Coronary nitric oxide production controls cardiac substrate metabolism during pregnancy in the dog

The aim of this study was to examine the role of nitric oxide (NO) in the control of cardiac metabolism at 60 days of pregnancy (P60) in the dog. There was a basal increase in diastolic coronary blood flow during pregnancy and a statistically significant increase in cardiac output (55 +/- 4%) and in cardiac NOx production (44 +/- 4 to 59 +/- 3 nmol/min, P < 0.05). Immunohistochemistry of the left ventricle showed an increase in endothelial nitric oxide synthase staining in the endothelial cells at P60. NO-dependent coronary vasodilation (Bezold-Jarisch reflex) was increased by 20% and blocked by N(G)-nitro-l-arginine methyl ester (l-NAME). Isotopically labeled substrates were infused to measure oleate, glucose uptake, and oxidation. Glucose oxidation was not significantly different in P60 hearts (5.4 +/- 0.5 vs. 6.2 +/- 0.4 micromol/min) but greatly increased in response to l-NAME injection (to 19.9 +/- 0.9 micromol/min, P < 0.05). Free fatty acid (FFA) oxidation was increased in P60 (from 5.3 +/- 0.6 to 10.4 +/- 0.5 micromol/min, P < 0.05) and decreased in response to l-NAME (to 4.5 +/- 0.5 micromol/min, P < 0.05). There was an increased oxidation of FFA for ATP production but no change in the respiratory quotient during pregnancy. Genes associated with glucose and glycogen metabolism were downregulated, whereas genes involved in FFA oxidation were elevated. The acute inhibition of NO shifts the heart away from FFA and toward glucose metabolism despite the downregulation of the carbohydrate oxidative pathway. The increase in endothelium-derived NO during pregnancy results in a tonic inhibition of glucose oxidation and reliance on FFA uptake and oxidation to support ATP synthesis in conjunction with upregulation of FFA metabolic enzymes.     

Free fatty acid-induced peripheral insulin resistance augments splanchnic glucose uptake in healthy humans

To investigate the effect of elevated plasma free fatty acid (FFA) concentrations on splanchnic glucose uptake (SGU), we measured SGU in nine healthy subjects (age, 44 +/- 4 yr; body mass index, 27.4 +/- 1.2 kg/m(2); fasting plasma glucose, 5.2 +/- 0.1 mmol/l) during an Intralipid-heparin (LIP) infusion and during a saline (Sal) infusion. SGU was estimated by the oral glucose load (OGL)-insulin clamp method: subjects received a 7-h euglycemic insulin (100 mU x m(-2) x min(-1)) clamp, and a 75-g OGL was ingested 3 h after the insulin clamp was started. After glucose ingestion, the steady-state glucose infusion rate (GIR) during the insulin clamp was decreased to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in GIR during the period after glucose ingestion from the ingested glucose load. [3-(3)H]glucose was infused during the initial 3 h of the insulin clamp to determine rates of endogenous glucose production (EGP) and glucose disappearance (R(d)). During the 3-h euglycemic insulin clamp before glucose ingestion, R(d) was decreased (8.8 +/- 0.5 vs. 7.6 +/- 0.5 mg x kg(-1) x min(-1), P < 0.01), and suppression of EGP was impaired (0.2 +/- 0.04 vs. 0.07 +/- 0.03 mg x kg(-1) x min(-1), P < 0.01). During the 4-h period after glucose ingestion, SGU was significantly increased during the LIP vs. Sal infusion study (30 +/- 2 vs. 20 +/- 2%, P < 0.005). In conclusion, an elevation in plasma FFA concentration impairs whole body glucose R(d) and insulin-mediated suppression of EGP in healthy subjects but augments SGU.     

