An analysis of the metabolic syndrome phenotype in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is associated with an increased risk of coronary heart disease (CHD) not fully explained by classic risk factors. Metabolic syndrome (MetS) is associated with an increased risk of CHD in the general population and whilst its prevalence is increased in SLE, its phenotypic expression may differ. We studied 200 women with SLE and 100 controls and compared the prevalence of MetS and its individual components. We examined whether any SLE features were associated with MetS and whether MetS in SLE patients was associated with carotid plaque. Patients with SLE were more likely to meet the MetS criteria (age-adjusted OR 2.1 (1.1-3.8)). However, this was not due to increased central obesity (median waist circumference 84 cm vs. 82 cm, p = 0.65) but rather increased prevalence of hypertension (p <0.01) and low HDL-cholesterol (p = 0.01). In a multivariable analysis, age, disease duration, low complement C3 and corticosteroid use ever, were associated with the presence of MetS in SLE. Overall MetS was not associated with the presence of carotid plaque in either SLE or controls. We have shown that MetS is more prevalent in SLE, but the lupus-MetS phenotype reflects risk factor changes driven by disease activity and steroid exposure, rather than obesity. Reliance on clinical measures of central obesity to consider MetS in SLE is not reliable and continued attention to individual CHD risk factors is recommended.

Anti-Mullerian hormone-tailored stimulation protocols improve outcomes whilst reducing adverse effects and costs of IVF.

BACKGROUND: Anti-Müllerian hormone (AMH) is increasingly used to quantify ovarian reserve, but it has not yet realized its full clinical potential in assisted reproduction technology. We investigated the possible benefits of using novel, stratified ovarian hyperstimulation protocols, tailored to individual AMH levels, compared with conventional stimulation. METHODS: Retrospective data were collected from 769 women (first cycle of IVF, using fresh embryos), in a UK tertiary care unit: 346 women using conventional stimulation protocols; 423 women treated under new AMH-tailored protocols. RESULTS: Embryo transfer rates increased significantly (79-87%: P= 0.002) after the introduction of AMH-tailored stimulation protocols. Pregnancy rate per cycle started and live birth rate also increased significantly compared with conventionally treated women (17.9-27.7%, P= 0.002 and 15.9-23.9%, P = 0.007, respectively). Moreover, in the AMH group, the incidence of the ovarian hyperstimulation syndrome (OHSS) fell significantly (6.9-2.3%, P = 0.002) and failed fertilization fell from 7.8 to 4.5%. The cost of fertility drug treatment fell by 29% per patient and the overall cost of clinical management of OHSS fell by 43% in the AMH group. GnRH antagonist protocols, introduced as part of AMH-tailored treatment, may have contributed to the observed improvements: however, within the AMH-tailored group, the live birth rate was not significantly different between agonist and antagonist-treated groups. CONCLUSIONS: Although large, prospective, multicentre studies are indicated, we have clearly demonstrated that individualized, AMH-guided, controlled ovarian hyperstimulation protocols significantly improved positive clinical outcomes, reduced the incidence of complications and reduced the financial burden associated with assisted reproduction.

Marked differences in the IGF system that are associated with migration in comparable populations of Gujaratis living in Sandwell, UK, and Gujarat, India.

AIMS/HYPOTHESES: We previously reported independent links between the IGF system and the development of impaired glucose tolerance and cardiovascular risk. This study tests the hypothesis that the lifestyle change which accompanies population migration, with attendant increases in cardiovascular risk, is reflected by changes in the IGF system. MATERIALS AND METHODS: We compared a specific Gujarati community in Sandwell, UK (n=205), with people still resident in the same villages of origin near Navsari, India (n=246). We performed anthropometry and measured fasting plasma insulin, IGF-I, insulin-like growth factor binding protein (IGFBP)-1 and IGFBP-3. RESULTS: Daily calorie intake, BMI and WHR were significantly higher in UK Gujaratis than in Indian Gujaratis. IGFBP-1 was significantly lower in UK migrants (mean 29.5 [95% CI 25.9-33.0] vs 56.5 [50.6-62.5] microg/l; F=48.4, p<0.001). Conversely, fasting insulin, IGFBP-3 and IGF-I were all higher in UK Gujaratis (mean IGF-I 145.9 [138.1-153.6]ng/ml in UK Gujaratis and 100.9 [94.6-107.3] ng/ml in Navsari Gujaratis; F=76.6, p<0.001). These differences were still apparent when adjustment was made for BMI by location for IGF-I (F=57.4, p<0.001) and IGFBP-3 (F=5.7, p=0.02), but were no longer apparent for IGFBP-1 and insulin. At the population level, the decrease in IGFBP-1 for a given increase in insulin was significantly smaller in UK Gujaratis, suggesting greater hepatic insulin resistance in this group. CONCLUSIONS/INTERPRETATION: Environmental factors have profound effects on circulating IGF system components and on the relationship between IGFBP-1, IGF-I and related metabolic variables. This may have long-term implications for the development of worsening glucose tolerance and cardiovascular disease.

