Mumol Kg-1 Min-1 Research Articles

Effect of thyroparathyroidectomy on urinary acidification in diabetic rats.

In previous studies we have shown stimulation of renal acid excretion in the proximal tubules of rats with diabetes of short duration, with no important alterations in glomerular hemodynamics; on the other hand, in thyroparathyroidectomized rats (TPTX model), a significant decrease in renal acid excretion, glomerular filtration rate (GFR) and renal plasma flow (RPF) was detected. Since important changes in the parathyroid hormone-vitamin D-Ca axis are observed in the diabetic state, the present study was undertaken to investigate the renal repercussions of thyroparathyroidectomy in rats previously made diabetic by streptozotocin (45 mg/kg). Four to 6 days after the induction of diabetes (DM), a group of rats were thyroparathyroidectomized (DM + TPTX). Renal functional parameters were evaluated by measuring the inulin and sodium para-aminohippurate clearance on the tenth day. The decrease in the GFR and RPF observed in TPTX was not reversed by diabetes since the same alterations were observed in DM + TPTX. Net acid (NA) excretion was unchanged in DM (6.19 +/- 0.54), decreased in TPTX (3.76 +/- 0.25) and returned to normal levels in DM + TPTX (5.54 +/- 0.72) when compared to the control group (6.34 +/- 0.14 mumol min-1 kg-1). The results suggest that PTH plays an important vasodilator role regarding glomerular hemodynamics, since in its absence the impairment in GFR and RPF was not reversed by the diabetic state. However, with respect to acid excretion, the presence of diabetes was able to overcome the negative stimulus represented by TPTX.

Effects of a sympathetic activation by a lower body negative pressure on glucose and lipid metabolism.

The effects of a sympathetic activation elicited by a lower body negative pressure (LBNP) (at -15 mmHg for 75 min) were assessed in 7 healthy subjects on two occasions: (i) in post-absorptive conditions, and (ii) during glucose infusion (22.2 mumol kg-1 min-1). LBNP increased plasma norepinephrine concentration and heart rate. It did not alter whole-body glucose metabolism (measured with [6,6-2H]glucose) and glycerol turnover (measured with [1,1,2,3,3-2H]glycerol). Interstitial glycerol concentrations were monitored with microdialysis in subcutaneous adipose tissue and in skeletal muscle. LBNP increased dialysate glycerol concentrations in muscle by 16% (P < 0.03) but not in adipose tissue in post-absorptive conditions, and by 37% in adipose tissue (P < 0.05) but not in muscle during glucose infusion. These results indicate that an LBNP-induced sympathetic activation (i) does not increase endogenous glucose production, and (ii) induces only a slight stimulation of lipolysis in adipose tissue during glucose infusion.

Adenosine triphosphate treatment for meconium aspiration-induced pulmonary hypertension in pigs.

To investigate the pulmonary haemodynamic effects of meconium aspiration and subsequent adenosine triphosphate (ATP) treatment, 12 anaesthetized and ventilated pigs (wt 24-28 kg) received either ATP or an equal volume of saline into the right heart in doses of 0.02 to 0.80 mumol kg-1 min-1 after intratracheal administration of 2 mL kg-1 of human meconium. Meconium instillation induced significant increases in pulmonary vascular pressures and total and postarterial resistances calculated from pulmonary artery occlusion studies, but did not affect the systemic haemodynamics, except for a fall in heart rate and increase in central venous pressure. Infusion of ATP at the lowest doses (0.02 and 0.08 mumol kg-1 min-1) selectively decreased the pulmonary arterial pressure and vascular resistance and at 0.32 and 0.80 mumol kg-1 min-1 reduced both the pulmonary and systemic resistances. In the lung circulation the increasing doses of ATP reduced preferably the arterial but also the postarterial resistance. Withdrawal of ATP infusion led to a significant rebound effect especially in the postarterial segment of the lung circulation. Meconium aspiration thus induces an acute, predominantly postarterial obstruction in the lung circulation and infusion of ATP at low doses selectively dilates the pulmonary vascular bed and may help to preclude elevation of capillary pressures in meconium aspiration-induced pulmonary hypertension.