Effect of hyperinsulinemia on amino acid utilization in the ovine fetus

We studied the effect of an acute 4-h period of hyperinsulinemia (H) on net utilization rates (AAUR(net)) of 21 amino acids (AA) in 17 studies performed in 13 late-gestation fetal sheep by use of a novel fetal hyperinsulinemic-euglycemic-euaminoacidemic clamp. During H [84 +/- 12 (SE) microU/ml H, 15 +/- 2 microU/ml control (C), P < 0. 00001], euglycemia was maintained by glucose clamp (19 +/- 0.05 micromol/ml H, 1.19 +/- 0.04 micromol/ml C), and euaminoacidemia (mean 4.1 +/- 3.3% increase for all amino acid concentrations [AA], nonsignificantly different from zero) was maintained with a mixed amino acid solution adjusted to keep lysine concentration constant and other [AA] near C values. H produced a 63.7% increase in AAUR(net) (3.29 +/- 0.66 micromol. min(-1). kg(-1) H, 2.01 +/- 0.55 micromol. min(-1). kg(-1) C, P < 0.001), accounting for a 60.1% increase in fetal nitrogen uptake rate (2,064 +/- 108 mg. day(-1). kg(-1) H, 1,289 +/- 73 mg. day(-1). kg(-1) C, P < 0.001). Mean AA clearance rate (AAUR(net)/[AA]) increased by 64.5 +/- 18.9% (P < 0. 001). Thus acute physiological H increases net amino acid and nitrogen utilization rates in the ovine fetus independent of plasma glucose and [AA].     

Effect of enteral vs. parenteral glucose delivery on initial splanchnic glucose uptake in nondiabetic humans

To determine if enteral delivery of glucose influences splanchnic glucose metabolism, 10 subjects were studied when glucose was either infused into the duodenum at a rate of 22 micromol x kg(-1) x min(-1) and supplemental glucose given intravenously or when all glucose was infused intravenously while saline was infused intraduodenally. Hormone secretion was inhibited with somatostatin, and glucose (approximately 8.5 mmol/l) and insulin (approximately 450 pmol/l) were maintained at constant but elevated levels. Intravenously infused [6,6-(2)H(2)]glucose was used to trace the systemic appearance of intraduodenally infused [3-(3)H]glucose, whereas UDP-glucose flux (an index of hepatic glycogen synthesis) was measured using the acetaminophen glucuronide method. Despite differences in the route of glucose delivery, glucose production (3.5 +/- 1.0 vs. 3.3 +/- 1.0 micromol x kg(-1) x min(-1)) and glucose disappearance (78.9 +/- 5.7 vs. 85.0 +/- 7.2 micromol x kg(-1) x min(-1)) were comparable on intraduodenal and intravenous study days. Initial splanchnic glucose extraction (17.5 +/- 4.4 vs. 14.5 +/- 2.9%) and hepatic UDP-glucose flux (9.0 +/- 2.0 vs. 10.3 +/- 1.5 micromol x kg(-1) x min(-1)) also did not differ on the intraduodenal and intravenous study days. These data argue against the existence of an "enteric" factor that directly (i.e., independently of circulating hormone concentrations) enhances splanchnic glucose uptake or hepatic glycogen synthesis in nondiabetic humans.     

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.     

Interaction of a selective serotonin reuptake inhibitor with insulin in the control of hepatic glucose uptake in conscious dogs

Whether hyperinsulinemia is required for stimulation of net hepatic glucose uptake (NHGU) by a selective serotonin reuptake inhibitor (SSRI) was examined in four groups of conscious 42-h-fasted dogs, using arteriovenous difference and tracer ([3-3H]glucose) techniques. Experiments consisted of equilibration (-120 to -30 min), basal (-30 to 0 min), and experimental periods (Exp; 0-240 min). During Exp, somatostatin, intraportal insulin [at basal (Ins groups) or 4-fold basal rates (INS groups)], basal intraportal glucagon, and peripheral glucose (to double hepatic glucose load) were infused. In the Fluv-Ins (n = 7) and Fluv-INS groups (n = 6), saline was infused intraportally from 0 to 90 min (P1), and fluvoxamine was infused intraportally at 2 microg x kg(-1) x min(-1) from 90 to 240 min (P2). Sal-Ins (n = 9) and Sal-INS (n = 8) received intraportal saline in P1 and P2. NHGU during P2 was 8.4 +/- 1.4 and 6.9 +/- 2.3 micromol x kg(-1) x min(-1) in Sal-Ins and Fluv-Ins, respectively (not significant), and 13.3 +/- 2.2 and 20.9 +/- 3.1 micromol x kg(-1) x min(-1) (P < 0.05) in Sal-INS and Fluv-INS. Unidirectional (tracer-determined) hepatic glucose uptake was twofold greater (P < 0.05) in Fluv-INS than Sal-INS. Net hepatic carbon retention during P2 was significantly greater in Fluv-INS than Sal-INS (18.5 +/- 2.7 vs. 12.2 +/- 1.9 micromol x kg(-1) x min(-1)). Nonhepatic glucose uptake was reduced in Fluv-INS vs. Sal-INS (20.0 +/- 1.3 vs. 38.4 +/- 5.4 micromol x kg(-1) x min(-1), P < 0.05). Intraportal fluvoxamine enhanced NHGU and net hepatic carbon retention in the presence of hyperinsulinemia but not euinsulinemia, suggesting that hepatocyte-targeted SSRIs may reduce postprandial hyperglycemia.     

