastorakos G, Valsamakis G, Paltoglou G, Creatsas G.

Management of obesity in menopause: diet, exercise, pharmacotherapy and bariatric surgery.

Maturitas. 2010 Mar;65(3):219-24. doi: 10.1016/j.maturitas.2009.12.003. Epub 2009 Dec 30.

Abstract: Menopause is characterized by the progressive reduction of estrogens resulting to cessation of menses. It is associated with an increase of cardiovascular risk factors such as hyperglycemia, hypertension, dyslipidemia and of abdominal and/or selective visceral fat mass deposition. Obesity, a modern day epidemic, is promoted by an obesogenic environment that interacts with the genetic background. The result is a positive energy balance materialized by the accumulation of the adipose tissue. This process is marked by great individual variation. Obesity is also associated with the presence of cardiovascular risk factors. In this review, the main pathophysiologic processes for the increase of obesity in menopause and the possible effects of pre-menopausal obesity regarding the cessation of ovarian function are described. The interactions among the hypothalamic-pituitary-gonadal and -adrenal (stress system) axes and the environment are explored. Furthermore, the therapeutic means that a clinician can employ to help menopausal women to overcome the menopause-associated increase of their weight are developed.

Bawazeer NM, Al-Daghri NM, Valsamakis G, Al-Rubeaan KA, Sabico SL, Huang TT, Mastorakos GP, Kumar S.

Sleep duration and quality associated with obesity among Arab children.

Obesity (Silver Spring). 2009 Dec;17(12):2251-3. doi: 10.1038/oby.2009.169. Epub 2009 Jun 4.

Abstract: The link between sleep duration and obesity has been well established in adults, but several epidemiological studies revealed inconsistent findings in adolescents and younger children. This study aimed to investigate the relationship between sleep length and obesity in Saudi students. A total of 5,877 Saudi students, boys (55.2%) and girls (44.8%), aged between 10 and 19 years were randomly selected from elementary, intermediate, and secondary schools in different regions of Riyadh. A questionnaire on sleep behaviors was given. Anthropometry included BMI and waist and hip circumferences. Sleeping

Vitoratos N, Valsamakis G, Mastorakos G, Boutsiadis A, Salakos N, Kouskouni E, Creatsas G.

Pre- and early post-partum adiponectin and interleukin-1beta levels in women with and without gestational diabetes.

Hormones (Athens). 2008 Jul-Sep;7(3):230-6.

CONCLUSIONS: Gestational diabetes is a state of insulin resistance associated with altered levels of proinflammatory cytokines, increased IL-1beta and decreased adiponectin values. Both of these alterations might be attributed to placental pathology in pregnancies with GDM.

Dixon AN, Valsamakis G, Hanif MW, Field A, Boutsiadis A, Harte A, McTernan PG, Barnett AH, Kumar S.

Effect of the orlistat on serum endotoxin lipopolysaccharide and adipocytokines in South Asian individuals with impaired glucose tolerance.

Int J Clin Pract. 2008 Jul;62(7):1124-9. doi: 10.1111/j.1742-1241.2008.01800.x.

CONCLUSION: The increase in adiponectin levels in the orlistat group would suggest that orlistat may reduce the progression to type 2 diabetes in South Asian individuals by raising serum adiponectin. The finding that LPS levels are also reduced by orlistat and that this reduction correlates with the increase in adiponectin raises the possibility that the increase in adiponectin may be mediated via an effect on LPS levels.

Valsamakis G, Jones A, Chetty R, McTernan PG, Boutsiadis A, Barnett AH, Banerjee AK, Kumar S.

MRI total sagittal abdominal diameter as a predictor of metabolic syndrome compared to visceral fat at L4-L5 level.

Curr Med Res Opin. 2008 Jul;24(7):1853-60. doi: 10.1185/03007990802185757 . Epub 2008 May 27.

CONCLUSIONS: MRI-calculated total sagittal abdominal diameter is a non-validated MRI method that predicts the adverse metabolic profile of the ATPIII definition of the metabolic syndrome. Antero-posterior fat is a dimension of central fat that seems to be more closely associated with cardiovascular risk compared to visceral fat.

Hanif MW, Valsamakis G, Dixon A, Boutsiadis A, Jones AF, Barnett AH, Kumar S.