Inhibition of GH releasing factor (GRF)-induced GH secretion by intraruminal infusion of volatile fatty acids (VFA) in sheep.

A VFA mixture solution containing acetate, propionate and butyrate (the molar ratio of acetate, propionate and n-butyrate = 61.7:24.3:14.0) was infused into the rumen at various rates (53.5, 107 and 214 mumol kg-1 min-1) over 6 h to examine the effects on basal and growth hormone-releasing factor (GRF, 0.25 micrograms kg-1)-induced increase in secretion of GH, insulin, glucagon and somatostatin (SRIF) in five castrated male sheep. Intraruminal infusion of the VFA mixture into the 18-h-fasted animals at the rates of 53.5, 107 and 214 mumol kg-1 min-1 finally raised the total intraruminal VFA concentration from 91.4 to 100.2 (P > 0.05), 175.9 (P < 0.05) and 234.5 (P < 0.05) mmol l-1, respectively. A preliminary experiment showed that an infusion rate of 107 mumol kg-1 min-1 mimics the postprandial increase in ruminal VFA. The basal plasma GH concentrations (2 to 4 h after the start of VFA infusion) and the area under the profiles for GH release in response to the intravenous GRF injection, which was done 4 h after the start of VFA infusion, were significantly decreased by the VFA infusion rates of 107 and 214 mumol kg-1 min-1. Furthermore, the VFA infusion noticeably increased basal plasma concentrations of insulin, but it scarcely changed the basal levels of glucagon, SRIF and glucose. From these results we conclude that an increase in the ruminal VFA concentration, even within the physiological range, would suppress GH secretion from the ovine anterior pituitary, and that the postprandial rise in the ruminal VFA concentration may be one of the factors normally suppressing GH secretion in sheep.

The effect of intravenous lactate on cerebral function during hypoglycaemia.

Any factor which protects the brain against hypoglycaemia induced cerebral dysfunction could have important therapeutic implications for intensive insulin therapy. This study tested the hypothesis that intravenous lactate protects cerebral function during hypoglycaemia. Four choice reaction time, Auditory Brain Stem Response (ABR), and P300 latency were used as measures of cerebral function. Nine healthy volunteers (six female) underwent two stepped hyperinsulinaemic clamps at least 4 weeks apart, achieving blood glucose levels of 4.5, 3.3, and 2.5 mmol l-1. On one occasion 40 mumol kg-1 min-1 sodium lactate was infused, and on the other, normal saline. Cerebral function tests were measured at each glucose level. At 3.3 mmol l-1, there was a significant slowing of four choice reaction time with saline (p < 0.02) but not with lactate; no changes in P300 latency or ABR occurred on either occasion. At 2.5 mmol l-1 results from all three tests deteriorated significantly during saline infusion (p < 0.001 reaction time, p < 0.02 ABR and p < 0.05 P300), but not lactate. Lactate infusion was associated with a reduction in noradrenaline (p < 0.05), adrenaline (p < 0.05), and growth hormone (p < 0.02) responses at a glucose of 2.5 mmol l-1. These results support the hypothesis that intravenous lactate protects cerebral function during hypoglycaemia.

Glucose, lactate and oxygen metabolism in the fetal pig during late gestation.

Using [U-14C]glucose tracer, rates of umbilical uptake, utilization and production of glucose, and of CO2 production from glucose carbon, were measured in seven chronically catheterized fetal pigs, when the sow was in the fed state, between 100 and 113 days of gestation (term, 114 +/- 2 days). At the same time, rates of umbilical O2 and lactate uptake were determined in all seven fetuses by the Fick principle. The mean fetal rates of umbilical glucose uptake, glucose utilization and CO2 production from glucose carbon were 38.4 +/- 4.2, 41.3 +/- 5.2 and 126.9 +/- 12.6 mumol min-1 (kg fetal body weight)-1, respectively (n = 7), No glucose production was therefore detected in the fetuses. Production of CO2 from glucose carbon accounted for 37.3 +/- 3.4% (n = 7) of the umbilical O2 uptake, which averaged 340 +/- 13 mumol min-1 kg-1 (n = 7). There was also significant umbilical lactate uptake in the fetal piglets when the sow was in the fed state (32.6 +/- 10.4 mumol min-1 kg-1, n = 7, P < 0.05). No significant changes in fetal glucose, O2 or lactate metabolism were observed with increasing age towards term. The fetal rates of glucose metabolism and of umbilical uptake of O2 and lactate were not correlated with fetal blood glucose level. Hence, glucose is used for both oxidative and non-oxidative metabolism in utero and is an important, although not the sole, source of carbon for metabolic processes in the fetal pig during late gestation.

