Measurement of platelet aggregation peptide inhibitors by ultrasonic interferometry

In healthy subjects, basal hepatic glucose production is (partly) regulated by paracrine intrahepatic factors. It is unknown if these paracrine factors also influence basal glucose production in infectious diseases with increased glucose production. We compared the effects of 150 mg indomethacin (n = 9), a nonendocrine stimulator of glucose production in healthy adults, and placebo (n = 7) on hepatic glucose production in Vietnamese adults with uncomplicated falciparum malaria. Glucose production was measured by primed, continuous infusion of [6,6-2H2]glucose. After indomethacin, the plasma glucose concentration and glucose production increased in all subjects from 5.3 +/- 0.1 mmol/L to a maximum of 7.1 +/- 0.3 mmol/L (P < .05) and from 17.6 +/- 0.8 micromol x kg(-1) x min(-1) to a maximum of 26.2 +/- 2.5 micromol x kg(-1) x min(-1) (P < .05), respectively. In the control group, the plasma glucose concentration and glucose production declined gradually during 4 hours from 5.4 +/- 0.2 mmol/L to 5.1 +/- 0.1 mmol/L (P < .05) and from 17.1 +/- 0.8 micromol x kg(-1) x min(-1) to 15.1 +/- 1.0 micromol x kg(-1) x min(-1) (P < .05), respectively. There were no differences in plasma concentrations of insulin, counterregulatory hormones, or cytokines between the groups. We conclude that indomethacin administration results in a transient increase in glucose production in patients with uncomplicated falciparum malaria in the absence of changes in plasma concentrations of glucoregulatory hormones or cytokines. Thus, this study indicates that in uncomplicated falciparum malaria, the rate of basal hepatic glucose production is also regulated by paracrine intrahepatic factors.     

Amylin-mediated reduction in insulin sensitivity corresponds to reduced insulin receptor kinase activity in the rat in vivo

Studies were undertaken to elucidate further the mechanism whereby the pancreatic peptide amylin induces insulin resistance. Sixteen male Sprague-Dawley rats underwent hyperinsulinemic (14 pmol/kg/min, 0 to 120 minutes) euglycemic clamps in the presence or absence of amylin (500 pmol/kg/min, 60 to 120 minutes). Amylin induced insulin resistance at both the hepatic level (mean +/- SE: hepatic glucose output [HGO] with amylin 1.4 +/- 0.2 v without amylin -1.9 +/- 0.3 mmol/kg/h, P < .001) and peripheral level (glucose disposal [Rd] with amylin 5.0 +/- 0.2 v without amylin 8.5 +/- 0.6 mmol/kg/h, P < .001). Serum insulin levels were similar in the presence or absence of amylin alone (661 +/- 89 v 636 +/- 50 pmol/L, respectively, P = NS), but were significantly less when somatostatin (SRIF) was simultaneously infused (408 +/- 15 pmol/L, P < .02 v the other two groups). This suggests that endogenous insulin production was not suppressed by amylin under these study conditions. Similar findings were obtained in 18 animals in the absence of exogenous insulin infusion. In vitro kinase activity toward histone of skeletal muscle insulin receptors (IRs) activated by insulin in vivo was reduced in the presence of amylin to 6.0 +/- 0.8 versus 9.1 +/- 1.2 fmol phosphate into histone (insulin-infused) and 3.9 +/- 0.7 versus 6.9 +/- 1.4 (non-insulin-infused; P < .03 by ANOVA). Serum calcium was significantly decreased in amylin-treated animals (1.93 +/- 0.04 v 2.30 +/- 0.05 mmol/L, P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of nonesterified fatty acids on glucose metabolism after glucose ingestion

Impaired suppression of plasma nonesterified fatty acids (NEFAs) after glucose ingestion may contribute to glucose intolerance, but the mechanisms are unclear. Evidence that insulin inhibits hepatic glucose output (HGO), in part by suppressing plasma NEFA levels, suggests that impaired suppression of plasma NEFA after glucose ingestion would impair HGO suppression and increase the systemic delivery of glucose. To test this hypothesis, we studied glucose kinetics (constant intravenous [3-3H]glucose [0.4 microCi/min], oral [1-14C]glucose [100 microCi]), whole-body substrate oxidation, and leg glucose uptake in eight normal subjects (age, 39 +/- 9 years [mean +/- SD]; BMI, 24 +/- 2 kg/m2) in response to 75 g oral glucose on two occasions. In one study, plasma NEFAs were prevented from falling by infusion of 20% Liposyn (45 ml/h) and heparin (750 U/h). Plasma glucose rose more rapidly during lipid infusion (P < 0.05), and mean levels tended to be higher after 120 min (6.45 +/- 0.41 vs. 5.81 +/- 0.25 SE, 0.1 < P < 0.05, NS); peak glucose levels were similar. Total glucose appearance (Ra) was higher during lipid infusion due to a higher HGO (28.4 +/- 1.0 vs. 21.2 +/- 1.5 g over 4 h, P < 0.005). Total glucose disposal (Rd) was also higher (88 +/- 2 vs. 81 +/- 3 g in 4 h, P < 0.05). Plasma insulin rose more rapidly after glucose ingestion with lipid infusion, and leg glucose uptake was 33% higher (P < 0.05) during the 1st hour. During lipid infusion, subjects oxidized less glucose (47 +/- 3 vs. 55 +/- 2 g, P < 0.05) and more fat (7.1 +/- 0.8 vs. 3.9 +/- 0.9 g, P < 0.02). In summary, 1) impaired suppression of NEFAs after oral glucose impairs insulin's ability to suppress HGO, and 2) in normal subjects the greater insulin response compensates for the increased systemic glucose delivery by increasing peripheral glucose Rd.     

