Amerigo Iaconelli

Bariatric surgery versus conventional medical therapy for type 2 diabetes

BACKGROUND Roux-en-Y gastric bypass and biliopancreatic diversion can markedly ameliorate diabetes in morbidly obese patients, often resulting in disease remission. Prospective, randomized trials comparing these procedures with medical therapy for the treatment of diabetes are needed. METHODS In this single-center, nonblinded, randomized, controlled trial, 60 patients between the ages of 30 and 60 years with a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 35 or more, a history of at least 5 years of diabetes, and a glycated hemoglobin level of 7.0% or more were randomly assigned to receive conventional medical therapy or undergo either gastric bypass or biliopancreatic diversion. The primary end point was the rate of diabetes remission at 2 years (defined as a fasting glucose level of <100 mg per deciliter [5.6 mmol per liter] and a glycated hemoglobin level of <6.5% in the absence of pharmacologic therapy). RESULTS At 2 years, diabetes remission had occurred in no patients in the medical-therapy group versus 75% in the gastric-bypass group and 95% in the biliopancreatic-diversion group (P<0.001 for both comparisons). Age, sex, baseline BMI, duration of diabetes, and weight changes were not significant predictors of diabetes remission at 2 years or of improvement in glycemia at 1 and 3 months. At 2 years, the average baseline glycated hemoglobin level (8.65±1.45%) had decreased in all groups, but patients in the two surgical groups had the greatest degree of improvement (average glycated hemoglobin levels, 7.69±0.57% in the medical-therapy group, 6.35±1.42% in the gastric-bypass group, and 4.95±0.49% in the biliopancreatic-diversion group). CONCLUSIONS In severely obese patients with type 2 diabetes, bariatric surgery resulted in better glucose control than did medical therapy. Preoperative BMI and weight loss did not predict the improvement in hyperglycemia after these procedures. (Funded by Catholic University of Rome; ClinicalTrials.gov number, NCT00888836.).

Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery.

Currently, there are no data in the literature regarding the pathophysiological mechanisms involved in the rapid resolution of type 2 diabetes after bariatric surgery, which was reported as an additional benefit of the surgical treatment for morbid obesity. With this question in mind, insulin sensitivity, using euglycemic-hyperinsulinemic clamp, and insulin secretion, by the C-peptide deconvolution method after an oral glucose load, together with the circulating levels of intestinal incretins and adipocytokines, have been studied in 10 diabetic morbidly obese subjects before and shortly after biliopancreatic diversion (BPD) to avoid the weight loss interference. Diabetes disappeared 1 week after BPD, while insulin sensitivity (32.96 ± 4.3 to 65.73 ± 3.22 μmol · kg fat-free mass−1 · min−1 at 1 week and to 64.73 ± 3.42 μmol · kg fat-free mass−1 · min−1 at 4 weeks; P < 0.0001) was fully normalized. Fasting insulin secretion rate (148.16 ± 20.07 to 70.0.2 ± 8.14 and 83.24 ± 8.28 pmol/min per m2; P < 0.01) and total insulin output (43.76 ± 4.07 to 25.48 ± 1.69 and 30.50 ± 4.71 nmol/m2; P < 0.05) dramatically decreased, while a significant improvement in β-cell glucose sensitivity was observed. Both fasting and glucose-stimulated gastrointestinal polypeptide (13.40 ± 1.99 to 6.58 ± 1.72 pmol/l at 1 week and 5.83 ± 0.80 pmol/l at 4 weeks) significantly (P < 0.001) decreased, while glucagon-like peptide 1 significantly increased (1.75 ± 0.16 to 3.42 ± 0.41 pmol/l at 1 week and 3.62 ± 0.21 pmol/l at 4 weeks; P < 0.001). BPD determines a prompt reversibility of type 2 diabetes by normalizing peripheral insulin sensitivity and enhancing β-cell sensitivity to glucose, these changes occurring very early after the operation. This operation may affect the enteroinsular axis function by diverting nutrients away from the proximal gastrointestinal tract and by delivering incompletely digested nutrients to the ileum.

