Theodore K. Alexandrides

Weight Loss, Appetite Suppression, and Changes in Fasting and Postprandial Ghrelin and Peptide-YY Levels After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy A Prospective, Double Blind Study

Background:Bariatric surgery is currently the most effective treatment in morbidly obese patients, leading to durable weight loss. Objective:In this prospective double blind study, we aim to evaluate and compare the effects of laparoscopic Roux-en-Y gastric bypass (LRYGBP) with laparoscopic sleeve gastrectomy (LSG) on body weight, appetite, fasting, and postprandial ghrelin and peptide-YY (PYY) levels. Methods:After randomization, 16 patients were assigned to LRYGBP and 16 patients to LSG. Patients were reevaluated on the 1st, 3rd, 6th, and 12th postoperative month. Blood samples were collected after an overnight fast and in 6 patients in each group after a standard 420 kcal mixed meal. Results:Body weight and body mass index (BMI) decreased markedly (P < 0.0001) and comparably after either procedure. Excess weight loss was greater after LSG at 6 months (55.5% ± 7.6% vs. 50.2% ± 6.5%, P = 0.04) and 12 months (69.7% ± 14.6% vs. 60.5% ± 10.7%, [P = 0.05]). After LRYGBP fasting ghrelin levels did not change significantly compared with baseline (P = 0.19) and did not decrease significantly after the test meal. On the other hand, LSG was followed by a marked reduction in fasting ghrelin levels (P < 0.0001) and a significant suppression after the meal. Fasting PYY levels increased after either surgical procedure (P ≤ 0.001). Appetite decreased in both groups but to a greater extend after LSG. Conclusion:PYY levels increased similarly after either procedure. The markedly reduced ghrelin levels in addition to increased PYY levels after LSG, are associated with greater appetite suppression and excess weight loss compared with LRYGBP.

Expression of Adiponectin and Adiponectin Receptors in Human Pituitary Gland and Brain

Background/Aims: Adiponectin and its receptors, AdipoR1 and AdipoR2, constitute integral components of energy homeostatic mechanism in peripheral tissues. Recent studies have implicated adiponectin in central neural networks regulating food intake and energy expenditure. The present study aimed at investigating the possible expression and distribution of adiponectin and its receptors in human pituitary gland, hypothalamus and different brain areas. Methods: Sections of the pituitary gland, hypothalamus and adjacent basal forebrain area, cerebrum and cerebellum from 35 autopsy cases, were examined using HE, PAS-Orange G, luxol fast blue/cresyl violet stains and single and double immunohistochemistry using adiponectin, AdipoR1, AdipoR2, choline acetyltransferase, FSH, LH, TSH, GH, ACTH and prolactin-specific antibodies. Age and BMI mean values ± SD of the autopsy cases were 56 ± 18 years and 27 ± 5 kg/m2, respectively. Results: Strong adiponectin expression was observed in pituitary gland. In pars distalis (PD), adiponectin localized in GH, FSH, LH and TSH-producing cells and in pars tuberalis (PT) in FSH, LH and TSH-producing cells. Strong to moderate expression of AdipoR1 and AdipoR2 was observed in PD by the same cell types as adiponectin. No immunoreactivity for adiponectin receptors was noted in cells of PT. Intense AdipoR1 immunostaining was observed in neurons of lateral hypothalamic area and of nucleus basalis of Meynert (NBM). Conclusions: Adiponectin and its receptors expression in human pituitary might indicate the existence of a local system, modulating endocrine axes. Furthermore, the presence of AdipoR1 in hypothalamus and NBM suggests that adiponectin may participate in central neural signaling pathways controlling energy homeostasis and higher brain functions.

Growth hormone and insulin-like growth factor I protect intestinal cells from radiation induced apoptosis.

We studied whether programmed cell death (or apoptosis) is the predominant mechanism in radiation-induced cell damage to rat intestinal mucosa and investigated the mechanism of the protective effect of GH and IGF-I in the same model. Male albino Wistar rats were divided into four groups: controls, radiation, radiation plus GH and radiation plus IGF-I. Radiation was administered on the first day and on day 4. All animals were sacrificed and segments of the terminal ileum were stained with hematoxylin-eosin. Apoptosis of the epithelial cells was identified at the cellular level by the TUNEL stain and was distinguished from necrosis by the characteristic morphology of the cells (cytoplasmic shrinkage, marginal chromatin condensation and generation of nuclear apoptotic bodies). Apoptotic cells in the control animals were few and detected only at the tips of the villi while in the irradiated animals almost all the epithelial cells were apoptotic, distributed from the crypts to the tips of the villi and the mucosa showed severe epithelial atrophy and ulceration. The histologic picture of the mucosa in the GH and IGF-I treated animals was similar to normal controls and apoptotic cells were restricted only at the tips of the villi. DNA and RNA from the mucosa cells were isolated and analyzed by electrophoresis. DNA fragmentation and RNA 28s band ribonuclease cleavage was observed only in the irradiated animals. We have shown that abdominal radiation causes intestinal epithelial cell damage mainly through the induction of apoptosis and the treatment with GH and IGF-I inhibits apoptosis of the cells and preserves the mucosal integrity.

