José Carlos Pareja

Ghrelin: A gut-brain hormone: Effect of gastric bypass surgery

Background: Ghrelin is a newly recognized gastric hormone with orexigenic and adipogenic properties, produced primarily by the stomach. Ghrelin is reduced in obesity.Weight loss is associated with an increase in fasting plasma ghrelin. We assessed the effect of massive weight loss on plasma ghrelin concentrations and its correlation with serum leptin levels and the presence of type 2 diabetes mellitus (DM) in severely obese patients. Methods: A prospective study was conducted on 28 morbidly obese women (BMI 56.3±10.2 kg/m2) who underwent gastric bypass, divided into 2 groups: 14 non-diabetics (NGT) and 14 type 2 diabetics (DM2). Ghrelin and leptin were evaluated before silastic ring transected vertical gastric bypass, and again 12 months postoperatively. Results: Fasting plasma ghrelin concentrations were 56% lower in NGT and 59% lower in DM2 compared with a lean control group (P<0.001). There was no difference in ghrelin levels between NGT and DM2 groups before and after surgery (P>0.05). Ghrelin was negatively correlated with leptin before gastric bypass surgery (r=0.51, P<0.01). The mean plasma ghrelin concentration decreased significantly after surgery in both groups (P<0.001). Conclusion: Ghrelin was inversely related to leptin concentrations. Presence of diabetes did not affect the ghrelin pattern. Reduced production of ghrelin after gastric bypass could be partly responsible for the lack of hyperphagia and thus for the weight loss.

HOMA1-IR and HOMA2-IR indexes in identifying insulin resistance and metabolic syndrome: Brazilian Metabolic Syndrome Study (BRAMS)

OBJECTIVE To investigate cut-off values for HOMA1-IR and HOMA2-IR to identify insulin resistance (IR) and metabolic syndrome (MS), and to assess the association of the indexes with components of the MS. METHODS Nondiabetic subjects from the Brazilian Metabolic Syndrome Study were studied (n = 1,203, 18 to 78 years). The cut-off values for IR were determined from the 90th percentile in the healthy group (n = 297) and, for MS, a ROC curve was generated for the total sample. RESULTS In the healthy group, HOMA-IR indexes were associated with central obesity, triglycerides and total cholesterol (p < 0.001). The cut-off values for IR were: HOMA1-IR > 2.7 and HOMA2-IR > 1.8; and, for MS were: HOMA1-IR > 2.3 (sensitivity: 76.8%; specificity: 66.7%) and HOMA2-IR > 1.4 (sensitivity: 79.2%; specificity: 61.2%). CONCLUSION The cut-off values identified for HOMA1-IR and HOMA2-IR indexes have a clinical and epidemiological application for identifying IR and MS in Westernized admixtured multi-ethnic populations.

Acute Effect of Roux-En-Y Gastric Bypass on Whole-Body Insulin Sensitivity: A Study with the Euglycemic-Hyperinsulinemic Clamp

CONTEXT Insulin resistance ameliorates after bariatric surgery, yet there is still a need for data on the acute effect of Roux-en-Y gastric bypass (RYGBP) on insulin sensitivity. OBJECTIVE The objective of the study was to describe the acute effect of RYGBP on insulin sensitivity, measured by both the euglycemic-hyperinsulinemic clamp and homeostasis model assessment insulin resistance index (HOMA-IR). DESIGN AND SETTING Evaluations were conducted before and 1 month after RYGBP at State University of Campinas (São Paulo, Brazil). PATIENTS Patients included 19 premenopausal women with metabolic syndrome aged 35.3 (6.7) yr, body mass index 45.50 (3.74) kg/m2 [mean (sd)]. Six had mild type 2 diabetes, seven impaired glucose tolerance, and six normal glucose tolerance. INTERVENTIONS AND MAIN OUTCOME MEASURES The volunteers underwent RYGBP either alone or combined with omentectomy. Euglycemic-hyperinsulinemic clamp, HOMA-IR, nonesterified fatty acids, leptin, ultrasensitive C-reactive protein, adiponectin, and IL-6 were assessed at baseline and 4.5 (0.9) wk postoperatively. RESULTS Fasting glucose decreased [99.2 (13.1) to 83.6 (8.1) mg/dl, P<0.01] along with a reduction in fasting insulin [30.4 (17.0) to 11.4 (6.3) mU/liter, P<0.01]. M value did not improve postoperatively [25.82 (6.30) to 22.02 (6.05) micromol/kgFFM.min] despite of a decrease in body weight [114.8 (14.5) to 102.3 (14.5) kg, P<0.001]. This finding was discordant to the observation of an improvement in HOMA-IR [3.85 (2.10) to 1.42 (0.76), P<0.01]. Nonesterified fatty acids increased. Leptin and C-reactive protein decreased. IL-6 and adiponectin remained unchanged. CONCLUSIONS A month after RYGBP, fasting glucose metabolism improves independent of a change in peripheral insulin sensitivity.

Partial Reversibility of Hypothalamic Dysfunction and Changes in Brain Activity After Body Mass Reduction in Obese Subjects

OBJECTIVE Inflammation and dysfunction of the hypothalamus are common features of experimental obesity. However, it is unknown whether obesity and massive loss of body mass can modify the immunologic status or the functional activity of the human brain. Therefore, the aim of this study was to determine the effect of body mass reduction on brain functionality. RESEARCH DESIGN AND METHODS In humans, changes in hypothalamic activity after a meal or glucose intake can be detected by functional magnetic resonance imaging (fMRI). Distinct fMRI analytic methods have been developed to explore changes in the brain’s activity in several physiologic and pathologic conditions. We used two analytic methods of fMRI to explore the changes in the brain activity after body mass reduction. RESULTS Obese patients present distinct functional activity patterns in selected brain regions compared with lean subjects. On massive loss of body mass, after bariatric surgery, increases in the cerebrospinal fluid (CSF) concentrations of interleukin (IL)-10 and IL-6 are accompanied by changes in fMRI patterns, particularly in the hypothalamus. CONCLUSIONS Massive reduction of body mass promotes a partial reversal of hypothalamic dysfunction and increases anti-inflammatory activity in the CSF.

