Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial.

BACKGROUND: Randomised controlled trials have shown that bariatric surgery is more effective than conventional treatment for the short-term control of type-2 diabetes. However, published studies are characterised by a relatively short follow-up. We aimed to assess 5 year outcomes from our randomised trial designed to compare surgery with conventional medical treatment for the treatment of type 2 diabetes in obese patients. METHODS: We did our open-label, randomised controlled trial at one diabetes centre in Italy. Patients aged 30-60 years with a body-mass index of 35 kg/m(2) or more and a history of type 2 diabetes lasting at least 5 years were randomly assigned (1:1:1), via a computer-generated randomisation procedure, to receive either medical treatment or surgery by Roux-en-Y gastric bypass or biliopancreatic diversion. Participants were aware of treatment allocation before the operation and study investigators were aware from the point of randomisation. The primary endpoint was the rate of diabetes remission at 2 years, defined as a glycated haemaglobin A1c (HbA1c) concentration of 6·5% or less (≤47·5 mmol/mol) and a fasting glucose concentration of 5·6 mmol/L or less without active pharmacological treatment for 1 year. Here we analyse glycaemic and metabolic control, cardiovascular risk, medication use, quality of life, and long-term complications 5 years after randomisation. Analysis was by intention to treat for the primary endpoint and by per protocol for the 5 year follow-up. This study is registered with ClinicalTrials.gov, number NCT00888836. FINDINGS: Between April 27, 2009, and Oct 31, 2009, we randomly assigned 60 patients to receive either medical treatment (n=20) or surgery by gastric bypass (n=20) or biliopancreatic diversion (n=20); 53 (88%) patients completed 5 years' follow-up. Overall, 19 (50%) of the 38 surgical patients (seven [37%] of 19 in the gastric bypass group and 12 [63%] of 19 in the bilipancreatic diversion group) maintained diabetes remission at 5 years, compared with none of the 15 medically treated patients (p=0·0007). We recorded relapse of hyperglycaemia in eight (53%) of the 15 patients who achieved 2 year remission in the gastric bypass group and seven (37%) of the 19 patients who achieved 2 year remission in the biliopancreatic diversion group. Eight (42%) patients who underwent gastric bypass and 13 (68%) patients who underwent biliopancreatic diversion had an HbA1c concentration of 6·5% or less (≤47·5 mmol/mol) with or without medication, compared with four (27%) medically treated patients (p=0·0457). Surgical patients lost more weight than medically treated patients, but weight changes did not predict diabetes remission or relapse after surgery. Both surgical procedures were associated with significantly lower plasma lipids, cardiovascular risk, and medication use. Five major complications of diabetes (including one fatal myocardial infarction) arose in four (27%) patients in the medical group compared with only one complication in the gastric bypass group and no complications in the biliopancreatic diversion group. No late complications or deaths occurred in the surgery groups. Nutritional side-effects were noted mainly after biliopancreatic diversion. INTERPRETATION: Surgery is more effective than medical treatment for the long-term control of obese patients with type 2 diabetes and should be considered in the treatment algorithm of this disease. However, continued monitoring of glycaemic control is warranted because of potential relapse of hyperglycaemia. FUNDING: Catholic University of Rome.

Monitoring of inosine monophosphate dehydrogenase activity and expression during the early period of mycophenolate mofetil therapy in de novo renal transplant patients.

