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.

Restoration of high-frequency glucose-entrained insulin oscillations in obese subjects with type 2 diabetes after biliopancreatic diversion.

BACKGROUND: Minimal glucose infusions are known to entrain insulin oscillations in patients with normal glucose tolerance (NGT) but not in patients with type 2 diabetes (T2D). OBJECTIVES: To investigate whether weight loss after a version of biliopancreatic diversion (BPD) can restore the glucose entrainment of high-frequency insulin oscillations in morbidly obese NGT or T2D patients. SETTING: University Hospital, Greece. METHODS: We prospectively studied 9 NGT controls (body mass index [BMI] 23.3±1.6 kg/m2), 9 obese NGT patients (BMI 51.1±12.7 kg/m2), and 9 obese T2D patients (BMI 56.8±11.6 kg/m2). Patients were studied before and 1.5 years after BPD. Insulin was sampled every minute for 90 minutes. Glucose (6 mg/kg weight) was infused every 10 minutes for 1 minute. Regularity of insulin pulses was estimated by autocorrelation analysis, spectral analysis, approximate entropy/sample entropy (ApEn/SampEn), and insulin pulsatility by deconvolution analysis. RESULTS: Postoperatively, glucose and insulin concentrations of NGT and T2D patients decreased to control levels and BMI to 31.3±6.3 for NGT patients and 34.9±9.9 kg/m2 for T2D patients. Preoperatively, glucose entrainment was absent in all T2D and in 4 NGT patients as assessed with spectral analysis and in 8 and 4, respectively, as assessed with autocorrelation and deconvolution analysis. Postoperatively, it was restored to normal in all patients. ApEn/SampEn decreased significantly only in the T2D group postoperatively. CONCLUSION: BPD restores the glucose entrainment of high-frequency insulin oscillations in obese NGT and T2D patients after marked weight loss and normalizes glucose levels and insulin sensitivity, thus demonstrating recovery of ß-cell glucose sensing.

Pregnancy outcomes and nutritional indices after 3 types of bariatric surgery performed at a single institution.

BACKGROUND: Nutritional status during pregnancy and the effects of nutritional deficiencies on pregnancy outcomes after bariatric surgery is an important issue that warrants further study. The objective of this study was to investigate pregnancy outcomes and nutritional indices after restrictive and malabsorptive procedures. METHODS: We investigated pregnancy outcomes of 113 women who gave birth to 150 children after biliopancreatic diversion (BPD), Roux-en-Y gastric bypass (RYGB), and sleeve gastrectomy (SG) between June 1994 and December 2011. Biochemical indices and pregnancy outcomes were compared among the different types of surgery and to overall 20-year hospital data, as well as to 56 presurgery pregnancies in 36 women of the same group. RESULTS: Anemia was observed in 24.2% and 15.6% of pregnancies after BPD and RYGB, respectively. Vitamin B12 levels decreased postoperatively in all groups, with no further decrease during pregnancy; however, low levels were observed not only after BPD (11.7%) and RYGB (15.6%), but also after SG (13.3%). Folic acid levels increased. Serum albumin levels decreased in all groups during pregnancy, but hypoproteinemia was seen only after BPD. Neonates after BPD had significantly lower average birth weight without a higher frequency of low birth weight defined as<2500 g. A comparison of neonatal data between babies born before surgery and siblings born after surgery (AS) showed that AS newborns had lower average birth weight with no significant differences in body length or head circumference and no cases of macrosomia. CONCLUSION: Our study showed reasonably good pregnancy outcomes in this sample population after all types of bariatric surgery provided nutritional supplement guidelines are followed. Closer monitoring is required in pregnancies after malabsorptive procedures especially regarding protein nutrition.

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.

Lower ghrelin levels and exaggerated postprandial peptide-YY, glucagon-like peptide-1, and insulin responses, after gastric fundus resection, in patients undergoing Roux-en-Y gastric bypass: a randomized clinical trial.

