Biomedical subjects

D B Lacy

Publications and source records attributed to D B Lacy.

At least 55 records · Page 3Linked to original sources

PubMed1994

The role of glucagon in the control of protein and amino acid metabolism in vivo.

The relative contribution of hyperglucagonemia to the mechanisms of nitrogen loss during catabolic states has not been clearly established. The present study examines the independent effect of physiologic elevations of plasma glucagon on whole-body protein kinetics, as well as on net amino acid balance across the liver and gastrointestinal tract tissues, in conscious 18-hour-fasted dogs (n = 7). Each study consisted of a 120-minute equilibration period, a 30-minute basal period, and a 150-minute experimental period. Leucine kinetics were measured using L-[1-14C]leucine. Pancreatic hormones were maintained by infusing intravenous somatostatin (0.8 micrograms/kg.min), intraportal insulin (275 microU/kg.min), and intraportal glucagon (0.65 ng/kg.min basally and 2.5 experimentally). Dextrose was infused to maintain plasma glucose constant (14.1 +/- 0.3 mumol/L), thereby providing a consistent metabolic steady state for the study of protein and amino acid metabolism. In the experimental period, plasma glucagon was fourfold basal levels (112 +/- 10 v 32 +/- 6 pg/mL), whereas plasma insulin remained stable (mean, 10 +/- 1 microU/mL). Hepatic glucose production was increased 30%, but leucine rates of appearance ([Ra] proteolysis), oxidative disappearance (Rd), and nonoxidative Rd (protein synthesis) were not altered during the experimental period. Furthermore, the net release of amino acids by the gastrointestinal tract was not increased by glucagon. However, uptake and extraction of amino acids by the liver were increased, resulting in a 17% decrease in total plasma amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMed1994

Impact of suprapharmacological androgenic steroid administration on basal and insulin-stimulated glucose and amino acid metabolism.

Effects of androgenic steroids at doses used by athletes were studied in a canine model system in which dosage, diet, and activity were controlled. Dogs were treated with 19-nortestosterone (200 mg/wk intramuscularly) or vehicle and were studied at 18 (n = 4 in steroid and vehicle) or 32 (n = 6 in steroid and n = 4 in vehicle) days. A laparotomy was performed under general anesthesia 17 days before experimentation, and catheters were placed in an artery, portal vein, and hepatic vein. Studies consisted of an equilibration (120 minutes) and a control (40 minutes) period and a three-step immunoreactive insulin euglycemic clamp (1, 2, and 15 mU/kg.min). Step 1 was 150 minutes, and steps 2 and 3 were 90 minutes. Data were collected during the last 30 minutes of each step. Glucose and leucine kinetics were assessed with 3H-glucose and 14C-leucine. Plasma glucose in steroid and vehicle groups was 104 +/- 5 (mean +/- SE) versus 108 +/- 3 mg/dL and 100 +/- 5 versus 107 +/- 4 mg/dL at 18 and 32 days. Glucose turnover was similar at 18 days in steroid and vehicle groups (3.9 +/- 0.3 v 3.6 +/- 0.3 mg/kg.min, respectively), but was elevated in the steroid group at 32 days (5.4 +/- 0.5 v 3.2 +/- 0.4 mg/kg.min). Glucose infusion rates were lower in the steroid group with 15 mU/kg.min immunoreactive insulin at 32 days (15.0 +/- 1.1 v 21.2 +/- 1.4 mU/kg.min). Immunoreactive insulin-independent glucose utilization (Rd) was unaffected at 18 days of steroid treatment, but was increased by almost fourfold at 32 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMed1994

The effects of acute hypercortisolemia on beta-hydroxybutyrate and glycerol metabolism during insulin deficiency.