Measurement of inosine-monophosphate dehydrogenase (IMPDH) activity or gene expression was used as a further approach in pharmacokinetics (PK)/pharmacodynamic (PD)-guided mycophenolate mofetil (MMF) therapy. Forty-four de novo kidney transplant patients were enrolled; 35 of these completed the study, and were followed for 24 weeks for clinical status, PK parameters, IMPDH activity and IMPDH1/2 gene expression. IMPDH activity and expression were measured in peripheral blood mononuclear cells before transplant and at week 2,4,12 and 24, drawn before (t0) and 2 h (t2 h) after MMF administration. No significant correlation was found between IMPDH activity/expression and PK parameters. For both genes, significant enhancement in t2 h expression was observed, then decreases towards week 24 with a trend following steroid dosages. Seven patients experienced acute rejection (AR) and exhibited significantly higher pre-transplant expression of both IMPDH1 (median 3.42 vs. 0.84; p=0.0025), and IMPDH2 genes (135 vs. 104; p=0.0218) with respect to non-rejecting patients. A significant association was also found between pre-transplant IMPDH1 mRNA and haematological complications (p=0.032). This study suggests that high steroid dosages may influence IMPDH1/2 expression, hampering their use as a PD biomarker, particularly during the early post-transplant period. The measurement of pre-transplant levels of IMPDH1/2 may contribute to prediction of individual drug responsiveness to improve the clinical management of patients in MMF therapy.

Effectiveness of the Transoral Endoscopic Vertical Gastroplasty (TOGa®): a good balance between weight loss and complications, if compared with gastric bypass and biliopancreatic diversion.

BACKGROUND: The effectiveness of restrictive procedures has been inferior to that of malabsorbitive ones. Recent variants of restrictive procedures, i.e., gastric banding and sleeve gastrectomy, confirm the strive for more efficacious solutions with less complications. We investigated the balance between effectiveness and complications for a new restrictive procedure, a Transoral Endoscopic Vertical Gastroplasty (TOGa®) METHODS: Seventy-nine morbidly obese patients were submitted to one out of three surgical procedures: TOGa® (29 patients), laparoscopic gastric bypass (LRYGBP; 20 patients), and biliopancreatic diversion (BPD; 30 patients). Mean BMI were 41.7 (35.4-46.6), 44.8 (36.4-54), and 47.5 (41-60.3), respectively. All the patients reached a 2-year follow-up. RESULTS: In TOGa® group BMI, respectively at 12 and 24 months, was 34.5 and 35.5, with 44 and 48.3% of patients with BMI lower than 35. In LRYGBP group, BMI was 30.7 and 29.2 kg/m(2), with 80 and 85% of patients with BMI < 35. In BPD group, BMI was 30 and 29.6 kg/m(2), with 100 and 93.3% of patients with BMI < 35. In TOGa® group, 59% of patients with an initial BMI < 45 reached a BMI < 35, in comparison to 48% recorded in the whole group and to 14.3% in patients with initial BMI ≥ 45. CONCLUSIONS: In selected patients, TOGa®, was associated with good results after two years in terms of weight loss, even in comparison with LRYGBP and BPD. Minimal trauma, absence of complications, and short hospital stay justify this procedure for patients with low BMI.

The effect of gastrointestinal surgery on insulin resistance and insulin secretion.

Diabesity is a term often used to indicate the association of type-2 diabetes mellitus (T2DM) with obesity; the prevalence of both conditions is rapidly increasing worldwide and has reached epidemic proportions. Insulin resistance represents the major determinant of T2DM, which becomes manifest once relative ß-cell failure ensues and insulin secretion is no longer sufficient to compensate for insulin resistance. In recent years, gastrointestinal surgery has emerged as the most effective option for the treatment of obesity and diabetes, with level-1 evidence of diabetes remission. Restrictive gastric operations such as gastric banding can improve insulin resistance in proportion to weight loss, while gastrointestinal bypass procedures, such as roux-en-y gastric-bypass (RYGB) and biliopancreatic diversion (BPD), can improve glucose homeostasis even before a significant weight loss is reached, suggesting weight-independent mechanisms of action. Studies comparing RYGB to BPD show that RYGB primarily enhances insulin secretion and reduces hepatic glucose output, whereas BPD rapidly improves glycemia primarily through the normalization of insulin sensitivity. Given the fact that BPD involves a significantly longer bypass of the proximal intestine than RYGB, these data suggest that the exclusion of a greater length of small bowel from the transit of food may cause broader and more profound influence on insulin sensitivity.

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.).

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/m(2)) 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.

