Oxygen consumption, lactate metabolism, and gastric intramucosal pH in an experimental liver transplantation model

We have evaluated whether myocardial uptake of the fatty acid analog 123I-15-(p-iodophenyl)-3-R,S-methyl pentadecanoic acid (BMIPP) is dependent on the dietary state. METHODS: We compared the biodistribution of 150 MBq of 123I-BMIPP in six healthy volunteers in two states: after at least 12 hr of fasting and after oral glucose loading (75 g) 60 min before tracer administration, followed by a meal enriched in carbohydrates and protein. Planar and tomographic acquisitions were performed over a 4-hr time period after tracer injection; data were corrected for radioactive decay and injected dose. Radioactivity was measured in blood samples drawn at several points. RESULTS: Significant increases of glycemia and insulinemia and a significant drop in plasma nonesterified acids were documented after glucose loading. Half-time values for plasma radioactivity were significantly shorter in the glucose-loaded state than in the fasted state (4.3 +/- 1.4 min compared to 6.3 +/- 1.3 min, p < 0.05). Activity in the heart and liver tended to be higher in the glucose-loaded state than in the fasted state. SPECT images at 0.5 hr after tracer injection demonstrated that the myocardial wall-to-cavity ratio was higher after glucose than in the fasted state (2.53 +/- 0.59 compared to 2.11 +/- 0.21, p = 0.15). Washout from the liver between 1 and 4 hr after injection increased from 18.6% +/- 4.4% in the fasted study to 24.1% +/- 2.4% after glucose (p = 0.04). Washout from the myocardium between 0.5 and 3.5 hr after injection increased from 13.1% +/- 8.8% in the fasted study to 24.0% +/- 3.7% after glucose (p = 0.05). CONCLUSION: These results indicate that fasting before BMIPP scintigraphy is not mandatory to obtain adequate SPECT images. At the tire when SPECT is usually performed, glucose loading may provide improved ratios between myocardial and blood pool activity.     

Comparison of fatty acid tracers FTHA and BMIPP during myocardial ischemia and hypoxia

To study the sensitivity of two fatty acid tracers to changes in beta-oxidation, the myocardial retention kinetics of 125I-iodine-15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid (BMIPP) and 14-18F-fluoro-6-thia-heptadecanoic acid (FTHA) were compared in states of oxygen deprivation due to ischemia and hypoxia. METHODS: Nineteen swine were studied by extracorporeal perfusion of the three coronary arteries. Fatty acid beta-oxidation rates were determined by infusion of tritiated palmitate into the left anterior descending artery (LAD) and by measurement of labeled water production in the LAD perfusion bed. After a baseline period of 30 min, animals were divided into three groups and subjected to a 50-min intervention period. For the control group, there was no change in perfusion; for the ischemia group, there was a 60% decrease in LAD perfusion; and for the hypoxia group, the perfusion rate was unchanged, but venous blood was used as the LAD perfusate. Continuous infusion of FTHA and BMIPP into the LAD started 10 min into the intervention period and continued until the end of the intervention period. Retention rates of the two tracers were compared between the LAD and circumflex perfusion beds. RESULTS: No difference in beta-oxidation rate occurred from the baseline to the intervention period in the control group. A 50% reduction in beta-oxidation occurred in the ischemia group, and an 80% reduction occurred in the hypoxia group. No difference in retention of BMIPP or FTHA occurred in the control group. In the ischemia group, reduction in retention of both tracers occurred. However, in the hypoxia group, FTHA uptake was unchanged, whereas BMIPP retention increased compared to the circumflex arterial bed. CONCLUSION: Decreased retention of both BMIPP and FTHA occurred with ischemia, despite the known differences in metabolism of the two tracers. This difference in metabolism was further highlighted in the setting of hypoxia with increased BMIPP uptake. Thus, these results suggest that uptake of both FTHA and BMIPP tracks reduction of fatty acid utilization in myocardial ischemia but fails in tracking reduction of fatty acid oxidation during hypoxia.     