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.     

Effect of intraportal glucagon-like peptide-1 on glucose metabolism in conscious dogs

Arteriovenous difference and tracer ([3-(3)H]glucose) techniques were used in 42-h-fasted conscious dogs to identify any insulin-like effects of intraportally administered glucagon-like peptide 1-(7-36)amide (GLP-1). Each study consisted of an equilibration, a basal, and three 90-min test periods (P1, P2, and P3) during which somatostatin, intraportal insulin (3-fold basal) and glucagon (basal), and peripheral glucose were infused. Saline was infused intraportally in P1. During P2 and P3, GLP-1 was infused intraportally at 0.9 and 5.1 pmol. kg(-1). min(-1) in eight dogs, at 10 and 20 pmol. kg(-1). min(-1) in seven dogs, and at 0 pmol. kg(-1). min(-1) in eight dogs (control group). Net hepatic glucose uptake was significantly enhanced during GLP-1 infusion at 20 pmol. kg(-1). min(-1) [21.8 vs. 13.4 micromol. kg(-1). min(-1) (control), P < 0.05]. Glucose utilization was significantly increased during infusion at 10 and 20 pmol. kg(-1). min(-1) [87.3 +/- 8.3 and 105.3 +/- 12.8, respectively, vs. 62.2 +/- 5.3 and 74.7 +/- 7.4 micromol. kg(-1). min(-1) (control), P < 0.05]. The glucose infusion rate required to maintain hyperglycemia was increased (P < 0.05) during infusion of GLP-1 at 5.1, 10, and 20 pmol. kg(-1). min(-1) (22, 36, and 32%, respectively, greater than control). Nonhepatic glucose uptake increased significantly during delivery of GLP-1 at 5.1 and 10 pmol. kg(-1). min(-1) (25 and 46% greater than control) and tended (P = 0.1) to increase during GLP-1 infusion at 20 pmol. kg(-1). min(-1) (24% greater than control). Intraportal infusion of GLP-1 at high physiological and pharmacological rates increased glucose disposal primarily in nonhepatic tissues.     

Combined intraportal infusion of acetylcholine and adrenergic blockers augments net hepatic glucose uptake

Portal glucose delivery in the conscious dog augments net hepatic glucose uptake (NHGU). To investigate the possible role of altered autonomic nervous activity in the effect of portal glucose delivery, the effects of adrenergic blockade and acetylcholine (ACh) on hepatic glucose metabolism were examined in 42-h-fasted conscious dogs. Each study consisted of an equilibration (-120 to -20 min), a control (-20 to 0 min), and a hyperglycemic-hyperinsulinemic period (0 to 300 min). During the last period, somatostatin (0.8 microg. kg(-1). min(-1)) was infused along with intraportal insulin (1.2 mU. kg(-1). min(-1)) and glucagon (0.5 ng. kg(-1). min(-1)). Hepatic sinusoidal insulin was four times basal (73 +/- 7 microU/ml) and glucagon was basal (55 +/- 7 pg/ml). Glucose was infused peripherally (0-300 min) to create hyperglycemia (220 mg/dl). In test protocol, phentolamine and propranolol were infused intraportally at 0.2 microg and 0.1 microg. kg(-1). min(-1) from 120 min on. ACh was infused intraportally at 3 microg. kg(-1). min(-1) from 210 min on. In control protocol, saline was given in place of the blockers and ACh. Hyperglycemia-hyperinsulinemia switched the net hepatic glucose balance (mg. kg(-1). min(-1)) from output (2.1 +/- 0.3 and 1.1 +/- 0.2) to uptake (2.8 +/- 0.9 and 2.6 +/- 0.6) and lactate balance (micromol. kg(-1). min(-1)) from uptake (7.5 +/- 2.2 and 6.7 +/- 1.6) to output (3.7 +/- 2.6 and 3.9 +/- 1.6) by 120 min in the control and test protocols, respectively. Thereafter, in the control protocol, NHGU tended to increase slightly (3.0 +/- 0.6 mg. kg(-1). min(-1) by 300 min). In the test protocol, adrenergic blockade did not alter NHGU, but ACh infusion increased it to 4.4 +/- 0.6 and 4.6 +/- 0.6 mg. kg(-1). min(-1) by 220 and 300 min, respectively. These data are consistent with the hypothesis that alterations in nerve activity contribute to the increase in NHGU seen after portal glucose delivery.     