Recurrent renal hyperparathyroidism due to parathyromatosis.

Parathyromatosis is the most severe type of recurrent secondary hyperparathyroidism (SHPT) after parathyroidectomy (PTX) in haemodialysis patients. It is difficult to completely remove all foci of parathyroid tissue and neck re-explorations are often required. Here, we report for the first time a case of recurrent SHPT due to parathyromatosis treated by radio-guided PTX. A haemodialysed 48-year-old woman with recurrent SHPT due to parathyromatosis was treated by radio-guided PTX. Preoperatively Ultrasonography, (99)Tc-SestaMIBI scintigraphy and magnetic resonances of the neck and thorax were performed. The preoperative imaging techniques detected four parathyroid nodules, while intraoperative gamma probe identified six nodules (three in atypical site). No frozen sections were performed during surgery. Post-operative intact parathyroid hormone levels were stabilized in the range 300-500 pg/mL during the 26 month follow-up by means of cinacalcet and paricalcitol therapy. In cases of parathyromatosis, the preoperative imaging techniques are inadequate, while intraoperative gamma probe is useful to detect the parathyroid tissue and allows a more extensive cytoreduction because it ensures the removal of undetectable and ectopic parathyroid foci. The operative time is reduced and frozen sections are unnecessary. However, the radio-guided PTX do not rule out parathyromatosis recurrence and complementary medical treatment is appropriate.

[Ultrasound parameter-based response to treatment with new drugs for secondary hyperparathyroidism: a retrospective analysis in a single dialysis center]. / Risposta terapeutica ai nuovi farmaci dell'iperparatiroidismo secondario in relazione al grado ecografico di iperplasia paratiroidea: analisi retrospettiva in un singolo centro dialisi.

In hemodialysis patients with secondary hyperparathyroidism (SHPT) ultrasonography of the parathyroid glands allows to assess the glandular growth and to define the limits of medical treatment. The present retrospective study evaluated the relationship between parathyroid gland hyperplasia and the effectiveness of new drugs. Fifty-three patients with SHPT (iPTH > 400 pg/mL) after treatment with oral calcitriol were included in the study. These patients underwent parathyroid ultrasonography and sequential therapy with intravenous calcitriol (first step), paracalcitol (second step), and paracalcitol + cinacalcet (third step). Patients with median PTH < 300 pg/mL during the period of therapy and follow-up were considered responders. The therapeutic response was correlated with ultrasound parameters (number of parathyroid glands, maximum longitudinal diameter, structural score, and vascular score). Four (10%) of 41 patients treated with IV calcitriol, 7 (27%) of 26 patients treated with paracalcitol, 7 (41%) of 17 patients treated with cinacalcet and paracalcitol, and 1 (20%) of 5 patients treated with cinacalcet alone were responders. ROC curve analysis showed that maximum longitudinal diameter (< 9 mm), number of parathyroid glands (< -1), structural score (< 2), and vascular score (< 2) predicted response to any treatment. New drugs (paracalcitol, cinacalcet) are more effective in SHPT than conventional ones. However, the traditional ultrasonographic cutoff for the efficacy of medical therapy remained unchanged. Thus parathyroid gland ultrasonography predicts the therapeutic response also to the new drugs.

Parathyroid gland ultrasound patterns and biochemical findings after one-year cinacalcet treatment for advanced secondary hyperparathyroidism.

