Stimulation of insulin and somatostatin release by two meglitinide analogs

Several meglitinide analogs are currently under investigation as potential insulinotropic tools for the treatment of noninsulin-dependent diabetes. The present study aimed to further insight into the effect of these agents on the secretion of insulin, glucagon, and somatostatin by the isolated perfused pancreas. Both repaglinide (0.01 μM) and A-4166 (1.0 μM) stimulated insulin and somatostatin release, but failed to affect glucagon output, from pancreases exposed to 5.6 mM d-glucose. The secretory response of the B- and D-cells to the hypoglycemic agents was much less marked than that caused by a rise in hexose concentration from 5.6–16.7 mM. Although repaglinide was tested at a concentration a hundred times lower than that of A-4166, the drug-induced increase in both insulin and somatostatin secretion persisted for a longer time after exposure to repaglinide, than to A-4166. The relevance of these findings to the use of meglitinide analogs as antidiabetic agents is double. First, they document that these drugs, although enhancing both insulin and somatostatin release, do not provoke an undesirable stimulation of glucagon secretion. Second, they indicate that even at a very low concentration, repaglinide provokes a protracted insulinotropic action, thus suggesting that the reversibility of the secretory response to this or other meglitinide analogs represents an intrinsic molecular attribute, unrelated to either their biological potency or the relative extent of B-cell stimulation.     

性腺切除及急性饥饿对大鼠垂体-甲状腺功能的影响

本实验采用性腺摘除或经假摘除手术的两性SD大鼠,其中部分动物分别予以睾酮(T)或雌二醇(E_2),观察它们在急性饥饿或非饥饿状态下血清T_4、TSH与T浓度变化。结果提示急性饥饿可使雄鼠甲状腺合成或分泌T_4和性腺分泌睾酮减少,从而不完全地抑制了雄激素所介导的对垂体TSH分泌的兴奋作用。外源性T替代虽然可以使去势雄鼠血清T浓度恢复正常,但却无兴奋TSH分泌的作用;饥饿组去势雄鼠接受外源性T后血清TSH更为减少。提示外源性T可抑制此组雄鼠垂体TSH合成及(或)释放。     

A clinically integrated curriculum in Evidence-based Medicine for just-in-time learning through on-the-job training: The EU-EBM project

Background

Little research has been conducted to investigate role stress experienced by faculty members in medical schools in developing countries. This becomes even more important when the process of reform in medical education has already taken place, such as the case of Iran. The objectives of this study were to investigate and assess the level and source of role-related stress as well as dimensions of conflict among the faculty members of Iranian medical schools. Variables like the length of academic work, academic rank, employment position, and the departments of affiliation were also taken into consideration in order to determine potentially related factors.

Methods

A survey was conducted at three different ranks of public medical schools. The validated Organizational Role Stress Scale was used to investigate the level of role stress and dimensions of role conflict among medical faculty members. The response rate was 66.5%.

Results

The findings show that role stress was experienced in high level among almost all faculty members. All three studied medical schools with different ranks are threatened with relatively the same levels of role stress. Specific differences were found among faculty members from different disciplines, and academic ranks. Also having permanent position and the length of services had significant correlation with the level of role stress. The major role- related stress and forms of conflict among faculty members were role overload, role expectation conflict, inter-role distance, resource inadequacy, role stagnation, and role isolation.

Conclusion

The most role-related stressors and forms of conflict among faculty members include too many tasks and everyday work load; conflicting demands from colleagues and superiors; incompatible demands from their different personal and organizational roles; inadequate resources for appropriate performance; insufficient competency to meet the demands of their role; inadequate autonomy to make decision on different tasks; and a feeling of underutilization. The findings of this study can assist administrators and policy makers to provide an attractive working climate in order to decrease side effects and consequences of role stress and to increase productivity of faculty members. Furthermore, understanding this situation can help to develop coping strategies in order to reduce role-related stress.     

Interference of glycogenolysis with glycolysis in pancreatic islets from glucose-infused rats.

