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Aim Bariatric surgery has been shown to effectively improve glycaemic control in morbidly obese subjects. However, the molecular bases of this association are still elusive and may act independently of weight loss. Here, our retrospective study has investigated the inflammatory molecule osteopontin (OPN) as a potential predictor of type 2 diabetes mellitus (T2DM) remission. Methods Baseline serum levels of OPN were analyzed in 41 T2DM patients who underwent bariatric surgery. Anthropometric measures and biochemical variables, including insulin sensitivity indices (HOMA2), were assessed at baseline and at 1 and 3 years after surgery. Results At baseline, patients who experienced T2DM remission had increased waist circumference, body weight and BMI, and higher serum OPN, compared with non-remitters. Patients with and without T2DM remission improved their lipid and glucose profiles, although insulin resistance indices were only improved in the T2DM remission group. In the overall cohort of both T2DM remission and non-remission patients, baseline circulating levels of OPN significantly correlated with reductions of body weight and BMI over time, and insulin sensitivity improved as well. However, only the HOMA2-%S remained independently associated with serum OPN on multivariate linear regression analysis (B: 0.227, 95% CI: 0.067–0.387, β = 0.831; P = 0.010). Baseline values of OPN predicted 3-year T2DM remission independently of body weight loss, lower BMI and duration of diabetes (OR: 1.046, 95% CI: 1.004–1.090; P = 0.033). Conclusion Although larger studies are still needed to confirm our preliminary results, pre-operative OPN serum levels might be useful for predicting 3-year T2DM remission independently of weight loss in patients undergoing bariatric surgery.

This study is concerned with an evaluation of the effects of glucocorticoids (GC) on adiponectin and leptin concentrations in patients with polymyalgia rheumatica (PMR). Seven patients diagnosed with PMR were studied at baseline and after one and three months of prednisone treatment. Serum leptin and adiponectin, serum glucose and insulin, erythrocyte sedimentation rate, C-reactive protein, and IL-6 were all measured by commercial assays. The treatment with GC normalized inflammation markers and significantly increased adiponectin and leptin concentrations without any impairment of insulin sensitivity measured by HOMA-IR. Adiponectin significantly increased only between baseline and 1 month (P= 0.013). A significant correlation was found between adiponectin and leptin concentrations both at baseline and after 3 months of treatment (both rho = 0.89, P= 0.03). In addition, adiponectin correlated also with serum glucose at baseline (rho = 0.81, P= 0.047). According to our results, adiponectin concentrations seem to be driven by inflammation, whereas leptin seems to be increased directly by the use of steroids.

Changes in body composition, hormone secretions, and heart function with increased risk of sudden death occur in eating disorders. In this observational clinical study, we evaluated sympathovagal modulation of heart rate variability (HRV) and cardiovascular changes in response to lying-to-standing in patients with anorexia (AN) or bulimia nervosa (BN) to analyze: a) differences in autonomic activity between AN, BN, and healthy subjects; b) relationships between autonomic and cardiovascular parameters, clinical data and leptin levels in patients with eating disorders. HRV, assessed by power spectral analysis of R-R intervals, blood pressure (BP) and heart rate (HR) were studied by tilt-table test in 34 patients with AN, 16 with BN and 30 healthy controls. Autonomic and cardiovascular findings were correlated with clinical data, and serum leptin levels. Leptin levels were lowered in AN vs BN and healthy subjects (p