Detection of impaired glucose tolerance and undiagnosed type 2 diabetes in UK South Asians: an effective screening strategy.

Diabetes Obes Metab. 2008 Sep;10(9):755-62. Epub 2007 Oct 15.

CONCLUSION: We describe a simple, stepwise strategy in a community setting, based on a health questionnaire and anthropometric measurements, to explain about 50% of cases with IGT and diabetes and diagnose about 50% of cases from the population screened. We have also identified factors that predict the risk.

Mastorakos G, Valsamakis G, Papatheodorou DC, Barlas I, Margeli A, Boutsiadis A, Kouskouni E, Vitoratos N, Papadimitriou A, Papassotiriou I, Creatsas G.

The role of adipocytokines in insulin resistance in normal pregnancy: visfatin concentrations in early pregnancy predict insulin sensitivity.

Clin Chem. 2007 Aug;53(8):1477-83. Epub 2007 Jun 22.

CONCLUSIONS: During normal pregnancy of nonobese, nondiabetic women, adipose tissue increases, accompanied by a significant progressive increase of insulin resistance. Visfatin concentrations in the 1st trimester positively predict insulin sensitivity during the 2nd trimester. Body fat mass during 1st trimester of pregnancy is negatively associated with insulin sensitivity during the 2nd trimester and perhaps should be kept under control.

Valsamakis G, Kanaka-Gantenbein C, Malamitsi-Puchner A, Mastorakos G.

Causes of intrauterine growth restriction and the postnatal development of the metabolic syndrome.

Ann N Y Acad Sci. 2006 Dec;1092:138-47.

Abstract: The term intrauterine growth restriction (IUGR) is assigned to newborns with a birth weight and/or birth length below the 10th percentile for their gestational age and whose abdominal circumference is below the 2.5th percentile with pathologic restriction of fetal growth. IUGR is usually due to maternal, fetal, or placental factors. However, many IUGR cases have unknown underlying cause. Recent studies focus on new factors that can influence fetal development and birth outcome like the timing and the type of fetal nutrition, maternal psychosocial stress and personality variables, 11beta-hydroxysteroid dehydrogenase type 2 placental activity, the activity of the neuroendocrine system that mediates the effects of psychosocial stress, and the role of proinflammatory cytokines and of oxidative stress. Data have shown that IUGR is associated with a late life increased prevalence of metabolic syndrome, a condition associating obesity with hypertension, type 2 diabetes mellitus (DM2), and cardiovascular disease. Recent data demonstrated that the diabetes-associated mortality appears to be disproportionately concentrated among individuals of abnormal birth weight.

Kyrou I, Valsamakis G, Tsigos C.

The endocannabinoid system as a target for the treatment of visceral obesity and metabolic syndrome.

Ann N Y Acad Sci. 2006 Nov;1083:270-305.

Abstract: The endogenous cannabinoid system is a novel, remarkably elaborate physiological signaling system, comprising the recently identified endogenous cannabinoid ligands, their corresponding selective receptors, and the machinery of proteins and enzymes that is involved in their biosynthesis, release, transport, and degradation. This system extends widely in both the central nervous system (CNS) and the periphery and exhibits a variety of actions implicated in vital functions (e.g., behavioral, antinociceptive, neuroprotective, immunosuppressive, cardiovascular, and metabolic). Particular interest has been focused on the apparent participation of endocannabinoids in metabolic homeostasis by modulating the activity of CNS circuits that control food intake and energy expenditure, the neuroendocrine response of the stress system, and the metabolic functions of crucial peripheral tissues, such as the adipose tissue, the gastrointestinal tract, the liver, and the skeletal muscles. These effects are predominantly CB(1) receptor mediated and, thus, selective antagonists of this receptor subtype are being vigorously investigated as potential therapeutic agents for the treatment of various metabolic derangements (e.g., obesity, insulin resistance, dyslipidemia, and metabolic syndrome). The first selective CB(1) receptor antagonist, rimonabant, has already successfully completed phase III clinical trials as adjunctive obesity treatment, with significant improvements in several associated metabolic and cardiovascular risk factors that led to the recent approval of its clinical use by the Food and Drug Administration.