Simulated first-phase insulin release using Humulin or insulin analog HIM2 is associated with prolonged improvement in postprandial glycemia

We examined the extent to which priming the liver with a pulse of Humulin or the insulin analog hexyl-insulin monoconjugate 2 (HIM2) reduces postprandial hyperglycemia. Somatostatin (0.5 microg.kg(-1).min(-1)) was given with basal intraportal insulin and glucagon for 4.5 h into three groups of 42-h-fasted conscious dogs. From 0-5 min, group 1 (BI, n = 6) received saline, group 2 (HI, n = 6) received a Humulin pulse (10 mU.kg(-1).min(-1)), and group 3 (HIM2, n = 6) received a HIM2 pulse (10 mU.kg(-1).min(-1)). Duodenal glucose was infused (5.0 mg.kg(-1).min(-1)) from 15 to 270 min. Arterial insulin in BI remained basal (6 +/- 1 microU/ml) and peaked at 52 +/- 15 (HI) and 164 +/- 44 microU/ml (HIM2) and returned to baseline by 30 and 60 min, respectively. Arterial plasma glucose plateaued at 265 +/- 20, 214 +/- 15, and 193 +/- 14 mg/dl in BI, HI, and HIM2. Glucose absorption was similar in all groups. Significant net hepatic glucose uptake occurred at 85, 55, and 25 min in BI, HI, and HIM2, respectively. Nonhepatic glucose clearance at 270 min differed among groups (BI, HI, HIM2): 0.62 +/- 0.11, 0.76 +/- 0.26, and 1.61 +/- 0.29 ml.kg(-1).min(-1) (P < 0.05). A brief (5-min) insulin pulse improved postprandial glycemia, stimulating hepatic glucose uptake and prolonging enhancement of nonhepatic glucose clearance. HIM2 was more effective than Humulin, perhaps because its lowered clearance caused higher levels at the liver and periphery and its biological activity was not reduced proportionally to its decreased clearance.     

Interaction of free fatty acids and epinephrine in regulating hepatic glucose production in conscious dogs

To determine the effects of an increase in lipolysis on the glycogenolytic effect of epinephrine (EPI), the catecholamine was infused portally into 18-h-fasted conscious dogs maintained on a pancreatic clamp in the presence [portal (Po)-EPI+FFA, n = 6] and absence (Po-EPI+SAL, n = 6) of peripheral Intralipid infusion. Control groups with high glucose (70% increase) and free fatty acid (FFA; 200% increase; HG+FFA, n = 6) and high glucose alone (HG+SAL, n = 6) were also included. Hepatic sinusoidal EPI levels were elevated (Delta 568 +/- 77 and Delta 527 +/- 37 pg/ml, respectively) in Po-EPI+SAL and EPI+FFA but remained basal in HG+FFA and HG+SAL. Arterial plasma FFA increased from 613 +/- 73 to 1,633 +/- 101 and 746 +/- 112 to 1,898 +/- 237 micromol/l in Po-EPI+FFA and HG+FFA but did not change in EPI+SAL or HG+SAL. Net hepatic glycogenolysis increased from 1.5 +/- 0.3 to 3.1 +/- 0.4 mg x kg(-1) x min(-1) (P < 0.05) by 30 min in response to portal EPI but did not rise (1.8 +/- 0.2 to 2.1 +/- 0.3 mg x kg(-1) x min(-1)) in response to Po-EPI+FFA. Net hepatic glycogenolysis decreased from 1.7 +/- 0.2 to 0.9 +/- 0.2 and 1.6 +/- 0.2 to 0.7 +/- 0.2 mg x kg(-1) x min(-1) by 30 min in HG+FFA and HG+SAL. Hepatic gluconeogenic flux to glucose 6-phosphate increased from 0.6 +/- 0.1 to 1.2 +/- 0.1 mg x kg(-1) x min(-1) (P < 0.05; by 3 h) and 0.7 +/- 0.1 to 1.6 +/- 0.1 mg x kg(-1) x min(-1) (P < 0.05; at 90 min) in HG+FFA and Po-EPI+FFA. The gluconeogenic parameters remained unchanged in the Po-EPI+SAL and HG+SAL groups. In conclusion, increased FFA markedly changed the mechanism by which EPI stimulated hepatic glucose production, suggesting that its overall lipolytic effect may be important in determining its effect on the liver.     