The effect of pegvisomant-induced serum IGF-I normalization on serum leptin levels in patients with acromegaly.

BACKGROUND: In humans, serum leptin correlates positively with fat mass. GH is lipolytic and patients with active acromegaly have lowered serum leptin compared to age, sex and body mass index (BMI)-matched controls, but a direct influence of GH on serum leptin remains unclear. In patients with acromegaly, total leptin increases following successful pituitary surgery and during somatostatin (SMS) analogue therapy (despite no change in BMI) but whether this represents changes in soluble leptin receptor, bound or free leptin is unclear. Pegvisomant, a GH receptor antagonist capable of normalizing serum IGF-I in over 97% of patients, represents a novel treatment strategy in acromegaly and its effect on leptin has not previously been reported. PATIENTS: Sixteen patients (nine male (M), seven female (F), median age 52 years, range 27-78 years) with active acromegaly (serum IGF-I at least 30% above the upper limit of an age-related reference range) were studied. Serum IGF-I was normalized in all subjects with pegvisomant [mean duration 7 months (range 3-11 months), median dose 20 mg/day (range 10-40 mg/day)]. A single batch measurement of leptin, bound leptin (BL), soluble leptin receptor (SLR), insulin and glucose were performed on samples from baseline and first occurrence of serum IGF-I normalization. RESULTS: As in normal subjects, females with acromegaly had higher baseline serum leptin [median M = 6.1 (range 1.6-58.7), F = 25.9 (range 3.19-54.1) ng/ml; P = 0.04], which correlated positively with BMI (R = 0.78, P = 0.0004). Forward step-wise regression analysis demonstrated that BMI and gender accounted for 90% of the variance in mean serum log10 leptin. Pegvisomant-induced serum IGF-I normalization was associated with a rise in serum leptin [8.9 (range 1.6-58.3) to 12.7 (range 2.3-90.8) ng/ml, P < 0.0001]. Although the absolute increase was not significantly different, mean percentage increase was greater in men (M = 66.6 +/- 51%, F = 11.8 +/- 16%, P = 0.017) despite similar serum IGF-I and BMI in male and female subjects at baseline. No change in BL or SLR accompanied serum IGF-I normalization [0.27 (range 0.15-1.26) to 0.27 (range 0.14-1.2) nmol/l, P = 0.27 and 3.2 (range 1.2-6.8) to 2.7 (range 1-7.4) nmol/l, P = 0.5, respectively]. After normalization of serum IGF-I, a correlation between BMI and leptin remained (R = 0.86, P < 0.0001) and together BMI and gender accounted for 87% of the variance in mean log10 serum leptin (P = 0.0002). CONCLUSION: Pegvisomant-induced serum IGF-I normalization in patients with active acromegaly is associated with a significant increase in total, and by implication, free leptin.

Serum lipoprotein changes following IGF-I normalization using a growth hormone receptor antagonist in acromegaly.