BACKGROUND: Laparoscopic Roux-en Y-Gastric bypass (LRYGBP) is the commonest available option for the surgical treatment of morbid obesity. Weight loss following bariatric surgery has been linked to changes of gastrointestinal peptides, shown to be implicated also in metabolic effects and appetite control. The purpose of this study was to evaluate whether gastric fundus resection in patients undergoing LRYGBP enhances the efficacy of the procedure in terms of weight loss, glucose levels, and hormonal secretion. METHODS: Twelve patients underwent LRYGBP and 12 patients LRYGBP plus gastric fundus resection (LRYGBP+FR). All patients were evaluated before and at 3, 6, and 12 months postoperatively. Blood samples were collected after an overnight fast and 30, 60, and 120 min after a standard 300-kcal mixed meal. RESULTS: Body weight and body mass index decreased markedly and comparably after both procedures. Fasting ghrelin decreased 3 months after LRYGBP, but increased at 12 months to levels higher than baseline while after LRYGBP+FR was markedly and persistently decreased. Postprandial GLP-1, PYY, and insulin responses were enhanced more and postprandial glucose levels were lower after LRYGBP+FR compared to LRYGBP. Postoperatively, ghrelin changes correlated negatively with GLP-1 changes. CONCLUSIONS: Resection of the gastric fundus in patients undergoing LRYGBP was associated with persistently lower fasting ghrelin levels; higher postprandial PYY, GLP-1, and insulin responses; and lower postprandial glucose levels compared to LRYGBP. These findings suggest that fundus resection in the setting of LRYGBP may be more effective than RYGBP for the management of morbid obesity and diabetes type 2.

Biliopancreatic diversion with Roux-en-Y gastric bypass and long limbs: advances in surgical treatment for super-obesity.

BACKGROUND: Over the past 14 years, we have used different malabsorptive bariatric operations to treat super-obesity. We compared the efficacy and safety of our preferred procedure for the last 8 years with previous methods used in super-obese. METHODS: Our first procedure was distal Roux-en-Y gastric bypass (distal RYGBP) (gastric pouch 15 ± 5 mL, 80 cm biliopancreatic limb, 100 cm common limb [CL]). The second was distal RYGBP with short alimentary limb (distal RYGBP-sAL) (gastric pouch 15 ± 10 mL, alimentary limb [AL] 250 cm, CL 100 cm). Our preferred procedure for the past 8 years has been biliopancreatic diversion with RYGB and long limbs (BPD-RYGB-LL) (gastric pouch 40 ± 10 mL, AL 400 cm, CL 100 cm). RESULTS: Seventy-five patients underwent distal RYGBP, 44 distal RYGBP-sAL, and 841 BPD-RYGB-LL. Eight years postoperatively, the mean BMIs were 39.0, 29.4, and 29.2, respectively. The greatest reduction of 47.6% was achieved with BPD-RYGB-LL (distal RYGBP 30.6%; distal RYGBP-sAL 43.1%). Mean excess weight loss was 51.3% for distal RYGBP, 76.5% for distal RYGBP-sAL, and 80.9% for BPD-RYGB-LL. Six patients died at the early postoperative period. Sixteen patients died during the first eight postoperative years, of whom significantly more were after distal RYGBP-sAL (P = 0.0003). Complications were significantly more frequent after distal RYGBP-sAL (P = 0.001). All procedures led to rapid and sustained resolution of major comorbidities in almost all patients affected. Metabolic and nutritional deficiencies were similar and manageable. CONCLUSIONS: Our variant of biliopancreatic diversion (BPD-RYGB-LL) results in substantial and sustained weight loss in super-obese, without compromising safety.

Bone mass decreases in morbidly obese women after long limb-biliopancreatic diversion and marked weight loss without secondary hyperparathyroidism. A physiological adaptation to weight loss?

