Effects of biliopancreatic diversion on diurnal leptin, insulin and free fatty acid levels

BACKGROUND: Free fatty acid (FFA) levels are raised in obesity as a consequence of increased production and reduced clearance. They may link obesity with insulin resistance. Bariatric surgery can result in considerable weight loss and reduced insulin resistance, but the mechanism of action is not well understood. Although drugs such as metformin that lower insulin resistance can contribute to weight loss, a better understanding of the links between obesity, weight loss and changes in insulin resistance might lead to new approaches to patient management. METHODS: Variations in circulating levels of leptin, insulin and FFAs over 24 h were studied in severely obese (body mass index over 40 kg/m(2) ) women before and 6 months after biliopancreatic diversion (BPD). Body composition was measured by dual-energy X-ray absorptiometry. A euglycaemic-hyperinsulinaemic clamp was used to assess insulin sensitivity. Levels of insulin, leptin and FFAs were measured every 20 min for 24 h. Pulsatile hormone and FFA analyses were performed. RESULTS: Among eight patients studied, insulin sensitivity more than doubled after BPD, from mean(s.d.) 39·78(7·74) to 96·66(27·01) mmol per kg fat-free mass per min, under plasma insulin concentrations of 102·29(9·60) and 93·61(9·95) µunits/ml respectively. The secretory patterns of leptin were significantly different from random but not statistically different before and after BPD, with the exception of the pulse height which was reduced after surgery. Both plasma insulin and FFA levels were significantly higher throughout the study day before BPD. Based on Granger statistical modelling, lowering of daily FFA levels was linked to decreased circulating leptin concentrations, which in turn were related to the lowering of daily insulin excursions. Multiple regression analysis indicated that FFA level was the only predictor of leptin level. CONCLUSION: Lowering of circulating levels of FFAs after BPD may be responsible for the reduction in leptin secretion, which in turn can decrease circulating insulin levels. Surgical relevance Insulin resistance is a common feature of obesity and type II diabetes. These patients are also relatively insensitive to the biological effects of leptin, a satiety hormone produced mainly in subcutaneous fat. Biliopancreatic diversion, a malabsorptive bariatric operation that drastically reduces circulating lipid levels, improves insulin resistance independently of weight loss. The mechanism of action, however, has still to be elucidated. This study demonstrated that normalization of insulin sensitivity after bariatric surgery was associated with a reduction in 24-h free fatty acid concentrations and changes in the pattern of leptin peaks in plasma. Bariatric surgery improves the metabolic dysfunction of obesity, and this may be through a reduction in circulating free fatty acids and modification of leptin metabolism

Insulin sensitivity and secretion changes after gastric bypass in normotolerant and diabetic obese subjects

To elucidate the mechanisms of improvement/reversal of type 2 diabetes after Roux-en-Y gastric bypass (RYGB)

Underestimation of urinary albumin to creatinine ratio in morbidly obese subjects due to high urinary creatinine excretion

Albuminuria, a chronic kidney and/or cardiovascular disease biomarker, is currently measured as albumin-to-creatinine ratio (ACR). We hypothesize that in severely obese individuals ACR might be abnormally low in spite of relatively high levels of urinary albumin due to increased creatininuria

Metabolic surgery versus conventional medical therapy in patients with type 2 diabetes:10-year follow-up of an open-label, single-centre, randomised controlled trial

Background: No data from randomised controlled trials of metabolic surgery for diabetes are available beyond 5 years of follow-up. We aimed to assess 10-year follow-up after surgery compared with medical therapy for the treatment of type 2 diabetes. Methods: We did a 10-year follow-up study of an open-label, single-centre (tertiary hospital in Rome, Italy), randomised controlled trial, in which patients with type 2 diabetes (baseline duration >5 years; glycated haemoglobin [HbA1c] >7\ub70%, and body-mass index 6535 kg/m2) were randomly assigned (1:1:1) to medical therapy, Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion (BPD) by a computerised system. The primary endpoint of the study was diabetes remission at 2 years (HbA1c <6\ub75% and fasting glycaemia <5\ub755 mmol/L without ongoing medication for at least 1 year). In the 10-year analysis, durability of diabetes remission was analysed by intention to treat (ITT). This study is registered with ClinicalTrials.gov, NCT00888836. Findings: Between April 30, 2009, and Oct 31, 2011, of 72 patients assessed for eligibility, 60 were included. The 10-year follow-up rate was 95\ub70% (57 of 60). Of all patients who were surgically treated, 15 (37\ub75%) maintained diabetes remission throughout the 10-year period. Specifically, 10-year remission rates in the ITT population were 5\ub75% for medical therapy (95% CI 1\ub70\u201325\ub77; one participant went into remission after crossover to surgery), 50\ub70% for BPD (29\ub79\u201370\ub71), and 25\ub70% for RYGB (11\ub72\u201346\ub79; p=0\ub70082). 20 (58\ub78%) of 34 participants who were observed to be in remission at 2 years had a relapse of hyperglycaemia during the follow-up period (BPD 52\ub76% [95% CI 31\ub77\u201372\ub77]; RYGB 66\ub77% [41\ub77\u201384\ub78]). All individuals with relapse, however, maintained adequate glycaemic control at 10 years (mean HbA1c 6\ub77% [SD 0\ub72]). Participants in the RYGB and BPD groups had fewer diabetes-related complications than those in the medical therapy group (relative risk 0\ub707 [95% CI 0\ub701\u20130\ub748] for both comparisons). Serious adverse events occurred more frequently among participants in the BPD group (odds ratio [OR] for BPD vs medical therapy 2\ub77 [95% CI 1\ub73\u20135\ub76]; OR for RYGB vs medical therapy 0\ub77 [0\ub73\u20131\ub79]). Interpretation: Metabolic surgery is more effective than conventional medical therapy in the long-term control of type 2 diabetes. Clinicians and policy makers should ensure that metabolic surgery is appropriately considered in the management of patients with obesity and type 2 diabetes. Funding: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Nutrient infusion bypassing duodenum-jejunum improves insulin sensitivity in glucose-tolerant and diabetic obese subjects