Effects of epinephrine on glucose metabolism in patients with alcoholic cirrhosis

The cirrhotic liver has been shown to be resistant to the actions of various glucoregulatory hormones. The objective of this study was to investigate the effects of epinephrine on hepatic glucose metabolism in cirrhotic patients. Thirteen cirrhotic and eight healthy subjects were studied. Hepatic glucose production and turnover of alanine and glycerol were measured using stable isotope technique before and during 70 and 150 minutes of epinephrine infusion (0.1 microgram/kg/min). beta-Adrenoreceptor binding sites and affinity in mononuclear leukocyte membranes also were determined. Hepatic glucose production and alanine turnover in normals significantly increased during epinephrine infusion, but did not change in cirrhotics. Glycerol turnover increased after 70 minutes of epinephrine infusion in both groups. Epinephrine induced a significant rise of high-affinity beta-adrenoreceptor binding sites in normals, yielding a significant correlation between hepatic glucose production and receptor density (r = .94, P < .0001). In cirrhotic patients, similar changes in the number of high-affinity beta-adrenoreceptors were observed, but no correlation with hepatic glucose production was detected. The cirrhotic liver did not respond normally to the stimulatory effect of epinephrine on hepatic glucose production. Because this blunted response was not related to changes of beta-adrenoreceptors, our findings suggest that epinephrine resistance in cirrhosis was caused by a postreceptor defect.     

Increased basal glucose production in type 1 Gaucher's disease

To evaluate the metabolic effects of Gaucher's disease, glucose metabolism and parameters of fat metabolism were studied by indirect calorimetry and primed continuous infusion of [3-3H]glucose in seven clinically stable untreated patients with type 1 Gaucher's disease and in seven healthy matched control subjects. Studies were performed in the postabsorptive state. In Gaucher patients, resting energy expenditure was increased by approximately 24% (29.4 +/- 0.7 vs. 23.7 +/- 0.8 kcal/kg.day; P < 0.01). Glucose production was increased by approximately 30% in patients compared to controls (14.00 +/- 0.51 vs. 10.77 +/- 0.26; P < 0.01), although plasma glucose concentrations and net glucose oxidation were not different. Although C peptide concentrations were not different, insulin concentrations were slightly increased in Gaucher patients (P < 0.05). The differences in basal glucose production were not related to differences in plasma concentrations of insulin or other glucoregulatory hormones. In conclusion, the increase in basal glucose production is a remarkable feature of type 1 Gaucher's disease, which cannot merely be explained by endocrine mechanisms. Because Gaucher's disease is manifested within the liver in macrophages, but not in hepatocytes, altered intrahepatic regulatory mechanisms might be involved in this increase in glucose production.     

Effect of continuous subcutaneous insulin infusion with lispro on hepatic responsiveness to glucagon in type 1 diabetes

OBJECTIVE: People with type 1 diabetes frequently develop a blunted counterregulatory hormone response to hypoglycemia coupled with a decreased hepatic response to glucagon, and consequently, they have an increased risk of severe hypoglycemia. We have evaluated the effect of insulin lispro (Humalog) versus regular human insulin (Humulin R) on the hepatic glucose production (HGP) response to glucagon in type 1 diabetic patients on intensive insulin therapy with continuous subcutaneous insulin infusion (CSII). RESEARCH DESIGN AND METHODS: Ten subjects on CSII were treated for 3 months with lispro and 3 months with regular insulin in a double-blind randomized crossover study After 3 months of treatment with each insulin, hepatic sensitivity to glucagon was measured in each subject. The test consisted of a 4-h simultaneous infusion of somatostatin (450 microg/h) to suppress endogenous glucagon, regular insulin (0.15 mU x kg(-1) x min(-1)), glucose at a variable rate to maintain plasma glucose near 5 mmol/l, and D-[6,6-2H2]glucose to measure HGP During the last 2 h, glucagon was infused at 1.5 ng x kg(-1) x min(-1). Eight nondiabetic people served as control subjects. RESULTS: During the glucagon infusion period, free plasma insulin levels in the diabetic subjects were 71.7+/-1.6 vs. 74.8+/-0.5 pmol/l after lispro and regular insulin treatment, with plasma glucagon levels of 88.3+/-1.8 and 83.7+/-1.5 ng/l for insulin:glucagon ratios of 2.8 and 3.0. respectively (NS). However, plasma glucose increased to 9.2+/-1.1 mmo/l after lispro insulin compared with 7.1+/-0.9 mmol/l after regular insulin (P < 0.01), and the rise in HGP was 5.7 +/-2.8 micromol x kg(-1) x min(-1) after lispro insulin versus 3.1+/-2.9 micromol x kg(-1) x min(-1) after regular insulin treatment (P=0.02). In the control subjects, HGP increased by 10.7+/-4.2 micromol x kg(-1) x min(-1) under glucagon infusion. CONCLUSIONS: Insulin lispro treatment by CSII was associated with a heightened response in HGP to glucagon compared with regular human insulin. This suggests that insulin lispro increases the sensitivity of the liver to glucagon and could potentially decrease the risk of severe hypoglycemia.     

