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

2004 ◽  
Vol 287 (3) ◽  
pp. E480-E488 ◽  
Author(s):  
Cynthia C. Connolly ◽  
Lisa N. Aglione ◽  
Marta S. Smith ◽  
D. Brooks Lacy ◽  
Mary Courtney Moore
Keyword(s):  
Steady State ◽  
Late Pregnancy ◽  
Conscious Dogs ◽  
Metabolic Responses ◽  
Hepatic Glucose Output ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
The Impact ◽  
Arteriovenous Difference ◽  
Arterial Glucose

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 (Δ3.01 ± 0.46 and Δ1.31 ± 0.13 nmol/l, P < 0.05). Net hepatic glucose output (NHGO; μmol·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 μmol·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 μmol·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.

scholarly journals Hepatic and muscle insulin action during late pregnancy in the dog

2007 ◽  
Vol 292 (1) ◽  
pp. R447-R452 ◽  
Author(s):  
Cynthia C. Connolly ◽  
Tracy Papa ◽  
Marta S. Smith ◽  
D. Brooks Lacy ◽  
Phillip E. Williams ◽  
...  
Keyword(s):  
Insulin Infusion ◽  
Late Pregnancy ◽  
Hepatic Insulin Resistance ◽  
Hepatic Glucose Output ◽  
Hepatic Glucose ◽  
High Insulin ◽  
Skeletal Muscle Glucose Uptake ◽  
Glucose Output ◽  
Muscle Insulin Action ◽  
Arteriovenous Difference

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·kg−1·min−1, and from 120 to 240 min (High Insulin) insulin was infused at 1.5 mU·kg−1·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 μU/ml (basal, Low Insulin, and High Insulin, respectively) in NP, and 5 ± 1, 7 ± 1, and 27 ± 3 μU/ml in P. Net hepatic glucose output was suppressed similarly in both subsets (≥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·kg−1·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.

Alterations in basal glucose metabolism during late pregnancy in the conscious dog

2000 ◽  
Vol 279 (5) ◽  
pp. E1166-E1177 ◽  
Author(s):  
Cynthia C. Connolly ◽  
Linda C. Holste ◽  
Lisa N. Aglione ◽  
Doss W. Neal ◽  
D. Brooks Lacy ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Hepatic Glucose Production ◽  
Late Pregnancy ◽  
Nonesterified Fatty Acid ◽  
Acid Uptake ◽  
Substrate Uptake ◽  
Hepatic Glucose Output ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
In Pregnancy

We assessed basal glucose metabolism in 16 female nonpregnant (NP) and 16 late-pregnant (P) conscious, 18-h-fasted dogs that had catheters inserted into the hepatic and portal veins and femoral artery ∼17 days before the experiment. Pregnancy resulted in lower arterial plasma insulin (11 ± 1 and 4 ± 1 μU/ml in NP and P, respectively, P < 0.05), but plasma glucose (5.9 ± 0.1 and 5.6 ± 0.1 mg/dl in NP and P, respectively) and glucagon (39 ± 3 and 36 ± 2 pg/ml in NP and P, respectively) were not different. Net hepatic glucose output was greater in pregnancy (42.1 ± 3.1 and 56.7 ± 4.0 μmol · 100 g liver−1· min−1in NP and P, respectively, P < 0.05). Total net hepatic gluconeogenic substrate uptake (lactate, alanine, glycerol, and amino acids), a close estimate of the gluconeogenic rate, was not different between the groups (20.6 ± 2.8 and 21.2 ± 1.8 μmol · 100 g liver−1· min−1in NP and P, respectively), indicating that the increment in net hepatic glucose output resulted from an increase in the contribution of glycogenolytically derived glucose. However, total glycogenolysis was not altered in pregnancy. Ketogenesis was enhanced nearly threefold by pregnancy (6.9 ± 1.2 and 18.2 ± 3.4 μmol · 100 g liver−1· min−1in NP and P, respectively), despite equivalent net hepatic nonesterified fatty acid uptake. Thus late pregnancy in the dog is not accompanied by changes in the absolute rates of gluconeogenesis or glycogenolysis. Rather, repartitioning of the glucose released from glycogen is responsible for the increase in hepatic glucose production.

scholarly journals Unlike mice, dogs exhibit effective glucoregulation during low-dose portal and peripheral glucose infusion