The present study was undertaken to determine whether an acute physiologic rise in plasma cortisol during selective insulin deficiency would have significant effects on glycerol and beta-hydroxybutyrate metabolism in conscious overnight-fasted dogs. Each experiment consisted of a two hour dye equilibration period, a 40 minute basal period, and a 3 hour experimental period. A continuous infusion of indocyanine green dye for blood flow estimation was initiated at the start of the equilibration period and continued throughout the experiment. In both of two protocols selective insulin deficiency was created during the experimental period by infusing somatostatin peripherally (0.8 microgram/kg-min) with basal replacement of glucagon intraportally (0.65 ng/kg-min). In the test protocol (CORTISOL, n = 5), 3.0 micrograms/kg-min of hydrocortisone was infused during the experimental period. In the control protocol (SALINE, n = 5), saline was infused. Net hepatic balances were determined using the (A-V) difference technique. During selective insulin deficiency alone (SALINE), the arterial blood glycerol level increased from 81 +/- 19 to 140 +/- 11 microM (p < 0.01) and net hepatic glycerol uptake (NHGlyU) tended to increase from 2.3 +/- 0.3 to 3.3 +/- 0.6 mumol/kg-min (0.05 < 0.1). The arterial plasma free fatty acid (FFA) level remained unchanged at 1041 +/- 35 microM. The arterial beta-hydroxybutyrate (BHOB) level increased slightly from 21 +/- 4 to 29 +/- 5 microM while net hepatic beta-hydroxybutyrate production (NHBP) remained unchanged (1.0 +/- 0.2 mumol/kg-min). During acute hypercortisolemia with selective insulin deficiency (CORTISOL), similar changes occurred in the arterial blood glycerol level and net hepatic glycerol uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗

PubMed1994

Effects of chronic hypercortisolemia on carbohydrate metabolism during insulin deficiency.

This study was undertaken to further investigate the effect of acute selective insulin deficiency on glycogenolysis and gluconeogenesis occurring during chronic physiological hypercortisolemia in conscious overnight fasted dogs. After an 80-min tracer and dye equilibration period and a 40-min basal period, selective insulin deficiency was created during the 180-min experimental period by infusing somatostatin peripherally (0.8 micrograms.kg-1.min-1) with basal replacement of glucagon intraportally (0.65 ng.kg-1.min-1). In the cortisol group (n = 5), a continuous infusion of hydrocortisone (3.5 micrograms.kg-1.min-1) was begun 5 days before the experiment. In the saline group (n = 5), there was no infusion of cortisol. [3-3H]glucose, [U-14C]alanine, and indocyanine green dye were used to assess glucose production and gluconeogenesis using tracer and arteriovenous difference techniques. During selective insulin deficiency in the saline group, the arterial plasma glucose level (Glc) increased from 109 +/- 2 to 285 +/- 19 mg/dl; glucose production increased from 2.7 +/- 0.2 to 4.5 +/- 0.3 mg.kg-1.min-1. Gluconeogenic efficiency and conversion of alanine to glucose (Conv) increased by 300 +/- 55 and 356 +/- 67%. During selective insulin deficiency in the cortisol group, Glc increased from 117 +/- 3 to 373 +/- 50 mg/dl; glucose production increased from 3.3 +/- 0.5 to 6.9 +/- 0.7 mg.kg-1.min-1. Gluconeogenic efficiency and Conv increased by 268 +/- 41 and 393 +/- 75%, respectively. The maximal glycogenolytic rate increased significantly more in the cortisol group than in the saline group, accounting for the difference in glucose production. These results suggest that, even during chronic hypercortisolemia, acute insulin deficiency has more pronounced effects on glycogenolysis than gluconeogenesis.

Alanine↗

PubMed1994

Acute adaptation of carbohydrate metabolism to decreased arterial PO2.

To assess the interaction of arterial PO2 (PaO2) and glucose metabolism, conscious 18-h-fasted dogs with chronically implanted sampling catheters (carotid artery, iliac vein) and flow probe (external iliac artery) were studied during inspiration of air containing 21 (n = 9), 14 (n = 6), 11 (n = 4), or 8% (n = 5) O2. Isotopic and arteriovenous methods were used to assess carbohydrate metabolism. PaO2 was 103 +/- 3, 64 +/- 4, 45 +/- 4, and 30 +/- 1 mmHg with decreased inspired O2. Although limb O2 delivery was reduced (51 +/- 6, 42 +/- 8, 39 +/- 7, and 34 +/- 5 ml/min), limb O2 uptake was not compromised. Plasma insulin was 9 +/- 1, 8 +/- 2, 14 +/- 2, and 16 +/- 3 microU/ml, and glucagon was 53 +/- 3, 49 +/- 3, 64 +/- 5, and 101 +/- 7 pg/ml with decreasing O2. Plasma epinephrine and cortisol were increased whereas norepinephrine was unaffected. Glycemia was unaffected by reduced O2, whereas hepatic glucose output (14 +/- 1, 19 +/- 3, 21 +/- 1, and 22 +/- 1 mumol.kg-1.min-1) and glucose disappearance (14 +/- 2, 18 +/- 3, 20 +/- 1, and 22 +/- 2 mumol.kg-1.min-1) rose similarly. Limb glucose uptake (LGU) rose (21.5 +/- 4.7, 21.2 +/- 5.6, 30.6 +/- 4.7, and 45.3 +/- 9.7 mumol/min) with decreasing O2 because of greater fractional extraction (0.023 +/- 0.005, 0.024 +/- 0.005, 0.031 +/- 0.004, and 0.043 +/- 0.004). Of the increased LGU, approximately 33 and 67% were metabolized oxidatively and nonoxidatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗

PubMed1994

Sensitivity of exercise-induced increase in hepatic glucose production to glucose supply and demand.

It was hypothesized that the exercise-induced changes in glucoregulatory hormones and glucose production (Ra) occur as a result of a small deficit in glucose availability. To test this, 18-h fasted dogs performed 150 min of treadmill exercise with either the liver as the sole source of glucose (controls, n = 5) or with glucose infused from 0 to 50 min (period 1) and from 100 to 150 min (period 3) at rates designed to track the glucose utilization (Rd) response (ExoGlc, n = 5). The liver alone supplied glucose from 50 to 100 min (period 2). Isotopic and arteriovenous methods were used to assess Ra, Rd, and gluconeogenesis (GNG). Variable [3H]glucose infusion and frequent sampling were used to facilitate Ra measurements. Arterial glucose declined by -3.1 +/- 1.4, -4.3 +/- 2.9, and -6.4 +/- 3.7 mg/dl in periods 1-3 in controls (changes are mean values during each of the 50-min periods; P < 0.05). In ExoGlc, arterial glucose did not deviate from basal in periods 1 (+0.1 +/- 1.8 mg/dl) and 3 (+1.5 +/- 4.5 mg/dl) but fell from basal (P < 0.05) by the same amount as controls in period 2 (-5.7 +/- 2.1 mg/dl). Matching the Rd response with exogenous glucose led to increases in arterial and portal vein plasma insulin levels (P < 0.05) but did not affect glucagon, norepinephrine, epinephrine, and cortisol levels. Ra was elevated by 3.1 +/- 0.5, 4.0 +/- 1.1, and 4.7 +/- 1.1 mg.kg-1.min-1 in periods 1-3 in controls (P < 0.05). In ExoGlc, Ra rose by 0.0 +/- 0.4, 4.1 +/- 1.4 (P < 0.05), and 0.4 +/- 0.7 mg.kg-1.min-1, respectively, in periods 1-3. The rise in Ra was reduced in periods 1 and 3 of ExoGlc compared with controls (P < 0.02). GNG rose to approximately 250% basal in controls and did not respond with any significant difference in ExoGlc. In summary, the exercise-induced increases in counterregulatory hormones and GNG are present even when a deficit in glucose supply is eliminated by an exogenous glucose infusion. In contrast, the fall in insulin and the rise in hepatic glycogenolysis are greatly attenuated. The regulatory components affected by exogenous glucose predominate at the liver as deviations in plasma glucose of approximately 4% correspond to approximately 60% changes in Ra.(ABSTRACT TRUNCATED AT 400 WORDS)

Alanine↗

PubMed1993

Effects of chronic elevation in plasma cortisol on hepatic carbohydrate metabolism.

This study was undertaken to investigate the effects of chronic physiological elevations in plasma cortisol on glycogenolysis and gluconeogenesis in conscious, overnight-fasted dogs. Experiments consisted of an 80-min tracer and dye equilibration period and a 40-min sampling period. Infusions of D-[3-3H]glucose, L-[U-14C]alanine, and indocyanine green dye were used to assess glucose production (Ra) and gluconeogenesis using tracer and arteriovenous (a-v) difference techniques. In the cortisol group, (n = 10), a continuous infusion of hydrocortisone (3.5 micrograms.kg-1 x min-1) was begun 5 days before the experiment and continued throughout the sampling period. In the saline group (n = 10), there was no infusion of cortisol. The fivefold elevation in plasma cortisol increased plasma insulin from 12 +/- 2 to 19 +/- 2 microU/ml. Glucose Ra was elevated in the cortisol group (3.5 +/- 0.2 vs. 2.8 +/- 0.2 mg.kg-1 x min-1) but net hepatic glucose output was markedly diminished (1.2 +/- 0.4 vs. 2.7 +/- 0.3 mg.kg-1 x min-1). Gluconeogenic conversion of alanine to glucose was increased slightly by cortisol (0.60 +/- 0.13 to 0.99 +/- 0.12 mumol.kg-1 x min-1), but the gluconeogenic efficiency of the liver was unchanged. Cortisol increased hepatic glycogen content evident at the end of the study greater than twofold (76.4 +/- 7.9 vs. 30.0 +/- 4.7 g/liver). These results suggest that cortisol 1) promotes glucose cycling through glycogen, 2) greatly inhibits nonhepatic glucose utilization, 3) increases hepatic gluconeogenesis in vivo primarily through enhanced substrate delivery to the liver, and 4) raises plasma insulin levels, which restrains intrahepatic gluconeogenesis.