The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog

The aim of the present experiments was to determine the role of insulin and glucagon in the regulation of basal glucose production in dogs fasted overnight. A deficiency of either or both pancreatic hormones was achieved by infusin somatostatin (1 mug/kg per min), a potent inhibitor of both insulin and glucagon secretion, alone or in combination with intraportal replacement infusions of either pancreatic hormone. Infusion of somatostatin alone caused the arterial levels of insulin and glucagon to drop rapidly by 72+/-6 and 81+/-8%, respectively. Intraportal infusion of insulin and glucagon at rates of 400 muU/kg per min and 1 ng/kg per min, respectively, resulted in the maintenance of the basal levels of each hormone. Glucose production was measured using tracer (primed constant infusion of [3-3H]glucose) and arteriovenous difference techniques. Isolated glucagon deficiency resulted in a 35+/-5% (P less than 0.05) rapid and sustained decrease in glucose production which was abolished upon restoration of the plasma glucagon level. Isolated insulin deficiency resulted in a 52+/-16% (P less than 0.01) increase in the rate of glucose production which was abolished when the insulin level was restored. Somatostatin had no effect on glucose production when the changes in the pancreatic hormone levels which it normally induces were prevented by simultaneous intraportal infusion of both insulin and glucagon. In conclusion, in the anesthetized dog fasted overnight; (a) basal glucagon is responsible for at least one-third of basal glucose production, (b) basal insulin prevents the increased glucose production which would result from the unrestrained action of glucagon, and (c) somatostatin has no acute effects on glucose turnover other than those it induces through perturbation of pancreatic hormone secretion. This study indicates that the opposing actions of the two pancreatic hormones are important in the regulation of basal glucose production in the postabsorptive state.     

Role of nitric oxide in the vasodilator response to mental stress in normal subjects

Vascular production of nitric oxide (NO) plays an important role in a variety of physiologic processes. This study examines the contribution of NO to the vasodilator response to mental stress. The effects of mental arithmetic testing on forearm vascular dynamics were analyzed in 15 normal subjects (9 men; age 45 +/- 12 years) during intraarterial infusion of either saline or N(G)-monomethyl-L-arginine (L-NMMA; 4 micromol/min for 15 minutes), an inhibitor of NO synthesis. The effect of L-NMMA on endothelium-independent vasodilation induced by intraarterial infusion of sodium nitroprusside was also studied in 11 of the 15 subjects. Forearm blood flow was measured by plethysmography. Mental stress increased forearm blood flow from 2.35 +/- 0.84 to 5.06 +/- 2.66 ml/min/dl (115%) during saline and from 1.72 +/- 0.59 to 2.81 +/- 0.99 ml/min/dl (63%) during L-NMMA infusion. The vasodilator effect of mental stress was significantly lower during L-NMMA infusion than during saline (1.1 +/- 0.65 vs 2.71 +/- 2.15 ml/min/dl; p = 0.01). L-NMMA administration did not significantly change mean arterial pressure and heart rate responses to mental stress. In contrast, the vasodilator effect of sodium nitroprusside (1.6 microg/min) was similar during infusion of L-NMMA and during saline (3.75 +/- 1.55 vs 2.85 +/- 1.38 ml/min/dl; p = 0.16). These findings indicate that local release of NO is involved in the forearm vasodilator response to mental stress.     