Cinacalcet efficacy is limited in severe secondary hyperparathyroidism (SHPT) and its effect on parathyroid gland (PTG) volume and morphology have not been sufficiently investigated. We evaluated the effect of cinacalcet treatment for one year on the laboratory parameters of calcium-phosphorus metabolism and PTG ultrasound (US) patterns in hemodialysis (HD) patients with severe SHPT and US results indicative of nodular hyperplasia. Thirteen HD patients with severe SHPT (intact parathyroid hormone >700 pg/mL), US/scintigraphic evidence of at least one PTG with a diameter >7 mm, and high surgical risk or refusal of surgery were included. The patients were treated with cinacalcet. The initial dose of 30 mg was increased up to 180 mg once daily. At baseline and after one year of cinacalcet treatment a neck US was performed, providing data on 22 parathyroid glands in eight patients. The mean diameter at baseline and at one year was 12.6 +/- 5.9 and 13.0 +/- 5.3 mm, respectively (P = 0.46). Similarly, the mean volume at baseline and at one year was 513.4 +/- 416.3 and 556.8 +/- 480.8 mm(3), respectively (P = 0.18). The US structural score remained unchanged in 16 parathyroid glands and increased in 6 (P < 0.03), while the vascular score remained unchanged in 16 parathyroid glands and decreased in 6 (P = 0.25). Thus it can be concluded that cinacalcet treatment for one year in HD patients with severe SHPT is not associated with significant changes in parathyroid gland US patterns.

Usefulness of the combination of ultrasonography and 99mTc-sestamibi scintigraphy in the preoperative evaluation of uremic secondary hyperparathyroidism.

BACKGROUND: The usefulness of the combination of technetium-99m-methoxyisobutylisonitrile (99mTc-MIBI) parathyroid scintigraphy and ultrasonography to detect parathyroid glands (PTGs) in secondary hyperparathyroidism (SHPT) is still controversial. METHODS: In all, 21 patients with SHPT underwent parathyroidectomy. The sensitivity and specificity of ultrasonography and scintigraphy related to site, size, hyperplasia type of PTG, concomitant thyroid disease, and the frequency of intraoperative frozen sections were determined. RESULTS: The sensitivities of scintigraphy and ultrasonography were 62% and 55%, and the specificity was 95% for both procedures. The sensitivity of combined techniques was 73%. The scintigraphy detected 7/9 (78%) ectopic PTGs, whereas ultrasonography was always negative. A PTG maximum longitudinal diameter <8 mm, the presence of diffuse hyperplasia, the upper localization of glands, and the presence of concomitant thyroid disease reduced the sensitivity and specificity of imaging techniques. In cases of positive imaging, the rate of intraoperative frozen sections was significantly lower. CONCLUSIONS: The ultrasonography and sestamibi scintigraphy, which showed a higher sensitivity than that of either ultrasonography or scintigraphy alone, led to a reduction of intraoperative frozen sections and to preoperative diagnosis of ectopic (29%) or supernumerary PTGs (10%) and concomitant nodular thyroid disease (24%).

Thyroid function and insulin sensitivity before and after bilio-pancreatic diversion.

BACKGROUND: Bilio-pancreatic diversion (BPD) induces permanent weight loss in previously severe obese patients through a malabsorptive mechanism. The aim of the study was to evaluate the modifications of circulating thyroid hormones after BPD, a surgical procedure which interferes with the entero-hepatic circulation of biliary metabolites. METHODS: Forty-five patients were studied before and 2 years after BPD. Thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), anti-thyroid antibodies, iodine urinary excretion, lipid profile, insulin and glucose plasma levels were assessed. The insulin-resistance HOMA IR index was calculated, and colour Doppler ultrasonography of the neck was performed. RESULTS: The subjects (23%) had subclinical hypothyroidism prior to BPD (TSH levels above the normal range with normal fT3 and fT4 levels). After 2 years 40.42% of the population showed subclinical hypothyroidism, while 6.3% became frankly hypothyroid, all of them with no evidence of auto-immune thyroiditis. Most of the patients, who became sub-clinically hypothyroid only following BPD, had already thyroid alterations at the sonogram (multi-nodular euthyroid goiter and thyroidal cysts) prior to surgery. CONCLUSIONS: BPD increases the prevalence of subclinical or even frank hypothyroidism, without causing a defect in thyroid function itself, through several integrated mechanisms. (1) It induces iodine malabsorption, which is partially compensated by iodine excretion contraction. (2) The entero-hepatic open circulation determines fT3 loss, which induces subclinical or frank hypothyroidism in patients with pre-existing thyroid alterations, interfering also with the weight loss progress. Iodine supplementation should be recommended in those patients reporting thyroid alterations at the sonogram prior to BPD, LT4 therapy should be strictly monitored in patients suffering of subclinical hypopthiroidism and T3 therapy should eventually be considered for patients diagnosed with frank hypothyroidism prior to BPD.