OBJECTIVE: To investigate the effect of marked weight loss after long limb-biliopancreatic diversion (BPD-LL) on bone mass and serum calcium, 25-OH-vitamin D, and PTH levels in relation to calcium supplementation. BACKGROUND DATA: BPD is the most effective type of bariatric surgery, but it is followed by bone mass loss, mainly attributed to calcium and vitamin D malabsorption leading to secondary hyperparathyroidism. METHODS: Two groups, each consisting of 26 healthy, morbidly obese, premenopausal women, underwent BPD-LL. Both groups received high-calcium diets, 200 IU of vitamin D and 100 mg elemental calcium daily and group B, in addition to an extra 2 g of calcium. Bone density and biochemical markers were measured before and 12 months after BPD-LL. RESULTS: One year after surgery, both groups had lost an average of 55 kg of body weight; albumin-corrected calcium concentration did not change. 25-OH-vitamin D levels in group A were 17.34 +/- 8.90 pre- and 20.51 +/- 14.71 microg/L postoperatively (p = 0.058), and in group B, 15.70 +/- 9.46 and 13.52 +/- 8.16 microg/L (p = 0.489), respectively. PTH levels in group A were 38.5 +/- 12.2 before and 51.2 +/- 32.8 pg/ml after surgery (p = 0.08), and in group B, 48.1 +/- 26.3 and 52.9 +/- 29.2 pg/ml (p = 0.147), respectively. Bone formation markers (alkaline phosphatase, osteocalcin and procollagen type 1), as well as the bone resorption marker CTx, increased significantly in both groups. Bone mineral density T score was 0.862 +/- 0.988 in group A and 0.851 +/- 1.44 in group B and declined postoperatively to -0.123 +/- 1.082 and 0.181 +/- 1.285, respectively. CONCLUSIONS: Marked weight loss after BPD-LL leads to increased bone turnover and normalization of the increased bone mass without calcium or vitamin D malabsorption and without the appearance of secondary hyperparathyroidism. We conclude that the bone mass reduction is a normal adaptation to the decreased loading of the bone following weight loss.

The insulin-like growth factor-I (IGF-I) generation test as an indicator of growth hormone status.

OBJECTIVE: The aim of the study was to evaluate the IGF-I generation test (IGF-I gen) as a possible indirect test of Growth Hormone (GH) secretory status. METHODS: Sixty-five GH deficient (GHD 1 and 2) and 86 control children were studied. Children in the GHD-1 subgroup (n=33) had low GH values (<10 microg/L) after clonidine and levo-dopa while those in the GHD-2 subgroup (n=32) had normal GH values after pharmacologic provocation but low 24-hour GH secretory rates compared to 187 Normal Statured (NS) children. Of the 86 controls, who underwent IGF-I gen,50 were NS and 36 Short-Statured (SS). Serum IGF-I was measured prior to and daily during hGH administration (hGH 0.033 mg/kg/dayx4 days). RESULTS: The prepubertal and pubertal GHD-1 and GHD-2 children had low baseline IGF-I values but their peak IGF-I values during the IGF-I gen reached those of the controls. The percent increase of IGF-I during the test was greater in the GHD groups than in the controls; in the prepubertal groups: 516+/-58% in the GHD-1, 433+/-50% in the GHD-2, 106+/-12% in the NS, and 102+/-18% in the SS (p=0.001); in the pubertal groups: 191+/-28% in the GHD-1, 141+/-20% in the GHD-2, 48+/-8% in the NS, and 61+/-17% in the SS (p=0.003). CONCLUSIONS: The IGF-I response during the IGF-I gen seems to reflect the GH status in children.

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/m(2), 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.

Combined growth hormone-releasing hormone and growth hormone-releasing peptide-6 test for the evaluation of growth hormone secretion in children with growth hormone deficiency and growth hormone neurosecretory dysfunction.

