Neurogenic insulin resistance in guinea-pigs with cisplatin-induced neuropathy.
The aim of the present work was to study whether neurotoxicity produced by cisplatin modified tissue insulin sensitivity in guinea-pigs. One week after selective sensory denervation of the anterior hepatic plexus by means of perineurial 2% capsaicin treatment, hyperinsulinaemic euglycaemic glucose clamp were performed to estimate insulin sensitivity in male guinea-pigs. The guinea-pigs underwent regional sensory denervation of the anterior hepatic plexus exhibited insulin resistance, whereas systemic capsaicin desensitization increased insulin sensitivity. Intraportal administration of L-nitro-arginine methyl ester (L-NAME decreased, whereas capsaicin increased insulin sensitivity. Neither atropine nor acetylcholine produced any significant effect. In animals with preceding regional capsaicin desensitization, none of the pharmacological maneuvers modified the resulting insulin resistant state. Cisplatin pretreatment induced sensory neuropathy and decreased insulin sensitivity. Insulin sensitivity did not change after either regional or systemic capsaicin desensitization in the cisplatin-treated animals. CGRP(8-37), a nonselective calcitonin gene-related peptide (CGRP) antagonist (50 microg/kg i.v.), significantly increased insulin sensitivity in normal animals but only a tendency to insulin sensitization was seen after cisplatin treatment. Cisplatin treatment, similar to regional capsaicin desensitization of the anterior hepatic plexus, produced a significant decrease in insulin-stimulated uptake of 2-deoxy-D [L-14C] glucose in cardiac and gastrocnemius muscle with no effect on percentage suppression of endogenous glucose production by hyperinsulinaemia. We conclude that the majority of cisplatin-induced insulin resistance is related to functional deterioration of the hepatic insulin sensitizing substance (HISS) mechanism.
Szilvássy
Judit
J
Department of Oto-rhino-laryngology, Medical University of Debrecen H-4032 Nagyerdei krt. 98. Debrecen, Hungary. szilva@king.pharmacol.dote.hu
Sziklai
István
I
Sári
Réka
R
Németh
József
J
Peitl
Barna
B
Porszasz
Robert
R
Lonovics
János
J
Szilvássy
Zoltán
Z
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity; D001285:Atropine / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002211:Capsaicin / Q000008:administration & dosage / Q000633:toxicity; D002447:Celiac Plexus / Q000187:drug effects / Q000503:physiopathology; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015309:Glucose Clamp Technique; D006168:Guinea Pigs; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000494:pharmacology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000503:physiopathology*; D014665:Vasodilator Agents / Q000494:pharmacology
D000970:Antineoplastic Agents; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D010446:Peptide Fragments; D014665:Vasodilator Agents; C058636:calcitonin gene-related peptide (8-37); D001285:Atropine; D003847:Deoxyglucose; D019001:Nitric Oxide Synthase; D015740:Calcitonin Gene-Related Peptide; D000109:Acetylcholine; D002945:Cisplatin; D002211:Capsaicin; D019331:NG-Nitroarginine Methyl Ester