Valsamakis G, Chetty R, Anwar A, Banerjee AK, Barnett A, Kumar S.

Association of simple anthropometric measures of obesity with visceral fat and the metabolic syndrome in male Caucasian and Indo-Asian subjects.

Diabet Med. 2004 Dec;21(12):1339-45.

CONCLUSIONS: Waist circumference is a simple anthropometric parameter that best correlates with single slice MRI-scan, but sagittal diameter (measured using abdominal calipers) better predicts the adverse metabolic profile of the metabolic syndrome. Although there is considerable variation in abdominal fat topography between ethnic groups, and also within populations, sagittal diameter assessment is a technique that is simple and best predicts the metabolic syndrome.

Valsamakis G, Anwar A, Tomlinson JW, Shackleton CH, McTernan PG, Chetty R, Wood PJ, Banerjee AK, Holder G, Barnett AH, Stewart PM, Kumar S.

11beta-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus.

J Clin Endocrinol Metab. 2004 Sep;89(9):4755-61.

Abstract: Glucocorticoids play an important role in the pathogenesis of obesity and insulin resistance. Impaired conversion of cortisone (E) to cortisol (F) by the type 1 isoenzyme of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) in obesity may represent a protective mechanism preventing ongoing weight gain and glucose intolerance. We have studied glucocorticoid metabolism in 33 male subjects with type 2 diabetes mellitus [age, 44.2 +/- 13 yr; body mass index (BMI), 31.1 +/- 7.5 kg/m(2) (mean +/- sd)] and 38 normal controls (age, 41.4 +/- 14 yr; BMI, 38.2 +/- 12.8 kg/m(2)). Circulating F:E ratios were elevated in the diabetic group and correlated with serum cholesterol and homeostasis model assessment-S. There was no difference in 11beta-HSD1 activity between diabetic subjects and controls. In addition, 11beta-HSD1 activity was unaffected by BMI in diabetic subjects. However, in control subjects, increasing BMI was associated with a reduction in the urinary tetrahydrocortisol+5alpha-tetrahydrocortisol:tetrahydrocortisone ratio (P < 0.05) indicative of impaired 11beta-HSD1 activity. The degree of inhibition correlated tightly with visceral fat mass. Changes in 11beta-HSD1 activity could not be explained by circulating levels of adipocytokines. Impaired E to F metabolism in obesity may help preserve insulin sensitivity and prevent diabetes mellitus. Failure to down-regulate 11beta-HSD1 activity in patients with diabetes may potentiate dyslipidemia, insulin resistance, and obesity. Inhibition of 11beta-HSD1 may therefore represent a therapeutic strategy in patients with type 2 diabetes mellitus and obesity.

Valsamakis G, McTernan PG, Chetty R, Al Daghri N, Field A, Hanif W, Barnett AH, Kumar S.

Modest weight loss and reduction in waist circumference after medical treatment are associated with favorable changes in serum adipocytokines.

Metabolism. 2004 Apr;53(4):430-4.

Abstract: Modest weight loss if maintained is associated with significant metabolic benefits and reduction in cardiovascular risk. Adipose tissue secretes cytokines believed to contribute to the pathogenesis of insulin resistance and cardiovascular risk. We therefore observed the effect of modest weight loss on serum adipocytokines and their relationship with changes in anthropometric and metabolic parameters within a period of 6 months in the setting of a routine obesity hospital clinic after various medical treatments. In this prospective, nonrandomized, nonblinded observational study, patients were first given treatment (sibutramine or orlistat) as decided by the treating clinician and then allocated into 1 of 2 groups according to the treatment prescribed. The first group included 21 Caucasian nondiabetic female subjects, with a mean (+/-SD) age of 43 +/- 11 years and a mean body mass index (BMI) of 46 +/- 8.6 kg/m(2); subjects were treated with sibutramine 10 or 15 mg/d for weight loss. The second group included 20 Caucasian nondiabetic female subjects, mean age 42 +/- 9 years and mean BMI 45.2 +/- 5.2 kg/m(2); orlistat was introduced after 1 month on a low-fat (5%) after medical treatment in a routine obesity hospital clinic is associated with improvements in insulin sensitivity and lipid profile. Modest weight loss is also associated with potentially favourably changes in serum adipocytokines, particularly in a rise of serum adiponectin. Reduction of waist circumference is associated with a change in serum resistin.