BACKGROUND: The combined growth hormone-releasing hormone and growth hormone-releasing peptide-6 (GHRH + GHRP-6) test is most potent in evaluating GH secretion. AIMS: To assess its capability in children with GH deficiency and low spontaneous GH secretion (GH neurosecretory dysfunction). METHODS: 35 children with GH <10 microg/l after levo-dopa/clonidine (GHD), 15 with normal provocative tests but abnormal 24-hour spontaneous GH secretion (GHND), and 20 controls (C) were given 1 microg/kg of GHRH and GHRP-6 i.v. and GH (microg/l) was measured at -15, 0, 5, 10, 15, 30, 45 and 60 min. RESULTS: Six were nonresponders to the combined test, with significantly lower peak GH 20.7 (7.8-31.8) than C and the rest of the patients (responders). Peak GH was similar between prepubertal (PP) controls 167 +/- 88, GHD 202 +/- 110 and GHND 155 +/- 83. Pubertal (P) controls had higher peak GH 328 +/- 149 than P-GHD 203 +/- 105 and P-GHND 186 +/- 105. While P-C had higher peak GH than PP-C, PP and P children had similar responses within the GHD and GHND groups. CONCLUSIONS: The GHRH + GHRP-6 test detects children with severe GH insufficiency. Patients with GHD respond similarly to those with GHND, indicating a possible hypothalamic GH neuroregulatory dysfunction in GHD. Responders to the combined test may be eligible for treatment with a synthetic GH secretagogue.

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 < or = 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.

Resolution of diabetes mellitus and metabolic syndrome following Roux-en-Y gastric bypass and a variant of biliopancreatic diversion in patients with morbid obesity.

BACKGROUND: Obesity is associated with increased prevalence of type 2 diabetes mellitus (DM2) and metabolic syndrome and increased morbidity and mortality. Bariatric surgery results in significant and long-term weight loss. Two of the most effective and popular bariatric procedures are Roux-en-Y gastric bypass (RYGBP) and biliopancreatic diversion (BPD). The objective of this study was to investigate the effects of RYGBP and BPD-RYGBP, a variant of BPD with a lower rate of metabolic deficiencies than BPD, on DM2 and the major components of metabolic syndrome in patients with morbid obesity and DM2. METHODS: The prospective database of our unit, from June 1994 until May 2006, was analyzed and 137 patients with DM2 were found. 26 underwent RYGBP (BMI 46.1 +/- 2.9 kg/m2) and 111 BPD-RYGBP (BMI 59.7 +/- 10.6 kg/m2). 7 of the patients were on insulin (4.90%) and 37 on oral hypoglycemic agents (25.87%). Pre- and postoperative medications, and clinical and biochemical parameters were considered in the analysis. The mean follow-up was 26.39 +/- 21.17 months. RESULTS: Excess weight loss was approximately 70% after either procedure. DM2 resolved in 89% and 99% of the cases following RYGBP and BPD-RYGBP, respectively. 2 years after BPD-RYGBP all the patients had blood glucose < 110 mg/dl, 95% had normal cholesterol, 92% normal triglycerides and 82% normal blood pressure. The respective values following RYGBP were 66%, 33%, 78% and 44%. Uric acid decreased significantly only after BPD-RYGBP. Liver enzymes improved in both groups. CONCLUSIONS: RYGBP and BPD-RYGBP are safe and lead to normalization of blood glucose, lipids, uric acid, liver enzymes and arterial pressure in the majority of patients, although this variant of BPD was more effective than RYGBP. We suggest that further studies should also investigate its usefulness in patients with milder degrees of obesity, DM2 and metabolic syndrome.

Growth hormone/JAK-STAT axis signal-transduction defect. A novel treatable cause of growth failure.

Primary cultured fibroblasts of four patients with idiopathic short stature and severe growth delay, which displayed normal growth hormone receptor expression presented a reduced ability for activation of signal transducer and activator of transcription-3 (STAT3). Impaired STAT3 activation was accompanied by cell-cycle arrest at the Go /G1 phase. Increased levels of the cyclin-dependent kinase inhibitor, p21(WAF/CIPI), and reduced levels of cyclins were also detected in these patients. High concentrations of human growth hormone (1000 ng x mL(-1)) added to the culture medium induced activation of STAT3 and reduced the levels of p21(WAF/CIPI) in the fibroblasts of the four idiopathic short stature children. Treatment of these children with exogenous human growth hormone significantly augmented their growth velocity. Overall, our study provides the first evidence linking the idiopathic short stature phenotype with a functional aberration in the growth hormone signal transduction cascade which can be successfully overcome by exposure to high doses of growth hormone.