3-Hydroxybutyric Acid↗

PubMed1993

Regulation of gluconeogenesis during rest and exercise in the depancreatized dog.

To assess the mechanism of the accelerated gluconeogenesis in the insulin-deficient state, chronically catheterized (carotid artery, portal vein, hepatic vein, vena cava) normal (C; n = 9) and depancreatized (PX; n = 7) dogs were studied during rest (40 min) and moderate exercise (150 min). Tracers ([14C]alanine, [3H]glucose) and dye were infused to measure determinants of gluconeogenesis in the gut and liver. Arterial levels, net gut output, hepatic load, and net hepatic uptake of alanine were similar in C and PX at rest. During exercise, alanine levels fell in C but rose approximately 100% in PX. Exercise did not affect gut output or liver uptake of alanine in C but increased these variables by approximately 50 and 100% in PX due to an increase in hepatic alanine load. Arterial lactate was similar at rest in C and PX but rose fourfold more in PX with exercise. Net gut lactate output was fivefold greater in PX during rest and exercise. Net hepatic lactate uptake was present in PX at rest, whereas net output was evident in C. In response to exercise, hepatic lactate uptake was increased further in PX due to a rise in hepatic lactate load. Net hepatic lactate uptake was not evident until the end of exercise in C. Net hepatic glycerol uptake was elevated at rest in PX and during the initial 60 min of exercise due to an elevated hepatic load. In contrast to the high rates of gut lactate and alanine output in PX, gut glycerol output was not present. Gluconeogenesis from lactate and alanine was 5- to 10-fold higher in PX than C during rest and exercise. At rest, this resulted, in part, from a twofold greater intrahepatic gluconeogenic efficiency. During exercise, the greater conversion occurred even though efficiency was not consistently greater. In summary, gluconeogenesis from alanine, lactate, and glycerol in the insulin-deficient diabetic state 1) is exaggerated at rest, due to an increased capacity for hepatic lactate extraction, increased hepatic precursor loads, and a greater gluconeogenic efficiency; 2) is accelerated further by exercise due to added increments in hepatic precursor loads; and 3) is exaggerated partly because of a greater net gut alanine and lactate output.

Alanine↗

PubMed1993

Role of glucose and insulin loads to the exercising limb in increasing glucose uptake and metabolism.

To assess the contributions of glucose load to the working hindlimb and local contraction-related events (changes related to the microvasculature and/or intrinsic muscle metabolic properties) to the exercise-induced increases in muscle glucose uptake and metabolism in vivo, dogs were studied with somatostatin infused to suppress insulin release, and glucose and insulin were replaced 1) during rest and treadmill exercise at rates that recreate limb glucose and insulin loads evident during exercise (n = 5), 2) at rest to selectively normalize the limb glucose load to rates present during exercise while retaining basal limb insulin loads (GL, n = 5), or 3) at rest to normalize both the limb glucose and insulin loads to those present during exercise (IGL, n = 5). Limb arteriovenous difference and isotopic ([U-14C]glucose) techniques were used to quantify muscle glucose uptake and metabolism. Limb glucose load rose from 819 +/- 141 mumol/min in the basal state to 1,568 +/- 190 mumol/min with exercise. Limb glucose loads were 1,423 +/- 88 and 1,502 +/- 165 mumol/min in GL and IGL. The limb insulin load rose from basal rates of 12.9 +/- 2.3 to 22.9 +/- 5.9 nmol/min during exercise. Limb insulin loads were similar to basal loads in GL (8.8 +/- 1.9 nmol/min) and exercise in IGL (28.2 +/- 5.5 nmol/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Relationship between arterial and portal vein immunoreactive glucagon during exercise.