2004 ◽  
Vol 286 (2) ◽  
pp. E226-E233 ◽  
Author(s):  
Mary Courtney Moore ◽  
Sylvain Cardin ◽  
Dale S. Edgerton ◽  
Ben Farmer ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Low Dose ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Glucose Output ◽  
Arterial Blood ◽  
Hepatic Glucose ◽  
Arterial Blood Glucose ◽  
Hepatic Portal ◽  
Glucose Output ◽  
Arteriovenous Difference

Portal infusion of glucose in the mouse at a rate equivalent to basal endogenous glucose production causes hypoglycemia, whereas peripheral infusion at the same rate causes significant hyperglycemia. We used tracer and arteriovenous difference techniques in conscious 42-h-fasted dogs to determine their response to the same treatments. The studies consisted of three periods: equilibration (100 min), basal (40 min), and experimental (180 min), during which glucose was infused at 13.7 μmol· kg–1·min–1 into a peripheral vein (PE, n = 5) or the hepatic portal (PO, n = 5) vein. Arterial blood glucose increased ∼0.8 mmol/l in both groups. Arterial and hepatic sinusoidal insulin concentrations were not significantly different between groups. PE exhibited an increase in nonhepatic glucose uptake (non-HGU; Δ8.6 ± 1.2 μmol·kg–1·min–1) within 30 min, whereas PO showed a slight suppression (Δ–3.7 ± 3.1 μmol·kg–1·min–1). PO shifted from net hepatic glucose output (NHGO) to uptake (NHGU; 2.5 ± 2.8 μmol·kg–1·min–1) within 30 min, but PE still exhibited NHGO (6.0 ± 1.9 μmol·kg–1·min–1) at that time and did not initiate NHGU until after 90 min. Glucose rates of appearance and disappearance did not differ between groups. The response to the two infusion routes was markedly different. Peripheral infusion caused a rapid enhancement of non-HGU, whereas portal delivery quickly activated NHGU. As a result, both groups maintained near-euglycemia. The dog glucoregulates more rigorously than the mouse in response to both portal and peripheral glucose delivery.

Influence of somatostatin on glucagon- and epinephrine-stimulated hepatic glucose output in the dog.

1979 ◽  
Vol 236 (2) ◽  
pp. E113
Author(s):  
L Saccà ◽  
R Sherwin ◽  
P Felig
Keyword(s):  
Plasma Glucose ◽  
Glucose Production ◽  
Conscious Dogs ◽  
Insulin Deficiency ◽  
Hepatic Glucose Output ◽  
Glucose Kinetics ◽  
Insulin Levels ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Insulin Replacement

Glucose kinetics were measured using [3-3H]glucose in conscious dogs during the infusion of: 1) glucagon alone; 2) glucagon plus somatostatin with insulin replacement; 3) epinephrine alone; and 4) epinephrine plus somatostatin with insulin and glucagon replacement. Infusion of glucagon alone resulted in a 10-15 mg/dl rise in plasma glucose and a transient 45% rise in glucose production. When somatostatin and insulin were added, a four- to fivefold greater rise in plasma glucose and glucose production was observed. Glucagon levels were comparable to those achieved with infusion of glucagon alone, whereas peripheral insulin levels increased three- to fourfold above baseline, suggesting adequate replacement of preinfusion portal insulin levels. Infusion of epinephrine alone produced a 40% rise in plasma glucose and a 100% rise in glucose production. When somatostatin, insulin, and glucagon were added to epinephrine, the rise in glucose production was reduced in 65% despite replacement of glucagon levels and presumably mild portal insulin deficiency. These findings suggest that somatostatin: 1) potentiates the stimulatory effect of physiologic hyperglucagonemia on glucose production independent of insulin availability and 2) blunts the stimulatory effect of physiologic increments of epinephrine independent of glucagon availability.