The effect of stevioside on glucose metabolism in rat

This study was conducted to determine the effect of stevioside (SVS) on glucose metabolism. The experiments were performed in male Wistar rats treated with SVS either by intravenous infusion or feeding. SVS infusion (150 mg/mL) was carried out in doses of 0.67, 1.00, and 1.33 mL.kg-1 body weight.h-1. The plasma glucose level significantly increased both during and after SVS infusion, whereas it was not affected by SVS feeding (13.3 mL.kg-1 body weight). The glucose turnover rate (GTR) of [14C(U)]glucose and [3(-3)H]glucose was not significantly different between control and SVS infusion animals. Percent glucose carbon recycling and glucose clearance were reduced from 28.7 +/- 1.3 to 23.0 +/- 1.6% (p < 0.05) and from 6.46 +/- 0.34 to 4.99 +/- 0.20 mL.min-1.kg-1 body weight (p < 0.01), respectively. The plasma insulin level did not change, whereas the plasma glucose level significantly increased from 120.3 +/- 5.9 to 176.8 +/- 10.8 mg% (p < 0.01) during SVS infusion. Animals pretreated with angiotensin II and arginine vasopressin showed no significant effect, while animals pretreated with prazosin had an attenuated hyperglycemic effect of SVS infusion. Pretreatment with indomethacin or N omega-nitro-L-arginine methyl ester (L-NAME) alleviated the plasma glucose level during the second period of SVS infusion. Pretreatment with the combination infusion of indomethacin and L-NAME reduced the plasma glucose level from 117.0 +/- 1.8 to 109.0 +/- 1.7 mg% (p < 0.001), and normalized the plasma glucose level in the second period of SVS infusion. Insulin infusion inhibited the hyperglycemic effect of SVS infusion. The present results show that the elevation of the plasma glucose level during SVS infusion is not due to the reduction of the insulin level. It is probably the effect of SVS on glucose transport across the cell. Insulin response to a high plasma glucose level is suppressed during SVS infusion. Several interactions among norepinephrine, prostaglandin, and nitric oxide are involved in modulating the hyperglycemia during SVS infusion.     

Renal lactate metabolism and gluconeogenesis during insulin-induced hypoglycemia

The contribution of gluconeogenic precursors to renal glucose production (RGP) during insulin-induced hypoglycemia was assessed in conscious dogs. Ten days after surgical placement of sampling catheters in the right and left renal veins and femoral artery and an infusion catheter in the left renal artery, systemic and renal glucose and glycerol kinetics were measured with peripheral infusions of [6-3H]glucose and [2-13C]glycerol. Renal blood flow was determined with a flowprobe, and the renal balance of lactate, alanine, and glycerol was calculated by arteriovenous difference. After baseline, six dogs received 2-h simultaneous infusions of peripheral insulin (4 mU x kg(-1) x min(-1)) and left intrarenal [6,6-2H]dextrose (14 micromol x kg(-1) x min(-1)) to achieve and maintain left renal normoglycemia during systemic hypoglycemia. Arterial glucose decreased from 5.3 +/- 0.1 to 2.2 +/- 0.1 mmol/l; insulin increased from 46 +/- 5 to 1,050 +/- 50 pmol/l; epinephrine, from 130 +/- 8 to 1,825 +/- 50 pg/ml; norepinephrine, from 129 +/- 6 to 387 +/- 15 pg/ml; and glucagon, from 52 +/- 2 to 156 +/- 12 pg/ml (all P < 0.01). RGP increased from 1.7 +/- 0.4 to 3.0 +/- 0.5 (left) and from 0.6 +/- 0.2 to 3.2 +/- 0.2 (right) micromol x kg(-1) x min(-1) (P < 0.01). Whole-body glycerol appearance increased from 6.0 +/- 0.5 to 7.7 +/- 0.7 micromol x kg(-1) x min(-1)(P < 0.01); renal conversion of glycerol to glucose increased from 0.13 +/- 0.04 to 0.30 +/- 0.10 (left) and from 0.11 +/- 0.03 to 0.25 +/- 0.05 (right) micromol x kg(-1) x min(-1), (P < 0.05). Net renal gluconeogenic precursor uptake increased from 1.5 +/- 0.4 to 5.0 +/- 0.4 (left) and from 0.9 +/- 0.2 to 3.8 +/- 0.4 (right) micromol x kg(-1) x min(-1) (P < 0.01). Renal lactate uptake could account for approximately 40% of postabsorptive RGP and for 60% of RGP during hypoglycemia. These results indicate that gluconeogenic precursor extraction by the kidney, particularly lactate, is stimulated by counterregulatory hormones and accounts for a significant fraction of the enhanced gluconeogenesis induced by hypoglycemia.     