Acute insulin administration does not affect plasma leptin levels in lean or obese subjects.

Whether leptin levels are related to insulin sensitivity or subject to acute regulation by insulin is not known. In 12 obese [body mass index (BMI) = 34.0 +/- 1.5 kg m-2] and 12 lean (BMI = 22.2 +/- 0.6 kg m-2) non-diabetic subjects, plasma leptin concentrations were measured in the fasting state and during 2 hours of euglycaemic hyperinsulinaemia (approximately 600 pmol L-1). Fasting plasma leptin was significantly higher in obese (26.6 +/- 3.2) than in lean subjects (6.4 +/- 1.2 ng mL-1, P = 0.0001), and in women (21.1 +/- 3.3) than in men (7.3 +/- 2.3 ng mL-1, P = 0.01). In univariate analysis, fasting plasma leptin was strongly related to all anthropometric measures (body weight, fat mass, percent fat mass, waist and hip circumferences). In multiple regression, per cent adiposity, hip circumference and duration of obesity explained 90% of the variability in fasting leptin concentrations. Fasting and stimulated (OGTT) insulin levels, insulin sensitivity (22.6 +/- 1.9 vs 36.7 +/- 2.0 mumol min-1 kg-1 in lean and obese subjects, respectively, P < 0.0001), glucose area, and serum triglycerides were positively related to fasting plasma leptin concentrations; none of these associations, however, was statistically significant after adjusting for BMI. During the clamp, plasma leptin concentrations remained constant in both lean and obese subjects. We conclude that neither insulin levels nor sensitivity relate to leptin levels independently of fat mass, and that leptin is not subject to acute (2 hours) regulation by insulin in lean or obese humans.

Insulin Secretion and Insulin Sensitivity in People with Impaired Glucose Tolerance

To assess the roles of pancreatic beta-cell (beta-cell) dysfunction and insulin resistance in the pathogenesis of non-insulin dependent diabetes mellitus, we used euglycaemic hyperinsulinaemic and hyperglycaemic clamps to compare insulin secretion and insulin sensitivity in Caucasian individuals of European ancestry with either normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). Both groups were carefully matched for age, gender, obesity and body fat distribution. During the hyperglycaemic clamps, IGT had significantly lower first phase (650 +/- 60 vs 992 +/- 92 pmol l-1, p = 0.001) and second phase (231 +/- 24 vs 326 +/- 21 pmol l-1, p < 0.001) plasma insulin responses while their insulin sensitivity index (0.126 +/- 0.012 mumol kg-1 pM-1) was not significantly different from that of NGT (0.144 +/- 0.012 mumol kg-1 min-1 pM-1), p = 0.69). Similarly, during the euglycaemic hyperinsulinaemic clamps, the insulin sensitivity index of the IGT (0.076 +/- 0.005 mumol kg-1 min-1 pM-1) was not significantly different from that of the NGT (0.086 +/- 0.007 mumol kg-1 min-1 pM-1), p = 0.28. We conclude that since beta-cell dysfunction is already evident in people with impaired glucose tolerance but insulin resistance is not, impaired insulin secretion is most likely the primary genetic factor predisposing to the development of non-insulin dependent diabetes mellitus in Caucasians of European ancestry.

Eccentric exercise decreases maximal insulin action in humans: muscle and systemic effects.