Influence of an early adrenergic blockade on thrombotic infarct size and myocardial metabolism

To evaluate the extent to which the protective effect of metoprolol was accompanied by changes in myocardial oxygen consumption and metabolism, thrombotic occlusion of coronary artery followed by infusion of metoprolol or placebo was performed in twenty four German Shepherds. To restore a coronary blood flow rt-PA was administered. Plasma levels of oxygen, glucose, lactic acid, non esterified fatty acids, triacylglyceride and adenosine breakdown products were measured before and at the end of the occlusion and in the early and late reperfusion periods. Regional myocardial blood flow was measured by means of radioactive tracer microspheres. Infarct size was estimated after perfusion and staining of excised hearts with Evans blue. Plasma levels of metoprolol were determinated before the end of occlusion and during reperfusion and therapeutic concentrations were confirmed. The infarct size was smaller in dogs receiving metoprolol (21.6 +/- 20.7 vs 43.0 +/- 17.3% p. < 0.02). Coronary collateral blood flow was greater in metoprolol than in placebo dogs (18.68 +/- 7.58 vs 11.05 +/- 6.10 ml/min/100g, p. < 0.01). As a consequence of myocardial ischemia a shift toward carbohydrate utilization, the myocardial lactate release and the accompanying symptoms of diminished myocardial lipid uptake were observed. A washout of adenosine degradation products during early reperfusion was also noticed. In beta 1 blocked animals the reduction of myocardial oxygen consumption and preserved myocardial uptake of lactate and non esterified fatty acids were documented.     

Fasting does not impair insulin-stimulated glucose uptake but alters intracellular glucose metabolism in conscious rats

Effects of 24-h and 48-h fasting on maximal insulin-stimulated whole-body and muscle glucose uptake, glycogen synthesis, and glycolysis were studied in conscious rats by combining the glucose clamp technique with tracer methods. Fasting decreased body weight and basal plasma glucose, plasma insulin, hepatic glucose output, and glucose clearance (P < 0.05 for all). However, maximal insulin-stimulated whole-body glucose uptake, normalized to body weight, was almost identical in fed, 24-h fasted, and 48-h fasted rats (191 +/- 8, 185 +/- 14, and 182 +/- 5 mumol.kg-1.min-1, respectively; P > 0.7). Similarly, rates of insulin-stimulated glucose uptake by four different skeletal muscles, estimated by the 2-deoxyglucose injection technique, were not different among the three groups. In contrast to glucose uptake, insulin-stimulated whole-body glycolysis was decreased significantly after fasting (36% after 48 h fasting; P < 0.05), whereas insulin-stimulated whole-body glycogen synthesis was increased (44% after 48 h fasting; P < 0.05). In fed rats, glycolysis was the major pathway for glucose metabolism during hyperinsulinemia, accounting for 60 +/- 5% of glucose uptake. This fraction was decreased significantly by fasting (P < 0.01), so that after a 48-h fast, glycolysis accounted for only 40 +/- 3% of insulin-stimulated glucose uptake and glycogen synthesis became predominant pathway, accounting for 60 +/- 3% of whole-body glucose utilization. Whole-body patterns of glucose metabolism during hyperinsulinemia were paralleled by glucose metabolism in individual muscles.(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.     

Comparison of uptake, oxidation and lipid distribution of 17-iodoheptadecanoic acid, 15-(p-iodophenyl)pentadecanoic acid and 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid in normal canine myocardium

