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Setting: Obesity surgery has been proposed as a treatment option for diabetic patients with body mass index (BMI)<35 kg/m(2), but the efficacy of metabolic surgery has not been conclusively determined., Objectives: To evaluate the long-term metabolic outcome of non-morbidly obese (NMO) patients with type 2 diabetes (T2D) after biliopancreatic diversion (BPD)., Material and Methods: Two groups of T2D patients with different degree of obesity (NMO, 17 cases, BMI 25-35 kg/m(2); and morbidly obese [MO], 13 cases, BMI>35 kg/m(2)) were studied before and at 1 and 5 years after BPD in a university hospital setting. Insulin secretion was assessed by acute insulin response (AIR) to intravenous glucose and by insulinogenic index (IGI)., Results: In all MO patients, T2D was remitted or controlled (1 case) at 1 year and results were maintained at 5 years; AIR (μU/mL) and IGI (μU/mg) improved (P<.001) at 1 year (from .1±3.1 to 18.52±21.9, and from 6.0±8.5 to 9.1±22.8, respectively) with a further increase (to 24.8±25.5 and to 14.3±13.8, respectively) at 5 years. Within the NMO group, T2D was remitted in 1/17 and controlled in 14/17 patients at 1 year, and in 2/17 and in 4/17 patients at 5 years, respectively; AIR (μU/mL) and IGI (μU/mg) remained unchanged throughout the postoperative period (from .31±9.26 to 1.5±2.8 at 1 yr and to .4±3.29 at 5 yr for AIR, and from 2.2±4.9 to 1.3±9.0 at 1 yr and to 2.3±3.3 at 5 yr for IGI)., Conclusions: After BPD, restoration of β-cell secretion/production plays a pivotal role in determining postoperative T2D remission., (Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background and Aim: 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., Methods and Results: 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, P<0.003). A positive correlation between fasting ghrelin and hunger rating (r=0.52, P<0.01) 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., Conclusions: In healthy subjects a longer fasting period increases ghrelin concentration but did not affect post-prandial ghrelin response to a mixed meal.

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.

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 associated kinase activity and its relationships with the insulin resistance of streptozotocin-induced diabetes were investigated in rats, using solubilized, partially purified insulin receptors from liver membranes. Insulin receptor kinase activity was measured by means of both autophosphorylation and phosphorylation of the exogenous substrate Glu4:Tyr1. Diabetes was associated with a 45% reduction in kinase activity, in the same number of insulin receptors, with no change in insulin binding affinity. To investigate the independent roles of hyperglycemia and hypoinsulinemia on the observed impairment of receptor kinase activity, diabetic rats were fasted for 24 h in order to normalize blood glucose levels only. After this short fast, no change in kinase activity, from the values measured in fed diabetic animals, was observed. Our findings suggest that streptozotocin diabetes is associated with a reduction of insulin receptor kinase activity, which a short fast is not able to reverse.

IGF I receptor is a tyrosine kinase capable of phosphorylating the receptor itself and other substrates. A high degree of homology does exist in tyrosine kinase domain among receptors for several polypeptide growth factor receptors and this enzymic activity has been indicated as a possible mediator of biological action. Nevertheless growth factor receptors possess peculiar specificities both in their functions and tissue distribution. A human polyclonal IgG (pIgG), previously characterized as anti insulin receptor antibody, able to inhibit insulin receptor kinase activity, was used to further investigate subunit homologies and differences in antigenicity and functional regulation between IGF I and insulin receptors, IGF I receptor tyrosine kinase was stimulated by a IGF I analog (aIGF I), produced by DNA recombinant technology, pIgG was able to inhibit IGF I receptor kinase activity, thus revealing antigenic homologies between the kinase domains of insulin and IGF I receptors. However the more pronounced inhibition of IGF I receptor-compared with insulin receptor kinase activity by pIgG suggests the existence of different regulatory mechanisms.

The immunoglobulin G of a polyclonal antiserum (pIgG) from a patient with insulin resistance and hypoglycemia was tested for its ability to inhibit insulin binding and to affect the autophosphorylation of partially-purified insulin receptors extracted from rat liver membranes. pIgG, when added 4 hr prior to insulin, inhibited subsequent insulin binding by 50% at 30 micrograms added protein; however, insulin previously bound to the receptor could not be displaced by a 4 hr subsequent exposure of up to 70 micrograms pIgG. pIgG, independent of its effect on insulin binding, inhibited both basal and insulin-stimulated autophosphorylation of the insulin receptor in a dose-dependent manner with a half maximal effect at 3.3 to 7 micrograms protein. Furthermore, pIgG also reduced basal autophosphorylation of the EGF receptor. The effect of pIgG to inhibit basal autophosphorylation of insulin and EGF receptors, together with its ability to reduce autophosphorylation of insulin receptors fully occupied by insulin, imply that the effect of pIgG on receptor autophosphorylation is largely independent of its effect on ligand binding. Moreover, these findings suggest that pIgG may inhibit autophosphorylation by acting on domains which are similar in the insulin and EGF receptors.