Tica V, Hanif MW, Andersson A, Valsamakis G, Barnett AH, Kumar S, Sanjeevi CB.

Frequency of latent autoimmune diabetes in adults in Asian patients diagnosed as type 2 diabetes in Birmingham, United Kingdom.

Ann N Y Acad Sci. 2003 Nov;1005:356-8.

Abstract: The aims of our study were to measure autoantibodies to glutamic acid decarboxylase and autoantibodies to protein tyrosine phosphatase in patients with type 2 diabetes mellitus, patients with impaired glucose tolerance, and healthy controls of Asian origin from Birmingham, United Kingdom. According to our findings, 27% (9/33) of patients initially diagnosed with type 2 diabetes mellitus carry autoantibodies to GAD65.

McTernan PG, Fisher FM, Valsamakis G, Chetty R, Harte A, McTernan CL, Clark PM, Smith SA, Barnett AH, Kumar S.

Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes.

J Clin Endocrinol Metab. 2003 Dec;88(12):6098-106.

Abstract: Resistin, an adipocyte secreted factor, has been suggested to link obesity with type 2 diabetes in rodent models, but its relevance to human diabetes remains uncertain. Although previous studies have suggested a role for this adipocytokine as a pathogenic factor, its functional effects, regulation by insulin, and alteration of serum resistin concentration by diabetes status remain to be elucidated. Therefore, the aims of this study were to analyze serum resistin concentrations in type 2 diabetic subjects; to determine the in vitro effects of insulin and rosiglitazone (RSG) on the regulation of resistin, and to examine the functional effects of recombinant human resistin on glucose and lipid metabolism in vitro. Serum concentrations of resistin were analyzed in 45 type 2 diabetic subjects and 34 nondiabetic subjects. Subcutaneous human adipocytes were incubated in vitro with insulin, RSG, and insulin in combination with RSG to examine effects on resistin secretion. Serum resistin was increased by approximately 20% in type 2 diabetic subjects compared with nondiabetic subjects (P = 0.004) correlating with C-reactive protein. No other parameters, including adiposity and fasting insulin levels, correlated with serum resistin in this cohort. However, in vitro, insulin stimulated resistin protein secretion in a concentration-dependent manner in adipocytes [control, 1215 +/- 87 pg/ml (mean +/- SEM); 1 nM insulin, 1414.0 +/- 89 pg/ml; 1 microM insulin, 1797 +/- 107 pg/ml (P < 0.001)]. RSG (10 nM) reduced the insulin-mediated rise in resistin protein secretion (1 nM insulin plus RSG, 971 +/- 35 pg/ml; insulin, 1 microM insulin plus RSG, 1019 +/- 28 pg/ml; P < 0.01 vs. insulin alone). Glucose uptake was reduced after treatment with 10 ng/ml recombinant resistin and higher concentrations (P < 0.05). Our in vitro studies demonstrated a small, but significant, reduction in glucose uptake with human recombinant resistin in differentiated preadipocytes. In human abdominal sc adipocytes, RSG blocks the insulin-mediated release of resistin secretion in vitro. In conclusion, elevated serum resistin in human diabetes reflects the subclinical inflammation prevalent in type 2 diabetes. Our in vitro studies suggest a modest effect of resistin in reducing glucose uptake, and suppression of resistin expression may contribute to the insulin-sensitizing and glucose-lowering actions of the thiazolidinediones.

Fisher FM, McTernan PG, Valsamakis G, Chetty R, Harte AL, Anwar AJ, Starcynski J, Crocker J, Barnett AH, McTernan CL, Kumar S.

Differences in adiponectin protein expression: effect of fat depots and type 2 diabetic status.

Horm Metab Res. 2002 Nov-Dec;34(11-12):650-4.