Gut microbiome-derived metabolites characterize a peculiar obese urinary metabotype

Obesity is a complex multifactorial disease involving genetic and environmental factors and influencing several different metabolic pathways. In this regard, metabonomics, that is the study of complex metabolite profiles in biological samples, may provide a systems approach to understand the global metabolic regulation of the organism in relation to this peculiar pathology. In this pilot study, we have applied a nuclear magnetic resonance (NMR)-based metabolomic approach on urinary samples of morbidly obese subjects. Urine samples of 15 morbidly obese insulin-resistant (body mass index>40; homeostasis assessment model of insulin resistance>3) male patients and 10 age-matched controls were collected, frozen and analyzed by high-resolution 1H-NMR spectroscopy combined with partial least squares-discriminant analysis. Furthermore, two obese patients who underwent bariatric surgery (biliopancreatic diversion and gastric bypass, respectively) were monitored during the first 3 months after surgery and their urinary metabolic profiles were characterized. NMR-based metabolomic analysis allowed us to identify an obesity-associated metabolic phenotype (metabotype) that differs from that of lean controls. Gut flora-derived metabolites such as hippuric acid, trigonelline, 2-hydroxyisobutyrate and xanthine contributed most to the classification model and were responsible for the discrimination. These preliminary results confirmed that in humans the gut microflora metabolism is strongly linked to the obesity phenotype. Moreover, the typical obese metabotype is lost after weight loss induced by bariatric surgery.

Influence of maternal obesity on insulin sensitivity and secretion in offspring.

OBJECTIVE—The purpose of this study was to clarify the effects of maternal obesity on insulin sensitivity and secretion in offspring. RESEARCH DESIGN AND METHODS—Fifty-one offspring of both sexes of obese (Ob group) and 15 offspring of normal-weight (control group) mothers were studied. Plasma glucose, insulin, and C-peptide were measured during an oral glucose tolerance test (OGTT). Insulin sensitivity was calculated using the oral glucose insulin sensitivity index, and insulin secretion and β-cell glucose sensitivity were computed by a mathematical model. Fasting leptin and adiponectin were also measured. Body composition was assessed by dual-X-ray absorptiometry. RESULTS—No birth weight statistical difference was observed in the two groups. Of the Ob group, 69% were obese and 19% were overweight. The Ob group were more insulin resistant than the control group (398.58 ± 79.32 vs. 513.81 ± 70.70 ml−1 · min−1 · m−2 in women, P < 0.0001; 416.42 ± 76.17 vs. 484.242 ± 45.76 ml−1 · min−1 · m−2 in men, P < 0.05). Insulin secretion after OGTT was higher in Ob group than in control group men (63.94 ± 21.20 vs. 35.71 ± 10.02 nmol · m−2, P < 0.01) but did not differ significantly in women. β-Cell glucose sensitivity was not statistically different between groups. A multivariate analysis of variance showed that maternal obesity and offspring sex concurred together with BMI and β-cell glucose sensitivity to determine the differences in insulin sensitivity and secretion observed in offspring. CONCLUSIONS—Obese mothers can give birth to normal birth weight babies who later develop obesity and insulin resistance. The maternal genetic/epigenetic transmission shows a clear sexual dimorphism, with male offspring having a higher value of insulin sensitivity (although not statistically significant) associated with significantly higher insulin secretion than female offspring.