OBJECTIVE: Active acromegaly is associated with altered lipid metabolism. The purpose of this study was to investigate the effect of serum IGF-I normalization on serum lipoproteins and insulin, in patients with acromegaly receiving the GH receptor antagonist pegvisomant. PATIENTS: Twenty patients (9 male, mean age 58.7 years, range 28-79) with active acromegaly (baseline serum IGF-I > 130% the age-related upper limit of normal) received pegvisomant and achieved a normal serum IGF-I [585.2 +/- 54.3 (mean +/- SEM) to 169.2 +/- 13.9 ng/ml, P < 0.0001]. MEASUREMENTS: Total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, triglyceride (TG), apolipoprotein B (apo B), apolipoprotein A1 (apo A1), lipoprotein a [Lp(a)] and insulin were measured in a single batch analysis on samples obtained at baseline and the first occasion of serum IGF-I normalization. Low-density lipoprotein (LDL) was calculated using the Friedewald formula. Paired analysis was performed using Student's paired t-test and the Wilcoxon signed rank test. RESULTS: Normalization of serum IGF-I resulted in an increase in TC (5.0 +/- 0.3 to 5.7 +/- 0.4 mmol/l, P = 0.0068), an increase in LDL (3.0 +/- 0.25 to 3.7 +/- 0.31 mmol/l, P = 0.0093) and an increase in apo B (110.6 +/- 7.76 to 127.1 +/- 8.86 mg/l, P = 0.014). TC and LDL increased in all but four patients. Despite a significant fall in fasting insulin levels (9.9 to 8.3 mU/l, range 8.85-19.8 to 6.33-11.6, P < 0.001) and insulin resistance (2.7 to 1.9, range 1.2-10.4 to 1-6.2, P < 0.001), mean serum TG and HDL levels were unaffected by IGF-I normalization. The protein component of HDL, apo A1, increased (153 +/- 4 to 166.4 +/- 5.43 mg/l, P = 0.026) and Lp(a) declined (median 342 to 235 mg/l, range 60-1013 to 74-671), P = 0.0035). Baseline serum TC and LDL were below the age- and sex-matched mean population value but after normalization of serum IGF-I the distribution of serum TC and LDL values was similar to that of the general population. CONCLUSIONS: Active acromegaly is associated with lowered mean serum TC and LDL. Successful management using pegvisomant increases lowered baseline serum TC and LDL levels, restoring the distribution of values to that of the general population, and improves insulin resistance. These findings are consistent with the reported lipoprotein changes following GH administration to normal and GH-deficient individuals.

Age-related increase in haemoglobin A1c and fasting plasma glucose is accompanied by a decrease in beta cell function without change in insulin sensitivity: evidence from a cross-sectional study of hospital personnel.

AIMS: To examine the influence of age on glucose homeostasis in a population of healthy, non-diabetic hospital personnel. METHODS: One hundred and twenty female and 71 male non-diabetic individuals (fasting plasma glucose < 7.0 mmol/l) were fasted overnight prior to blood sampling. Glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and fasting plasma insulin (FPI) were measured using a BioRad Diamat automated HPLC, a Hitachi 747 analyser and a sensitive in-house radioimmunoassay, respectively. Mathematical modelling of the fasting glucose and insulin pairs (homeostasis model assessment (HOMA)) generated indices of pancreatic beta cell function, HOMA-B and tissue insulin sensitivity HOMA-S. RESULTS: Spearman rank correlation analysis showed that in the whole group there was a significant negative correlation between age and HOMA-B (rs = -0.218, P = 0.0022) and a significant positive correlation between age and both HbA1c (rs = 0.307, P = 0.0001) and FPG (rs = 0.26, P = 0.0003). There was no correlation between age and either FPI (rs = -0.08, P = 0.266) or HOMA-S (rs = 0.024, P = 0.75). Analysis by gender showed the above associations to be present in the females (rs = -0.243, P = 0.0076; rs = 0.304, P = 0.0007; rs = 0.32, P = 0.0004 for age vs. HOMA-B, HbA1c, and FPG, respectively). Again there was no correlation of age with FPI or insulin sensitivity. In the males there was a significant correlation of HbA1c with age (rs = 0.35, P = 0.002), but no significant correlation of age with any of the other parameters. CONCLUSIONS: Glycaemic control deteriorates with age in healthy, non-diabetic individuals. Age-related rises in FPG and haemoglobin A1c result from a small but steady decline in pancreatic beta cell function.

Increased susceptibility to streptozotocin-induced beta-cell apoptosis and delayed autoimmune diabetes in alkylpurine-DNA-N-glycosylase-deficient mice.