Neck circumference as a simple tool for identifying the metabolic syndrome and insulin resistance: results from the Brazilian Metabolic Syndrome Study

To investigate the relationship of the neck circumference (NC) with the metabolic syndrome (MetS) and insulin resistance (IR) in a large Brazilian population‐based sample, within a wide range of adiposity and glucose tolerance, and to establish cut‐off values of the NC for MetS and IR.

Defective regulation of adipose tissue autophagy in obesity

Objectives:Autophagy is a highly regulated process that has an important role in the control of a wide range of cellular functions, such as organelle recycling, nutrient availability and tissue differentiation. A recent study has shown an increased autophagic activity in the adipose tissue of obese subjects, and a role for autophagy in obesity-associated insulin resistance was proposed. Body mass reduction is the most efficient approach to tackle insulin resistance in over-weight subjects; however, the impact of weight loss in adipose tissue autophagy is unknown.Subjects:Adipose tissue autophagy was evaluated in mice and humans.Results:First, a mouse model of diet-induced obesity and diabetes was maintained on a 15-day, 40% caloric restriction. At baseline, markers of autophagy were increased in obese mice as compared with lean controls. Upon caloric restriction, autophagy increased in the lean mice, whereas it decreased in the obese mice. The reintroduction of ad libitum feeding was sufficient to rapidly reduce autophagy in the lean mice and increase autophagy in the obese mice. In the second part of the study, autophagy was evaluated in the subcutaneous adipose tissue of nine obese-non-diabetic and six obese-diabetic subjects undergoing bariatric surgery for body mass reduction. Specimens were collected during the surgery and approximately 1 year later. Markers of systemic inflammation, such as tumor necrosis factor-1α, interleukin (IL)-6 and IL-1β were evaluated. As in the mouse model, human obesity was associated with increased autophagy, and body mass reduction led to an attenuation of autophagy in the adipose tissue.Conclusion:Obesity and caloric overfeeding are associated with the defective regulation of autophagy in the adipose tissue. The studies in obese-diabetic subjects undergoing improved metabolic control following calorie restriction suggest that autophagy and inflammation are regulated independently.

Serum Leptin Levels After Bariatric Surgery Across a Range of Glucose Tolerance from Normal to Diabetes

Background: A longitudinal, clinical intervention study with bariatric surgery was done to investigate the relationship between leptin levels, BMI, and insulin during weight loss across a range of glucose tolerance from normal to diabetes. Methods: 43 morbidly obese patients (BMI: 42-75 kg/m2) undergoing vertical banded gastroplasty Roux-en-Y gastric bypass (VBG-RGB), were divided into 3 groups: 21 normal (NGT), 12 impaired glucose tolerance (IGT) and 10 type 2 diabetes (DM). Leptin, insulin, glucose, lipids and uric acid were measured at baseline and 2, 4, 6, and 12 months following surgery. Results: BMI fell from 54.1 ± 9.1 to 34.6 ± 6.3 kg/m2, similarly in all groups. Leptin decreased from 73.9 ± 8.7 to 16.9 ± 10.2 ng/ml and was strongly correlated with BMI during 1-year follow-up (r=0.78; p<0.001). Linear univariate analysis for repeated evaluation showed a positive correlation between leptin and glucose, triglycerides, uric acid, and insulin. Multivariate regression analysis indicated that BMI was independently correlated with the decrease in leptin (p<0.001), accounting for 66% of the variance in leptin levels during weight loss. These results were found in the NGT and IGT groups. In the DM group, a small additional influence in leptin levels was attributed to glucose decrease. Conclusions: A strong link between leptin and BMI was found after surgery. BMI was the main determinant of the decrease of leptin. In these patients submitted to bariatric surgery, ranging from normal glucose tolerance to diabetes, changes in insulin levels and metabolic parameters, except for glucose in the DM group, did not appear to be correlated with changes in leptin levels.

TyG index performs better than HOMA in a Brazilian population: A hyperglycemic clamp validated study

The TyG index was evaluated as a surrogate method for estimation of insulin resistance (IR). TyG index correlated with adiposity, metabolic and atherosclerosis markers related to IR and presented a moderate degree of agreement with hyperglycemic clamp. TyG index represents an accessible tool for assessment of IR in clinical practice.

Visceral Fat Resection in Humans: Effect on Insulin Sensitivity, Beta-Cell Function, Adipokines, and Inflammatory Markers

Objective: The visceral fat is linked to insulin resistance, the metabolic syndrome, type 2 diabetes and an increased cardiovascular risk, but it is not clear whether it has a causative role.

Appetite‐regulating hormones from the upper gut: disrupted control of xenin and ghrelin in night workers

Shift work is associated with circadian rhythm disorder, impaired sleep and behavioural changes, including eating habits, predisposing to obesity and metabolic dysfunctions. It involves a neuro‐hormonal dysregulation of appetite towards positive energy balance, including increased ghrelin and decreased leptin, but little is known about other hormones, such as xenin, derived from the upper gut (like ghrelin), and lower gut hormones. Our objective was to compare night workers with day workers in relation to appetite‐regulating hormones and other metabolic parameters.