Effects of Bilio-Pancreatic Diversion on Diabetic Complications: A 10-year follow-up

OBJECTIVE The surgical option could represent a valid alternative to medical therapy in some diabetic patients. However, no data are available on long-term effects of metabolic surgery on diabetic complications. We aimed to determine whether patients with newly diagnosed type 2 diabetes who underwent bilio-pancreatic diversion (BPD) had less micro- and macrovascular complications than those who received conventional therapy. RESEARCH DESIGN AND METHODS This was an unblinded, case-controlled trial with 10-years’ follow-up, conducted from July 1998 through October 2009 at the Day Hospital of Metabolic Diseases, Catholic University, Rome, Italy. A consecutive sample of 110 obese patients (BMI >35 kg/m2) with newly diagnosed type 2 diabetes was enrolled. The study was completed by 50 subjects. The main outcome measure was long-term effects (10 years) of BPD versus those associated with conventional therapy on microvascular outcome, micro- and macroalbuminuria, and glomerular filtration rate (GFR). Secondary measures included macrovascular outcomes, type 2 diabetes remission, glycated hemoglobin, and hyperlipidemia. RESULTS Ten-year GFR variation was −45.7 ± 18.8% in the medical arm and 13.6 ± 24.5% in the surgical arm (P < 0.001). Ten-year hypercreatininemia prevalence was 39.3% in control subjects and 9% in BPD subjects (P = 0.001). After 10 years, all BPD subjects recovered from microalbuminuria, whereas microalbuminuria appeared or progressed to macroalbuminuria in control subjects. Three myocardial infarctions, determined by electrocardiogram, and one stroke occurred in control subjects. After the 10-year follow-up, coronary heart disease (CHD) probability was 0.22 ± 0.10 and 0.05 ± 0.04 in the medical and surgical groups, respectively (P < 0.001). Remission from type 2 diabetes was observed in all patients within 1 year of surgery. Surgical and medical subjects had lost 34.60 ± 10.25 and 0.38 ± 6.10% of initial weight at the 10-year follow-up (P < 0.001). CONCLUSIONS Renal and cardiovascular complications were dramatically reduced in the surgical arm, indicating long-term benefits of BPD on diabetic complications, at least in the case of morbid obesity with decompensated type 2 diabetes.

Effects of bilio-pancreatic diversion on diabetic complications: a 10-year follow-up

OBJECTIVE The surgical option could represent a valid alternative to medical therapy in some diabetic patients. However, no data are available on long-term effects of metabolic surgery on diabetic complications. We aimed to determine whether patients with newly diagnosed type 2 diabetes who underwent bilio-pancreatic diversion (BPD) had less micro- and macrovascular complications than those who received conventional therapy. RESEARCH DESIGN AND METHODS This was an unblinded, case-controlled trial with 10-years’ follow-up, conducted from July 1998 through October 2009 at the Day Hospital of Metabolic Diseases, Catholic University, Rome, Italy. A consecutive sample of 110 obese patients (BMI >35 kg/m2) with newly diagnosed type 2 diabetes was enrolled. The study was completed by 50 subjects. The main outcome measure was long-term effects (10 years) of BPD versus those associated with conventional therapy on microvascular outcome, micro- and macroalbuminuria, and glomerular filtration rate (GFR). Secondary measures included macrovascular outcomes, type 2 diabetes remission, glycated hemoglobin, and hyperlipidemia. RESULTS Ten-year GFR variation was −45.7 ± 18.8% in the medical arm and 13.6 ± 24.5% in the surgical arm (P < 0.001). Ten-year hypercreatininemia prevalence was 39.3% in control subjects and 9% in BPD subjects (P = 0.001). After 10 years, all BPD subjects recovered from microalbuminuria, whereas microalbuminuria appeared or progressed to macroalbuminuria in control subjects. Three myocardial infarctions, determined by electrocardiogram, and one stroke occurred in control subjects. After the 10-year follow-up, coronary heart disease (CHD) probability was 0.22 ± 0.10 and 0.05 ± 0.04 in the medical and surgical groups, respectively (P < 0.001). Remission from type 2 diabetes was observed in all patients within 1 year of surgery. Surgical and medical subjects had lost 34.60 ± 10.25 and 0.38 ± 6.10% of initial weight at the 10-year follow-up (P < 0.001). CONCLUSIONS Renal and cardiovascular complications were dramatically reduced in the surgical arm, indicating long-term benefits of BPD on diabetic complications, at least in the case of morbid obesity with decompensated type 2 diabetes.