The importance of changes in glucagon in the regulation of hepatic glucose production (Ra) during exercise has been questioned, as an increase in arterial immunoreactive glucagon (IRG) is not always detectable. However, IRG in the portal vein (PV) and not in the artery is most relevant, as flow through PV is approximately 80% of liver blood flow. To assess the extent that arterial IRG reflects the levels the liver is exposed to in PV, dogs (n = 5) were implanted with catheters in a carotid artery, hepatic vein (HV), and PV. Dogs were studied > or = 16 days later during rest and 150 min of moderate treadmill exercise, with indocyanine green and [3-3H]glucose infused to assess hepatic plasma flow (HPF) and hepatic Ra. IRG was 66 +/- 7, 73 +/- 8, and 81 +/- 7 pg/ml in the artery, HV, and PV at rest; it rose at 10 and 150 min of exercise to 89 +/- 9 and 127 +/- 13 pg/ml in the artery, 106 +/- 17 and 186 +/- 21 pg/ml in HV, and, by considerably more, to 153 +/- 20 and 261 +/- 25 pg/ml in PV. HPF fell by approximately 30% with exercise. The fall in HPF accounted for < 11% of the increased arterial-to-PV IRG gradient during exercise, with increased splanchnic IRG release comprising the remainder. Ra was linearly related to IRG levels in the three vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Regulation of glucose uptake and metabolism by working muscle. An in vivo analysis.

To assess the mechanisms whereby muscular work stimulates glucose uptake and metabolism in vivo, dogs were studied during rest (-40-0 min), moderate exercise (0-90 min), and exercise recovery (90-180 min) with plasma glucose clamped at 5.0, 6.7, 8.3, and 10.0 mM (n = 5 at 5.0 mM and n = 4 at all other levels) using a variable glucose infusion. Basal insulin was maintained with somatostatin and insulin replacement. Whole-body glucose uptake, limb glucose uptake, and oxidative and nonoxidative glucose plus lactate metabolism, were assessed with tracers ([3H]glucose and [14C]glucose) and arteriovenous differences. The combined effects of glucose and exercise on the increment above resting values for limb glucose uptake, arteriovenous glucose difference, LGO, LGNO, and rate of glucose disappearance were synergistic (approximately 112, 90, 125, 76, and 90% greater than the additive values, respectively). Neither exercise nor recovery affected the Km for limb glucose uptake (4.7 +/- 1.1, 4.8 +/- 0.4, and 5.2 +/- 0.3 mM during rest, exercise, and recovery, respectively), but both conditions increased the Vmax (44 +/- 16, 217 +/- 30, and 118 +/- 14 mumol/min during rest, exercise, and recovery, respectively). Similarly, the Km for arteriovenous glucose differences were unaffected by exercise recovery (4.9 +/- 0.6, 5.0 +/- 0.4, and 5.3 +/- 0.3 mM during rest, exercise, and recovery, respectively), but the maximum rose (272 +/- 50, 650 +/- 78, and 822 +/- 111 microM during rest, exercise, and recovery, respectively). The LGO was unchanged by glycemia at rest (15 +/- 4 mumol/min at 10.0 mM). The Km for LGO during exercise was 5.1 +/- 0.3 mM, and the Vmax was 163 +/- 15. The capacity for LGO returned to basal during recovery. LGNO increased gradually with increasing glycemia during rest, exercise, and recovery and did not approach saturation (38 +/- 13, 105 +/- 36, and 132 +/- 45 mumol/min during rest, exercise, and recovery, respectively, at 10.0 mM). In general, the LGNO was elevated at every glucose level during exercise (approximately twofold) and recovery (approximately threefold) compared with rest. Arterial free fatty acid and glycerol levels decreased with increasing glycemia within all periods. Free fatty acids were suppressed by a greater amount during exercise compared with rest and recovery.(ABSTRACT TRUNCATED AT 400 WORDS)

Alanine↗

PubMed1992

The effects of acute elevations in plasma cortisol levels on alanine metabolism in the conscious dog.