Effect of phentolamine on the insulin, glucagon, and glucose responses to exercise in adrenal-denervated sheep

1985 ◽  
Vol 63 (4) ◽  
pp. 346-349 ◽  
Author(s):  
Ronald P. Brockman
Keyword(s):  
Sympathetic Innervation ◽  
Adrenergic Innervation ◽  
Metabolic Responses ◽  
Metabolic Clearance ◽  
Adrenergic Stimulation ◽  
Hepatic Glucose Output ◽  
Optimal Response ◽  
Hepatic Glucose ◽  
Alpha Blockade ◽  
Glucose Output

Hyperglycemia and increased hepatic glucose output are characteristic responses to exercise in sheep. They appear to be due in part to α-adrenergic stimulation. To delineate the contributions of sympathetic innervation and adrenal catecholamines to the hormonal and metabolic responses to exercise, adrenal-denervated sheep were exercised with and without α-blockade (phentolamine treatment). Alpha blockade exaggerated the hyperinsulinemia during exercise (increment of 61 ± 8 vs. 34 ± 7 μU/mL for the control). This was associated with a reduction in glucose appearance (increments of 63 ± 8 vs. 236 ± 23 μmol/min, respectively). The metabolic clearance rates were not altered by α-blockade. It appears that both the adrenal catecholamines and adrenergic innervation to the pancreas contribute to the prevention of a rise in insulin concentrations during exercise in sheep. While this may not be essential for glucose appearance to rise during exercise, it appears necessary for an optimal response.

The effect of ingestion of meat on hepatic extraction of insulin and glucagon and hepatic glucose output in conscious dogs

Metabolism ◽  
1983 ◽  
Vol 32 (6) ◽  
pp. 558-567 ◽  
Author(s):  
Toshihiko Ishida ◽  
Jesse Chou ◽  
Robert M. Lewis ◽  
Craig J. Hartley ◽  
Mark Entman ◽  
...  
Keyword(s):  
Conscious Dogs ◽  
Hepatic Extraction ◽  
Hepatic Glucose Output ◽  
Hepatic Glucose ◽  
Glucose Output

Constant infusion and bolus injection of stable-label tracer give reproducible and comparable fasting HGO

1997 ◽  
Vol 273 (1) ◽  
pp. E192-E201 ◽  
Author(s):  
R. Hovorka ◽  
D. J. Eckland ◽  
D. Halliday ◽  
S. Lettis ◽  
C. E. Robinson ◽  
...  
Keyword(s):  
Steady State ◽  
Isotope Dilution ◽  
Coefficient Of Variation ◽  
Bolus Injection ◽  
Normal Subjects ◽  
Constant Infusion ◽  
Hepatic Glucose Output ◽  
Hepatic Glucose ◽  
Glucose Output

We have investigated the reproducibility of fasting hepatic glucose output (HGO) estimates by use of isotope dilution methodology of stable-label tracers. Six normal subjects were studied on two occasions 1 wk apart. After an overnight fast, the subjects received a bolus injection of 7 mg/kg of [U-13C]glucose and, simultaneously, a primed constant infusion of 0.05 mg.kg-1.min-1 of [6,6(-2)H]glucose. The bolus injection provided one estimate of HGO (HGOBOL), and the constant infusion provided two estimates of HGO, namely, HGO at 2 h (HGOINF2) and HGO at 4 h (HGOINF4), both with the assumption of steady-state conditions. All estimates were similar in value; HGOBOL was highest, followed by HGOINF2 and HGOINF4 [2.30 +/- 0.11 (SE), 2.17 +/- 0.12, and 2.01 +/- 0.13 mg.kg-1.min-1]. The constant infusion gave highly reproducible results. In the case of HGOINF2, the within-subject coefficient of variation (CV) was only 3% compared with 5% of HGOINF4. The reproducibility of HGOBOL was comparable with the within-subject CV of 7%. We conclude that a constant infusion and a bolus injection of stable-label tracer give reproducible and comparable estimates of HGO.

Selective insulinization of liver in conscious diabetic dogs

1985 ◽  
Vol 249 (2) ◽  
pp. E152-E159
Author(s):  
R. S. Spangler
Keyword(s):  
Steady State ◽  
Glucose Utilization ◽  
Dose Range ◽  
Lipid Vesicles ◽  
Glucose Load ◽  
Hepatic Glucose Output ◽  
Hepatic Glucose ◽  
Diabetic Dogs ◽  
Glucose Output ◽  
Hepatic Glucose Uptake