Type 1 diabetes is thought to occur as a result of the loss of insulin-producing pancreatic beta cells by an environmentally triggered autoimmune reaction. In rodent models of diabetes, streptozotocin (STZ), a genotoxic methylating agent that is targeted to the beta cells, is used to trigger the initial cell death. High single doses of STZ cause extensive beta-cell necrosis, while multiple low doses induce limited apoptosis, which elicits an autoimmune reaction that eliminates the remaining cells. We now show that in mice lacking the DNA repair enzyme alkylpurine-DNA-N-glycosylase (APNG), beta-cell necrosis was markedly attenuated after a single dose of STZ. This is most probably due to the reduction in the frequency of base excision repair-induced strand breaks and the consequent activation of poly(ADP-ribose) polymerase (PARP), which results in catastrophic ATP depletion and cell necrosis. Indeed, PARP activity was not induced in APNG(-/-) islet cells following treatment with STZ in vitro. However, 48 h after STZ treatment, there was a peak of apoptosis in the beta cells of APNG(-/-) mice. Apoptosis was not observed in PARP-inhibited APNG(+/+) mice, suggesting that apoptotic pathways are activated in the absence of significant numbers of DNA strand breaks. Interestingly, STZ-treated APNG(-/-) mice succumbed to diabetes 8 months after treatment, in contrast to previous work with PARP inhibitors, where a high incidence of beta-cell tumors was observed. In the multiple-low-dose model, STZ induced diabetes in both APNG(-/-) and APNG(+/+) mice; however, the initial peak of apoptosis was 2.5-fold greater in the APNG(-/-) mice. We conclude that APNG substrates are diabetogenic but by different mechanisms according to the status of APNG activity.

Selective inhibition of glucose-stimulated beta-cell activity by an anion channel inhibitor.

4,4'-Dithiocyanatostilbene-2,2'-disulfonic acid (DIDS), an inhibitor of the volume-sensitive anion channel, was used to investigate the role of this channel in the stimulation of rat pancreatic beta-cells by glucose and by tolbutamide. Glucose-stimulated electrical activity in beta-cells was markedly and reversibly inhibited by DIDS. The increase in cytosolic [Ca2+] and stimulated insulin release evoked by glucose were also inhibited by DIDS. In contrast to its inhibitory effect on glucose-induced beta-cell activity, DIDS had no effect on electrical activity, the rise in [Ca2+]i or insulin release induced by tolbutamide. DIDS failed to increase beta-cell input conductance, an index of whole-cell K(ATP) channel activity, or the rate of efflux of 86Rb+ from perifused islets, a measure of net K+ permeability. Furthermore, DIDS had no effect on intracellular pH or on regulatory volume increase following exposure of cells to hypertonic solutions, indicating that the effects of DIDS were not the result of inhibition of Cl- transport systems. It is suggested that the DIDS-induced repolarization is caused by inactivation of the volume-sensitive anion channel. The stimulation of beta-cell electrical and secretory activity by glucose, but not tolbutamide, may therefore involve activation of the anion channel.

Stimulus-secretion coupling of arginine-induced insulin release: comparison between the cationic amino acid and its methyl ester.

The role currently ascribed to the accumulation of L-arginine in the pancreatic islet B-cell as a determinant of its insulinotropic action was reevaluated by comparing the uptake and the metabolic, ionic, electric, and secretory effects of the cationic amino acid with those of its more positively charged methyl ester in rat pancreatic islets. The response to L-arginine methyl ester differed from that evoked by the unesterified amino acid by a lower uptake and oxidation, lack of inhibitory action on D-glucose metabolism, more severe inhibition of the catabolism of endogenous L-glutamine, inhibition of 45Ca net uptake, decrease in both 86Rb outflow from prelabeled islets perifused at normal extracellular Ca2+ concentration and 45Ca efflux from prelabeled islets perifused in the absence of extracellular Ca2+, and delayed and lesser insulinotropic action. These findings reinforce the view that the carrier-mediated entry of L-arginine into the islet B-cells, with resulting depolarization of the plasma membrane, represents the essential mechanism for stimulation of insulin release by this cationic amino acid.

Effects of methylglyoxal on rat pancreatic beta-cells.