The value of scintigraphy and ultrasonography in the preoperative localization of parathyroid glands in patients with primary hyperparathyroidism and concomitant thyroid disease.

UNLABELLED: Parathyroid scintigraphy and high-resolution ultrasonography are frequently used as preoperative localization procedures in primary hyperparathyroidism. However, when thyroid disease coexists, their diagnostic accuracy is probably abated. DESIGN: 56 patients with primary hyperparathyroidism were prospectively evaluated with parathyroid scintigraphy (with either thallium or technetium-99m agents or both) and 44 of them were also evaluated with ultrasonography. RESULTS: 33 patients (59%) had coexistent thyroid disease. Upon operation, 48 patients were found to have a solitary parathyroid adenoma and were all cured. One patient had a carcinoma and 7 had multiglandular parathyroid disease. Regarding solitary lesions, the sensitivity of parathyroid scintigraphy with Tc-agents was 97% and thallium 78%, while that of ultrasonography was 74%. The false positive rate was 2.6%, 18%, and 22%, respectively. Concomitant thyroid disease had a non-significant effect on the results of parathyroid scintigraphy and ultrasonography. The efficiency of both modalities in diagnosing multiglandular disease was low (only 3/7 patients, 43%). CONCLUSIONS: Parathyroid scintigraphy, in conjunction with Sestamibi or Tetrofosmin, constitutes the most sensitive localizing technique as regards solitary lesions. Ultrasonography is also useful in confirming scintigraphic findings, offers more precise anatomic information, and is valuable in the evaluation of concomitant thyroid disease. The complementary use of parathyroid scintigraphy and ultrasonography is beneficial and efficacious in areas with high prevalence of thyroid disease. The value of these modalities is considerably lower in multiglandular disease.

Restoration of euglycemia and normal acute insulin response to glucose in obese subjects with type 2 diabetes following bariatric surgery.

Insulin resistance and loss of glucose-stimulated acute insulin response (AIR) are the two major and earliest defects in the course of type 2 diabetes. We investigated whether weight loss after bariatric surgery in patients with morbid obesity and type 2 diabetes could restore euglycemia and normal AIR to an intravenous glucose tolerance test (IVGTT). We studied 25 morbidly obese patients-12 with type 2 diabetes, 5 with impaired glucose tolerance, and 8 with normal glucose tolerance (NGT)-before and after a biliopancreatic diversion (BPD) with Roux-en-Y gastric bypass (RYGBP). Twelve individuals with normal BMI served as control subjects. Twelve months after surgery, in the diabetes group, BMI decreased from 53.2 +/- 2.0 to 29.2 +/- 1.7 kg/m(2), fasting glucose decreased from 9.5 +/- 0.83 to 4.5 +/- 0.13 mmol/l, and fasting insulin decreased from 168.4 +/- 25.9 to 37.7 +/- 4.4 pmol/l (mean +/- SE; P < 0.001). AIR, the mean of insulin concentration at 2, 3, and 5 min over basal in the IVGTT, increased by 770 and 935% at 3 and 12 months after surgery, respectively (from 24.0 +/- 22.7 to 209 +/- 43.4 and 248 +/- 33.1 pmol/l, respectively; P < 0,001). Conversely, in the NGT group, the AIR decreased by 40.5% (from 660 +/- 60 to 393 +/- 93 pmol/l; P = 0.027) 12 months after surgery. BPD with RYGBP performed in morbidly obese patients with type 2 diabetes leads to significant weight loss, euglycemia, and normal insulin sensitivity; but most importantly, it restores a normal beta-cell AIR to glucose and a normal relationship of AIR to insulin sensitivity. This is the first study to demonstrate that the lost glucose-induced AIR in patients with type 2 diabetes of mild or moderate severity is a reversible abnormality.