1. Unaccustomed eccentric exercise decreases whole-body insulin action in humans. To study the effects of one-legged eccentric exercise on insulin action in muscle and systemically, the euglycaemic clamp technique combined with arterial and bilateral femoral venous catheterization was used. Seven subjects participated in two euglycaemic clamps, performed in random order. One clamp was preceded 2 days earlier by one-legged eccentric exercise (post-eccentric exercise clamp (PEC)) and one was without the prior exercise (control clamp (CC)). 2. During PEC the maximal insulin-stimulated glucose uptake over the eccentric thigh was marginally lower when compared with the control thigh, (11.9%, 64.6 +/- 10.3 vs. 73.3 +/- 10.2 mumol kg-1 min-1, P = 0.08), whereas no inter-thigh difference was observed at a submaximal insulin concentration. The glycogen concentration was lower in the eccentric thigh for all three clamp steps used (P < 0.05). The glucose transporter GLUT4 protein content was on average 39% lower (P < 0.05) in the eccentric thigh in the basal state, whereas the maximal activity of glycogen synthase was identical in the two thighs for all clamp steps. 3. The glucose infusion rate (GIR) necessary to maintain euglycaemia during maximal insulin stimulation was lower during PEC compared with CC (15.7%, 81.3 +/- 3.2 vs. 96.4 +/- 8.8 mumol kg-1 min-1, P < 0.05). 4. Our data show that 2 days after unaccustomed eccentric exercise, muscle and whole-body insulin action is impaired at maximal but not submaximal concentrations. The local effect cannot account for the whole-body effect, suggesting the release of a factor which decreases insulin responsiveness systemically.

Renovascular hypertension and insulin sensitivity.

We tested the hypothesis that the status of the renin-angiotensin-aldosterone system affects insulin sensitivity. Insulin sensitivity (by the euglycaemic insulin clamp technique) was measured in eight patients with angiographically proven renovascular hypertension and in eight normotensive subjects matched for age, gender, body mass index and glucose tolerance. In the patients, insulin sensitivity was measured both at baseline and following 7 days of ACE inhibition. Following glucose ingestion, patients and controls showed similar insulin and glucose responses. Insulin infusion (7 pmol min-1 kg-1) promoted similar glucose utilization in the hypertensives and normotensives: 24.8 +/- 2.3 vs. 26.0 +/- 3.0 mumol min-1 kg-1 respectively. One week of ACE inhibition caused a 20 +/- 4 mmHg decrease in mean blood pressure and a 20 +/- 6% decrease in peripheral vascular resistance. Plasma angiotensin II concentrations dropped from 24.6 +/- 6.3 to 13.5 +/-5.0 pg mL-1 (P < 0.05) and plasma aldosterone from 17 +/- 4 to 9 +/- 2 ng dL-1 (P < 0.05), and plasma renin activity doubled (from 1.6 +/- 0.3 to 3.4 +/- 1.7 ng mL-1 h-1, P < 0.02). Nevertheless, insulin sensitivity was unchanged (before, 24.8 +/- 2.3; after 25.8 +/- 2.2 mumol min-1 kg-1, P = Ns). During insulin infusion, forearm blood flow did not change from baseline in either set of studies. Also, the antinatriuretic (before, -26 +/- 18; after, -22 +/- 14%) and antikaliuretic (before: -36 +/- 13%, after -39 +/- 11%) action of the hormone was unaffected by the therapy. In conclusion, renovascular hypertension is not associated with insulin resistance. Furthermore, a selective, drastic reduction of the renin-angiotensin-aldosterone system activity and vascular tone does not alter insulin action on glucose and electrolyte metabolism.