When pancreatic islets isolated from rats infused for 48-72 h with a hypertonic solution of D-glucose were incubated for two successive periods of 10 min each, in the presence first of 16.7 mM and then 2.8 mM D-[U-14C]glucose, the total output of L-lactic acid during the second incubation was as high as that recorded during the first incubation, while the specific radioactivity of L-lactic acid dramatically decreased during the second incubation. In islets from normoglycemic rats, however, the total output of L-lactic acid decreased and its specific radioactivity modestly increased as the concentration of D-glucose was lowered from 16.7 to 2.8 mM. Such contrasting results indicate that in the glycogen-rich islets isolated from glucose-infused rats, the fall in extracellular D-glucose concentration was not accompanied by a parallel fall in glycolytic flux, the decreased utilization of exogenous D-[U-14C]glucose coinciding with stimulation of glycogenolysis. This unusual metabolic situation also coincided with a transient and paradoxical stimulation of insulin release in response to the decrease in extracellular D-glucose concentration. It is proposed, therefore, that the interference of glycogenolysis with glycolysis in pancreatic islets from glucose-infused rats participates in the paradoxical changes in insulin output which represent a typical feature of B-cell glucotoxicity.     

Differences in T cell subsets between men and women with idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder, occurring predominantly in women. We studied by flow cytofluorimetry the T cell subsets in men and women with ITP and compared them with healthy sex-matched volunteers. In healthy controls, women were found to have higher proportions of T helper/inducer (Th/i) and lower T suppressor/cytotoxic (Ts/c) lymphocytes and consequently higher Th/i:Ts/c ratios than men. Accordingly, in clinical surveys, patients and controls should be matched for sex for proper comparisons. In patients with ITP in its active phase, an imbalance in T cell subsets was found in both sexes. The perturbation was more severe in women who had a marked decrease in number and proportion of Th/i lymphocytes and an increase in the proportion of Ts/c lymphocytes, whereas in men only, the proportion of Th/i lymphocytes was decreased. When patients with active disease were compared to those with ITP in remission, the decrease in Th/i subsets still persisted in both sexes but the Ts/c subset in women had returned to normal proportions. Therefore, the immune imbalance in ITP is more marked in women than men; imbalances in both Th/i and Ts/c are present in women while Ts/c appears not to be involved in men.     

Chronic effects of insulin and glucagon upon islet function

Summary Chronic administration of insulin to normal rats provokes a progressive reduction in both the pancreatic insulin content and the secretory responsiveness to glucose. The reduction of the secretory capacity is more marked than that of the stores of hormone. These results suggest that hyperinsulinism inhibits the secretory process within the beta-cell independently of its effects upon insulin synthesis. Prolonged treatment with zincglucagon also causes a reduction of the amount of insulin stored and secreted by the pancreas, but the ratio of insulin output to content is not significantly modified. The chronic influence of hyperglucagonism could thus correspond to a net catabolic effect upon the beta-cell. It is suggested that the reduced insulin-secretory capacity observed in experimental hyperinsulinism and hyperglucagonism could play a role in the impairment of glucose tolerance seen in the corresponding clinical conditions.

---

Chronische Effekte von Insulin und Glucagon auf die Inselfunktion

Zusammenfassung Chronische Verabreichung von Insulin an normale Ratten bewirkt eine fortschreitende Verringerung des Insulingehaltes und der Stimulierbarkeit des Inselzellsystems durch Glucose. Die Einschränkung der Sekretionskapazität ist dabei ausgeprägter als die der Hormonreserven. Die Ergebnisse deuten darauf hin, daß der Hyperinsulinismus den Sekretionsprozeß in der B-Zelle unabhängig von seinen Effekten auf die Insulinsynthese beeinträchtigt. Längere Behandlung mit Zink-Glucagon verringert ebenfalls die Menge des vom Pankreas gespeicherten und sezernierten Insulins, verändert aber das Verhältnis von Insulinausschüttung zum Insulingehalt nicht signifikant. Die chronischen Auswirkungen des Hyperglucagonismus könnten also einen rein katabolen Effekt auf die B-Zelle darstellen. Es ist anzunehmen, daß die Einschränkung der Sekretionskapazität für Insulin, die beim experimentellen Hyperinsulinsmus und Hyperglucagonismus beobachtet wird, im Zusammenhang mit den Störungen der Glucostoleranz steht, wie sie unter den entsprechenden klinischen Bedingungen auftreten.