The present study was undertaken to determine whether an acute physiological increase in plasma cortisol level had significant effects on alanine metabolism and gluconeogenesis within 3 hours in conscious, overnight-fasted dogs. Each experiment consisted of an 80-minute tracer and dye equilibration period, a 40-minute basal period, and a 3-hour experimental period. A primed, continuous infusion of [3-3H]glucose and continuous infusions of [U-14C]alanine and indocyanine green dye were initiated at the start of the equilibration period and continued throughout the experiment. Dogs were studied with (1) a hydrocortisone infusion ([CORT] 3.0 micrograms.kg-1.min-1, n = 5), (2) hydrocortisone infused as in CORT, but with pancreatic hormones clamped using somatostatin and basal intraportal replacement of insulin and glucagon (CLAMP+CORT, n = 5), or (3) saline infusion during a pancreatic clamp (CLAMP, n = 5). Glucose production and gluconeogenesis were determined using tracer and arteriovenous difference techniques. During CLAMP, all parameters were stable except for a modest 67% +/- 6% increase in gluconeogenic conversion of alanine to glucose and a 53% +/- 26% increase in gluconeogenic efficiency. When plasma cortisol levels were increased fourfold during CLAMP+CORT, there was no change in the concentration, production, or clearance of glucose. Gluconeogenic conversion of alanine to glucose increased 10% +/- 34% and gluconeogenic efficiency increased 65% +/- 43%, while net hepatic alanine uptake (NHAU) increased 60% +/- 19% and hepatic fractional extraction of alanine increased 38% +/- 12%. Cortisol did not cause an increase in the arterial glycerol level or net hepatic glycerol uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗

PubMed1992

Glucoregulation during rest and exercise in depancreatized dogs: role of the acute presence of insulin.

To determine the effects of the presence of insulin in poorly controlled diabetes, depancreatized (PX) dogs (n = 5) were studied during rest and 150 min of exercise in paired experiments in which saline alone was infused (IDEF) and in which insulin was replaced intraportally (200 microU.kg-1.min-1) with glucose clamped at the levels in IDEF (IR+G). PX dogs (n = 4) were also studied with insulin, but glucose was allowed to fall (IR). Insulin was not detectable, 6 +/- 1 and 6 +/- 2 microU/ml in IDEF, IR+G, and IR. Plasma glucose was 470 +/- 47, 480 +/- 48, and 372 +/- 35 mg/dl at rest in IDEF, IR+G, and IR, respectively. Levels were unchanged with exercise in IDEF and IR+G, but fell by 139 +/- 13 mg/dl in IR. Basal glucose rate of appearance (Ra) was 7.0 +/- 0.9, 1.3 +/- 1.1, and 6.0 +/- 0.7 mg.kg-1.min-1 in IDEF, IR+G, and IR, respectively. Exercise elicited a rise in Ra in only IDEF. The rises in Rd and metabolic clearance rate in IDEF were reduced (delta 2.6 +/- 0.7 and delta 0.8 +/- 0.3 ml.kg-1.min-1 at 150 min) compared with IR+G (delta 5.3 +/- 1.9 and delta 1.7 +/- 0.2 ml.kg-1.min-1 at 150 min) and IR (delta 3.7 +/- 1.2 and delta 2.4 +/- 0.8 ml.kg-1.min-1). The insulin sensitivity of glucose utilization (Rd) was elevated by approximately 75% at 150 min. Basal glycerol was similar in IDEF and IR but was reduced by approximately 70% in IR+G. Glycerol rose similarly with exercise in IDEF and IR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Role of leucine and other amino acids in regulating protein metabolism in vivo.

The present study examines the independent effects of amino acids and leucine in modulating insulin's effect on leucine kinetics in 24-h fasted conscious dogs during an experimental period where insulin was infused at 600 mU.kg-1.h-1. Group I (n = 7) received saline, group II (n = 10) received sequential infusions of L-leucine at 0, 1, 3, and 1 mumol.kg-1.min-1 each lasting for 90 min, and group III (n = 6) received L-amino acids with doses of L-leucine matching those of group II. Plasma leucine (mumol/l) was 120 +/- 5 basally and 135 +/- 23 and 129 +/- 12 during the infusion of 3.0 mumol.kg-1.min-1 in groups II and III compared with 40 +/- 3 in group I. Leucine rate of appearance (mumol.kg-1.min-1) was 3.5 +/- 0.3 during the basal period and was suppressed 80% in both groups II and III as compared with 40% in group I (P less than 0.01). Leucine oxidation (basal = 0.7 +/- 0.15 mumol.kg-1.min-1) dropped 20% in group I but increased to threefold basal in group II and twofold in group III (P less than 0.05). Nonoxidative rate of disposal (basal = 2.6 +/- 0.2 mumol.kg-1.min-1) dropped 25% in group I and 55% in group II but did not change in group III. These data show that, in addition to insulin, amino acids and particularly leucine cause a marked suppression of proteolysis. Availability of all amino acids to prevent hypoaminoacidemia is necessary to sustain basal rates of protein synthesis. The infusion of leucine alone resulted in significant stimulation of leucine oxidation.