Decreased release of glutathione into the systemic circulation of patients with HIV infection

Low glutathione (GSH) in patients with HIV infection could contribute to their immune deficiency since GSH plays an important role in the function of lymphocytes and sulphydryls decrease the expression of HIV in vitro. In order to gain more insight into the mechanisms responsible for the deranged sulphydryl homeostasis in HIV infection, the release of GSH into the circulation, an estimate of the systemic production of GSH, was determined using a pharmacokinetic approach. The basal plasma concentrations of free GSH (3.3 +/- 1.3 vs. 5.3 +/- 1.9 mumol L(-1)) and cysteine (7.7 +/- 2.6 vs. 13.4 +/- 4.9 mumol L(-1)) were significantly lower in eight HIV-infected patients than in eight controls. Upon infusion of GSH at a constant rate of 1 mumol min-1 kg-1, GSH in plasma reached a new plateau. The increment in plasma GSH was significantly larger in the HIV-infected patients than in the controls. The input of GSH into the circulation (12.9 +/- 5.7 vs. 30.1 +/- 11.7 mumol min-1; P < 0.01) and the clearance of GSH (25 +/- 7 vs. 35 +/- 7 mL min-1 kg-1) were significantly lower in patients with HIV-infection. During infusion of GSH the concentration of cysteine in peripheral blood mononuclear cells of the HIV-infected patients increased significantly. Nevertheless, intracellular GSH did not increase. Thus, the consumption of GSH is not increased in HIV infection. Rather, the present data suggest that GSH in patients with HIV infection is low because of a decreased systemic synthesis of GSH.

Microdialysis assessment of adipose tissue metabolism in post-absorptive obese NIDDM subjects.

Lactate and glycerol turnover is enhanced in obesity and NIDDM. To evaluate the influence of NIDDM on subcutaneous adipose tissue metabolism microdialysis combined with 133Xe clearance and measurements in arterialized plasma were carried out using samples of subcutaneous abdominal fat from nine obese NIDDM subjects (glucose, 7.9 +/- 0.7 mmol L-1) (mean +/- SEM) and nine obese non-diabetic subjects (glucose, 4.9 +/- 0.1) matched for age, BMI and body fat. After an overnight fast arterialized plasma levels were 1145 +/- 110 vs. 876 +/- 59 mumol L-1 (P < 0.05) for lactate and 75 +/- 10 vs. 66 +/- 8 mumol L-1 for glycerol in the diabetic and control group, respectively. The corresponding abdominal subcutaneous interstitial lactate and glycerol concentrations were 1278 +/- 63 vs 1107 +/- 64 mumol L-1 and 314 +/- 28 vs. 311 +/- 17 mumol L-1, respectively. However, adipose tissue blood flow in the same region was lower in NIDDM subjects (1.5 +/- 0.2 vs 2.4 +/- 0.3 mL 100 g-1 min-1) (P < 0.05). Consequently, apparent subcutaneous lactate and glycerol release, estimated according to Fick, were not statistically different in the two groups (1.8 +/- 0.4 vs 2.4 +/- 0.8 and 2.1 +/- 0.4 vs 3.1 +/- 0.5 mumol kg-1 min-1 in NIDDM and control subjects, respectively). Thus, in the post-absorptive state apparent lactate and glycerol release by the abdominal subcutaneous tissue in obese NIDDM subjects was similar to that in a matched group of obese non-diabetic controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin Resistance with Respect to Lipolysis in Non‐diabetic Relatives of European Patients with Type 2 Diabetes

Type 2 diabetes is characterized by resistance to insulin action of glucose metabolism and lipolysis. First-degree relatives of diabetic patients are at increased risk of developing diabetes themselves and early metabolic abnormalities in these relatives may represent primary defects in the pathogenesis of diabetes. Our previous work has demonstrated impaired suppression of lipolysis after an oral glucose load in glucose-tolerant relatives of Asian origin, but not in European relatives. To investigate whether a more subtle defect exists in the European population we studied 8 first-degree relatives of European patients and 9 matched control subjects. All had normal glucose tolerance. Glycerol and glucose turnovers were measured using a primed constant infusion of the stable isotopic tracers [1,1,1,2,3(2)H5] glycerol and [6,6(2)H] glucose, basally and in response to a very low dose insulin infusion (0.005 units kg-1 h-1). The relatives had higher basal insulin concentrations (median (range): 49 (30 to 113) vs 28 (18 to 66) pmol 1(-1), p < 0.05) compared to controls, but basal glycerol and glucose turnovers and plasma concentrations of glycerol, glucose, and non-esterifed fatty acids (NEFA) were similar. Following insulin, the suppression of glycerol appearance in the circulation measured isotopically was significantly less complete in the relatives compared with controls (mean change +/- SEM: + 0.06 +/- 0.21 vs - 0.51 +/- 0.16 mumol kg-1 min-1, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Nitric oxide-related pancreatic endocrine responses to hyperglycaemia in the conscious calf.