The kinetics of 17-[123I]iodoheptadecanoic acid (IHDA), 15-(p-[125I]iodophenyl)pentadecanoic acid (pIPPA) and 15-(p-[131I]iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPPA) were investigated in normal canine myocardium. After simultaneous intravenous injection, myocardial biopsy specimens and samples of arterial blood were taken over 80 min. IHDA showed the highest myocardial uptake (995 +/- 248 dpm/mg.mCi versus pIPPA: 785 +/- 197 dpm/mg.mCi, ns) and the largest size of oxidation (74% +/- 4% versus pIPPA: 65% +/- 5%, p < 0.05). Myocardial activity of IHDA decreased with a half-time value of 11.2 min (pIPPA: 13.2 min). Phospholipids were the main lipid fraction into which IHDA was incorporated, whereas pIPPA was predominantly incorporated into triacylglycerols. DMIPPA myocardial activity remained constant during the assay period and instead of being oxidized, DMIPPA was mainly incorporated into triacylglycerols (55% +/- 12%). The myocardium-to-blood ratios of DMIPPA were greater than 10:1. The ratios at peak for IHDA and pIPPA were 4.1:1 and 3.9:1, respectively (both p < 0.0001 versus DMIPPA). In conclusion, differences have been found in the myocardial uptake, oxidation and lipid distribution of IHDA, pIPPA and DMIPPA. DMIPPA is a promising tracer for fatty acid uptake studies with single-photon emission computerized tomography because of its prolonged retention and high myocardium-to-blood ratios.     

Impaired regional fatty acid uptake and systolic dysfunction in hypertrophied right ventricle

Little information is available regarding the determinants of systolic contractile function of the hypertrophied right ventricle (RV). The purpose of this study was to clarify the relationship between myocardial metabolism and contractile function in the hypertrophied RV due to pulmonary hypertension (PH). METHODS: Iodine-123-labeled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) and 99mTc-sestamibi (MIBI) SPECT were performed to calculate the RV-to-left ventricle (LV) tracer uptake ratio (RV/LV) in 21 patients with PH (6 with primary PH and 15 with chronic thromboembolic PH). The patients also underwent electron-beam CT to assess RV ejection function (RVEF) and percentage systolic wall thickening (%SWT) and right heart catheterization to measure mean pulmonary arterial pressure (mPAP). RESULTS: There were significant positive correlations between mPAP and MIBI-RV/LV (r = 0.89, p < 0.001) and between mPAP and BMIPP-RV/LV (r = 0.86, p < 0.001). However, 8 patients showed lower BMIPP-RV/LV than MIBI-RV/LV, indicating the impairment of myocardial fatty acid uptake in the RV. These patients had lower RVEF and %SWT compared to those with normal myocardial fatty acid uptake (RVEF = 28% +/- 10% compared to 40% +/- 9% and %SWT = 33% +/- 27% compared to 74% +/- 30%, respectively; p < 0.05 for both comparisons). Although mPAP did not differ between the groups, the RVEF-mPAP and %SWT-mPAP regression lines drawn from the patients with impaired myocardial fatty acid uptake were located below the lines from the patients with normal myocardial fatty acid uptake, suggesting disproportionately decreased RV myocardial contractility for a given mPAP in patients with impaired myocardial fatty acid uptake. The patients with the impaired fatty acid uptake in the RV had a significantly higher death rate (log-rank test, p < 0.05). CONCLUSION: The results from this preliminary study suggest that myocardial fatty acid uptake is impaired in the failing hypertrophied RV due to PH.     

Assessment of 123I-beta-methyl iodophenyl pentadecanoic acid (BMIPP) myocardial scintigraphy in patients of chronic right ventricular overload--fatty acid metabolism in right ventricular myocardium

An investigation on the right ventricular pressure level and the abnormalities in the fatty acid metabolism of myocardium was made using 123I-beta-methyl-iodophenyl pentadecanoic acid (BMIPP) myocardial SPECT in patients with chronic right ventricular overloading. Twenty patients who presented with right ventricular systolic pressure (RVSP) of 35 mmHg or more were used as the subjects. Dual myocardial SPECT with 201TlCl (Tl) and BMIPP was carried out for the subjects and RVc/LVc, a ratio of radioactivity count incorporated in the right ventricular free wall to the left one was determined for Tl and BMIPP. And the correlations between RVc/LVc and RVSP, and RVc/LVc and RVSP/LVSP were examined. The subjects were classified into 3 groups based on the RVSP levels and the count ratio, BMIPP/Tl was compared among the three groups. With respect of Tl uptake, there were significant, positive correlations between RVc/LVc and RVSP (correlation coefficient r = 0.51, p < 0.05) and between RVc/LVc and RVSP/LVSP (correlation coefficient r = 0.59, p < 0.01). On the other hand, no significant correlation was found between them with respect of the uptake of BMIPP. The BMIPP/Tl ratio in the group with higher than 80 mmHg of RVSP was 0.82 +/- 0.06, which was significantly lower than the ratio's for two groups of less than 80 mmHg; 0.91 +/- 0.07 and 0.98 +/- 0.04 in the group with 35-49 and 50-79 mmHg of RVSP, respectively. These results show that when compared with BMIPP, Tl is superior for the estimation of right ventricular pressure. For the patients with right ventricular overloading, it was suggested that when RVSP reaches 80 mmHg or more, there appear some disorders in the fatty acid metabolism in the right ventricular myocardium.     