Amino Acids↗

PubMed1992

Metabolic regulation in peripheral tissues and transition to increased gluconeogenic mode during prolonged exercise.

To assess the means by which peripheral metabolism facilitates the transition to a gluconeogenic state, dogs were studied during 150 min of moderate treadmill exercise. Metabolism in the working hindlimb was assessed with arteriovenous difference and isotopic techniques (n = 9). In a separate group (n = 6), hepatic metabolism was assessed using arteriovenous differences. Limb glucose uptake (LGU) and oxidation (GOX) rose from 33 +/- 10 and 5 +/- 2 to 101 +/- 20 and 54 +/- 15 mumol/min at 10 min of exercise. LGU continued to rise (151 +/- 21 mumol/min at 150 min), while GOX declined. Nonoxidative glucose metabolism (GNOX) was 28 +/- 10 mumol/min at rest and 47 +/- 24 and 108 +/- 16 mumol/min at 10 and 150 min of exercise. Limb nonglycemic (predominantly glycogen) pyruvate formation rose from 52 +/- 22 to 198 +/- 54 and 242 +/- 74 mumol/min at 10 and 150 min of exercise. The gradual increase in GNOX and the high glycogenolytic rate were paralleled by accelerated lactate, pyruvate, and glutamine releases. Limb glycerol release rose promptly and remained elevated during exercise. Plasma nonesterified fatty acids (NEFAs) rose gradually and paralleled the gradual rise in GNOX (r = 0.93). The resulting rise in hepatic NEFA delivery was highly correlated to hepatic O2 uptake (r = 0.87), hepatic vein lactate-to-pyruvate ratio (r = 0.90), and intrahepatic gluconeogenic efficiency (r = 0.96). In summary, during exercise, 1) the primary fate of the added glucose consumed by the working limb is initially oxidation, but becomes GNOX as exercise duration progresses; 2) glycogenolysis rises promptly, but attains its highest rate at the end of exercise; 3) the late increases in GNOX and glycogenolysis relate to an increased gluconeogenic precursor release from the working limb; 4) although lipolysis increases promptly and is sustained, circulating NEFAs rise only gradually; and 5) the gradual rise in plasma NEFAs is highly correlated to the shift from GOX to GNOX and the adjustments in hepatic metabolism that are necessary for the full gluconeogenic response.

Amino Acids↗

PubMed1992

Importance of basal glucagon in maintaining hepatic glucose production during a prolonged fast in conscious dogs.

We undertook studies in conscious dogs to assess the role of basal glucagon in stimulating glucose production after a 7-day fast. Two protocols consisting of a 40-min basal period (-40 to 0 min), and a 180-min test period (0-180 min) were used. During the test period of the first protocol (hormone replacement; n = 4), somatostatin was infused (0.8 micrograms.kg-1.min-1) along with basal intraportal replacement amounts of insulin and glucagon, whereas in the second protocol (glucagon deficiency; n = 5), somatostatin plus insulin alone were infused. Glucose production and gluconeogenesis were measured using tracer and arteriovenous difference techniques. Plasma insulin levels were similar during the test period in both protocols (6 +/- 1 microU/ml). The plasma immunoreactive glucagon level in the control protocol averaged 50 +/- 8 pg/ml, whereas in the glucagon-deficiency protocol the level fell from 50 +/- 8 to 29 +/- 8 pg/ml (P less than 0.05). The plasma glucose level and the rate of glucose production were unchanged during bihormonal replacement. During glucagon deficiency the plasma glucose level was held constant at 100 +/- 4 mg/dl by glucose infusion. Tracer-determined endogenous glucose production fell from 1.8 +/- 0.1 to 1.0 +/- 0.1 mg.kg-1.min-1 by 30 min (P less than 0.05). After 3 h of glucagon deficiency, gluconeogenic conversion of alanine to glucagon was reduced 40% and the hepatic fractional extraction of alanine was reduced by 45%. The efficiency of the gluconeogenic process within the liver was not altered by glucagon deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗

PubMed1992

Impact of insulin deficiency on glucose fluxes and muscle glucose metabolism during exercise.