Mean plasma insulin concentration was reduced and mean plasma glucose concentration increased following the administration of N-nitro-L-arginine methyl ester (L-NAME; 100 mumol kg-1 i.a.) in conscious calves given continuous infusions of exogenous glucose (30-60 mumol min-1 kg-1 i.v.). It is concluded that the rise in plasma insulin concentration which occurs in these animals in response to glucose is mediated, at least in part, by a nitric oxide-related factor (NOx).

Pulmonary effects of type V cyclic GMP specific phosphodiesterase inhibition in the anaesthetized guinea‐pig

1. We have investigated the bronchodilator potential of type V phosphodiesterase (PDE V) inhibitors in anaesthetized ventilated guinea-pigs using the potent and selective PDE V inhibitor, SK&F 96231. We have compared its activity to that of salbutamol, the PDE III inhibitors, siguazodan and SK&F 95654 and to the PDE IV inhibitor rolipram. 2. Administered as an i.v. infusion SK&F 96231 (0.6 and 1 mg kg-1 min-1, i.v.) caused a slowly developing inhibition of histamine (100 nmol kg-1, i.v.)-induced bronchoconstriction and elevated tracheal cyclic GMP levels in the anaesthetized guinea-pig. SK&F 96231 (0.1 and 0.3 mg kg-1 min-1, i.v.) was without effect on histamine-induced bronchoconstriction. In the presence of a sub-threshold infusion of SNP (0.1 mumol kg-1 min-1, i.v.) there was a marked enhancement of SK&F 96231-induced inhibition of histamine responses such that at infusion rates that were ineffective alone, SK&F 96231 caused a > 50% inhibition of histamine responses. The stimulation of tracheal cyclic GMP accumulation by SK&F 96231 was also potentiated. 3. Administered directly into the airway, SK&F 96231 (300 micrograms in 5 mg lactose carrier) was largely without effect on histamine-induced bronchoconstriction (4.9 +/- 1.9% inhibition). In the presence of SNP (0.1 mumol kg-1 min-1, i.v.) or isosorbide dinitrate (200 micrograms administered by insufflation into the trachea) there was a marked potentiation of the inhibitory activity of SK&F 96231 (40 +/- 4% and 62 +/- 1.8% respectively). 4. Salbutamol and rolipram (3-300 microg by insufflation) caused a dose-related inhibition of histamine responses with a maximum of 91 +/- 2% and 59 +/- 10% respectively. The PDE III inhibitor, siguazodan,was without effect on histamine responses but they were reduced (27.7 +/- 4.8% at 300 microg) by SK&F95654. There was a marked enhancement of the inhibitory activity of rolipram in the presence of SK&F 95654.5. We conclude that SK&F 96231 has weak anti-spasmogenic activity in the guinea-pig in vivo, we suggest that this is primarily a consequence of a low endogenous guanylate cyclase activity in the airway. The potentiation of the anti-spasmogenic activity of SK&F 96231 by SNP suggests that a combination of PDE V inhibitor and guanylate cyclase agonist might provide significant bronchodilator activity.6. We have established that PDE IV inhibitors are bronchodilators when administered directly into the airway of anaesthetized guinea-pigs but that PDE III inhibitors are only weakly active. The marked enhancement of the inhibitory activity of rolipram by the PDE III inhibitor, SK&F 95654, indicates that inhibitors of both PDE III and PDE IV might offer greater potential as bronchodilators than inhibitors of either isoenzyme alone.

Effect of noradrenaline on glycerol turnover and lipolysis in the whole body and subcutaneous adipose tissue in humans in vivo.