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.     

Exogenous insulin reduces proteolysis and protein synthesis in extremely low birth weight infants

OBJECTIVE: To determine the effect of a continuous insulin infusion on protein and glucose metabolism in extremely low birth weight (ELBW) infants. STUDY DESIGN: We measured the rate of appearance (Ra) of the essential amino acids leucine and phenylalanine (reflecting proteolysis), utilization of phenylalanine for protein synthesis, and glucose Ra using stable isotope tracers during a basal infusion of glucose (6 mg/kg/min) and in response to a continuous infusion of insulin (0.05 U/kg/hr) by means of the euglycemic hyperinsulinemic clamp technique. Four clinically stable, euglycemic ELBW infants (26 +/- 0 weeks' gestation, 894 +/- 44 gm birth weight, 2.8 +/- 0.8 days of age) were studied. RESULTS: In response to a greater than tenfold increase in insulin concentration (from 7 +/- 2 to 79 +/- 13 microU/ml), there was a 20% decrease in leucine Ra (Basal: 272 +/- 27 mumol/kg/hr; Insulin: 226 +/- 29 mumol/kg/hr; p < 0.01) and in phenylalanine Ra (Basal: 91 +/- 5 mumol/kg/hr; Insulin: 72 +/- 2 mumol/kg/hr; p < 0.05). Use of phenylalanine for protein synthesis also decreased by a similar magnitude (Basal: 77 +/- 4 mumol/kg/hr; Insulin: 62 +/- 1 mumol/kg/hr; p < 0.05). Glucose utilization doubled (from 8 +/- 0.9 to 15.7 +/- 1.1 mg/kg/min; p = 0.0003) and plasma lactate concentrations tripled (from 2.1 +/- 0.5 to 5.7 +/- 1.0 mmol/L; p < 0.05) during the insulin infusion. CONCLUSIONS: During an infusion of glucose alone, pharmacologic concentrations of insulin in ELBW infants produced no net protein anabolic effect. Furthermore, euglycemic hyperinsulinemia was accompanied by development of significant metabolic acidosis.     