Transoral gastroplasty for morbid obesity: a multicenter trial with a 1-year outcome

BACKGROUND Bariatric surgery is associated with specific complications and mortality. Transoral gastroplasty (TOGA) is a transoral restrictive bariatric procedure that might offer the benefits of surgery with a reduced complication rate. OBJECTIVE To evaluate the safety and efficacy of TOGA at 12-month follow-up. DESIGN Prospective, multicenter, single-arm trial. SETTING Two tertiary-care referral medical centers. PATIENTS This study involved 67 patients (average age 41.0 years, 47 women, baseline body mass index [BMI] 41.5 kg/m(2); 20 patients with BMI <40). INTERVENTION The TOGA procedures were performed by using 2 stapling devices that were used to create a small, restrictive pouch along the lesser gastric curvature. The pouch is designed to give the patient a sustained feeling of satiety after small meals. MAIN OUTCOME MEASUREMENTS Excess weight loss, excess BMI loss, safety, and improvements in quality of life, obesity-related comorbidities, and medication use. RESULTS Fifty-three patients were available at the 12-month follow-up. Excess BMI loss was 33.9%, 42.6%, and 44.8% at 3, 6, and 12 months, respectively. At 12 months, excess BMI loss was 52.2% for patients with a baseline BMI of <40.0 and 41.3% for patients with a baseline BMI of ≥ 40.0 (P < .05). At 12 months, hemoglobin A(1c) levels decreased from 7.0% at baseline to 5.7% (P = .01); triglyceride levels decreased from 142.9 mg/dL to 98 mg/dL (P < .0001); high-density lipoprotein levels increased from 47.0 mg/dL to 57.5 mg/dL (P < .0001). Two complications occurred: a case of respiratory insufficiency and an asymptomatic pneumoperitoneum treated conservatively. LIMITATIONS Small number of patients. Short-term follow-up. Twenty-one percent of patients were not available for the 12-month follow-up. CONCLUSION The TOGA procedure allowed a substantial weight loss 1 year after the operation without severe complications. A long-term evaluation is needed before definitive conclusions can be drawn.

Absence of Allergic Reactions to Egg White Lysozyme Additive in Grana Padano Cheese

Objective: The negative effects on cheese quality of milk contaminated by spores of Clostridium butyricum and Cl.tyrobutyricum is prevented by the use of egg white lysozyme as additive. Since the presence of lysozyme in cheese could be possibly risky in allergic subjects, we aimed at investigating its absorption as well as serum IgE antibody titers after ingestion of Grana Padano cheese, an Italian DPO, long-ripened hard cheese, in white egg allergic subjects. Methods: Cheese lysozyme was measured by HPLC. Ten healthy volunteers and 20 patients with hen egg hypersensitivity, RAST positive (binding≥3%) to lysozyme and/or ovomucoid and ovalbumin received 15, 30 and 60 g of cheese at distance of at least 2 weeks each. Serum lysozyme was measured by ELISA and specific IgE binding to lysozyme by the radioallergosorbent test (RAST). Results: The concentration of lysozyme in cheese was 155 ± 5 mg/kg. The area-under-the-curve of serum lysozyme after 15 g of cheese was 244.5 ± 14.0 in controls and 330.2 ± 9.9 in patients (p < 0.01). Similar results were obtained with 30 and 60 g of cheese. Only 3 patients (15%) showed positive IgE antibody responses to cheese (overall RAST mean 4.45 ± 1.25 % vs. 4.24 ± 1.02 % baseline, p = ns). Conclusions: The amount of lysozyme absorbed with cheese was globally very low, although it was significantly lower in healthy controls than in allergic patients, where it induced an increase of IgE RAST score in 15% of subjects, without any clinical reaction. Therefore, the use of lysozyme as additive in Grana Padano cheese, does not appear to be harmful in egg allergic subjects.