1. The effect of infusion of noradrenaline (0.42 mumol min-1 kg-1) on the exchange of nonesterified fatty acids, glycerol and other metabolites across subcutaneous abdominal adipose tissue was investigated in five healthy subjects using an arteriovenous catheterization technique and measurement of adipose tissue blood flow using the 133Xe clearance technique. At the same time, the net rate of fat oxidation in the whole body was assessed by indirect calorimetry, and the turnover of glycerol in the whole body and in subcutaneous adipose tissue was estimated using [5-2H]glycerol, which was administered as a primed constant infusion for 1 h before (basal turnover) noradrenaline administration and continued during the 1 h of noradrenaline infusion. 2. The noradrenaline infusion increased the plasma noradrenaline concentration from a basal value of 0.9 +/- 0.1 to 12.6 +/- 1.2 nmol/(mean +/- SEM) at 60 min. It also increased the arterialized concentration of glycerol by 50% (basal value 81 +/- 11 mumol/l-1) and that of plasma non-esterified fatty acids three-fold (basal value 357 +/- 86 mumol/l). 3. Noradrenaline increased the net release of glycerol by adipose tissue three-fold and that of non-esterified fatty acids three- to four-fold. Although the ratio of non-esterified fatty acid to glycerol release by adipose tissue increased in all subjects from a mean value of 2.7 in the basal period to 3.6 and 3.9 at 50 and 60 min of the noradrenaline infusion, respectively (P < 0.02), at no time point did the ratio differ significantly from 3.0.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of NG‐nitro‐L‐arginine methyl ester on regional haemodynamic responses to MgSO4 in conscious rats

1. We assessed regional haemodynamic responses to the vasodilator, MgSO4, in the absence and presence of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), in conscious chronically instrumented Long Evans rats (n = 9). 2. MgSO4 (loading dose 220 mumol kg-1 min-1 for 7 min, maintenance dose 56 mumol kg-1 min-1 for 7 min), alone, caused slight bradycardia and hypotension accompanied by reductions in renal and mesenteric flows, but a marked hyperaemic vasodilatation in the hindquarters (flow, delta 54 +/- 6%, vascular conductance, delta 77 +/- 5%). 3. L-NAME (183 nmol kg-1 min-1) caused hypertension (29 +/- 2 mmHg) accompanied by bradycardia (-51 +/- 6 beats min-1) and reductions in flow and vascular conductance in the renal (-18 +/- 4% and -35 +/- 3%, respectively), mesenteric (-35 +/- 3% and -49 +/- 3%, respectively), and hindquarters (-26 +/- 3% and -42 +/- 3%, respectively) vascular beds. In the presence of L-NAME, the hypotensive and bradycardic effects of MgSO4 were still apparent, but its hindquarters hyperaemic vasodilator effect was significantly attenuated. 4. In order to determine if the inhibitory action of L-NAME on the hindquarters hyperaemic vasodilator action of MgSO4 was a non-specific effect, due to the change in baseline conditions caused by L-NAME, we also examined responses to MgSO4 in the presence of endothelin-1 (12.5 pmol kg-1 min-1) or angiotensin II (50 pmol kg-1 min-1). In the presence of either peptide, the overall effects of MgSO4 on hindquarters flow and vascular conductance were unchanged. 5. In a separate experiment (n = 8) we determined that the inhibitory effect of L-NAME on the hyperaemic vasodilator response to MgSO4 was prevented by L-arginine, and also demonstrated that the Beta2-adrenoceptor antagonist, ICI 118551, caused significant inhibition of the hindquarters haemodynamic effects of MgSO4.6. We conclude that the hindquarters haemodynamic effects of MgSO4 in conscious rats involve a substantial L-NAME-sensitive component which depends on activation of Beta2-adrenoceptors, probably asa consequence of adrenal medullary adrenaline release.