Beneficial effects of growth hormone and insulin-like growth factor I on intestinal bacterial translocation, endotoxemia, and apoptosis in experimentally jaundiced rats

BACKGROUND This study was undertaken to investigate the effect of growth hormone (GH) and insulin-like growth factor I (IGF-I), two well-known growth factors, on bacterial translocation, endotoxemia, enterocyte apoptosis, and intestinal and liver histology in a model of experimental obstructive jaundice in rats. STUDY DESIGN One hundred six male Wistar rats were divided into five groups: I (n = 21), controls; II (n = 22), sham operated; III (n = 22), bile duct ligation (BDL); IV (n = 21), BDL and GH treatment; and V (n = 20), BDL and IGF-I administration. By the end of the experiment, on day 10, blood bilirubin was determined, and mesenteric lymph nodes, liver specimens, and bile from the bile duct stump were cultured. Endotoxin was measured in portal and aortic blood. Tissue samples from the terminal ileum and liver were examined histologically and apoptotic body count (ABC) in intestinal mucosa was evaluated. Mucosal DNA and protein content were also determined. RESULTS Bilirubin increased significantly after BDL (p < 0.001). Bile from the bile duct was sterile. In group III, MLN and liver specimens were contaminated by gut origin bacteria (significant versus group I and II, p < 0.001, respectively). GH reduced significantly positive cultures (p < 0.01), and IGF-I had no effect. BDL resulted in significant increase in portal and aortic endotoxemia (p < 0.001); treatment with GH and IGF-I reduced it (p < 0.001). Mucosal DNA and protein content were reduced in animals with BDL and after treatment with GH or IGF-I; an increase to almost normal levels was noted in DNA, but not in protein. Overall the ileal architecture remained intact in all animal groups. The ABC increased after BDL. After GH and IGF-I administration, the ABC decreased significantly, and there was no difference between GH and IGF-I treated animals. After BDL, liver biopsies displayed typical changes of biliary obstruction, which were significantly improved after administration of GH and IGF-I. CONCLUSIONS Treatment with GH and IGF-I in rats with experimental obstructive jaundice reduces endotoxemia, and it improves liver histology. Apoptosis, in the intestinal epithelium, may serve as a morphologic marker of the ileal mucosal integrity, demonstrating the proliferative potential of GH and IGF-I in cases of obstructive jaundice, and this might be of potential value in patients with such conditions.

Hormone changes and diabetes resolution after biliopancreatic diversion and laparoscopic sleeve gastrectomy: a comparative prospective study

BACKGROUND Biliopancreatic diversion (BPD) is the most effective bariatric procedure in terms of weight loss and remission of diabetes type 2 (T2DM), but it is accompanied by nutrient deficiencies. Sleeve gastrectomy (SG) is a relatively new operation that has shown promising results concerning T2DM resolution and weight loss. The objective of this study was to evaluate and compare prospectively the effects of BPD long limb (BPD) and laparoscopic SG on fasting, and glucose-stimulated insulin, glucagon, ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1) secretion and also on remission of T2DM, hypertension, and dyslipidemia in morbidly obese patients with T2DM. METHODS Twelve patients (body mass index [BMI] 57.6 ± 9.9 kg/m(2)) underwent BPD and 12 (BMI 43.7 ± 2.1 kg/m(2)) underwent SG. All patients had T2DM and underwent an oral glucose tolerance test (OGTT) before and 1, 3, and 12 months after surgery. RESULTS BMI decreased more after BPD, but percent excess weight loss (%EWL) was similar in both groups (P = .8) and T2DM resolved in all patients at 12 months. Insulin sensitivity improved more after BPD than after SG (P = .003). Blood pressure, total and LDL cholesterol decreased only after BPD (P<.001). Triglycerides decreased after either operation, but HDL increased only after SG (P<.001). Fasting ghrelin did not change after BPD (P = .2), but decreased markedly after SG (P<.001). GLP-1 and PYY responses during OGTT were dramatically enhanced after either procedure (P = .001). CONCLUSIONS SG was comparable to BPD in T2DM resolution but inferior in improving dyslipidemia and blood pressure. SG and BPD enhanced markedly PYY and GLP-1 responses but only SG suppressed ghrelin levels.