Oxyntomodulin ameliorates glucose intolerance in mice fed a high-fat diet

We evaluated the acute effects of OXM on glucose metabolism in diet-induced insulin-resistant male C57Bl/6 mice. To determine the effects on glucose tolerance, mice were intraperitoneally injected with OXM (0.75, 2.5, or 7.5 nmol) or vehicle prior to an ip glucose tolerance test. OXM (0.75 nmol/h) or vehicle was infused during a hyperinsulinemic euglycemic clamp to quantify insulin action on glucose production and disposal. OXM dose-dependently improved glucose tolerance as estimated by AUC for glucose (OXM: 7.5 nmol, 1,564 +/- 460, P < 0.01; 2.5 nmol, 1,828 +/- 684, P < 0.01; 0.75 nmol, 2,322 +/- 303, P < 0.05; control: 2,790 +/- 222 mmol.l(-1).120 min). Insulin levels in response to glucose administration were higher in 7.5 nmol OXM-treated animals compared with controls. In basal clamp conditions, OXM increased EGP (82.2 +/- 14.7 vs. 39.9 +/- 5.7 micromol.min(-1).kg(-1), P < 0.001). During insulin infusion, insulin levels were twice as high in OXM-treated mice compared with controls (10.6 +/- 2.8 vs. 4.4 +/- 2.2 ng/ml, P < 0.01). Consequently, glucose infusion rate (118.6 +/- 30.8 vs. 38.8 +/- 26.4 microl/h, P < 0.001) and glucose disposal (88.1 +/- 13.0 vs. 45.2 +/- 6.9 micromol.min(-1).kg(-1), P < 0.001) were enhanced in mice that received OXM. In addition, glucose production was more suppressed during OXM infusion (35.7 +/- 15.5 vs. 15.8 +/- 11.4% inhibition, P < 0.05). However, if these data were expressed per unit concentration of circulating insulin, OXM did not affect insulin action on glucose disposal and production. These results indicate that OXM beneficially affects glucose metabolism in diet-induced insulin-resistant C57Bl/6 mice. It ameliorates glucose intolerance, most likely because it elevates glucose-induced plasma insulin concentrations. OXM does not appear to impact on insulin action.     

Alterations in carbohydrate metabolism in response to short-term dietary carbohydrate restriction

Dietary carbohydrate restriction (CR) presents a challenge to glucose homeostasis. Despite the popularity of CR diets, little is known regarding the metabolic effects of CR. The purpose of this study was to examine changes in whole body carbohydrate oxidation, glucose availability, endogenous glucose production, and peripheral glucose uptake after dietary CR, without the confounding influence of a negative energy balance. Postabsorptive rates of glucose appearance in plasma (R(a); i.e., endogenous glucose production) and disappearance from plasma (R(d); i.e., glucose uptake) were measured using isotope dilution methods after a conventional diet [60% carbohydrate (CHO), 30% fat, and 10% protein; kcals = 1.3 x resting energy expenditure (REE)] and after 2 days and 7 days of CR (5% CHO, 60% fat, and 35% protein; kcals = 1.3 x REE) in eight subjects (means +/- SE; 29 +/- 4 yr; BMI 24 +/- 1 kg/m(2)) during a 9-day hospital visit. Postabsorptive plasma glucose concentration was reduced (P = 0.01) after 2 days but returned to prediet levels the next day and remained at euglycemic levels throughout the diet (5.1 +/- 0.2, 4.3 +/- 0.3, and 4.8 +/- 0.4 mmol/l for prediet, 2 days and 7 days, respectively). Glucose R(a) and glucose R(d) were reduced to below prediet levels (9.8 +/- 0.6 micromol x kg(-1) x min(-1)) after 2 days of CR (7.9 +/- 0.3 micromol x kg(-1) x min(-1)) and remained suppressed after 7 days (8.3 +/- 0.4 micromol x kg(-1) x min(-1); both P < 0.001). A greater suppression in carbohydrate oxidation, compared with the reduction in glucose R(d), led to an increased (all P 相似文献   