Balance of transforming growth factor-beta1 and platelet-derived growth factor-BB is associated with kidney allograft rejection.

BACKGROUND: About 50% of kidney-transplant patients undergo organ rejection within 10 years. Chronic allograft nephropathy (CAN) represents the dominant cause of kidney transplant failure and accounts for 50-80% of graft loss in long-term surviving patients. CAN pathogenesis is multifactorial and not-completely elucidated; several reports indicate TGF-beta1 and platelet-derived growth factor (PDGF)-BB expression in CAN suggesting a possible role of these factors in the allograft arteriosclerosis and graft failure. METHODS: We investigated the plasma expression concentrations of human growth factors with enzyme-linked immunosorbent assays and appropriate statistical analysis. RESULTS: We present evidences showing statistically significant association of CAN with a specific balance between TGF Beat1 and PDGF-BB plasma concentrations, in 129 kidney-transplant patients and 15 healthy controls. Odds ratios were computed to correlate expression-levels with CAN occurrence. CONCLUSION: We believe these data may suggest a novel non-invasive method to identify early molecular markers of graft deterioration.

Ultrasound patterns of parathyroid glands in chronic hemodialysis patients with secondary hyperparathyroidism.

BACKGROUND: The role ofparathyroid glands (PTG) ultrasonography (US) in hemodialysis patients with secondary hyperparathyroidism (SHPT) is still controversial. The present study aimed at evaluating the relationship between US findings and SHPT degree as well as therapeutic outcome. METHODS: Twenty hemodialysis patients with moderate SHPT and 15 with severe SHPT underwent US to assess the PTG number, maximum longitudinal diameter (MLD), structural (1-hypoechoic, 2-slight heterogeneous, 3-high heterogeneous, 4-nodular) and vascular patterns (1-slight, 2-medium and 3-high). RESULTS: PTG number, MLD and US patterns were correlated with iPTH levels. MLD of patients with moderate or severe SHPT was 7.2 +/- 2.3 and 15 +/- 5.1 mm (p < 0.001). Most patients with moderate SHPT showed a single PTG with an MLD <9 mm associated with 1-2 structural and vascular pattern, whereas patients with severe SHPT exhibited more than one PTG with MLD >9 mm and 3-4 structural and vascular patterns. Thirteen patients were responders to treatment and 22 nonresponders. In nonresponders, a higher number of PTG was observed as well as higher echostructural and vascular patterns. In 14 patients who underwent parathyroidectomy, no differences were found between PTG US MLD and pathology diameter. All PTG with evidence of 3-4 structural and vascular score at ultrasound showed nodular hyperplasia at pathological examination. CONCLUSIONS: The adopted classification of US findings is correlated with SHPT degree and therapeutic outcome and might be an adjunctive predictive method useful to assess the SHPT severity and to plan the therapeutic strategy.

Massive weight loss decreases corticosteroid-binding globulin levels and increases free cortisol in healthy obese patients: an adaptive phenomenon?