Medical options for early pregnancy termination

OBJECTIVES: We sought to assess the relation between glucose metabolism, myocardial perfusion and cardiac work after orthotopic heart transplantation. BACKGROUND: The metabolic profile of the transplanted cardiac muscle is affected by the lack of sympathetic innervation, impaired inotropic function, chronic vasculopathy, allograft rejection and immunosuppressive therapy. In relation to myocardial perfusion and cardiac work, glucose metabolism has not previously been studied in heart transplant recipients. METHODS: Regional myocardial blood flow (ml.min-1.g-1) and 18F-2-fluoro-2-deoxyglucose (18FDG) uptake rate (ml.s-1.g-1) were measured after an overnight fast in 9 healthy male volunteers (mean age +/- SD 32 +/- 7 years) and in 10 male patients (mean age 50 +/- 10 years) who had a nonrejecting heart transplant, normal left ventricular function and no angiographic evidence of epicardial coronary sclerosis. Measurements were made by using dynamic positron emission tomography (PET) with 15O-labeled water and 18FDG, respectively. Heart rate and blood pressure were also measured for calculation of rate-pressure product. RESULTS: 18FDG uptake was similar in all heart regions in the patients and volunteers (intrasubject regional variably 12 +/- 8% and 16 +/- 12%, respectively, p = 0.51). Regional myocardial blood flow was similarly evenly distributed (intrasubject regional variability 14 +/- 10% and 12 +/- 8%, respectively, p = 0.67). Mean 18FDG uptake and myocardial blood flow values for the whole heart are given because no regional differences were identified. 18FDG uptake was on average 196% higher in the patients than in the volunteers (2.90 +/- 1.79 x 10(-4) vs. 0.98 +/- 0.38 x 10(-4) ml.s-1.g-1, p = 0.006). Regional myocardial blood flow and rate-pressure product were similarly increased in the patient group, but by only 41% (1.14 +/- 0.3 vs. 0.81 +/- 0.13 ml.min-1.g-1, p = 0.008) and 53% (11,740 +/- 2,830 vs. 7,689 +/- 1,488, p = 0.001), respectively. CONCLUSIONS: 18FDG uptake is homogeneously increased in normally functioning nonrejecting heart transplants. This finding suggests that glucose may be a preferred substrate in the transplanted heart. The magnitude of this observed increase is significantly greater than that observed for myocardial blood flow or cardiac work. In the patient group, the latter two variables were increased to a similar degree over values in control hearts, indicating a coupling between cardiac work load and myocardial blood flow. The disproportionate rise in 18FDG uptake may be accounted for by inefficient metabolic utilization of glucose by the transplanted myocardium or by the influence of circulating catecholamines, which may stimulate glucose uptake independently of changes in cardiac work load.     

Mechanism of impaired left ventricular wall motion in the diabetic heart without coronary artery disease

OBJECTIVE: To elucidate whether impairment of the myocardial free fatty acid (FFA) metabolism and small vessel abnormalities in the myocardium are etiologic or contributory factors of myocardial dysfunction in patients with NIDDM without any significant coronary artery disease. RESEARCH DESIGN AND METHODS: We performed myocardial imaging with 123I-labeled beta-methyl-p-iodophenyl pentadecanoic acid (BMIPP), a branched analog of FFA, and dipyridamole-infusion 201thallium scintigraphy (Dip) in nine patients who demonstrated left ventricular wall motion abnormalities without any significant coronary artery disease and in fifteen control cases. As an index of myocardial FFA metabolism, the heart-to-mediastinum count ratio (H/M) of BMIPP was calculated from the mean count in the regions of interest at the heart and the upper mediastinum. RESULTS: Nine patients with reduced wall motion documented by left ventriculography (LVG), (hypokinetic group) demonstrated significantly lower BMIPP uptake (2.1 +/- 0.2, mean +/- SD) than fifteen patients with normal wall motion (normokinetic group) (2.3 +/- 0.2, P < 0.05). Regional ventricular wall motion observed by LVG, regional BMIPP uptake, and regional redistribution phenomenon (RD) were evaluated for five regions of the left ventricle: anterior, septal, apical, lateral, and inferoposterior regions. Wall motion was abnormal in 24 out of 120 regions. Regional BMIPP uptake was reduced in 47 regions. RD in Dip was observed in 23 regions. In regional analysis, the existence of defect in the BMIPP image showed significant correlation with wall motion abnormality (P < 0.01), but there was no significant relationship between the RD in Dip and regional wall motion abnormality (P = 0.16). Myocardial biopsy specimens obtained from the right ventricle of 20 patients showed no pathologic changes, with the exception of two patients. CONCLUSIONS: Our findings suggest that impairment of myocardial FFA metabolism rather than small vessel abnormalities in the myocardium is responsible for modest left ventricular dysfunction in patients with diabetes.     

Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity

We tested the hypothesis that endothelium-dependent vasodilatation is a determinant of insulin resistance of skeletal muscle glucose uptake in human obesity. Eight obese (age 26+/-1 yr, body mass index 37+/-1 kg/m2) and seven nonobese males (25+/-2 yr, 23+/-1 kg/m2) received an infusion of bradykinin into the femoral artery of one leg under intravenously maintained normoglycemic hyperinsulinemic conditions. Blood flow was measured simultaneously in the bradykinin and insulin- and the insulin-infused leg before and during hyperinsulinemia using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET). Glucose uptake was quantitated immediately thereafter in both legs using [18F]- fluoro-deoxy-glucose ([18F]FDG) and PET. Whole body insulin-stimulated glucose uptake was lower in the obese (507+/-47 mumol/m2 . min) than the nonobese (1205+/-97 micromol/m2 . min, P < 0.001) subjects. Muscle glucose uptake in the insulin-infused leg was 66% lower in the obese (19+/-4 micromol/kg muscle . min) than in the nonobese (56+/-9 micromol/kg muscle . min, P < 0.005) subjects. Bradykinin increased blood flow during hyperinsulinemia in the obese subjects by 75% from 16+/-1 to 28+/-4 ml/kg muscle . min (P < 0.05), and in the normal subjects by 65% from 23+/-3 to 38+/-9 ml/kg muscle . min (P < 0.05). However, this flow increase required twice as much bradykinin in the obese (51+/-3 microg over 100 min) than in the normal (25+/-1 mug, P < 0.001) subjects. In the obese subjects, blood flow in the bradykinin and insulin-infused leg (28+/-4 ml/kg muscle . min) was comparable to that in the insulin-infused leg in the normal subjects during hyperinsulinemia (24+/-5 ml/kg muscle . min). Despite this, insulin-stimulated glucose uptake remained unchanged in the bradykinin and insulin-infused leg (18+/-4 mumol/kg . min) compared with the insulin-infused leg (19+/-4 micromol/kg muscle . min) in the obese subjects. Insulin-stimulated glucose uptake also was unaffected by bradykinin in the normal subjects (58+/-10 vs. 56+/-9 micromol/kg . min, bradykinin and insulin versus insulin leg). These data demonstrate that obesity is characterized by two distinct defects in skeletal muscle: insulin resistance of cellular glucose extraction and impaired endothelium-dependent vasodilatation. Since a 75% increase in blood flow does not alter glucose uptake, insulin resistance in obesity cannot be overcome by normalizing muscle blood flow.     

Insulin and amino acid infusion after cardiac operations: effects on systemic and renal perfusion

OBJECTIVE: The purpose of this study was to answer two questions: (1) Does a mixed amino acid infusion enhance systemic and renal perfusion in the early postoperative period after heart operations? (2) Does the addition of insulin (glucose-insulin-potassium solution) provide additional effects to those of an amino acid infusion? METHODS: Thirty-three male patients undergoing coronary artery bypass grafting (mean age 65.9 +/- 1.2 years) were included in a prospective, controlled, randomized study. Eleven patients (AA group) received infusion of mixed amino acids (11.4 gm), 11 patients (AA + GIK group) received infusion of mixed amino acids (11.4 gm) and insulin solution (225 IU insulin, glucose with glucose clamp technique, and potassium), and 11 patients served as control subjects. RESULTS: Amino acid infusion alone had no effect on systemic vascular resistance or cardiac index but increased renal blood flow 51% +/- 11% (from 114 +/- 13 to 172 +/- 24 ml.min-1.m-2 in one kidney, p < 0.05 vs the control group). Insulin solution in addition to amino acid infusion reduced systemic vascular resistance 24% +/- 3% (from 1280 +/- 85 to 960 +/- 57 dyn.sec.cm-5, p < 0.05 vs the control and AA groups) and increased cardiac index 13% +/- 3% (from 2.3 +/- 0.2 to 2.6 +/- 0.2 L.min-1.m-2, p < 0.05 vs the control and AA groups). Insulin had no significant additive effect on renal blood flow. CONCLUSIONS: Our data imply that (1) infusion of mixed amino acids enhances renal blood flow after cardiac operations but has no effect on systemic perfusion and (2) the addition of insulin solution improves systemic perfusion. The combined treatment may potentially reduce the risk of renal hypoperfusion injury in the postoperative period after coronary artery bypass grafting.     