High prevalence of diabetes mellitus among adult β-thalassaemic patients with chronic hepatitis C

AIM The aim of this study was to assess the prevalence of diabetes mellitus in patients with hepatitis C virus (HCV) chronic hepatitis and secondary haemochromatosis as a consequence of beta-thalassaemia major. This group of patients was studied in order to reveal subtle effects of early stages of HCV infection on glucose metabolism, made more apparent by the coexistence of the diabetogenic effect of haemochromatosis. PATIENTS AND METHODS The study included 108 beta-thalassaemic multitransfused patients, 55 females and 53 males, age 26.8+/-9 years. Sixty-four patients were seropositive for HCV by ELISA-3 (61/64 HCV-polymerase chain reaction-positive by Amplicor). In 51 of these, chronic hepatitis C was documented by liver biopsy, which also showed incomplete cirrhosis for eight and cirrhosis for four patients. Diabetes was diagnosed according to the criteria of the National Diabetes Data Group of the National Institutes of Health. RESULTS (1) Patients with thalassaemia and HCV infection were diabetic more often than thalassaemic patients without HCV infection (45.3% versus 11.3%; P<0.001). This highly significant difference was also found when patients with definite cirrhosis or incomplete cirrhosis were excluded (41% versus 11.3%; P<0.01). (2) The high frequency of diabetes in thalassaemic patients with HCV chronic hepatitis is not related to body mass index or iron load, but it seems especially evident in patients over 25 years of age (50% of HCV-positive were diabetic versus 9.5% of HCV-negative; P<0.01). CONCLUSION The frequency of diabetes in adult thalassaemic patients is significantly increased by HCV infection, even in the absence of cirrhosis. It is probable that the coexistence of haemochromatosis makes the effect of HCV infection on glucose metabolism clinically evident, even in the stage of chronic hepatitis.

The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement

Non-alcoholic fatty liver disease (NAFLD), the most common liver disease, is characterized by accumulation of fat (>5% of the liver tissue), in the absence of alcohol abuse or other chronic liver diseases. It is closely related to the epidemic of obesity, metabolic syndrome or type 2 diabetes mellitus (T2DM). NAFLD can cause liver inflammation and progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis or hepatocellular cancer (HCC). Nevertheless, cardiovascular disease (CVD) is the most common cause of death in NAFLD/NASH patients. Current guidelines suggest the use of pioglitazone both in patients with T2DM and in those without. The use of statins, though considered safe by the guidelines, have very limited use; only 10% in high CVD risk patients are on statins by tertiary centers in the US. There are data from several animal studies, 5 post hoc analyses of prospective long-term survival studies, and 5 rather small biopsy proven NASH studies, one at baseline and on at the end of the study. All these studies provide data for biochemical and histological improvement of NAFLD/NASH with statins and in the clinical studies large reductions in CVD events in comparison with those also on statins and normal liver. Ezetimibe was also reported to improve NAFLD. Drugs currently in clinical trials seem to have potential for slowing down the evolution of NAFLD and for reducing liver- and CVD-related morbidity and mortality, but it will take time before they are ready to be used in everyday clinical practice. The suggestion of this Expert Panel is that, pending forthcoming randomized clinical trials, physicians should consider using a PPARgamma agonist, such as pioglitazone, or, statin use in those with NAFLD/NASH at high CVD or HCC risk, alone and/or preferably in combination with each other or with ezetimibe, for the primary or secondary prevention of CVD, and the avoidance of cirrhosis, liver transplantation or HCC, bearing in mind that CVD is the main cause of death in NAFLD/NASH patients.

Association between the changes in renal function and serum uric acid levels during multifactorial intervention and clinical outcome in patients with metabolic syndrome. A post hoc analysis of the ATTEMPT study