Different Acute and Chronic Effects of Acipimox Treatment on Glucose and Lipid Metabolism in Patients with Type 2 Diabetes

To study whether therapeutic reduction of non-esterified fatty acids (NEFA) can be used to improve glucose metabolism, we administered the antilipolytic agent, acipimox, 250 mg four times daily for 4 weeks in eight obese Type 2 diabetic patients. Glucose and NEFA metabolism were assessed before and after treatment with a two-step euglycaemic hyperinsulinaemic clamp (0.25 and 1 mU kg-1 min-1 insulin) combined with infusions of [3-3H] glucose and [1-14C] palmitate. Three days of acipimox treatment reduced 24-h serum NEFA levels by 10%, but the difference disappeared after 4 weeks of treatment mainly due to a two-fold rise in morning NEFA concentrations (p < 0.01). After 3 days of acipimox treatment, fasting and 24-h plasma glucose and serum triglyceride concentrations were significantly reduced (p < 0.05), but no longer after 4 weeks of treatment. Despite the rebound rise in NEFA, acute administration of acipimox still inhibited both oxidative and non-oxidative NEFA metabolism in the basal state (p < 0.01-0.001) and during insulin infusion (p < 0.05-0.001). Inhibition of NEFA metabolism was associated with increased insulin-stimulated glucose uptake (from 3.56 +/- 0.28 to 5.14 +/- 0.67 mumol kg-1 min-1, p < 0.05), mainly due to stimulation of non-oxidative glucose disposal (from 1.74 +/- 0.23 to 3.03 +/- 0.53 mumol kg-1 min-1, p < 0.05). In conclusion, acipimox administered acutely inhibits NEFA appearance (lipolysis), which is associated with improved glucose uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Indomethacin Stimulates Basal Glucose Production in Humans without Changes in Concentrations of Glucoregulatory Hormones

1. To investigate whether indomethacin affects basal glucose production, we measured hepatic glucose production in six healthy postabsorptive subjects on two occasions: once after administration of indomethacin (150 mg orally) and once after administration of placebo. 2. Glucose production was measured by primed, continuous infusion of [3-3H]-glucose. 3. Indomethacin administration resulted in an increase in glucose production from 10.9 (SEM 0.3) mumol min-1 kg-1 to a maximum of 16.5 (SEM 1.6) mumol min-1 kg-1 (P < 0.05) within approximately 1 h, whereas in the control experiment glucose production declined gradually (P < 0.01) (P < 0.05 indomethacin versus control). There were no differences in plasma concentrations of insulin, C-peptide and counter-regulatory hormones between the two experiments. 4. Since indomethacin administration resulted in an increase in glucose production in the absence of any changes in concentrations of glucoregulatory hormones, we conclude that indomethacin stimulates hepatic glucose production through other mechanisms.

Dose‐response effects of lactate infusions on gluconeogenesis from lactate in normal man

Lactate is the predominant gluconeogenic precursor in man. To determine the dose-response relationships between plasma lactate concentration and rates of lactate incorporation in plasma glucose (lactate gluconeogenesis, LGN), we infused 17 normal volunteers with sodium lactate for 180 min at rates ranging from 6 to 40 mumol kg-1 min-1 and measured [U-14C]lactate incorporation into plasma glucose, as well as rates of lactate and glucose appearance in plasma. With the highest lactate infusions, plasma lactate increased up to 7 mM (compared to 1.1 +/- 0.13 mM during control sodium bicarbonate infusions, n = 10) and LGN averaged 4.73 +/- 0.23 mumol kg-1 min-1 (compared to 1.57 +/- 0.26 mumol kg-1 min-1 in bicarbonate control experiments, P < 0.001). The data relating plasma lactate concentration to LGN best fit a sigmoidal curve which plateaued at plasma lactate concentrations of approximately 6 mM and yielded an ED50 of 2.04 +/- 0.20 (SD) mM and a Vmax (6.25 +/- 1.2) (SD) (mumol kg-1 min-1). The sum of the basal rate of lactate appearance and the rate of lactate infusion was not significantly different from the overall rates of lactate appearance during the lactate infusions (35.8 +/- 2.2 vs. 34.8 +/- 2.9 mumol kg-1 min-1, P = 0.23). Thus, our results support the view that infusion of exogenous lactate does not suppress endogenous lactate appearance in plasma.