The addition of the alpha-ketoaldehyde methylglyoxal (0.5 or 1 mmol/L) to single isolated rat pancreatic beta-cells caused a rapid, marked depolarization resulting in electrical activity. This effect of methylglyoxal on beta-cell was reversible upon removal of the alpha-ketoaldehyde, and could be inhibited by the anion channel blockers 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). Methylglyoxal also resulted in elevated cytosolic [Ca2+] and an intracellular acidification in intact rat islets. In perifused islets, methylglyoxal provoked a modest, transient stimulation of secretion but inhibited glucose-induced insulin release. Incubation of islets with methylglyoxal resulted in the formation of large quantities of D-lactate, indicating metabolism of the alpha-ketoaldehyde via the glyoxalase pathway. The effects of methylglyoxal on beta-cell membrane potential, cytosolic [Ca2+] and intracellular pH were also observed in response to phenylglyoxal which is also effectively metabolized via the glyoxalase pathway. However, t-butylglyoxal which is poorly metabolized via the glyoxalase pathway, caused neither depolarization of the membrane potential nor intracellular acidification, but did inhibit glucose-induced insulin release. These findings suggests that the depolarization and acidification evoked by methyl- and phenylglyoxal are dependent upon their metabolism via the glyoxalase pathway. The possible mechanisms coupling alpha-ketoaldehyde metabolism via the glyoxalase pathway with membrane depolarization are discussed.

Activation of an anion conductance and beta-cell depolarization during hypotonically induced insulin release.

The perforated patch technique was used to study the effects of hypotonic extracellular solutions on membrane potential and whole-cell currents in intact rat pancreatic beta-cells. A 30% reduction in osmolarity resulted in activation of an outwardly rectifying CI(-)-selective conductance in rat beta-cells. This conductance was inhibited by the anion channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS). Exposure to a hypotonic medium also led to a transient stimulation of electrical activity accompanied by cell swelling and a gradual return towards control volume. These effects were also associated with the generation of an inward current at a holding potential of -70mV, and a stimulation of insulin release from intact perifused islets. All of the above effects were inhibited by DIDS. It is suggested that the stimulation of insulin release by hypotonic solutions results from activation of a volume-sensitive anion conductance generating an inward current and leading to a subsequent depolarization of the beta-cell.

Stimulation of HIT-T15 insulinoma cells by glyceraldehyde does not require its metabolism.

The addition of the triose D-glyceraldehyde (5-20 mM) to HIT-T15 hamster insulinoma cells caused a rapid, marked depolarisation of the plasma membrane accompanied by a pronounced intracellular acidification, an increase in the cytosolic free calcium concentration [Ca2+]i and enhanced secretion of insulin. D-glyceraldehyde did not reduce the rate of efflux of 86Rb+ from loaded perifused cells. All of the above effects of D-glyceraldehyde were also observed in response to L-glyceraldehyde. The changes in membrane potential and intracellular pH (pHi) caused by D-glyceraldehyde were unaffected by the glycolytic inhibitor iodoacetate, by K(+)-channel blockers (tolbutamide and tetraethylammonium), or by inhibitors of the transport of lactate (alpha-fluorocinnamate), alanine (methylaminoisobutyrate) or glucose (phloretin, phlorrizin). The glyceraldehyde-induced depolarisation and acidification were also observed in the absence of extracellular Ca2+ or Na+. The increase in [Ca2+]i evoked by D-glyceraldehyde was reversed by removal of Ca2+ from the medium. The formation of lactate by HIT-T15 cells was not significantly increased by addition of 10 mM D-glyceraldehyde or L-glyceraldehyde. In contrast, 10 mM glucose caused an approximately fourfold rise in lactate production. The oxidation of D-glyceraldehyde by HIT-T15 cells was also extremely modest compared to glucose oxidation by these cells. These results suggest that the stimulation of HIT-T15 cells by either D-glyceraldehyde of L-glyceraldehyde does not require metabolism of the triose within the cell and may not involve closure of nucleotide-sensitive K+ channels. We propose that the electrogenic transport of glyceraldehyde across the plasma membrane, possibly via H+ cotransport, might lead to depolarisation and hence to Ca2+ entry into the cell.

Stimulation of insulin secretion by glucose in the absence of diminished potassium (86Rb+) permeability.