Abstract Aim: To assess the effects of long-term multifactorial intervention on renal function and serum uric acid (SUA) levels and their association with estimated cardiovascular disease (eCVD) risk and actual CVD events. Methods: This prospective, randomized, target-driven study included 1123 subjects (45.6% men, age 45–65 years) with metabolic syndrome (MetS) but without diabetes or CVD. Patients were randomized to multifactorial treatment. Atorvastatin was titrated from 10–80 mg/day aiming at a low density lipoprotein cholesterol (LDL-C) target of <100 mg/dl (group A) or an LDL-C target of <130 mg/dl (group B). Changes in estimated glomerular filtration rate (eGFR) and SUA levels were recorded in all patients and in the subgroup with stage 3 chronic kidney disease (CKD; eGFR = 30–59 ml/min/1.73 m2; n = 349). We used ANOVA to compare changes within the same group, unpaired Student t-test to compare results between groups at specific time points, and log-rank test to compare event free survival. Results: The eCVD-risk reduction was greater in group A. In the overall study population, eGFR increased by 3.5% (p < 0.001) and SUA levels fell by 5.6% (p < 0.001). In patients from group A with stage 3 CKD (group A1; n = 172), eGFR increased by 11.1% (p < 0.001) from baseline and by 7.5% (p < 0.001) in group B1 (n = 177; p < 0.001 vs. the change in group A1). The corresponding fall in SUA levels was 10.7% in group A1 (p < 0.001 vs. baseline) and 8.3% in group B1 (p < 0.001 vs. baseline and group A1). These changes were mainly attributed to atorvastatin treatment. Among the CKD stage 3 patients there were no CVD events in group A1, while 6 events occurred in group B1 (p = 0.014). Conclusions: Multifactorial intervention in patients with MetS without established CVD improved renal function and reduced SUA levels. These changes were more prominent in stage 3 CKD patients and might have contributed to the reduction in eCVD risk and clinical events. Trial registration: ClinicalTrials.gov identifier: NCT00416741.

Ghrelin and peptide YY levels after a variant of biliopancreatic diversion with Roux-en-Y gastric bypass versus after colectomy: a prospective comparative study.

Background: The gastrointestinal peptide hormones ghrelin and PYY have been shown to play a role in the regulation of metabolism and appetite. We investigate the effect of Biliopancreatic diversion with Roux-en-Y gastric bypass (BPD-RYGBP) on the circulating levels of ghrelin and peptide YY during the first 3 months postoperatively as compared to the effects of colectomy, an abdominal operation of similar severity. Methods: Fasting plasma levels of ghrelin and PYY were determined in 20 super-obese patients (BMI≥50) who underwent BPD-RYGBP and in 13 patients who underwent colectomy for large bowel cancer. Fasting plasma ghrelin and PYY levels were measured preoperatively and during the postoperative period on days 1, 3, 7, 30 and 90 in all patients of both groups, and at 1 year for 10 of the patients who had attained 1-year follow up. Results: Preoperatively, both plasma ghrelin and PYY levels were lower in the BPD-RYGBP group of patients. A temporary decrease in plasma ghrelin levels was observed in both groups of patients during the immediate postoperative period, with a gradual return to preoperative levels by the 3rd month. In addition, ghrelin concentrations increased at 1 year to levels 40% higher than those at baseline, in 10 of the BPD-RYGBP patients who had completed the 1-year follow-up (P=0.004). Plasma PYY levels in the colectomy group decreased in the first 3 postoperative days and then returned to baseline. In contrast, PYY levels in the BPD-RYGBP group did not change during the early postoperative period but increased to levels 50% higher at 3 months (P<0.001) and 170% higher at 1 year (P<0.001) than the baseline. Conclusions: The great postoperative increase in the levels of the anorexigenic peptide PYY following BPD-RYGBP may contribute to the reduced appetite observed after this type of bariatric surgery. The changes in ghrelin levels postoperatively make its contribution to the appetite suppression less likely.

Assessing the treatment effect in metabolic syndrome without perceptible diabetes (ATTEMPT): a prospective-randomized study in middle aged men and women.

Aim: To assess the reduction in estimated cardiovascular disease (e-CVD) risk after multifactorial treatment for 6 months and follow this change during the next 3-years. Patients-Methods: This prospective, randomized, target driven study included 1,123 subjects (512/611 men/women, aged 45-65 years) with metabolic syndrome (MetS) without diabetes or CVD referred to specialist outpatient clinics. Patients were randomized to two treatment groups: group A with low density lipoprotein cholesterol (LDL-C) target of > 100 mg/dl and group B with a target of 50%in all patients, but were superior in group A and in women. Reductions were even greater during the next 3-years and were mainly attributed to changes in lipid profile. Actual CVD events were 1 in group A and 13 in group B; p=0.0012. Conclusions: Attaining the treatment target of LDL-C < 100 mg/dl within multifactorial treatment of MetS by expert clinics, is achievable and beneficial even in patients without diabetes or known CVD. This induces a considerable e-CVD risk reduction in MetS patients. Actual CVD events were negligible, suggesting that e-CVD risk overestimates actual CVD risk in MetS, at least in patients achieving LDL-C < 100 mg/dl [ClinicalTrials.gov ID: NCT00416741].