Plasma levels of TNF and IL-6 following induction of acute pancreatitis and pentoxifylline treatment in rats

Activation of cytokine cascade is a decisive factor in determining the pathobiology of different inflammatory processes including acute pancreatitis. The purposes of this study were to determine the TNF and IL-6 levels after the induction of acute necrotizing pancreatitis, and to establish the effects of pentoxifylline on the cytokine production and the severity of pancreatitis. Acute necrotizing pancreatitis was induced by the retrograde injection of 200 microliters taurocholic acid into the pancreatic duct in male Wistar rats. TNF was titrated in a bioassay on cell line WEHI clone 164. IL-6 was measured via its proliferative action on the IL-6 dependent mouse hybridoma cell line B-9. Seven mg/kg pentoxifylline was administered intraperitoneally at the time of operation and/or 24 hours later. Rats were sacrificed, 48 or 72 hours after the operation. The TNF bioassay revealed high levels of TNF (36.6 +/- 6.0 U/ml) in the control group whereas levels decreased to zero in the pentoxifylline-treated group. The IL-6 bioassay likewise demonstrated high levels of IL-6 in the control group and markedly decreased levels in the pentoxifylline treated group (7083 +/- 2844 pg/ml, 6463 +/- 1307 pg/ml vs. 137.5 +/- 85.5 pg/ml, respectively, p < 0.05). The high mortality observed in the control group (43%) was sharply decreased by pentoxifylline administration to 11%. The data suggest that pentoxifylline is capable of modifying the cytokine production after 48 hours of induction of acute pancreatitis.     

Importance of endogenous adenosine during ischemia and reperfusion in neonatal porcine hearts

BACKGROUND: Adenosine has several potentially cardioprotective effects. We hypothesized that the effects of endogenous adenosine vary with degree of ischemia and that elevating endogenous levels is protective. METHODS AND RESULTS: Isolated blood-perfused piglet hearts underwent 120 minutes of low-flow ischemia (10% flow) or 90 minutes of zero-flow ischemia, all with 60 minutes of reperfusion. Hearts were treated with either saline, the adenosine receptor blocker 8-sulfophenyltheophylline (8SPT, 300 micromol x L(-1)), or the nucleoside transport inhibitor draflazine (1 micromol x L(-1)). In separate groups, biopsies were obtained before and at the end of ischemia. Compared with saline, 8SPT did not significantly alter functional recovery in either protocol. Draflazine significantly improved percent recovery of left ventricular systolic pressure both in the low-flow protocol (92+/-3% versus 75+/-2% [saline] and 73+/-3% [8SPT], P<.001 for both) and in the zero-flow protocol (76+/-3% versus 59+/-4% [saline] and 46+/-9% [8SPT], P<.05 for both). In the zero-flow protocol, draflazine also significantly reduced ischemic contracture and release of creatine kinase. Tissue adenosine at the end of ischemia was elevated by draflazine compared with saline-treated hearts: after low-flow ischemia to 0.10+/-0.05 versus 0.00+/-0.00 micromol x g(-1) dry wt (P<.05) and after zero-flow ischemia to 1.73+/-0.82 versus 0.15+/-0.03 micromol x g(-1) dry wt (P<.05). CONCLUSIONS: In neonatal porcine hearts, endogenous adenosine produced during ischemia does not influence ischemic injury or functional recovery. Elevating endogenous adenosine by draflazine elicits cardioprotection in both low-flow and zero-flow conditions.     

Impaired regulation of hepatic fructose-1,6-biphosphatase in the New Zealand Obese mouse: an acquired defect

Increased hepatic glucose production, a feature of (non-insulin-dependent diabetes mellitus [NIDDM]), is present at an early age in the New Zealand Obese (NZO) mouse and is associated with impaired suppression of the gluconeogenic enzyme, fructose-1,6-bisphosphatase (FBPase). The aim of this study was to further characterize the abnormality in the regulation of hepatic FBPase in NZO mice versus New Zealand Chocolate (NZC) control mice. At 20 weeks of age, NZO mice have elevated FBPase activity (65.3 +/- 7.9 v 46.7 +/- 5.0 micromol/min/mg protein, P =.07) and protein levels (31.7 +/- 3.1 v 22.5 +/- 2.8 arbitrary units, P < .05), but not mRNA levels (0.18 +/- 0.03 v 0.16 +/- 0.03 arbitrary units). Elevated FBPase activity and protein levels in NZO mice were also shown at 4 to 6 weeks of age, but not in 1-day-old mice, suggesting that the increase occurs between birth and weaning. The Km of the enzyme was the same in NZO and NZC mice (3.7 +/- 0.5 v 5.0 +/- 0.9 micromol/L, NZO v NZC). The regulation of FBPase by the competitive inhibitor, fructose-2,6-bisphosphate ([Fru(2,6)Pz] 5 micromol/L) measured over a range of substrate concentrations (2.5 to 80 micromol/L) was similar between NZO and control mice (Km in the presence of Fru(2,6)Pz, 10.8 +/- v 1.9 v 13.2 +/- 3.3 micromol/L, NZO v NZC). It is concluded that increased FBPase activity in the NZO mouse is due to elevated protein levels, and that this appears to be due to a failure of the normal decrease that occurs following birth in control animals.     