Abstract: Adiponectin is an adipocyte-derived hormone associated with insulin sensitivity and atherosclerotic risk. As central rather than gluteofemoral fat is known to increase the risk of type 2 diabetes and cardiovascular disease, we investigated the mRNA and protein expression of adiponectin in human adipose tissue depots. RNA was extracted from 46 human adipose tissue samples from non-diabetic subjects aged 44.33 +/- 12.4 with a BMI of 28.3 +/- 6.0 (mean +/- SD). The samples were as follows: 21 abdominal subcutaneous, 13 omentum, 6 thigh; samples were also taken from diabetic subjects aged 66.6 +/- 7.5 with BMI 28.9 +/- 3.17; samples were: 6 abdominal subcutaneous; 3 thigh. Quantitative PCR and Western analysis was used to determine adiponectin content. Protein content studies determined that when compared with non-diabetic abdominal subcutaneous adipose tissue (Abd Sc AT) (values expressed as percentage relative to Abd Sc AT -100 %). Adiponectin protein content was significantly lower in non-diabetic omental AT (25 +/- 1.6 %; p < 0.0001, n = 6) and in Abd Sc AT from diabetic subjects (36 +/- 1.5 %; p < 0.0001, n = 4). In contrast, gluteal fat maintained high adiponectin protein content from non-diabetic patients compared with diabetic patients. An increase in BMI was associated with lower adiponectin protein content in obese ND Abd Sc AT (25 +/- 0.4 %; p < 0.0001). These findings were in agreement with the mRNA expression data. In summary, this study indicates that adiponectin protein content in non-diabetic subjects remains high in abdominal subcutaneous fat, including gluteal fat, explaining the high serum adiponectin levels in these subjects. Omental fat, however, expresses little adiponectin. Furthermore, abdominal and gluteal subcutaneous fat appears to express significantly less adiponectin once diabetic status is reached. In conclusion, the adipose tissue depot-specific expression of adiponectin may influence the pattern of serum adiponectin concentrations and subsequent disease risk.

Valsamakis G, Chetty R, McTernan PG, Al-Daghri NM, Barnett AH, Kumar S.

Fasting serum adiponectin concentration is reduced in Indo-Asian subjects and is related to HDL cholesterol.

Diabetes Obes Metab. 2003 Mar;5(2):131-5.

CONCLUSIONS: Serum adiponectin is associated with HDL cholesterol and central obesity. Caucasians have higher serum adiponectin levels compared with Indo-Asians. Further studies are needed to explore basis for the association of adiponectin with HDL cholesterol and the reason for lower levels in Indo-Asians.

Valsamakis G, Chetty RK, Kumar S.

The management of obesity in type 2 diabetes mellitus.

Curr Med Res Opin. 2002;18 Suppl 1:s75-81.

Abstract: Prevalence of obesity in the United Kingdom has tripled in the last 20 years and this is driving an epidemic of type 2 diabetes. Indeed, today the vast majority of patients with type 2 diabetes are overweight or obese. Effective weight management leading to modest weight loss to the order of 5-10% of body weight can lead to significant clinically meaningful benefits provided it can be maintained. Thus weight management can lead to improved glycaemic control, better blood pressure control and lipid control in addition to other benefits. Management of diabetic patients who are obese requires management also of other associated co-morbid conditions and it is important to ensure that glycaemic control does not deteriorate during weight management. An integrated approach to weight management in the diabetic patient is recommended which helps to promote lifestyle modification for all patients. Drug therapy may be appropriate for many obese patients who do not reach target weight loss with lifestyle modification alone. Surgery should be reserved for those wfth BMI >40 only after failed medical therapy.

Valsamakis G, Kumar S.

Insulin action enhancers for the management of type 2 diabetes mellitus.

Expert Opin Pharmacother. 2000 Dec;1(7):1413-21.

Abstract: Type 2 diabetes mellitus is a common metabolic disorder that has become a major public health problem because of the long-term microvascular and macrovascular complications associated with it. Tight glycaemic control has been shown to prevent complications, but a number of studies have shown that many patients with Type 2 diabetes have sub-optimal control. Insulin resistance is a fundamental abnormality in Type 2 diabetes but there have not been drugs that are able to reverse this defect. Thiazolidinediones (TZD) may, therefore, represent a breakthrough in the management of Type 2 diabetes as it is the first class of oral agents for diabetes that act as an insulin action enhancer to reduce insulin resistance. This review will examine available data on the currently available TZDs and consider its place in the management of Type 2 diabetes.