OBJECTIVE: Obesity, insulin resistance, and weight loss have been associated with changes in hypothalamic-pituitary-adrenal (HPA) axis. So far, no conclusive data relating to this association are available. In this study, we aim to investigate the effects of massive weight loss on cortisol suppressibility, cortisol-binding globulin (CBG), and free cortisol index (FCI) in formerly obese women. RESEARCH DESIGN AND METHODS: Ten glucose-normotolerant, fertile, obese women (BMI >40 kg/m2, aged 38.66 +/- 13.35 years) were studied before and 2 years after biliopancreatic diversion (BPD) when stable weight was achieved and were compared with age-matched healthy volunteers. Cortisol suppression was evaluated by a 4-mg intravenous dexamethasone suppression test (DEX-ST). FCI was calculated as the cortisol-to-CBG ratio. Insulin sensitivity was measured by an euglycemic-hyperinsulinemic clamp, and insulin secretion was measured by a C-peptide deconvolution method. RESULTS: No difference was found in cortisol suppression after DEX-ST before or after weight loss. A decrease in ACTH was significantly greater in control subjects than in obese (P = 0.05) and postobese women (P < or = 0.01) as was the decrease in dehydroepiandrosterone (P < or = 0.05 and P < or = 0.01, respectively). CBG decreased from 51.50 +/- 12.76 to 34.33 +/- 7.24 mg/l (P < or = 0.01) following BPD. FCI increased from 11.15 +/- 2.85 to 18.16 +/- 6.82 (P < or = 0.05). Insulin secretion decreased (52.04 +/- 16.71 vs. 30.62 +/- 16.32 nmol/m(-2); P < or = 0.05), and insulin sensitivity increased by 163% (P < or = 0.0001). Serum CBG was related to BMI (r(0) = 0.708; P = 0.0001), body weight (r(0) = 0.643; P = 0.0001), body fat percent (r(0) = 0.462; P = 0.001), C-reactive protein (r(0) = 0.619; P = 0.004), and leptin (r(0) = 0.579; P = 0.007) and negatively to M value (r(0) = -0.603; P = 0.005). CONCLUSIONS: After massive weight loss in morbidly obese subjects, an increase of free cortisol was associated with a simultaneous decrease in CBG levels, which might be an adaptive phenomenon relating to environmental changes. This topic, not addressed before, adds new insight into the complex mechanisms linking HPA activity to obesity.

Effect of massive weight loss on inflammatory adipocytokines and the innate immune system in morbidly obese women.

CONTEXT: Obesity may be regarded as a low-grade inflammatory state. OBJECTIVE: The aim of this study was to evaluate changes in pro-inflammatory adipocytokines and the innate immune system, cardiovascular risk, and insulin sensitivity after massive weight loss. DESIGN: This was a longitudinal study. SETTING: The study was conducted at Catholic University, Rome. SUBJECTS AND METHODS: There were 10 normoglucose-tolerant obese women evaluated before and 36 months after bilio-pancreatic diversion (BPD). Glucose sensitivity (M value) was estimated using the euglycemic-hyperinsulinemic clamp. Mannan-binding lectin (MBL), bactericidal/permeability increasing protein (BPI), alpha-defensins, soluble CD14 receptor (sCD14), C-reactive protein, adiponectin, leptin, visfatin, IL-6, and TNF-alpha were assayed. RESULTS: After massive weight loss (53% of excess body weight), leptin (P

Medium-chain, even-numbered dicarboxylic acids as novel energy substrates: an update.

Medium-chain dicarboxylic acids are produced by higher plants and animals via fatty acid omega-oxidation or by beta-oxidation of longer-chain dicarboxylic acids. In plants, dicarboxylic acids are components of the natural protective polymers cutin and suberin; in animals, dicarboxylic acids are mainly oxidized in mitochondria, where they are transported through four different pathways. Their energy density is intermediate between glucose and fatty acids. Dicarboxylic acid administration does not require insulin or stimulate insulin secretion, and the beta-oxidation of dicarboxylic acids produces succinic acid, a gluconeogenic substrate. Therefore, dicarboxylic acids might be a suitable fuel substrate, particularly in clinical conditions in which marked insulin resistance and/or impairment of aerobic glycolysis occur.

The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes.

