Pregnancy augments hepatic glucose storage in response to a mixed meal.

Studies were carried out on conscious female non-pregnant (NP) and pregnant (P; third-trimester) dogs (n 16; eight animals per group) to define the role of the liver in mixed meal disposition with arteriovenous difference and tracer techniques. Hepatic and hindlimb substrate disposal was assessed for 390 min during and after an intragastric mixed meal infusion labelled with [¹4C]glucose. The P dogs exhibited postprandial hyperglycaemia compared with NP dogs (area under the curve (AUC; change from basal over 390 min) of arterial plasma glucose: 86 680 (sem 12 140) and 187 990 (sem 33 990) mg/l in NP and P dogs, respectively; P < 0·05). Plasma insulin concentrations did not differ significantly between the groups (AUC: 88 230 (sem 16 314) and 69 750 (sem 19 512) pmol/l in NP and P dogs, respectively). Net hepatic glucose uptake totalled 3691 (sem 508) v. 5081 (sem 1145) mg/100 g liver in NP and P dogs, respectively (P = 0·38). The AUC of glucose oxidation by the gut and hindlimb were not different in NP and P dogs, but hepatic glucose oxidation (84 (sem 13) v. 206 (sem 30) mg/100 g liver) and glycogen synthesis (0·4 (sem 0·5) v. 26 (sem 0·7) g/100 g liver) were greater in P dogs (P < 0·05). The proportion of hepatic glycogen deposited via the direct pathway did not differ between the groups. Hindlimb glucose uptake and skeletal muscle glycogen synthesis was similar between the groups, although final glycogen concentrations were higher in NP dogs (9·6 (sem 0·6) v. 70 (sem 0·6) mg/g muscle; P < 0·05). Thus, hepatic glucose oxidation and glycogen storage were augmented in late pregnancy. Enhanced hepatic glycogen storage following a meal probably facilitates the maintenance of an adequate glucose supply to maternal and fetal tissues during the post-absorptive period.

Hepatic and muscle insulin action during late pregnancy in the dog.

We evaluated the effects of physiologic increases in insulin on hepatic and peripheral glucose metabolism in nonpregnant (NP) and pregnant (P; 3rd trimester) conscious dogs (n = 9 each) using tracer and arteriovenous difference techniques during a hyperinsulinemic euglycemic clamp. Insulin was initially (-150 to 0 min) infused intraportally at a basal rate. During 0-120 min (Low Insulin), the rate was increased by 0.2 mU x kg(-1) x min(-1), and from 120 to 240 min (High Insulin) insulin was infused at 1.5 mU x kg(-1) x min(-1). Insulin concentrations were significantly higher in NP than P during all periods. Matched subsets (n = 5 NP and 6 P) were identified. In the subsets, insulin was 7 +/- 1, 9 +/- 1, and 28 +/- 3 microU/ml (basal, Low Insulin, and High Insulin, respectively) in NP, and 5 +/- 1, 7 +/- 1, and 27 +/- 3 microU/ml in P. Net hepatic glucose output was suppressed similarly in both subsets (> or =50% with Low Insulin, 100% with High Insulin), as was endogenous glucose rate of appearance. During High Insulin, NP dogs required more glucose (10.8 +/- 1.5 vs. 6.2 +/- 1.0 mg x kg(-1) x min(-1), P < 0.05), and hindlimb (primarily skeletal muscle) glucose uptake tended to be greater in NP than P (18.6 +/- 2.5 mg/min vs. 13.6 +/- 2.0 mg/min, P = 0.06). The normal canine liver remains insulin sensitive during late pregnancy. Differing insulin concentrations in pregnant and nonpregnant women and excessive insulin infusion rates may explain previous findings of hepatic insulin resistance in healthy pregnant women.

Chronic estradiol and progesterone treatment in conscious dogs: effects on insulin sensitivity and response to hypoglycemia.