---

Influences chroniques de l'insuline et du glucagon sur la fonction insulaire

Résumé L'administration chronique d'insuline à des rats normaux provoque un abaissement progressif des réserves pancréatiques d'insuline et de la riposte sécrétoire du pancréas au glucose. La réduction de la capacité sécrétoire est plus marquée que celle des réserves hormonales. Ces données suggèrent que l'hyperinsulinisme inhibe l'activité sécrétoire des cellules beta indépendamment de ses effets sur la biosynthèse d'insuline. L'administration prolongée de zinc-glucagon entraîne également une réduction des réserves pancréatiques d'insuline et de la capacité insulino-sécrétoire; le rapport entre le débit et le contenu insuliniques n'est cependant pas significativement modifié. Les modifications de la fonction insulaire au cours de l'hyperglucagonisme chronique semblent donc correspondre à un effet net catabolique sur les cellules beta. La réduction de la capacité insulino-sécrétoire au cours de l'hyperinsulinisme et de l'hyperglucagonisme expérimentaux pourrait expliquer l'intolérance glucidique qui caractérise les états cliniques correspondants.

     

Defective platelet-fibrinogen interaction in hereditary canine thrombopathia

A unique, intrinsic, hereditary canine platelet disorder attributable to abnormal fibrinogen receptor availability is described. Thrombopathic platelets from 13 severely affected basset hounds failed to aggregate in response to all agonists tested except thrombin. Normal platelet interaction with the various stimuli was inferred on the basis of their ability to elicit unimpaired shape change in thrombopathic platelets. No quantitative differences in major platelet membrane glycoproteins, intraplatelet fibrinogen, adenine nucleotides, or serotonin uptake were detected. Dense granule secretion was impaired. The ultrastructural appearance of thrombopathic platelets was normal. Fibrinogen-platelet interaction was evaluated by reacting platelet-rich plasma (PRP) with fibrinogen coupled to polymeric acrylonitrile beads and scoring the extent of stimulus-induced agglutination. The aggregatory responses of normal and thrombopathic platelets were closely correlated with fibrinogen receptor availability. In contrast to human platelets, epinephrine-stimulated canine platelets did not interact with immobilized fibrinogen, and arachidonate generally induced only weak agglutination. Thrombopathic platelets agglutinated fibrinogen beads at reduced rates when stimulated with physiologic doses of thrombin and high-dose calcium ionophore, A23187. Our data suggest that thrombin-mediated induction of canine platelet fibrinogen receptors may proceed by pathway(s) alternate to those shared by other platelet agonists, and/or that secreted granule constituents may act synergistically with thrombin to overcome inhibition of signal-response- coupled reactions mediating the interaction of fibrinogen with its receptor. This congenital platelet defect provides further evidence, in a species other than human, for the pivotal role of fibrinogen receptor induction in platelet aggregation.     

Molecular genetic rearrangements distinguish pre- and post-bone marrow transplantation lymphoproliferative processes

Chronic myelocytic leukemia (CML) may display a lymphoproliferative phase (lymphoid blast crisis) that is generally of B cell phenotype. Since lymphoproliferative disorders may occur following bone marrow transplantation (BMT), it may be difficult to distinguish posttransplant relapse of CML lymphoid blast crisis from de novo lymphoproliferation. Lymphoid blast crisis cells from a patient with CML displayed immunoglobulin heavy chain gene (C mu) rearrangement before BMT. Following BMT the patient developed a lymphoproliferative disorder involving multiple organs. Clonal rearrangement of C mu was demonstrated in several involved tissues. The rearranged C mu restriction fragment was distinct from that displayed before BMT. Additionally, rearrangement of the breakpoint cluster region (bcr) was demonstrated in the pretransplant blast crisis sample, but not in the posttransplant lymphoproliferation samples, thus confirming that these lymphoproliferative disorders were distinct. Molecular genetic techniques offer powerful diagnostic tools for monitoring the course of patients with CML undergoing BMT.     

Influence of amino acids upon insulin release evoked by 3-phenylpyruvate

Summary Insulin release induced by 3-phenylpyruvate in rat pancreatic islets was unaffected by L-norleucine, L-valine, L-alanine and L-asparagine, but potentiated by L-glutamine, glycine and L-serine. The latter two amino acids also enhanced insulin secretion evoked by the combination of 3-phenylpyruvate and L-glutamine. Since 3-phenylpyruvate is known to stimulate insulin release by acting as a transamination partner and facilitating the catabolism of endogenous amino acids, the present findings suggest that the secretory efficiency of such a biochemical sequence depends upon the subcellular location of the transamination reaction and upon the interference of 3-phenylpyruvate with the transport of 2-keto acids into mitochondria.