The inhibitory effect of food on ghrelin secretion is reduced in several eating disorders such as restricting type anorexia nervosa, bulimia and obesity. These conditions are frequently characterised by irregular distribution of meals during the day. It is unknown whether two short fasting periods different duration affect ghrelin response to a mixed meal. Aim of the present study was to examine, in healthy volunteers, the effects of two fasting periods of different duration on pre- and post-prandial ghrelin concentrations after a standard mixed meal.Nine healthy men (mean age+/-S.E.M., 25.1+/-0.2 years; mean body mass index+/-S.E.M., 22.6+/-0.3kg/m2) were studied in 2 days after 12h of fasting (12F) and 17h of fasting (17F) with a within-subject repeated measure design. On both days they ate a standardized mixed meal. Before each meal hunger rating was evaluated with a visual analogue score. Blood samples for ghrelin, insulin, and glucose were collected at 0, 45, 60, 90, 120, 150 and 180min after meal. Comparing fasting values of 17F with 12F there was a significant increase in plasma ghrelin (160+/-20 vs. 146+/-18fmol/mL, P=0.015) and hunger rating (evaluated with a visual analogue scores) (7.0+/-0.3 vs. 5.1+/-0.4, P0.003). A positive correlation between fasting ghrelin and hunger rating (r=0.52, P0.01) was found. Circulating ghrelin decreased after both meals without any significant difference in relation with the previous length of fasting. Also postmeal ghrelin AUC as well as fasting and postmeal concentrations of insulin and glucose were similar after 12F and 17F.In healthy subjects a longer fasting period increases ghrelin concentration but did not affect post-prandial ghrelin response to a mixed meal.

Objective. To investigate the relationship between insulin resistance and viral load decay in nondiabetic and noncirrhotic genotype 1 chronic HCV patients during peginterferon and ribavirin treatment and the possible influence of BMI and leptin as metabolic confounders.Methods. 75 consecutive noncirrhotic, nonobese, and nondiabetic patients with genotype 1 chronic hepatitis C treated with peginterferon alpha 2a plus ribavirin were evaluated. HOMA-IR, serum leptin, and BMI were measured in all patients at baseline and at weeks 12 and 48, whereas viral load was measured at the same time points and then 24 weeks after the end of treatment.Results. HOMA-IR was significantly associated with both BMI and leptin at baseline. During peginterferon plus ribavirin treatment, there was a significant reduction of HOMA-IR at weeks 12 and 48 from baseline (P=0.033and 0.048, resp.) in patients who achieved an early viral load decay (EVR), a trend not observed in patients who not achieved EVR. No variations during treatment were observed regarding BMI and leptin irrespective of EVR.Conclusion. The early reduction of HOMA-IR but not of BMI and leptin during antiviral treatment in noncirrhotic, chronic hepatitis C genotype 1 patients who achieved EVR suggests a viral genesis of insulin resistance in patients with nonmetabolic phenotype.

Objective: Ghrelin is a recently discovered hormone that is produced mainly by the stomach and that increases food intake in rodents and humans. It has been postulated that the weight loss after gastric bypass surgery for obesity might be related to changes in serum ghrelin concentration. Research Methods and Procedures: Serum leptin and ghrelin concentrations were measured in a group of obese patients before biliopancreatic diversion (BPD) and 2 and 12 months postoperatively. Insulin sensitivity was determined from serum glucose and insulin levels according to the homeostatic model of assessment for insulin resistance (HOMA IR). Results: A sharp drop was observed in body weight, in BMI values, in HOMA IR data, and in serum leptin concentration at 2 and 12 months after BPD, whereas a significant increase of serum ghrelin level was observed at 12 months, when food intake had returned to preoperative levels. A negative correlation between the postoperative changes of serum ghrelin concentration and those of HOMA IR values was observed at 2 and 12 months after BPD. Discussion: No evidence upholding a relationship between serum ghrelin concentration and food intake after BPD was seen; the postoperative changes likely reflected the achievement of a new state of energy balance. The negative relationship observed between post-BPD changes in HOMA IR values and changes in serum ghrelin concentration supported the role of insulin in the modulation of ghrelin production.