Neonatal de-afferentation of capsaicin-sensitive sensory nerves increases in vivo insulin sensitivity in conscious adult rats

Sensory neuropeptides, released from the peripheral nervous system, might modulate glucose homeostasis by antagonizing insulin action. The effects of de-afferentation of functional small diameter unmyelinated C-fibres (sensory nerves) on in vivo insulin-mediated intracellular glucose metabolism were investigated by using euglycaemic insulin (6 and 18 mU/kg x min) clamps with [3-(3)H]-glucose infusion in 24 adult rats, treated neonatally with either capsaicin (CAP) (50 mg/kg) or vehicle (CON). Following the clamp, skeletal muscle groups, liver and adipose tissue were freeze-clamped. At plasma insulin levels of approximately 90 mU/l, CAP-rats showed a 21% increase in whole body glucose uptake compared with CON (24.4 +/- 1.6 vs 20.1 +/- 0.8 mg/kg min, p < 0.02), which was paralleled by a 20% increase in whole body glycolysis (12.6 +/- 0.8 vs 10.5 +/- 0.5 mg/ kg.min p < 0.05) (concentration of 3H2O in plasma). Whole body skeletal muscle glycogenesis was increased by 80% in CAP-rats (5.7 +/- 0.7 vs 3.1 +/- 0.7 mg/kg x min, p < 0.05) with increased muscle glycogen synthase activity. Whole body (muscle, liver and adipose tissue combined) de novo lipogenesis also was increased in CAP-rats compared with CON (0.69 +/- 0.10 vs 0.44 +/- 0.06 mg/kg x min, p < 0.05) (incorporation of [3-(3)H]-glucose counts into glycogen or fat). Hepatic glucose production was lower in CAP-rats compared with CON (0.6 +/- 0.6 vs 2.1 +/- 0.7 mg/kg x min, p < 0.05). Plasma glucagon, corticosterone, epinephrine and norepinephrine levels were reduced in CAP-rats: 43 +/- 2 compared with 70 +/- 6 pg/ml, 855 +/- 55 compared with 1131 +/- 138 nmol/l, 513 +/- 136 compared with 1048 +/- 164 pmol/l and 928 +/- 142 compared with 1472 +/- 331 pmol/l, respectively, p < 0.05. At plasma insulin levels of approximately 400 mU/l, CAP-rats showed no differences in peripheral and hepatic insulin action compared with CON. We conclude that the removal of endogenous sensory neuropeptides, by de-afferentation of capsaicin-sensitive sensory nerves, increases in vivo insulin sensitivity, but not responsiveness: 1) primarily through an increased sensitivity of skeletal muscle glycogen synthesis to insulin; 2) through a reduction in the levels of counter-regulatory hormones, thereby creating a milieu which favours overall in vivo insulin sensitivity with respect to glucose uptake, glucose production, glycolysis, glycogenesis and lipogenesis.     

In vitro study of the effect of miglitol on carbohydrate digestion and intestinal metabolism in normal and non-insulin-dependent diabetic rats

The effect of miglitol was studied (20 mg/kg body weight), administered intraduodenally alone or together with maltose, on the absorption and intestinal metabolism of glucose during its translocation from the lumen of the intestine to the blood, using in vitro perfused preparations of complete small intestine-pancreas, proximal small intestine alone, or distal small intestine alone, isolated from normal and non-insulin-dependent diabetic rats. In the absence of a luminal administration of maltose in normal rats, the glucose uptake from the vascular perfusate was greater in the presence (0.52 +/- 0.04 mmol/h) than in the absence (0.39 +/- 0.02 mmol/h) of miglitol (p < 0.05). In diabetic rats, no significant variations were observed in glucose uptake from the vascular perfusate as an effect of miglitol, but the glucose uptake in the presence of this drug was significantly less (p < 0.05) than that observed in normal rats. Portal lactate was significantly greater (p < 0.05) in diabetic than in normal rats and, after administration of miglitol, rose in both normal and diabetic rats, the rise being significantly greater in normal than in diabetic rats (p < 0.01). When maltose was administered luminally (2 g/kg body weight), the values of portal glucose in both normal and diabetic rats were significantly less in the presence of miglitol in the complete as well as in the distal and proximal small intestine preparations (p < 0.05); the glucose uptake from luminal administered maltose was greater in the presence of miglitol in diabetic (p < 0.05) and in normal (p < 0.05) rats except in the complete small intestine of normal rats; and no significant differences were observed in portal lactate levels between normal and diabetic rats in the presence of miglitol. In conclusion, our results show that miglitol administered luminally at the doses employed here, as well as reducing the transport of glucose from the lumen of the intestine into the blood supply, significantly stimulate intestinal glucose metabolism.     