Exercise in the insulin-deficient diabetic state is characterized by a further increase in elevated circulating glucose and NEFA levels and by excessive counterregulatory hormone levels. The aim of this study was to distinguish the direct glucoregulatory effects of insulinopenia during exercise from the indirect effects that result from the metabolic and hormonal environment that accompanies insulin deficiency. For this purpose, dogs underwent 90 min of treadmill exercise during SRIF infusion with (SRIF + INS, n = 8) or without (SRIF - INS, n = 6) intraportal insulin replacement. Glucagon was not replaced, thus allowing assessment of the direct effect of insulinopenia at the liver independent of the potentiation of glucagon action. Glucose was infused to maintain euglycemia. Hepatic glucose production (Ra); glucose utilization (Rd); and LGlcU, LGlcE, and LGlcO were assessed with tracers ([3H]glucose, [14C]glucose) and arteriovenous differences. With exercise, insulin fell from 66 +/- 6 to 42 +/- 6 pM in the SRIF + INS group, and was undetectable in the SRIF - INS group. Plasma glucose was 6.33 +/- 0.38 and 6.26 +/- 0.30 mM at rest in the SRIF + INS and SRIF - INS groups, respectively, and was unchanged with exercise. Ra rose from 7.5 +/- 2.3 to 16.5 +/- 2.2 mumol.kg-1.min-1 and 9.1 +/- 2.0 to 31.4 +/- 3.9 mumol.kg-1.min-1 with exercise in the SRIF + INS and SRIF - INS groups, whereas Rd rose from 19.5 +/- 2.0 to 46.8 +/- 3.9 mumol.kg-1.min-1 and 15.1 +/- 1.8 to 29.9 +/- 3.3 mumol.kg-1.min-1. LGlcU rose from 36 +/- 9 to 112 +/- 25 mumol/min and 15 +/- 4 to 59 +/- 13 mumol/min and LGlcO rose from 5 +/- 2 to 61 +/- 12 mumol/min and 5 +/- 3 to 32 +/- 9 mumol/min with exercise in the SRIF+INS and SRIF-INS groups, respectively. Arterial levels and limb balances of NEFAs and glycerol were similar in the two groups. In summary, during exercise: 1) marked insulinopenia attenuates the increases in muscle glucose uptake and oxidation by approximately 50%, independent of changes in circulating metabolic substrate levels; 2) substantial increases in muscle glucose uptake and oxidation are, however, still present even in the absence of detectable insulin levels; and 3) insulinopenia facilitates the increase in Ra, independent of the potentiation of basal glucagon action. In conclusion, marked insulinopenia contributes directly to the exacerbation of glucoregulation during exercise in the diabetic state by limiting the rises in glucose uptake and metabolism and by enhancing hepatic glucose production.

Analysis of Variance↗

PubMed1991

Interaction of gut and liver in nitrogen metabolism during exercise.

The role of the gut and liver in nitrogen metabolism was studied during rest, 150 minutes of moderate-intensity treadmill exercise, and 90 minutes of recovery in 18 hour-fasted dogs (n = 6). Dogs underwent surgery 16 days before an experiment for implantation of catheters in a carotid artery and in the portal and hepatic veins, and Doppler flow cuffs on the hepatic artery and portal vein. Arterial glutamine, alanine, and alpha-amino nitrogen (AAN) levels decreased gradually with exercise (P less than .05), while arterial glutamate, NH3, and urea were unchanged. Net gut glutamine uptake was 1.3 +/- 0.5 mumol/kg.min at rest, and increased transiently to 2.5 +/- 0.3 mumol/kg.min at 60 minutes of exercise (P less than .05) as gut extraction increased. Net hepatic glutamine uptake was 0.6 +/- 0.4 mumol/kg.min at rest, and increased to 3.4 +/- 0.6 and 2.6 +/- 0.5 mumol/kg.min after 60 and 150 minutes of exercise (P less than .05) as hepatic extraction increased. Net gut glutamate and NH3 output both increased transiently with exercise (P less than .05). These increases were matched by parallel increments in the net hepatic uptakes of these compounds. Alanine output by the gut and uptake by the liver were unchanged with exercise. Net gut AAN output was -2.1 +/- 1.8 mumol/kg.min at rest (uptake occurred), and increased transiently to 11.2 +/- 3.5 mumol/kg.min after 30 minutes of exercise (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