We investigated the effects of a ser for cys 860 mutation, located in the extracellular portion of insulin receptor beta subunit, on several receptor functions. CHO cells, stably transfected with the mutated cDNA, were used for this study. In the present paper, we show that the ser 860 mutation does not affect the 125I-insulin binding, but severely impairs the insulin-insulin receptor complex internalization. The kinetic analysis of internalization indicates that this process is inhibited at steps preceding the coated pit endocytosis. The beta subunit autophosphorylation of the mutated receptor is higher both in the basal and insulin stimulated states, compared with autophosphorylation measured in wild type insulin receptors. The ser 860 mutation impairs also the insulin receptor down regulation, thus suggesting an effect on the intracellular sorting of insulin-insulin receptor complex. On the basis of these results we suggest that the cys 860 plays an important role in insulin receptor lateral moving on cell surface, after insulin binding, and on the intracellular sorting to degradation pathways.

The plant hormone abscisic acid (ABA) is released from glucose-challenged human pancreatic β cells and stimulates insulin secretion. We investigated whether plasma ABA increased during oral and intravenous glucose tolerance tests (OGTTs and IVGTTs) in healthy human subjects. In all subjects undergoing OGTTs (n=8), plasma ABA increased over basal values (in a range from 2- to 9-fold). A positive correlation was found between the ABA area under the curve (AUC) and the glucose AUC. In 4 out of 6 IVGTTs, little or no increase of ABA levels was observed. In the remaining subjects, the ABA increase was similar to that recorded during OGTTs. GLP-1 stimulated ABA release from an insulinoma cell line and from human islets, by ∼10- and 2-fold in low and high glucose, respectively. Human adipose tissue also released ABA in response to high glucose. Nanomolar ABA stimulated glucose uptake, similarly to insulin, in rat L6 myoblasts and in murine 3T3-L1 cells differentiated to adipocytes, by increasing GLUT-4 translocation to the plasma membrane. Demonstration that a glucose load in humans is followed by a physiological rise of plasma ABA, which can enhance glucose uptake by adipose tissues and muscle cells, identifies ABA as a new mammalian hormone involved in glucose metabolism.-Bruzzone, S., Ameri, P., Briatore, L., Mannino, E., Basile, G., Andraghetti, G., Grozio, A., Magnone, M., Guida, L., Scarfì, S., Salis, A., Damonte, G., Sturla, L., Nencioni, A., Fenoglio, D., Fiory, F., Miele, C., Beguinot, F., Ruvolo, V., Bormioli, M., Colombo, G., Maggi, D., Murialdo, G., Cordera, R., De Flora, A., Zocchi, E. The plant hormone abscisic acid increases in human plasma after hyperglycemia and stimulates glucose consumption by adipocytes and myoblasts.

Beneficial effects of BPD on T2DM in BMI >35 kg/m2 patients are far better than those in patients with BMI 25–35. This study was aimed at investigating if a similar difference exists between patients with mild obesity (OB, BMI 30–35) or simple overweight (OW, BMI 25–30). Fifteen OB (six M) and 15 OW (13 M), diabetic for ≥3 years, with HbA1c ≥7.5% despite medical therapy, underwent BPD. OB/OW: age 55.1 ± 8.0/57.8 ± 6.7 years, BMI 33.1 ± 1.5/28.0 ± 1.3 kg/m2, diabetes duration 11.6 ± 8.0/11.1 ± 6.1 years, insulin therapy 4/8 p. FSG and HbA1c were determined preoperatively and up to 2 years. Insulin resistance and beta-cell function were explored by means of HOMA-IR and IVGTT (AIR). Thirty-eight diabetic patients on medical therapy served as controls. Mean BMI stabilized around 27 since the 4th month in OB, and 24 since 1st month in OW. FSG in OB/OW preop, 1, 12, 24 months: 234 ± 76/206 ± 62 mg/dL, 154 ± 49/176 ± 75, 131 ± 32/167 ± 48, 134 ± 41/154 ± 41 (cross-sectional n.s. at all times); HbA1c: 9.5 ± 1.6/9.1 ± 1.3, 7.3 ± 1.1/7.3 ± 1.2, 5.9 ± 0.6/7.1 ± 1.1 (p