Effect of theophylline on substrate metabolism during exercise

We tested the hypothesis that adenosine is involved in regulating substrate metabolism during exercise. Seven trained cyclists were studied during 30 minutes of exercise at approximately 75% maximal oxygen uptake (VO2max). Lipid metabolism was evaluated by infusing [2H5]glycerol and [1-13C]palmitate, and glucose kinetics were evaluated by infusing [6,6-2H]glucose. Fat and carbohydrate oxidation were also measured by indirect calorimetry. The same subjects performed two identical exercise tests, but in one trial theophylline, a potent adenosine receptor antagonist, was infused for 1 hour before and throughout exercise. Theophylline did not increase whole-body lipolysis (glycerol rate of appearance [Ra]) or free fatty acid (FFA) release during exercise, but fat oxidation was lower than control values (9.5 +/- 3.0 v 18.0 +/- 4.2 micromol x min(-1) x kg(-1), P < .01). Glucose Ra was not affected by theophylline infusion, but glucose uptake was lower (31.6 +/- 4.1 v 40.4 +/- 5.0 micromol x min(-1) x kg(-1), P < .05) and glucose concentration was higher (6.4 +/- 0.6 v 5.8 +/- 0.4 mmol/L, P < .05) than in the control trial. Total carbohydrate oxidation (302.3 +/- 26.2 v 265.5 +/- 11.7 micromol x min(-1) x kg(-1), P < .06), estimated muscle glycogenolysis (270.7 +/- 23.1 v 225.1 +/- 9.7 micromol x min(-1) x kg(-1), P < .05), and plasma lactate concentration (7.9 +/- 1.6 v 5.9 +/- 1.1 mmol/L, P < .001) were also higher during the theophylline trial. These data suggest that adenosine may play a role in stimulating glucose uptake and restraining glycogenolysis but not in limiting lipolysis during exercise.     

Normal glucose-induced suppression of glucose production but impaired stimulation of glucose disposal in type 2 diabetes: evidence for a concentration-dependent defect in uptake

The present studies were undertaken to determine whether people with type 2 diabetes are resistant to the effects of glucose as well as insulin. Diabetic and nondiabetic subjects were studied on three occasions. Hormone secretion was inhibited with somatostatin. Insulin concentrations were kept at "basal" levels (referred to as low insulin infusion) from 0 to 180 min then increased to approximately 200 pmol/l from 181 to 360 min (referred to as high insulin infusion). Glucose concentrations were clamped at either approximately 95, approximately 130, or approximately 165 mg/dl on each occasion. In the presence of basal insulin concentrations, a progressive increase in glucose from 95 to 130 to 165 mg/dl was accompanied by a comparable and progressive decrease (P = 0.001 to 0.003 by analysis of variance [ANOVA]) in endogenous glucose production (measured with [6-(3)H]glucose) and total glucose output (measured with [2-(3)H]glucose) and incorporation of 14CO2 into glucose (an index of gluconeogenesis) in both diabetic and nondiabetic subjects, indicating normal hepatic (and perhaps renal) response to glucose. In the nondiabetic subjects, an increase in glucose concentration from 95 to 130 to 165 mg/dl resulted in a progressive increase in glucose disappearance during both the low (19.9 +/- 1.8 to 23.6 +/- 1.8 to 25.4 +/- 1.6 micromol x kg(-1) x min(-1); P = 0.003 by ANOVA) and high (36.4 +/- 3.1 to 47.6 +/- 4.5 to 61.1 +/- 7.0 micromol x kg(-1) x min(-1); P = 0.001 by ANOVA) insulin infusions. In contrast, in the diabetic subjects, whereas an increase in glucose from 95 to 130 mg/dl resulted in an increase in glucose disappearance during both the low (P = 0.001) and high (P = 0.01) dose insulin infusions, a further increase in glucose concentration to 165 mg/dl had no further effect (P = 0.41 and 0.38) on disappearance at either insulin dose (low: 14.2 +/- 0.8 to 18.2 +/- 1.1 to 18.7 +/- 2.4 micromol x kg(-1) x min(-1); high: 21.0 +/- 3.2 to 33.9 +/- 6.4 to 32.5 +/- 8.0 micromol x kg(-1) x min(-1) for 95, 130, and 165 mg/dl, respectively). We conclude that whereas glucose-induced stimulation of its own uptake is abnormal in type 2 diabetes, glucose-induced suppression of endogenous glucose production and output is not. The abnormality in uptake occurs in the presence of both basal and high insulin concentrations and is evident at glucose concentrations above but not below 130 mg/dl, implying a defect in a glucose-responsive step.     