Twenty-four hour insulin secretion and beta cell NEFA oxidation in type 2 diabetic, morbidly obese patients before and after bariatric surgery

Aims/hypothesisWe have previously demonstrated that type 2 diabetes resolves after bariatric surgery. To study the role of NEFA in the prompt normalisation of beta cell glucose sensitivity, insulin secretion and beta cell glucose and lipid metabolism were investigated by a model of nutrient-stimulated insulin secretion using a multiple-meal test.MethodsHourly glucose, C-peptide and NEFA were measured in nine morbidly obese, type 2 diabetic patients before and 1 week after bariatric surgery and in six matched healthy volunteers over 24 h. A mathematical model of glucose–NEFA comodulation of insulin secretion rate (ISR) was used to compute ISR and β-oxidation. Insulin sensitivity was measured by an OGTT minimal model.ResultsBeta cell sensitivity to glucose and NEFA was doubled after surgery, while the 24 h insulin secretion decreased from 277.1 ± 144.4 to 198.0 ± 107.6 nmol/m2 (p < 0.02). Insulin sensitivity was restored. The β-oxidation rate of beta cells was completely normalised (from 0.032 ± 0.012 × 10−12 to 0.103 ± 0.031 × 10−12 mmol/min per cell, p < 0.005). The best predictor of beta cell function improvement was the duration of diabetes.Conclusions/interpretationBariatric surgery in type 2 diabetes restores β-oxidation in beta cells, doubles glucose–NEFA sensitivity and reverses diabetes. It is likely that ISR is reduced to match insulin-sensitivity normalisation, in spite of no significant reduction in NEFA levels. We hypothesise that insulin sensitivity normalisation might appear as a consequence of nutrient exclusion from proximal intestinal transit, and that secondarily the need for insulin secretion diminishes. The insulin sensitivity increase is much higher than usually obtained by insulin-sensitising agents and is independent of weight changes.

Effect of gastric bypass versus diet on cardiovascular risk factors.

Objective:To assess the effect of Roux-en-Y gastric bypass (RYGB) on high-density lipoprotein cholesterol (HDL-C) concentration and its apolipoprotein A4 (ApoA4) content at 1 year after bariatric surgery in comparison with a hypocaloric diet. Secondary aim was to measure total cholesterol and triglycerides levels and insulin sensitivity after interventions. Background:Very few prospective uncontrolled studies have investigated the effects of RYGB on cardiovascular risk factors. No controlled studies had as primary goal the changes in HDL-C after gastric bypass. Methods:Forty subjects with a body mass index more than 40 or 35 kg/m2 or more in the presence of diabetes were enrolled. Twenty of them underwent RYGB, whereas 20 received lifestyle modification suggestions and medical therapy for obesity complications (diabetes, hypertension, and hyperlipidemia). Results:A significant (P < 0.0001) increase in HDL-C concentrations was observed only in the surgical arm (from 41.95 ± 7.24 to 56.55 ± 9.01 mg/dL). Mean systolic and diastolic blood pressures were significantly reduced (P < 0.0001) in both groups with no between-group differences, probably in relation to the optimization of the antihypertensive treatment. Plasma concentration of ApoA4, a major HDL-C protein fraction, significantly increased 1 year after RYGB (from 496.61 ± 400.41 to 987.88 ± 637.41&mgr;g/L, P < 0.01). Circulating triglycerides concentration significantly decreased after surgery, whereas both peripheral and hepatic insulin resistance increased significantly. Conclusions:Our study shows that HDL-C and ApoA4 significantly increase after gastric bypass and that this increase is associated with a net improvement in hepatic insulin sensitivity. Furthermore, we speculate that ApoA4, which induces satiety in animals, can eventually play a role on the appetite reduction after RYGB because there is a strict and inverse relationship between weight and ApoA4 changes. (NCT01707771)