In subjects with obesity and type 2 diabetes mellitus (T2DM), biliopancreatic diversion (BPD) improves glucose stimulated insulin secretion, whereas the effects on other secretion mechanisms are still unknown. Our objective was to evaluate the early effects of BPD on nonglucose-stimulated insulin secretion. In 16 morbid obese subjects (9 with T2DM and 7 with normal fasting glucose (NFG)), we measured insulin secretion after glucose-dependent arginine stimulation test and after intravenous glucose tolerance test (IVGTT) before and 1 month after BPD. After surgery the mean weight lost was 13% in both groups. The acute insulin response during IVGTT was improved in T2DM after BDP (from 55 +/- 10 to 277 +/- 91 pmol/l, P = 0.03). A reduction of insulin response to arginine was observed in NFG, whereas opposite was found in T2DM. In particular, acute insulin response to arginine at basal glucose concentrations (AIR(basal)) was reduced but insulin response at 14 mmol/l of plasma glucose (AIR(14)) was increased. Therefore, after BPD any statistical difference in AIR(14) between NFG and T2DM disappeared (1,032 +/- 123 for NFG and 665 +/- 236 pmol/l for T2DM, P = ns). The same was observed for Slope(AIR), a measure of glucose potentiation, reduced in T2DM before BPD but increased after surgery, when no statistically significant difference resulted compared with NFG (Slope(AIR) after BPD: 78 +/- 11 in NFG and 56 +/- 18 pmol/l in T2DM, P = ns). In conclusion, in obese T2DM subjects 1 month after BPD we observed a great improvement of both glucose- and nonglucose-stimulated insulin secretions. The mechanisms by which BDP improve insulin secretion are still unknown.

Background: Some extra-thyroid effects of TSH have been described in vitro and in vivo. TSH has recently been suggested to induce interleukin-6 secretion by adipocytes. Leptin is the main protein secreted by adipose tissue. Objective: The aim of our study was to evaluate the acute effect of the recombinant human TSH (rhTSH)-induced TSH surge on serum leptin levels in thyroidectomized patients undergoing levothyroxine (L-T4) suppressive therapy for differentiated thyroid carcinoma (DTC). Design: A cohort of 15 female DTC patients was evaluated. Standard rhTSH testing was performed. Leptin, TSH, thyroid hormones, and thyroglobulin were measured before and 3, 6, and 9 days after rhTSH testing. Some metabolic parameters were also evaluated at the baseline. Results: Baseline leptin levels were 12.2±3.2 μg/l. Only body mass index (BMI) correlated significantly (p

Gender differences in leptin, ghrelin, and adiponectinlevels have been described in a normal population. This is importantfor understanding differences between males and females in theregulation of food intake, weight gain, body fat distribution, andcardiovascular risk. It is unclear how endogenous and exogenoussex hormones may regulate circulating levels of these factors.Transsexuals during hormonal treatment may represent an idealmodel to ascertain the role of exogenous sex hormones on theseparameters. In this study, our objective was to evaluate adiponectin,ghrelin, and leptin levels in transsexual subjects during hormonetherapy and to compare the results of males and females. Subjectswere 26 nondiabetic transsexuals, which included 15 male-to-female(M-to-F, group 3) and 11 female-to-male (F-to-M, group 4)individuals, and 29 age- and BMI-matched controls, which included15 males (group 1) and 14 females (group 2). Results showed thatleptin levels were significantly lower in group 1 compared with group2(P 5 .04) and group 3 (P 5 .01); no differences were recordedbetween the other groups. Adiponectin levels were significantlyhigher in group 3 compared with group 4 (P 5 .03). No differenceswere found between the 4 groups for ghrelin levels. In conclusion,our data confirm the sexual dimorphism in serum leptin levels innormal subjects and demonstrate an increase in M-to-F transsexu-als. While ghrelin does not show any sexual differences and seemsnot to be influenced by exogenous sex hormone administration, thelower adiponectin levels in F-to-M transsexuals during treatmentconfirm that androgens may decrease plasma adiponectin levels.This latter observation suggests that F-to-M transsexual patientscould have a higher cardiovascular risk.Key words: Cardiovascular risk, sexual hormones, metabolicparameters.J Androl 2008;29:580–585