Two inhibitors of the nucleotide-sensitive K+ (KATP) channel, tolbutamide and quinine, were utilized in order to assess the role of this channel in glucose-stimulated insulin release from perifused rat islets. In the absence of these drugs, the addition of 15 mM glucose elicited a marked biphasic stimulation of insulin secretion concomitant with a reduction in the rate of 86Rb+ efflux. In the presence of either 500 microM tolbutamide or 100 microM quinine, a reduced rate of efflux of 86Rb+ was observed together with an elevated rate of insulin release. Under such conditions, the addition of 15 mM glucose retained the ability to stimulate insulin secretion though this was associated with a marked increase in 86Rb+ efflux. It is concluded that a net reduction in beta-cell K+ permeability is not an obligatory step in glucose-stimulated insulin release. Thus, glucose is likely to exert depolarizing actions on the beta-cell in addition to the closure of K+ channels.

Activation of insulin-secreting cells by pyruvate and halogenated derivatives.

Addition of pyruvate to rat islets perifused in the presence of 5 mM-glucose elicited an immediate pronounced biphasic stimulation of insulin secretion. At lower concentrations of glucose (2.5 mM), only the initial, transient, phase of secretion was observed. Pyruvate inhibited 45Ca2+ efflux from islets at 2.5 mM-glucose and stimulated efflux at 5 mM-glucose. Pyruvate also decreased the rate of efflux of 86Rb+ from perifused islets. A marked stimulation of insulin secretion and 45Ca2+ efflux rate was observed in response to 3-fluoropyruvate and 3-bromopyruvate, compounds which inhibited oxidative metabolism of [14C]glucose and [14C]pyruvate in islets. The stimulatory effects of 3-fluoro- and 3-bromo-pyruvate were associated with enhanced 86Rb+ efflux. Withdrawal of pyruvate or halogenated analogues from the perfusate resulted in a secondary stimulation of insulin release, 45Ca2+ efflux and, to some extent, 86Rb+ efflux rates. Pyruvate, 3-fluoropyruvate and 3-bromopyruvate were all effective in promoting intracellular acidification and a rise in cytosolic Ca2+ concentration, as judged from fluorescence measurements in HIT-T15 cells loaded with 2',7'-biscarboxyethyl-5'(6')-carboxyfluorescein and Quin 2 respectively. It is proposed that oxidative metabolism of pyruvate is not a prerequisite for its stimulatory actions on pancreatic beta-cells. An alternative mechanism of activation by pyruvate and its halogenated derivatives is proposed, based on the possible electrogenic flux of these anions across the cell membrane.

Total respiratory compliance during anaesthesia in infants and young children.

The multiple occlusion technique was used to study the effects of paralysis on ventilatory mechanics during anaesthesia. Total respiratory compliance (Crs) was measured during spontaneous breathing and following neuromuscular block with controlled ventilation in 23 infants. There was marked variation in response to paralysis: some infants demonstrated no change in Crs between the two states; others had values of Crs which were significantly higher during paralysis with controlled ventilation than during spontaneous breathing. A possible cause of these differences may be the type of controlled ventilation given during paralysis, with tidal volume directly influencing values of Crs obtained. The results of this study suggest that values of Crs obtained during spontaneous breathing and paralysis should not be used interchangeably until further studies have been performed to assess factors influencing Crs during controlled ventilation.

Effects of lactate on pancreatic islets. Lactate efflux as a possible determinant of islet-cell depolarization by glucose.

The secretion of insulin from perifused rat pancreatic islets was stimulated by raising the glucose concentration from 5.6 to 20 mM or by exposure to tolbutamide. The addition of sodium lactate (40 mM) to islets perifused in the presence of glucose (5.6 mM) resulted in a small, transient, rise in the rate of secretion. The subsequent removal of lactate, but not glucose or tolbutamide, from the perifusate produced a dramatic potentiation of insulin release. The rate of efflux of 45Ca2+ was also increased when islets were exposed to a high concentration of glucose or lactate or to tolbutamide, and again subsequently upon withdrawal of lactate. Efflux of 86Rb+ was modestly inhibited upon addition of lactate and markedly enhanced by the subsequent withdrawal of lactate from islets. The output of [14C]lactate from islets incubated in the presence of [U-14C]glucose increased linearly with increasing concentrations of glucose (1-25 mM). It is proposed that the activation of islets by the addition or withdrawal of lactate is not due to increased oxidative flux, but occurs as a result of the electrogenic passage of lactate ions across the plasma membrane, resulting in islet-cell depolarization, Ca2+ entry and insulin secretion. The production of lactate via the glycolytic pathway, and the subsequent efflux of lactate from the islet cells with concomitant exchange of H+ for Na+, could be a major determinant of depolarization and hence insulin secretion, in response to glucose.

