Fig. 4: Insr knockout increases glucose-stimulated insulin secretion in vitro and in vivo.

a, b Insulin levels (nM) from perifused islets isolated from 16 week old chow-fed control, βInsr^HET, βInsr^KO female (two parallel runs per n = 3, 3, 5), and male (2 parallel runs per n = 6, 5, 5) mice were exposed to 20 mM glucose (20 G), 10 mM glucose (10 G), and 30 mM KCL (KCL) from a baseline of 3 mM glucose. Data analyzed using repeated measures mixed effects model. *p-values are italicized when βInsr^KO was compared to controls, p-values are underlined when βInsr^HET was compared to controls. Quantification of 1st phase and 2nd phase during 20 mM glucose stimulation, total response during 10 mM glucose stimulation, and during 30 mM KCL stimulation. AUC’s were analyzed with 1-way ANOVA analysis. c–h Glucose infusion rates (mg/kg/min), plasma glucose levels (mM), and plasma insulin (nM) levels during 2-h hyperglycemic clamps in awake LFD-fed, 10-week old control and βInsr^KO female (n = 14, 15) and male (n = 4, 4) mice. Data were analyzed using repeated measures mixed-effects model. i, j Insulin levels (% basal insulin) following a single glucose injection (2 g glucose/kg body mass,i.p) of 11 week old LFD-fed control, βInsr^HET, βInsr^KO female (n = 33, 34, 23) and male (n = 22, 29, 17) mice. Data were analyzed using repeated measures mixed-effects model. k, l Islet protein synthesis measured (fold change) for 30 minutes by S³⁵ labeling in islets isolated from individual control, βInsr^HET, βInsr^KO female (n = 7, 5, 6) and male (n = 5, 4, 3) mice. Data were analyzed by one-way ANOVA. m, n Insulin content (nM) of ten islets isolated from control, βInsr^HET, βInsr^KO female (n = 4, 3, 5) and male (n = 5, 4, 5) mice. Data were analyzed by one-way ANOVA. βInsr^WT (black bars, lines, circles), βInsr^HET (female = light pink bars, lines, squares; male = light blue bars, lines, squares) and βInsr^KO (female = dark red bars, lines, triangles; male = dark blue bars, lines, triangles). All animals/samples were handled in a strictly blinded manner. All data are presented as mean values +/− SEM. Source data are provided as Source Data file.