The mechanism (both at the whole body and cellular level) by which metformin improves insulin sensitivity has yet to be defined. In the present study, we examined in vivo insulin-mediated whole-body glucose disposal, glycogen synthesis, hepatic glucose production, and insulin secretion, as well as in vitro muscle insulin receptor tyrosine kinase activity in eight control, eight neonatal streptozotocin diabetic rats, and eight diabetic rats before and after treatment with metformin. Ten weeks after birth diabetic rats had higher fasting (132 + 5 v 101 + 2 mg/dL) and postmeal (231 + 10 v 133 + 3) plasma glucose levels compared with controls (P less than .001). Metformin treatment was followed by a significant decrease in the growth rate and normalized glucose tolerance without enhancing the deficient insulin response. Insulin-mediated glucose uptake in diabetic versus control rats was reduced (P less than .01) during the high-dose (15.4 + 0.6 v 18.3 + 1.0 mg/kg.min) insulin clamp study and was increased to values greater (P less than .05) than controls following metformin treatment. Muscle glycogen synthetic rate in vivo, measured by incorporation of 3H-3-glucose radioactivity, was diminished by 25% (P less than .01) in diabetic rats, restored to normal values with metformin, and correlated closely (r = .82, P less than .002) with total-body glucose uptake during the insulin clamp in all three groups. Insulin receptor tyrosine kinase activity, measured in partially purified insulin receptors, was reduced in diabetic rats and increased to supernormal levels after metformin. The decrease in muscle tyrosine kinase activity in diabetic versus control animals was entirely accounted for by a reduction in maximal velocity (Vmax) (32 v 45 pmol/mg.min, P less than .01) and increased to supernormal levels following metformin (91 pmol/mg.min, P less than .001) without any change in affinity (Km). Muscle tyrosine kinase activity was closely correlated with both the muscle glycogen synthetic rate (r = .82, P less than .002) and total-body insulin-mediated glucose disposal (r = .64, P less than .01) in vivo. The close correlation between in vivo insulin action, muscle glycogen synthesis, and muscle insulin receptor tyrosine kinase activity is consistent with an important role of the enzyme in the insulin resistance of diabetes and its improvement following metformin treatment.

Background: Ghrelin is a hormone that increases food intake in rodents and in humans. After gastric bypass surgery, a marked decrease in circulating ghrelin levels has been observed, and it was suggested that this may contribute to the weight-reducing effect of gastric bypass. In this study, the changes in circulating ghrelin levels following biliopancreatic diversion (BPD) were investigated. Materials and Methods: Serum ghrelin concentration was measured in obese patients prior to and 5 days and 2 months following BPD. Results: At the short-term following BPD, marked reduction of serum ghrelin was observed, while thereafter the values returned to initial levels. Conclusion: Unlike following reducing diet or gastric bypass, following BPD only an initial reduction of serum ghrelin concentration was observed, while at 2 months following the operation, when food intake had nearly completely resumed, the values returned to the preoperative levels. This is consistent with the hypothesis that ghrelin production from the stomach is greatly influenced by the direct contact of ingested food with the gastric cells.