Influence of reduced glutathione infusion on glucose metabolism in patients with non-insulin-dependent diabetes mellitus

To evaluate the relationship between oxidative stress and glucose metabolism, insulin sensitivity and intraerythrocytic reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio were measured in 10 non-insulin-dependent diabetes mellitus (NIDDM) patients and 10 healthy subjects before and after the intravenous administration of GSH. In particular, after baseline insulin sensitivity was assessed by a 2-hour euglycemic hyperinsulinemic clamp, either glutathione (1.35 g x m2 x min(-1)) or placebo (saline) were infused over a period of 1 hour. The same protocol was repeated at a 1-week interval, in cross-over, according to a randomized, single-blind design. In healthy subjects, baseline intraerythrocytic GSH/GSSG ratio (P < .0005) and total glucose uptake (P < .005) were significantly higher than in NIDDM patients. In the same subjects, GSH infusion significantly increased total glucose uptake (from 37.1 +/- 6.7 micromol kg(-1) x min(-1) to 39.5 +/- 7.7 micromol x kg(-1) x min(-1), P < .05), whereas saline infusion was completely ineffective. In addition, the mean intraerythrocytic GSH/GSSG ratio significantly increased after GSH infusion (from 21.0 +/- 0.9 to 24.7 +/- 1.3, P < .05). Similar findings were found in diabetic patients, in whom GSH infusion significantly increased both total glucose uptake (from 25.3 +/- 9.0 micromol x kg(-1) x min(-1) to 31.4 +/- 10.0 micromol x kg(-1) x min(-1), P < .001) and intraerythrocytic GSH/GSSG ratio (from 14.8 +/- 4.1 to 21.7 +/- 6.7, P < .01). Pooling diabetic patients and controls, significant correlations were found between intraerythrocytic GSH/GSSG ratio and total glucose uptake (r = .425, P < .05), as well as between increments of the same variables after GSH infusion (r = .518, P < .05). In conclusion, our data support the hypothesis that abnormal intracellular GSH redox status plays an important role in reducing insulin sensitivity in NIDDM patients. Accordingly, intravenous GSH infusion significantly increased both intraerythrocytic GSH/GSSG ratio and total glucose uptake in the same patients.     

ISCOMs: an adjuvant with multiple functions

Glucagon causes transient hyperglycemia and persistent hypoaminoacidemia, but the mechanisms of this action are unclear. To address this question, the present study measured the effects of glucagon on glucose, leucine, phenylalanine, and glutamine kinetics. Seven healthy subjects each underwent three pancreatic clamp studies (octreotide 30 ng/kg/min, insulin 0.15 mU/kg/min, and glucagon 1.4 ng/kg/min) lasting 7 hours. During the last 3.5 hours of the studies, glucagon infusion was either unchanged (study 0) or increased to 4 and 7 ng/kg/min (studies 1 and 2). The higher glucagon infusion rates increased the glucagon concentration by 50% and 100%, respectively. [6,6-(2)H2]glucose, [2-(15)N]glutamine, 2H5-phenylalanine, and 2H3-leucine were infused to quantify the respective fluxes. Glucagon transiently increased glucose concentrations by stimulating glucose production, which peaked in 15 minutes to 3.82 +/- 0.36 and 4.21 +/- 0.33 mg/kg/min in studies 1 and 2 and then returned to the postabsorptive levels. Glucagon decreased the glutamine concentration (-10% +/- 2% and -22% +/- 2% in studies 1 and 2 v study 0, P < .05), because glutamine uptake became greater than glutamine release (balance from -1.9 +/- 0.9 in study 0 to -8.1 +/- 1.1 and -13.6 +/- 1.0 micromol/kg/h in studies 1 and 2, P < .01). Glucagon decreased the leucine concentration (-11% +/- 3% in study 2 v study 0, P < .02) and caused a small increment in proteolysis (+6% in study 2 v study 0, P < .01) that was related to the decrement in glutamine concentrations. Phenylalanine kinetics were not significantly affected. These results show that glucagon promotes the uptake of gluconeogenic substrates but does not increase their release, suggesting that glucagon-induced hyperglycemia is short-lived because glucagon fails to provide more fuel for gluconeogenesis. The small increase in proteolysis and the depletion of circulating glutamine prove that physiologic hyperglucagonemia can contribute to protein catabolism.     

Identification of HLA-A2-restricted epitopes of the tumor-associated antigen MUC2 recognized by human cytotoxic T cells

BACKGROUND: Dopexamine is a specific dopaminergic and beta2-adrenergic agonist. Using newborn piglets, we have previously shown that (1) dopexamine increases cardiac output and mesenteric blood flow; (2) indomethacin reduces mesenteric blood flow. METHODS: Ultrasonic blood flow probes were placed around the ascending aorta, cranial mesenteric artery, and a renal artery of 0 to 2-day-old and 2-week-old piglets. Animals of each age were grouped (5 to 8 animals per group) and subjected to one of three experimental protocols: (1) 0.4 mg/kg indomethacin infusion, (2) 10 microg/kg/min dopexamine infusion begun 10 minutes before indomethacin, or (3) no treatment. RESULTS: Control animals demonstrated no significant alterations in mesenteric blood flow. Compared with baseline, indomethacin produced significant (P< .05, analysis of variance) declines in cranial mesenteric artery blood flow in 0 to 2-day old (37.2+/-5.7 mL/min v 17.9+/-3.7 mL/min at 90 min), and 2-week-old (80.2+/-12.5 mL/min v 29.7+/-5.7 mL/min at 90 minutes) piglets. In both animal groups treated with dopexamine before indomethacin, the decreases in cranial mesenteric artery blood flow were eliminated (38.4+/-7.6 mL/min at baseline v 36.5+/-6.8 mL/min at 90 minutes in 0 to 2 day olds; 79.9+/-10.0 mL/min at baseline v 77.5+/-14.7 mL/min in 2 week olds). Indomethacin-induced declines in renal blood flow were similarly abrogated by dopexamine. CONCLUSION: Dopexamine may prove of clinical benefit when a neonate is considered a candidate for indomethacin therapy.     