The mechanisms of type 2 diabetes remission after bariatric surgery is still not fully elucidated. In the present study, we tried to simulate the Roux-en-Y gastric bypass with a canonical or longer biliary limb by infusing a liquid formula diet into different intestinal sections. Nutrients (Nutrison Energy) were infused into mid- or proximal jejunum and duodenum during three successive days in 10 diabetic and 10 normal glucose-tolerant subjects. Plasma glucose, insulin, C-peptide, glucagon, incretins, and nonesterified fatty acids (NEFA) were measured before and up to 360 min following. Glucose rate of appearance (Ra) and insulin sensitivity (SI), secretion rate (ISR), and clearance were assessed by mathematical models. SI increased when nutrients were delivered in mid-jejunum vs. duodenum (SI 7 10\u2074 min\u207b\ub9\ub7pM\u207b\ub9: 1.11 \ub1 0.44 vs. 0.62 \ub1 0.22, P < 0.015, in controls and 0.79 \ub1 0.34 vs. 0.40 \ub1 0.20, P < 0.05, in diabetic subjects), whereas glucose Ra was not affected. In controls, Sensitivity of NEFA production was doubled in mid-jejunum vs. duodenum (2.80 \ub1 1.36 vs. 1.13 \ub1 0.78 7 10\u2076, P < 0.005) and insulin clearance increased in mid-jejunum vs. duodenum (2.05 \ub1 1.05 vs. 1.09 \ub1 0.38 l/min, P < 0.03). Bypass of duodenum and proximal jejunum by nutrients enhances insulin sensitivity, inhibits lipolysis, and increases insulin clearance. These results may further our knowledge of the effects of bariatric surgery on both insulin resistance and diabetes

Fasting insulin has a stronger association with an adverse cardiometabolic risk profile than insulin resistance: the RISC study

Objective: Fasting insulin concentrations are often used as a surrogate measure or insulin resistance. We investigated the relative contributions Of fasting insulin and insulin resistance to cardiometabolic risk and preclinical atherosclerosis. Design and methods: The Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) cohort consists of 1326 European non-diabetic. overall healthy men and women aged 30-60 years. We performed standard oral glucose tolerance tests and hyperinsulinemic euglycemic clamps. As a general measure of cardiovascular risk, we assessed the prevalence of the metabolic syndrome ill 1177 participants. Carotid artery intima media thickness (IMT) was measured by ultrasound to assess preclinical atherosclerosis. Results: Fasting insulin was correlated with all elements of the metabolic syndrome. Insulin sensitivity (M/I) was correlated with most. elements. The odds ratio for the metabolic syndrome of those ill the highest quartile of fasting insulin compared with those in the lower quartiles was 5.4 (95%, confidence interval (CI) 2.8-10.3. adjusted for insulin sensitivity) in men and 5.1 (2.6-9.9) in women. The odds ratio for metabolic syndrome of those With insulin sensitivity in the lowest. quartile of the cohort compared with those in the higher quartiles was 2.4 (95% CI 1.3-4.7, adjusted for fasting insulin) ill men and 1.6 (0.8-3.1) in women. Carotid IMT was only statistically significantly associated with fasting insulin in both men and women. Conclusions: Fasting insulin, a simple and practical measure. may be a stronger and independent contributor to cardiometabolic risk and atherosclerosis in a healthy Population than hyperinsulinemic euglycemic clamp-derived insulin sensitivity

Paradoxical preservation of vascular function in severe obesity

BACKGROUND: Obesity is associated with a high risk of coronary artery disease morbidity and mortality. Yet, postmortem studies have shown that severely obese subjects exhibit smooth coronary arteries, thus suggesting that they may be protected from atherosclerosis. We assessed vascular function and its possible determinants in a cohort of normal-weight to severely obese insulin-sensitive subjects (body mass index [BMI] 23.2-49 kg/m(2)). METHODS: Seventy-one healthy, insulin-sensitive subjects (Homeostasis Model Assessment of Insulin Resistance index <2.5), divided into normal-weight (n = 13; BMI = 23.2 +/- 1.6), obese (n = 35; BMI=32.6+/-2.5), and severely obese (n=23; BMI=49.0+/-7.9) groups, were enrolled. Vascular function was evaluated by flow-mediated dilation and carotid intima-media thickness. High-sensitivity C-reactive protein, leptin, adiponectin, vascular growth factors, and CD34+KDR+/CD133+ endothelial progenitor cells, known markers of vascular health/protection, also were measured. RESULTS: Flow-mediated dilation was higher in severely obese than in obese and normal-weight individuals (P=.019 and P=.011 respectively). Intima-media thickness was consistently lower in severely obese than in obese individuals (P=.040) and similar in severely obese and normal-weight individuals (P >.99). Levels of high-sensitivity C-reactive protein and leptin were higher in severely obese than in obese and normal-weight individuals (high-sensitivity C-reactive protein: P=.018 and P=.05, respectively; leptin: P <.001 for both comparisons). CD34+KDR+ endothelial progenitor cells were significantly higher in severely obese versus obese individuals (P=.039). CONCLUSION: Our study demonstrates that vascular function is paradoxically better in severely obese than in obese subjects and similar to that found in normal-weight subjects. Despite higher levels of high-sensitivity C-reactive protein and leptin, severely obese individuals may be partially protected from atherosclerosis, possibly by a greater mobilization of endothelial progenitor cells