SUMMARY BACKGROUND DATA: Most patients who undergo Roux-en-Y gastric bypass (RYGB) experience rapid resolution of type 2 diabetes. Prior studies indicate that this results from more than gastric restriction and weight loss, implicating the rearranged intestine as a primary mediator. It is unclear, however, if diabetes improves because of enhanced delivery of nutrients to the distal intestine and increased secretion of hindgut signals that improve glucose homeostasis, or because of altered signals from the excluded segment of proximal intestine. We sought to distinguish between these two mechanisms. METHODS: Goto-Kakizaki (GK) type 2 diabetic rats underwent duodenal-jejunal bypass (DJB), a stomach-preserving RYGB that excludes the proximal intestine, or a gastrojejunostomy (GJ), which creates a shortcut for ingested nutrients without bypassing any intestine. Controls were pair-fed (PF) sham-operated and untreated GK rats. Rats that had undergone GJ were then reoperated to exclude the proximal intestine; and conversely, duodenal passage was restored in rats that had undergone DJB. Oral glucose tolerance (OGTT), food intake, body weight, and intestinal nutrient absorption were measured. RESULTS: There were no differences in food intake, body weight, or nutrient absorption among surgical groups. DJB-treated rats had markedly better oral glucose tolerance compared with all control groups as shown by lower peak and area-under-the-curve glucose values (P < 0.001 for both). GJ did not affect glucose homeostasis, but exclusion of duodenal nutrient passage in reoperated GJ rats significantly improved glucose tolerance. Conversely, restoration of duodenal passage in DJB rats reestablished impaired glucose tolerance. CONCLUSIONS: This study shows that bypassing a short segment of proximal intestine directly ameliorates type 2 diabetes, independently of effects on food intake, body weight, malabsorption, or nutrient delivery to the hindgut. These findings suggest that a proximal intestinal bypass could be considered for diabetes treatment and that potentially undiscovered factors from the proximal bowel might contribute to the pathophysiology of type 2 diabetes.

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 mumol . kg fat-free mass(-1) . min(-1) at 1 week and to 64.73 +/- 3.42 mumol . 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 m(2); P < 0.01) and total insulin output (43.76 +/- 4.07 to 25.48 +/- 1.69 and 30.50 +/- 4.71 nmol/m(2); P < 0.05) dramatically decreased, while a significant improvement in beta-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 beta-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.

Ultradian ghrelin pulsatility is disrupted in morbidly obese subjects after weight loss induced by malabsorptive bariatric surgery.

BACKGROUND: Suppression of ghrelin production after Roux-en-Y gastric bypass that suggested its contribution to appetite reduction has been reported. OBJECTIVE: Because biliopancreatic diversion (BPD) does not affect appetite, we compared ghrelin production and 24-h pulsatility between healthy control subjects and obese subjects before and after BPD. DESIGN: A computerized algorithm identified peak heights, clearance rate, and peak frequency of ghrelin over 24 h. Twenty-four-hour energy expenditure was measured in the calorimetric chamber, and energy intakes were computed. Insulin sensitivity was measured with a euglycemic-hyperinsulinemic clamp. RESULTS: Mean (+/-SD) 24-h plasma ghrelin concentrations were significantly (P < 0.0001) higher in control than in obese subjects (338.17 +/- 22.09 and 164.47 +/- 29.19 microg/L, respectively), but they increased to 204.64 +/- 28.51 microg/L in the obese subjects after BPD (P < 0.01). The pulsatility index was 0.098 +/- 0.016 and 0.041 +/- 0.014 microg . L(-1) . min(-1) in control and obese subjects, respectively (P < 0.01), and decreased to 0.025 +/- 0.007 microg . l(-1) . min(-1) after BPD (P < 0.05). Energy intakes before and after BFP did not differ significantly. Although metabolizable energy after BPD was 40% of the energy intake, that (per kg fat-free mass) after BPD did not different significantly from that before BPD. CONCLUSIONS: Weight loss induced by malabsorptive bariatric surgery is associated with greater ghrelin concentrations, which, however, remain consistently lower than those in control subjects, whereas ghrelin pulsatility is subverted. Higher ghrelin concentrations may contribute to the high calorie intakes observed in post-BPD subjects. The lack of normal pulsatility may explain the new impulse of these subjects to eat very frequently.