Portal 5-hydroxytryptophan infusion enhances glucose disposal in conscious dogs

Intraportal serotonin infusion enhances net hepatic glucose uptake (NHGU) during glucose infusion but blunts nonhepatic glucose uptake and can cause gastrointestinal discomfort and diarrhea at high doses. Whether the serotonin precursor 5-hydroxytryptophan (5-HTP) could enhance NHGU without gastrointestinal side effects during glucose infusion was examined in conscious 42-h-fasted dogs, using arteriovenous difference and tracer ([3-3H]glucose) techniques. Experiments consisted of equilibration (-120 to -30 min), basal (-30 to 0 min), and experimental (EXP; 0-270 min) periods. During EXP, somatostatin, fourfold basal intraportal insulin, basal intraportal glucagon, and peripheral glucose (to double the hepatic glucose load) were infused. In one group of dogs (HTP, n = 6), saline was infused intraportally from 0 to 90 min (P1), and 5-HTP was infused intraportally at 10, 20, and 40 microg x kg(-1) x min(-1) from 90 to 150 (P2), 150 to 210 (P3), and 210 to 270 (P4) min, respectively. In the other group (SAL, n = 7), saline was infused intraportally from 0 to 270 min. NHGU in SAL was 14.8 +/- 1.9, 18.5 +/- 2.3, 16.3 +/- 1.4, and 19.7 +/- 1.6 micromol x kg(-1) x min(-1) in P1-P4, whereas NHGU in 5-HTP averaged 16.4 +/- 2.6, 18.5 +/- 1.4, 20.8 +/- 2.0, and 27.6 +/- 2.6 micromol x kg(-1) x min(-1) (P < 0.05 vs. SAL). Nonhepatic glucose uptake (micromol x kg(-1) x min(-1)) in SAL was 30.2 +/- 4.3, 36.8 +/- 5.8, 44.3 +/- 5.8, and 54.6 +/- 11.8 during P1-P4, respectively, whereas in HTP the corresponding values were 26.3 +/- 6.8, 44.9 +/- 10.1, 47.5 +/- 11.7, and 51.4 +/- 13.2 (not significant between groups). Intraportal 5-HTP enhances NHGU without significantly altering nonhepatic glucose uptake or causing gastrointestinal side effects, raising the possibility that a related agent might have a role in reducing postprandial hyperglycemia.     

Importance of the hepatic arterial glucose level in generation of the portal signal in conscious dogs

The aim of this study was to determine whether the elimination of the hepatic arterial-portal (A-P) venous glucose gradient would alter the effects of portal glucose delivery on hepatic or peripheral glucose uptake. Three groups of 42-h-fasted conscious dogs (n = 7/group) were studied. After a 40-min basal period, somatostatin was infused peripherally along with intraportal insulin (7.2 pmol x kg(-1) x min(-1)) and glucagon (0.65 ng x kg(-1) x min(-1)). In test period 1 (90 min), glucose was infused into a peripheral vein to double the hepatic glucose load (HGL) in all groups. In test period 2 (90 min) of the control group (CONT), saline was infused intraportally; in the other two groups, glucose was infused intraportally (22.2 micromol x kg(-1) x min(-1)). In the second group (PD), saline was simultaneously infused into the hepatic artery; in the third group (PD+HAD), glucose was infused into the hepatic artery to eliminate the negative hepatic A-P glucose gradient. HGL was twofold basal in each test period. Net hepatic glucose uptake (NHGU) was 10.1 +/- 2.2 and 12.8 +/- 2.1 vs. 11.5 +/- 1.6 and 23.8 +/- 3.3* vs. 9.0 +/- 2.4 and 13.8 +/- 4.2 micromol x kg(-1) x min(-1) in the two periods of CONT, PD, and PD+HAD, respectively (* P < 0.05 vs. same test period in PD and PD+HAD). NHGU was 28.9 +/- 1.2 and 39.5 +/- 4.3 vs. 26.3 +/- 3.7 and 24.5 +/- 3.7* vs. 36.1 +/- 3.8 and 53.3 +/- 8.5 micromol x kg(-1) x min(-1) in the first and second periods of CONT, PD, and PD+HAD, respectively (* P < 0.05 vs. same test period in PD and PD+HAD). Thus the increment in NHGU and decrement in extrahepatic glucose uptake caused by the portal signal were significantly reduced by hepatic arterial glucose infusion. These results suggest that the hepatic arterial glucose level plays an important role in generation of the effect of portal glucose delivery on glucose uptake by liver and muscle.     