We evaluated the effect of chronic (3 wk) subcutaneous treatment with progesterone and estradiol (PE; producing serum levels observed in the 3rd trimester of pregnancy) or placebo (C) on hepatic and whole body insulin sensitivity and response to hypoglycemia in conscious, overnight-fasted nonpregnant female dogs, using tracer and arteriovenous difference techniques. Insulin was infused peripherally for 3 h at 1.8 mU x kg(-1) x min(-1). Glucose was allowed to fall to 3 mM (Hypo) or maintained at 6 mM (Eugly) by peripheral glucose infusion. Insulin concentrations were significantly higher in Eugly-PE (n = 7) and Hypo-PE (n = 7) than in Eugly-C (n = 6) and Hypo-C groups (n = 7), but there were no significant differences in hepatic insulin extraction. Concentrations of glucagon, cortisol, epinephrine, and norepinephrine did not differ significantly between Eugly groups or between Hypo groups. Whole body glucose disposal, adjusted for the differences in insulin between groups, was 35% higher in Eugly-C vs. Eugly-PE groups (P < 0.05). Eugly-C and Eugly-PE groups exhibited similar rates of net hepatic glucose uptake, but the rate of glucose appearance was greater in Eugly-PE in the last hour (P < 0.05). Net hepatic glucose output was greater (P < 0.05) in Hypo-PE than in Hypo-C groups, and the glucose infusion rate required to maintain equivalent hypoglycemia was less (P < 0.05). The rate of gluconeogenic flux did not differ between Hypo groups. Chronic progesterone and estradiol exposure caused whole body (primarily skeletal muscle) insulin resistance and enhanced the liver's response to hypoglycemia without altering counterregulatory hormone concentrations.

Pregnancy impairs the counterregulatory response to insulin-induced hypoglycemia in the dog.

The impact of pregnancy on the counterregulatory response to insulin-induced hypoglycemia was examined in six nonpregnant (NP) and six pregnant (P; 3rd trimester) conscious dogs by tracer and arteriovenous difference techniques. After basal sampling, insulin was infused intraportally at 30 pmol.kg(-1).min(-1) for 180 min. Insulin rose from 70 +/- 15 to 1,586 +/- 221 pmol/l and 27 +/- 4 to 1,247 +/- 61 pmol/l in the 3rd h in NP and P, respectively. Arterial glucose fell from 5.9 +/- 0.2 to 2.3 +/- 0.2 mmol/l in P. Glucose was infused in NP to equate the rate of fall of glucose and the steady-state concentrations in the groups (5.9 +/- 0.2 to 2.3 +/- 0.1 mmol/l in NP). Glucagon was 32 +/- 6, 69 +/- 11, and 48 +/- 10 ng/l (basal and 1st and 3rd h) in NP, but the response was attenuated in P (34 +/- 5, 46 +/- 6, 41 +/- 9 ng/l). Cortisol and epinephrine rose similarly in both groups, but norepinephrine rose more in NP (Delta3.01 +/- 0.46 and Delta1.31 +/- 0.13 nmol/l, P < 0.05). Net hepatic glucose output (NHGO; micromol.kg(-1).min(-1)) increased from 10.6 +/- 1.8 to 21.2 +/- 3.3 in NP (3rd h) but did not increase in P (15.1 +/- 1.5 to 15.3 +/- 2.8 micromol.kg(-1).min(-1), P < 0.05 between groups). The glycogenolytic contribution to NHGO in NP increased from 5.8 +/- 0.7 to 10.4 +/- 2.5 micromol.kg(-1).min(-1) by 90 min but steadily declined in P. The increase in glycerol levels and the gluconeogenic contribution to NHGO were 50% less in P than in NP, but ketogenesis did not differ. The glucagon and norepinephrine responses to insulin-induced hypoglycemia are blunted in late pregnancy in the dog, impacting on the magnitude of the metabolic responses to the fall in glucose.

Insulin action during late pregnancy in the conscious dog.

Our aim was to assess the magnitude of peripheral insulin resistance and whether changes in hepatic insulin action were evident in a canine model of late (3rd trimester) pregnancy. A 3-h hyperinsulinemic (5 mU.kg(-1).min(-1)) euglycemic clamp was conducted using conscious, 18-h-fasted pregnant (P; n = 6) and nonpregnant (NP; n = 6) female dogs in which catheters for intraportal insulin infusion and assessment of hepatic substrate balances were implanted approximately 17 days before experimentation. Arterial plasma insulin rose from 11 +/- 2 to 192 +/- 24 and 4 +/- 2 to 178 +/- 5 microU/ml in the 3rd h in NP and P, respectively. Glucagon fell equivalently in both groups. Basal net hepatic glucose output was lower in NP (1.9 +/- 0.1 vs. 2.4 +/- 0.2 mg.kg(-1).min(-1), P < 0.05). Hyperinsulinemia completely suppressed hepatic glucose release in both groups (-0.4 +/- 0.2 and -0.1 +/- 0.2 mg.kg(-1).min(-1) in NP and P, respectively). More exogenous glucose was required to maintain euglycemia in NP (15.2 +/- 1.3 vs. 11.5 +/- 1.1 mg.kg(-1).min(-1), P < 0.05). Nonesterified fatty acids fell similarly in both groups. Net hepatic gluconeogenic amino acid uptake with high insulin did not differ in NP and P. Peripheral insulin action is markedly impaired in this canine model of pregnancy, whereas hepatic glucose production is completely suppressed by high circulating insulin levels.