Proximity to Delivery Alters Insulin Sensitivity and Glucose Metabolism in Pregnant Mice

Abstract

In late pregnancy, maternal insulin resistance occurs to support fetal growth, but little is known about insulin-glucose dynamics close to delivery. This study measured insulin sensitivity in mice in late pregnancy at day 16 (D16) and near term at D19. Nonpregnant (NP) and pregnant mice were assessed for metabolite and hormone concentrations, body composition by DEXA, tissue insulin signaling protein abundance by Western blotting, glucose tolerance and utilization, and insulin sensitivity using acute insulin administration and hyperinsulinemic-euglycemic clamps with [(3)H]glucose infusion. Whole-body insulin resistance occurred in D16 pregnant dams in association with basal hyperinsulinemia, insulin-resistant endogenous glucose production, and downregulation of several proteins in hepatic and skeletal muscle insulin signaling pathways relative to NP and D19 values. Insulin resistance was less pronounced at D19, with restoration of NP insulin concentrations, improved hepatic insulin sensitivity, and increased abundance of hepatic insulin signaling proteins. At D16, insulin resistance at whole-body, tissue, and molecular levels will favor fetal glucose acquisition, while improved D19 hepatic insulin sensitivity will conserve glucose for maternal use in anticipation of lactation. Tissue sensitivity to insulin, therefore, alters differentially with proximity to delivery in pregnant mice, with implications for human and other species.

Figure 1

Mean ± SEM changes in blood glucose concentrations from basal pre-treatment values with time after intraperitoneal administration of (A) glucose (1 g/kg) and (B) insulin (0.25 U/kg) in non-pregnant (NP) females (n=8-11, open symbols) and pregnant dams at day (D)16 (n=6-9, grey symbols) and D19 (n=6-8, black symbols). Inserts show area (a) under the glucose curve (AUC) and (b) above the glucose curve (AAC). In (a) and (b), *significant increment above baseline values in each group (p<0.05, paired t-test). In (b) values at each sampling time with different letters indicate significant differences between groups (p<0.05, one way ANOVA).

Figure 2

Mean ± SEM concentrations of (A) blood glucose and (B) plasma insulin in the basal (stippled columns) and hyperinsulinaemic (Stripped columns) periods of the hyperinsulinaemic-euglycaemic clamp, rates of glucose infusion (GIR), appearance (R_a) and disappearance (R_d) measured directly (C) or derived indirectly as differences in rates (D) from tritiated glucose infusion and the HEC protocol (whole body and hepatic insulin sensitivity and endogenous glucose production, EGP) in non-pregnant (NP) females (n=7, white columns) and pregnant dams at D16 (n=5, grey columns) and D19 (n=6, black columns). In (B) *significant difference in concentration from the basal period (p<0.01, paired t-test) while, within each period of the clamp, values with different superscripts are significantly different from each other (p<0.05, one-way ANOVA). In (C) and (D) rates with different superscripts are significantly different from each other (p<0.05, one-way ANOVA). In (D) * significant difference between the values in the two states of the clamp (P<0.02, paired t-test).

Figure 3

Mean ± SEM abundance of insulin signalling (a,b) and lipid metabolism (c,d) proteins in liver (A, C) and skeletal muscle (B, D) of non-pregnant (NP) females (n=10, white columns) and pregnant dams at D16 (n=5, grey columns) and D19 (n=5-6, black columns). Values with different superscripts are significantly different from each other (p<0.05, one way ANOVA). *significant difference between D16 and D19 dams (p<0.05, t-test).