Glucose infusion attenuates endogenous glucose production and enhances glucose use of horses during exercise.

We examined the effects of increased glucose availability on glucose kinetics and substrate utilization in horses during exercise. Six conditioned horses ran on a treadmill for 90 min at 34 +/- 1% of maximum oxygen uptake. In one trial [glucose (Glu)], glucose was infused at a mean rate of 34.9 +/- 1.1 micromol. kg(-1). min(-1), whereas in the other trial [control (Con)] an equivalent volume of isotonic saline was infused. Plasma glucose increased during exercise in Glu (90 min: 8.3 +/- 1.7 mM) but was largely unchanged in Con (90 min: 5.1 +/- 0.4 mM). In Con, hepatic glucose production (HGP) increased during exercise, reaching a peak of 38.6 +/- 2.7 micromol. kg(-1). min(-1) after 90 min. Glucose infusion partially suppressed (P < 0.05) the rise in HGP (peak value 25.8 +/- 3.3 micromol. kg(-1). min(-1)). In Con, glucose rate of disappearance (R(d)) rose to a peak of 40.4 +/- 2.9 micromol. kg(-1). min(-1) after 90 min; in Glu, augmented glucose utilization was reflected by values for glucose R(d) that were twofold higher (P < 0.001) than in Con between 30 and 90 min. Total carbohydrate oxidation was higher (P < 0.05) in Glu (187.5 +/- 8.5 micromol. kg(-1). min(-1)) than in Con (159.2 +/- 7.3 micromol. kg(-1).min(-1)), but muscle glycogen utilization was similar between trials. We conclude that an increase in glucose availability in horses during low-intensity exercise 1) only partially suppresses HGP, 2) attenuates the decrease in carbohydrate oxidation during such exercise, but 3) does not affect muscle glycogen utilization.     

Comparison of local and systemic effects of insulin on myocardial glucose extraction in ischemic heart disease

Physiological increases in circulating insulin level significantly increase myocardial glucose uptake in vivo. To what extent this represents a direct insulin action on the heart or results indirectly from reduction in circulating concentrations of free fatty acids (FFA) is uncertain. To examine this, we measured myocardial glucose, lactate, and FFA extraction in 10 fasting men (ages 49-76 yr) with stable coronary artery disease during sequential intracoronary (10 mU/min, coronary plasma insulin = 140 +/- 20 microU/ml) and intravenous (100 mU/min, systemic plasma insulin = 168 +/- 26 microU/ml) insulin infusion. Basally, hearts extracted 2 +/- 2% of arterial glucose and extracted 27 +/- 6% of FFA. Coronary insulin infusion increased glucose extraction to 5 +/- 3% (P < 0.01 vs. basal) without changing plasma FFA or heart FFA extraction. Conversion to intravenous infusion lowered plasma FFA by approximately 50% and heart FFA extraction by approximately 75%, increasing heart glucose extraction still further to 8 +/- 3% (P < 0. 01 vs. intracoronary). This suggests the increase in myocardial glucose extraction observed in response to an increment in systemic insulin concentration is mediated equally by a reduction in circulating FFA and by direct insulin action on the heart itself. Coronary insulin infusion increased myocardial lactate extraction as well (from 20 +/- 10% to 29 +/- 9%, P < 0.05), suggesting the local action may include stimulation of a metabolic step distal to glucose transport and glycolysis.     

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

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 micromol.kg(-1).min(-1) into a peripheral vein (p.e., n = 5) or the hepatic portal (p.o., n = 5) vein. Arterial blood glucose increased approximately 0.8 mmol/l in both groups. Arterial and hepatic sinusoidal insulin concentrations were not significantly different between groups. p.e. exhibited an increase in nonhepatic glucose uptake (non-HGU; Delta8.6 +/- 1.2 micromol.kg(-1).min(-1)) within 30 min, whereas p.o. showed a slight suppression (Delta-3.7 +/- 3.1 micromol.kg(-1).min(-1)). p.o. shifted from net hepatic glucose output (NHGO) to uptake (NHGU; 2.5 +/- 2.8 micromol.kg-1.min-1) within 30 min, but p.e. still exhibited NHGO (6.0 +/- 1.9 micromol.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.     

