BACKGROUND & AIMS. Raised plasma gastrin secondary to achlorhydria is associated with increased expression of several genes in ECL cells, notably histidine decarboxylase (HDC) and vesicular monoamine transporter type 2 (VMAT2). It is not clear whether endogenous gastrin regulates expression of these genes when gastric acid secretion is uninhibited. We have examined expression of these genes in ECL cells in INS-GAS transgenic mice that express the coding sequence of the human gastrin gene in pancreatic 13-cells and in which parietal cell function is uninhibited. METHODS. Plasma gastrin was measured by radioimmunoassay using antibody L2 (COOH-terminal specific for amidated gastrins) and L6 (specific for human G17). Gastrin release from 13-cells was stimulated by oral glucose. ECL cell function was assessed by Northem analysis of HDC and VMAT2 mRNAs. RESULTS. In INS-GAS mice fasted for 6hr, plasma human G17 was 67-+ 11 pM. When fasted mice were then allowed access to 20% glucose, plasma human G17 significantly increased (30min, 242 ± 33; 120min, 133 _+ 19 pM; n = 6; both p<0.01). Following glucose, corpus VMAT2 and HDC mRNA abundances increased to 119--. 6% and 147 ± 14%, relative to control (both p<0.05), respectively. In INS-GAS mice fed ab libitum with access to 20% glucose for 5 days, plasma gastrin was 283 ± 50 pM compared with 85 ± 29 pM in control INS-GAS mice (n = 6, p<0.01). Moreover, in INS-GAS mice with access to glucose for 5 days, VMAT2 mRNA abundance was increased by 255 ± 28% and HDC mRNA by 163 + 24% compared to INS-GAS mice fed ad libitum (both p<0.05). In wild type mice, human G17 was not detected in the plasma, and access to glucose did not influence plasma amidated, ie antral, gastrin (control, 82 ± 18: glucose, 86 ± I0 pM); neither did glucose influence HDC (control, 100 ± 18; glucose, 111 ± 8%) and VMAT2 (control, 100 ± 9; glucose, 95 ± 8%) mRNA abundances. CONCLUSIONS. 1. Oral glucose stimulates human G17 release in INS-GAS mice, but has no effect on antral gastrin release. 2. Moderate hypergastrinemia is associated with increases in HDC and VMAT2 mRNA in gastric corpus. 3. Hypergastrinemia-induced expression of HDC and VMAT2 in ECL ceils does not depend on achlorhydria.