Modulation by cytosolic pH of calcium and rubidium fluxes in rat pancreatic islets.

Cytosolic pH (pHi) of pancreatic islet cells was assessed using the fluorescent dye 2'7'-biscarboxyethyl-5'(6')-carboxyfluorescein (BCECF). pHi was rapidly lowered by addition of the sodium salt of a weak acid or by treatment with amiloride. In the latter case, no recovery of pHi occurred. NH4Cl produced a rise in pHi. Stimulation of islet cells with glyceraldehyde produced a sustained fall in pHi, whereas glucose and alpha-ketoisocaproate caused a small, gradual rise in pHi. Intracellular acidification, particularly with amiloride, resulted in an immediate potentiation of glucose-induced insulin secretion from perifused islets. In the case of weak acid treatment, subsequent removal of the weak acid produced a paradoxical stimulation of insulin release which was not observed upon removal of amiloride. NH4Cl produced a transient stimulation followed by a reduction in the rate of glucose-induced insulin secretion. A reduction in pHi, either in response to weak acid or amiloride treatment, was associated with a diminution in the rate of efflux of 86Rb+ and of 45Ca2+. Removal of weak acid produced a marked "rebound" stimulation of 86Rb+ and 45Ca2+ efflux. Treatment of islets with NH4Cl, either in the presence or absence of glucose or Ca2+, resulted in a marked stimulation of efflux of 86Rb+ and 45Ca2+. The stimulatory effect of NH4Cl on 45Ca2+ efflux was markedly impaired in the absence of Na+. It is concluded that pHi can influence the secretory activity of pancreatic islets, possibly via effects on potassium permeability and sodium-calcium exchange across the plasma membrane, resulting in altered mobilisation of calcium in the islet cell. However, it is unlikely that glucose or other nutrient stimuli activate islets solely via an effect on pHi.

Anaesthesia and angiotensin-converting enzyme inhibitors. The effect of enalapril on peri-operative cardiovascular stability.

The effect of enalapril pretreatment on the haemodynamic response to tracheal intubation and surgical stimulation has been studied in 22 patients. Enalapril 5 mg given 4 hours before operation was associated with a significant reduction in the pressor response associated with intubation (p less than 0.05) and surgical stimulation (p less than 0.005) compared with control. Heart rate changes were similar in the two groups. The role of the renin-angiotensin system in relation to the pressor response to sympathetic stimulation is discussed and it is concluded that angiotensin-converting enzyme inhibitors may help improve peri-operative cardiovascular stability.

Pulmonary blood flow during closed heart surgery. Use of a modified Qp/Qs ratio to assess adequacy of palliation of systemic-pulmonary artery shunts.

The ability to assess changes in pulmonary blood flow, using a modified Qp/Qs ratio (Qp/Qsmod), was evaluated in 12 infants with congenital heart disease and complete intracardiac mixing who underwent modified Blalock-Taussig shunt procedures. At the various measuring stages there were no major changes in mean arterial pressure or heart rate. Arterial oxygen tensions and saturation increased (P less than 0.01) and the arterial to end-tidal carbon dioxide difference (PaCO2-PE'CO2) was significantly reduced (P less than 0.001) after completion of the shunt procedure. There was a significant increase in mean Qp/Qsmod after chest closure (P less than 0.001), which was seen to correlate well with early clinical outcome. Two patients who did not demonstrate any increase in Qp/Qsmod over the course of the procedure had failed shunts. The limitations of use of the Qp/Qsmod are discussed. A modified Qp/Qs ratio of less than unity after surgery is strongly indicative of inadequate palliation.