The objective of this project is to establish that histamine, as an immunochemical mediator whose secretion is stimulated by interleukin-1 (IL-1), interleukin-3 (IL-3), IgE, histamine releasing factor (HRF), nerve growth factor (NGF), histamine-producing cell stimulating factor (HCSF), and complement factors C3a, C5a can alter metabolic homeostasis through specific histamine receptor interactions on adipocytes, hepatocytes, and islets of Langerhans. The project will focus on mechanisms by which histamine, through interaction with specific membrane receptors (H1, H2, or H3) can influence lipid and carbohydrate homeostasis. The research is also intended to prove that the canine species, sensitive to histamine liberating challenges such as compound 48/80 and Ascaris suum, has several advantages over rodent models when assessing the clinical implications of histamine effects on metabolic homeostasis. The significance of the study is that histamine has been implicated as a potential immunologic mediator involved in early phases of lipid infiltration in atherosclerosis as well as in islet damage associated with autoimmune Type I diabetes mellitus.
Specific aims of the study will be (1) to test the hypothesis that membrane bound H2-histamine receptors mediate histamine-activated adenylate cyclase and resulting lipolysis in isolated canine adipocytes at a site which can be dissociated from catecholamine receptors and from potential direct effects of IL-1, IL-6, TNF, Ascaris suum, and compound 48/80; (2) to test the hypothesis that the adipocyte histamine receptor can be activated in vivo by challenging dogs sensitive to Ascaris suum with an extract of Ascaris suum, by IV human IL-1B, by IV compound 48/80, or by IV administration of the H2-receptor agonist, impromidine. In each case plasma histamine levels will be monitored with a new highly sensitive radioimmunoassay, and correlated with changes in plasma free fatty acid (FFA) levels in the presence and absence of histaminergic or adrenergic blocking agents; (3) to determine the ability of histamine, histamine agonists, and histamine liberators to influence insulin secretion in dogs in vivo and to ascertain whether this is a direct islet effect or an effect secondary to FFA, glucose, or glucagon release and; (4) to determine the capability of histamine, histamine agonists, Il-1B, IL-6, and TNF to stimulate glucose mobilization from isolated canine hepatocytes or glucose uptake in isolated canine adipocytes.