Tinnitus after head injury: evidence from otoacoustic emissions

The ability of portal vein insulin to control hepatic glucose production (HGP) is debated. The aim of the present study was to determine, therefore, if the liver can respond to a selective decrease in portal vein insulin. Isotopic ([3H]glucose) and arteriovenous difference methods were used to measure HGP in conscious overnight fasted dogs. A pancreatic clamp (somatostatin plus basal portal insulin and glucagon) was used to control the endocrine pancreas. A 40-min control period was followed by a 180-min test period. During the latter, the portal vein insulin level was selectively decreased while the arterial insulin level was not changed. This was accomplished by stopping the portal insulin infusion and giving insulin peripherally at half the basal portal rate (PID, n=5). In a control group (n=5), the portal insulin infusion was not changed and glucose was infused to match the hyperglycemia that occurred in the PID group. A selective decrease of 120 pmol/l in portal vein insulin was achieved (basal, 150+/-36 to last 30 min, 30+/-12 pmol/l) in the absence of a change in the arterial insulin level (basal, 30+/-3 to last 30 min, 36+/-4 pmol/l). Neither arterial nor portal insulin levels changed in the control group (30+/-6 and 126+/-30 pmol/l, respectively). In response to the selective decrease in portal vein insulin, net hepatic glucose output (NHGO) increased significantly, from 8+/-1 (basal) to 30+/-6 and 14+/-2 micromol x kg(-1) x min(-1) by 15 min and the last 30 min (P < 0.05) of the experimental period, respectively. Arterial plasma glucose increased from 5.9+/-0.2 (basal) to 10.5+/-0.4 micromol/l (last 30 min). Three-carbon gluconeogenic precursor uptake fell from 11.2+/-2.9 (basal) to 5.9+/-0.7 micromol x kg(-1) x min(-1) (last 30 min), and thus a change in gluconeogenesis could not account for any of the increase in NHGO. With matched hyperglycemia (basal, 5.5+/-0.3 to last 30 min, 10.5+/-0.8 micromol/l) but no change in insulin, NHGO decreased from 12+/-1 (basal) to 0 (-1+/-6 micromol x kg(-1) x min(-1), last 30 min, P < 0.05) and hepatic gluconeogenic precursor uptake did not change (basal, 8.0+/-1.7 to last 30 min, 8.9+/-2.2 micromol x kg[-1] x min[-1]). Thus, the liver responds rapidly to a selective decrease in portal vein insulin by markedly increasing HGP as a result of increased glycogenolysis. These studies indicate that after an overnight fast, basal HGP (glycogenolysis) is highly sensitive to the hepatic sinusoidal insulin level.     

Predictors of homelessness among families in New York City: from shelter request to housing stability

OBJECTIVE: To compare the effect of captopril with that of placebo on peripheral and hepatic insulin action in essential hypertension, in light of evidence that insulin resistance is associated with cardiovascular risk. DESIGN: Randomized, double-blind, placebo-controlled, crossover trial, with 8 week treatment periods of captopril and placebo preceded and separated by 6 weeks of placebo. SETTING: Belfast teaching hospital. PATIENTS: Eighteen Caucasian nondiabetic patients (10 males), aged under 65 years, with essential hypertension, recruited from general practices in the greater Belfast area. INTERVENTIONS: Captopril at 50 mg twice a day or placebo twice a day for two 8 week treatment periods. MAIN OUTCOME MEASURES: Peripheral and hepatic insulin sensitivity assessed by glucose clamps. RESULTS: Fourteen patients completed the study. Mean (+/- SEM) levels of fasting glucose, fasting insulin and postabsorptive hepatic glucose production were similar after captopril and placebo (5.4+/-0.1 versus 5.4+/-0.1 mmol/l, 10.6+/-2.2 versus 9.5+/-1.1 mU/l, 11.2+/-0.6 versus 11.0+/-0.5 mmol/kg per min, respectively). During hyperinsulinaemia, hepatic glucose production was suppressed to comparable levels after both treatments (4.8+/-0.6 versus 4.3+/-0.6 mmol/kg per min) and exogenous glucose infusion rates required to maintain euglycaemia were also similar (30.0+/-2.6 versus 30.3+/-2.6 mmol/kg per min). CONCLUSION: Captopril therapy in uncomplicated essential hypertension has no effect on peripheral or hepatic insulin sensitivity.