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Renato Laffranchi and Giatgen A Spinas

Laffranchi R, Spinas GA. Interleukin 10 inhibits insulin release from and nitric oxide production in rat pancreatic islets. Eur J Endocrinol 1996;135:374–8. ISSN 0804–4643

Interleukin 10 was found to prevent cytokine-induced nitric oxide production in murine macrophages. Because, in rat islets, interleukin 1β induces β-cell dysfunction, mainly due to overproduction of nitric oxide, we studied if this effect could be counteracted by interleukin 10. Rat pancreatic islets were cultured for 24 h in the presence or absence of 0.02–20 ng/ml recombinant human interleukin 10. Interleukin 10 dose-dependently inhibited insulin secretion with maximal inhibition (27 ±4%, p < 0.05) at 2 ng/ml without impairment of islet cell viability. However, incubation of pancreatic islets with interleukin 10 resulted in a 61.5% decrease of nitric oxide production. Co-incubation of islets with interleukin 10 (2 ng/ml) and recombinant human interleukin 1β (0.15 ng/ml) resulted in a more pronounced suppression of basal insulin release than with interleukin 1β alone (55 ± 3.6% vs 44 ± 3.6% with interleukin 1β alone, p < 0.05) but did not reduce interleukin 1β-stimulated NO production or reverse the effect of interleukin 1β on cell viability. Thus, in pancreatic islets interleukin 10 is not capable of counteracting the interleukin 1β-induced β-cell dysfunction, but rather enhances the inhibitory effect of interleukin 1β by a different mechanism.

Renato Laffranchi, Division of Endocrinology and Metabolism, Department of Internal Medicine, University Hospital, Rämistrasse 100, CH-8091 Zürich, Switzerland

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Peter Wiesli, Beat Schwegler, Beat Schmid, Giatgen A Spinas, and Christoph Schmid

Objective: To determine whether systematic evaluation of cognitive function by the Mini-Mental State Examination (MMSE) allows the objective detection and documentation of cognitive deterioration in patients referred for evaluation of suspected hypoglycaemic disorders by the 72-h fast.

Design: Prospective case series.

Methods: In 50 patients referred for evaluation of suspected hypoglycaemic disorders, the MMSE score (maximum 30 points) was assessed at the start and at the end of the fast.

Results: The fast was terminated before 72 h in 14 patients because they developed neuroglycopenic symptoms due to hypoglycaemic disorders. Their MMSE score fell from a median of 29 points (range 20–30) at the beginning to 17 points (range 0–24) at the termination of the fast. The score dropped by ≥6 points in all patients with hypoglycaemic disorders. Median (range) plasma glucose concentration at the end of the fast was 2.1 (1.1–2.5) mmol/l. Thirty-six individuals developed no neuroglycopenic symptoms throughout the 72-h fast, their MMSE score remained between 27 and 30 throughout the fast and their median plasma glucose concentration dropped to 2.9 (2–3.6) mmol/l.

Conclusions: Systematic evaluation of cognitive function by the MMSE at the beginning and at the termination of the fast allows objective determination and documentation of the deterioration of the cognitive state in patients with hypoglycaemic disorders. A decline in the cognitive performance by ≥6 points in the MMSE score rather than a distinct plasma glucose concentration should be used as the criterion to terminate the prolonged fast before 72 h.

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Giatgen A. Spinas, Thomas Mandrup-Poulsen, Jens Mølvig, Leif Bæk, Klaus Bendtzen, Charles A. Dinarello, and Jørn Nerup

Abstract. Isolated rat islets were incubated either with crude, affinity-purified or recombinant human interleukin-1 for 1 to 6 days. A significant (20–60%) increase of insulin release was observed at low concentrations of all three interleukin-1-containing preparations. In contrast, higher concentrations dose-dependently inhibited the insulin release. The increased insulin secretion occurred at concentrations below those necessary to augment the mitogen response to phytohaemagglutinin of murine thymocytes in vitro. These doses (0.05-0.5 U/ml) correspond to 0.2-2 ng of recombinant interleukin-1 per ml, equal to approximately 0.01-0.1 pmol/ml. In doses of 0.6-1.8 U/ml affinitypurified interleukin-1 significantly increased the islet insulin content per ng of DNA, indicating a stimulation of insulin-biosynthesis. The data support the concept that low concentrations of interleukin-1 may play a role in priming the physiological secretion of insulin.

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Giatgen A. Spinas, Jerry P. Palmer, Thomas Mandrup-Poulsen, Henrik Andersen, Jens Høiriis Nielsen, and Jørn Nerup

Abstract. To investigate the hypothesis that interleukin 1 initially stimulates and then suppresses beta-cell function and that this sequential effect is directly related to interleukin 1 dose, duration of exposure, and ambient glucose concentration, insulin release was measured from cultured newborn rat islets exposed for 6 h to 6 days to interleukin 1 at doses ranging from 20 to 2000 ng/l at glucose concentrations of 3.3, 5.5 and 11 mmol/l. After 6 h of exposure and at all three glucose levels, all doses of interleukin 1 stimulated insulin release, maximal stimulation (370% of control) being observed at 5.5 mmol/l glucose and 100 ng/l interleukin 1. In contrast, after 6 days, all doses of interleukin 1 were inhibitory irrespective of glucose level, maximal inhibition (90%) being observed at 11 mmol/l glucose and 2000 ng/l interleukin 1. At 24 and 48 h of exposure, the biphasic effect of interleukin 1 was observed: lower doses of interleukin 1 at lower glucose concentrations at 24 h being more stimulatory with transition to inhibition directly related to higher glucose levels, higher interleukin 1 doses, and longer exposure. After 48 h, 200 ng/l of interleukin 1 increased insulin release to 220% at 3.3 mmol/l glucose, but at 11 mmol/l glucose a 60% suppression was seen. On the basis of these data we suggest that interleukin l's effect on beta-cells is bimodal: stimulation followed by inhibition. Increasing interleukin 1 dose and ambient glucose concentration shift this response to the left. Experimental results will, and in vivo effects may, depend upon these three variables.