Portal infusion of a selective serotonin reuptake inhibitor enhances hepatic glucose disposal in conscious dogs

Intraportal delivery of serotonin enhanced net hepatic glucose uptake (NHGU) during a hyperinsulinemic hyperglycemic clamp, but serotonin elevated catecholamines and can cause gastrointestinal distress. We hypothesized that the selective serotonin reuptake inhibitor (SSRI) fluvoxamine would enhance NHGU without side effects. Arteriovenous difference and tracer ([3-(3)H]glucose) techniques were used in conscious 42-h-fasted dogs. Experiments consisted of equilibration (-120 to -30 min), basal (-30 to 0 min), and experimental (EXP; 0-270 min) periods. During EXP, somatostatin, fourfold basal intraportal insulin, basal intraportal glucagon, and peripheral glucose (to double the hepatic glucose load) were infused. Saline (SAL) was infused intraportally during 0-90 min (P1), and fluvoxamine was infused intraportally at 0.5, 1, and 2 mug.kg(-1).min(-1) from 90 to 150 (P2), 150 to 210 (P3), and 210 to 270 (P4) min, respectively, in the FLUV group (n = 8). The SAL group (n = 9) received intraportal saline during 0-270 min. NHGU in SAL was 13.9 +/- 1.7 and 17.0 +/- 2.0 mumol.kg(-1).min(-1) in P3-P4, respectively, while NHGU in FLUV averaged 19.7 +/- 2.8 and 26.6 +/- 3.0 mumol.kg(-1).min(-1) (P < 0.05 vs. SAL). Net hepatic carbon retention was greater (P < 0.05) in FLUV than in SAL (17.6 +/- 2.6 vs. 13.9 +/- 2.7 and 23.8 +/- 3.0 vs. 14.4 +/- 3.3 mumol.kg(-1).min(-1) in P3-P4, respectively), and final hepatic glycogen concentrations were 50% greater in FLUV (P < 0.005). Nonhepatic glucose uptake was greater in SAL than in FLUV at 270 min (P < 0.05). Catecholamine concentrations remained basal, and the animals evidenced no distress. Thus fluvoxamine enhanced NHGU and hepatic carbon storage without raising circulating serotonin concentrations or causing stress, suggesting that hepatic-targeted SSRIs might be effective in reducing postprandial hyperglycemia in individuals with diabetes or impaired glucose tolerance.     

Effects of beta-adrenergic receptor stimulation and blockade on substrate metabolism during submaximal exercise

We used beta-adrenergic receptor stimulation and blockade as a tool to study substrate metabolism during exercise. Eight moderately trained subjects cycled for 60 min at 45% of VO(2 peak) 1) during a control trial (CON); 2) while epinephrine was intravenously infused at 0.015 microg. kg(-1) x min(-1) (beta-STIM); 3) after ingesting 80 mg of propranolol (beta-BLOCK); and 4) combining beta-BLOCK with intravenous infusion of Intralipid-heparin to restore plasma fatty acid (FFA) levels (beta-BLOCK+LIPID). beta-BLOCK suppressed lipolysis (i.e., glycerol rate of appearance) and fat oxidation while elevating carbohydrate oxidation above CON (135 +/- 11 vs. 113 +/- 10 micromol x kg(-1) x min(-1); P < 0.05) primarily by increasing rate of disappearance (R(d)) of glucose (36 +/- 2 vs. 22 +/- 2 micromol x kg(-1) x min(-1); P < 0.05). Plasma FFA restoration (beta-BLOCK+LIPID) attenuated the increase in R(d) glucose by more than one-half (28 +/- 3 micromol x kg(-1) x min(-1); P < 0.05), suggesting that part of the compensatory increase in muscle glucose uptake is due to reduced energy from fatty acids. On the other hand, beta-STIM markedly increased glycogen oxidation and reduced glucose clearance and fat oxidation despite elevating plasma FFA. Therefore, reduced plasma FFA availability with beta-BLOCK increased R(d) glucose, whereas beta-STIM increased glycogen oxidation, which reduced fat oxidation and glucose clearance. In summary, compared with control exercise at 45% VO(2 peak) (CON), both beta-BLOCK and beta-STIM reduced fat and increased carbohydrate oxidation, albeit through different mechanisms.