The C860S mutation (IRC860S) in the extracellular domain of the insulin receptor beta-subunit has previously been shown to result in an inhibition of insulin receptor internalization. The present work aims at further dissecting the consequences of this mutation not only on insulin receptor internalization, but also on the signaling of the receptor. Following transfection of Chinese hamster ovary (CHO) cells with insulin receptors with the C860S mutation (CHO-IRC860S) and quantitative electron microscopic analysis of [125I]insulin localization in these cells, the inhibition of receptor internalization appears to be due to an inhibition of the lateral translocation of the receptor from microvilli to nonvillous domains of the cell surface. At 37 C, insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation is inhibited by 50% in CHO-IRC860S, whereas Shc phosphorylation remains unaffected. The inhibition of IRS-1 phosphorylation is still present when experiments are conducted at 4 C, a temperature at which insulin receptor internalization is prevented, suggesting that the defect in IRS-1 phosphorylation is not due to the reduced internalization of the receptor. In terms of biological effects, the mutation has negative consequences on insulin-stimulated c-fos expression and DNA synthesis as well as on glycogen synthase activity. Eventually, the events observed are specific for Cys860, as individual substitution of the two more proximal Cys residues (795 and 872) to Ser is not accompanied by any change in either insulin-induced insulin receptor internalization or IRS-1 phosphorylation. Thus, the present analysis of CHO-IRC860S 1) reveals that insulin receptor surface redistribution is not solely dependent on receptor autophosphorylation, 2) emphasizes that IRS-1 phosphorylation is not dependent on receptor internalization and can be triggered from microvilli, and 3) stresses divergent aspects between two of the major signaling pathways of the insulin receptor.

We investigated the influence of the relative abundance of insulin and IGF-1 receptors on cellular growth, by measuring the stimulation of c-fos expression and of H3-thymidine incorporation into DNA by insulin and IGF-1 in CHO cells overexpressing insulin Receptor (CHO-IR). We found that CHO-IR cells were resistant to the action of IGF-1, but were more responsive to insulin, compared to parental clone. This result suggest the presence of a limiting step, distal to the IGF-1 receptor, in the transduction pathway. To address this question we measured the IGF-1 effect on c-fos expression in CHO-IR cells, transiently transfected with the cDNA for IRS-1, the common intracellular substrate for both insulin and IGF-1 receptors (CHO-IR/IRS-1 cells). In these cells IGF-1 stimulated a 10 fold higher c-fos expression compared to CHO-IR cells. These results suggest that the abundance of IRS-1, relative to the number of insulin and IGF-1 receptors, represents a limiting step for the intracellular transduction of insulin and IGF-1 biological messages.

Sodium vanadate activates "in vitro" insulin receptor autophosphorylation and protein tyrosine kinase in a dose-dependent manner. Insulin receptor protein tyrosine kinase is directly activated also by the anti-insulin receptor beta subunit monoclonal antibody 18-44. We previously demonstrated that the anti-insulin receptor monoclonal antibody MA-10 decreases insulin-stimulated receptor protein tyrosine kinase activity "in vitro", without inhibiting insulin receptor binding. In this report we show that insulin receptor protein tyrosine kinase, activated by sodium vanadate or by monoclonal antibody 18-44, is inhibited by MA-10 antibody. These data suggest that insulin receptor protein tyrosine kinase activity can be either activated and inhibited through mechanisms different from insulin binding.

Insulin receptor beta-subunit autophosphorylation, the first event occurring after insulin binding, plays a crucial role in modulation of receptor-associated kinase activity towards exogenous substrates and possibly in the transmission of biological signals of insulin. Receptor autophosphorylation strongly depends on insulin receptor occupancy. Till now the effects of receptor phosphorylation on insulin binding itself have not been clarified. In the present report we demonstrate the absence of any feedback mechanism by which insulin receptor activation by phosphorylation affects binding affinity of insulin receptor itself.

We have studied the ability of mature red cells to regulate the number and affinity of their insulin receptors, in vitro. Our data show that mature red cells are not able to change either the number and the affinity of their insulin receptors, after preincubation with high concentrations of insulin alone or insulin and glucose. We conclude that mature red cells possess an insulin receptor system not completely similar to that of major target cells such as hepatocytes and adipocytes, and therefore we suggest some criticism in evaluating these cells in clinical studies, regarding the insulin receptor status.