Insulin encapsulated in lipid vesicles and targeted to hepatocytes by means of a digalactosyl diglyceride moiety [(designated vesicle encapsulated insulin (VEI)] was administered intravenously to conscious catheterized diabetic dogs to determine the effects of hepatic and extrahepatic glucose utilization. Our results indicate that VEI administered intravenously to diabetic dogs over a dose range of 0.5 to 2.0 mU X kg-1 X min-1 reduces hepatic glucose output or induces hepatic glucose uptake without causing any significant alteration in the rate of extrahepatic glucose utilization. Steady-state comparisons of 1.0 mU X kg-1 X min-1 VEI with intraportal and peripherally administered insulin revealed that VEI and intraportal insulin result in significantly less extrahepatic glucose utilization than does an equivalent dose of peripherally administered insulin (6.36 +/- 1.21 and 5.08 +/- 0.97 vs. 8.82 +/- 1.61 mg X kg-1 X min-1; P less than 0.03). Through the use of VEI, we were able to significantly alter the deposition of intravenously administered glucose from 11% hepatic and 89% extrahepatic noted with peripheral insulin to 35% hepatic and 65% extrahepatic with VEI (P less than 0.03). Thus, by encapsulating insulin into a lipid carrier specifically targeted to the liver, selective hepatic insulinization can be achieved. As a result of this approach, one can alter the distribution of a glucose load to favor hepatic deposition.

scholarly journals Interaction of glucagon and epinephrine in the control of hepatic glucose production in the conscious dog

2003 ◽  
Vol 284 (4) ◽  
pp. E695-E707 ◽  
Author(s):  
Stephanie M. Gustavson ◽  
Chang An Chu ◽  
Makoto Nishizawa ◽  
Ben Farmer ◽  
Doss Neal ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Conscious Dogs ◽  
Hepatic Glucose Output ◽  
Conscious Dog ◽  
Hormone Administration ◽  
Hepatic Glucose ◽  
Glycogenolytic Effect ◽  
Glucose Output

Epinephrine increases net hepatic glucose output (NHGO) mainly via increased gluconeogenesis, whereas glucagon increases NHGO mainly via increased glycogenolysis. The aim of the present study was to determine how the two hormones interact in controlling glucose production. In 18-h-fasted conscious dogs, a pancreatic clamp initially fixed insulin and glucagon at basal levels, following which one of four protocols was instituted. In G + E, glucagon (1.5 ng · kg−1 · min−1; portally) and epinephrine (50 ng · kg−1 · min−1; peripherally) were increased; in G, glucagon was increased alone; in E, epinephrine was increased alone; and in C, neither was increased. In G, E, and C, glucose was infused to match the hyperglycemia seen in G + E (∼250 mg/dl). The areas under the curve for the increase in NHGO, after the change in C was subtracted, were as follows: G = 661 ± 185, E = 424 ± 158, G + E = 1,178 ± 57 mg/kg. Therefore, the overall effects of the two hormones on NHGO were additive. Additionally, glucagon exerted its full glycogenolytic effect, whereas epinephrine exerted its full gluconeogenic effect, such that both processes increased significantly during concurrent hormone administration.

Estimation of Hepatic Glucose Output in Non-Steady State. The Simultaneous Use of 2-3H-glucose and 14C-glucose in the Dog

1974 ◽  
Vol 52 (2) ◽  
pp. 215-224 ◽  
Author(s):  
Thomas B. Issekutz ◽  
Bela Issekutz Jr. ◽  
Dariush Elahi
Keyword(s):  
Steady State ◽  
Specific Activity ◽  
Base Line ◽  
Glucose Load ◽  
Hepatic Glucose Output ◽  
Constant Rate ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Infusion Technique ◽  
Single Exponential Function

The rate of appearance of glucose (Ra) was estimated in a non-steady state caused by the infusion of glucose (exogenous increase of Ra) or glucagon (increase of hepatic glucose output) in unanesthetized dogs with indwelling arterial and venous catheters. First, Ra was measured with 2-3H-glucose according to the primed constant rate infusion technique in steady state, then with the onset of the perturbation the infusion of a second tracer, (U) 14C-glucose, was started. Exponential functions were fitted to the two specific activity curves. The second tracer made it possible to calculate Ra during the non-steady state without the need to assume a definite value for the "miscible" glucose space (V). The latter could also be calculated and it proved to be a single exponential function of time elapsed from the start of the perturbation. In the first few minutes the glucose load (10 or 15 mg/kg min for 120 min) caused a sharp fall of hepatic glucose output. This was followed by a rise of various degrees before the endogenous glucose output reached the steady state at about 50 or 70% below the base-line values. During the glucose load, in steady state (U) 14C-glucose as a tracer gave about 10% lower values for Ra than tritiated glucose.

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