Effects of antipyrine on umbilical and regional metabolism in late gestation in the fetal lamb

OBJECTIVE: Antipyrine has been used extensively in fetal metabolic studies and is now known to inhibit prostaglandin synthesis; therefore we wished to determine the effects of antipyrine on fetal umbilical and regional metabolism. STUDY DESIGN: Chronically catheterized fetal lambs were randomly assigned to antipyrine (n = 6) or control (n = 5) groups. Animals in the antipyrine group were infused with antipyrine (mean +/- SD 9.6 +/- 0.9 mg/min for 165 +/- 38 minutes), and control group animals were not infused. Measurements were made of fetal blood gases, oxygen content, glucose, lactate, lower-body blood flow, upper-body flow distribution, and substrate uptakes across the umbilical and hind limb circulations. The unpaired t test, correlation coefficient, and regression analysis were used for comparisons. RESULTS: There were no differences in antipyrine and control group animals with respect to blood gases, metabolite levels, umbilical blood flow, or umbilical uptakes. Hind limb blood flow (p < 0.10) and oxygen uptake (p < 0.05) were lower and lactate production was higher (p < 0.01) in antipyrine animals than in control group animals. Duration of antipyrine exposure correlated directly with hind limb lactate production (r = 0.85, p < 0.001) and inversely with hind limb oxygen uptake (r = -0.65, p < 0.05). The distribution of blood flow within the fetal upper body also differed between groups, with higher cardiac distribution in the antipyrine group (p < 0.025). CONCLUSIONS: Antipyrine does not affect umbilical metabolism but does affect carcass metabolism and fetal blood flow distribution.     

Evaluation of myocardial uptake of beta-methyl-(123I)-iodophenylpentadecanoic acid (123I-BMIPP)

To evaluate the myocardial uptake of beta-methyl-(123I)-iodophenylpentadecanoic acid (123I-BMIPP), nineteen patients with ischemic heart disease including left ventricular hypertrophy (mean age 63 +/- 7.8, 14 males and 5 females) underwent BMIPP myocardial scintigraphy. Myocardial uptake (MU) of BMIPP to the total injected dose was calculated from anterior view of the planar image in all subjects, and was compared with plasma glucose (BS), triglyceride (TG), and free fatty acid (FFA). It was also compared with left ventricular mass (LVM) calculated with echocardiography. MU was not related to BS, TG, and FFA, however had the positive correlation with LVM (r = 0.676, p < 0.01). Myocardial uptake per left ventricular mass (MU/LVM) had the negative correlation with LVM (r = -0.671, p < 0.01). Further studies for the significance of MU/LVM will be required.     

Protein-nucleic acid interactions and DNA conformation in a complex of human immunodeficiency virus type 1 reverse transcriptase with a double-stranded DNA template-primer

Myocardial glucose metabolism has been shown to be heterogeneous in patients with hypertrophic cardiomyopathy (HCM). We tested the hypothesis that myocardial glucose metabolism differs between patients with HCM and those with hypertensive heart disease (HHD) associated with asymmetrical septal hypertrophy. We studied 12 patients with HCM, 7 HHD patients associated with asymmetrical septal hypertrophy using 18F 2-deoxyglucose (FDG) and positron emission tomography. We calculated % FDG fractional uptake in the inter-ventricular septum and posterolateral wall. Heterogeneity of FDG uptake was evaluated by % interregional coefficient of variation of FDG fractional uptake in each wall segment. In both the interventricular septum and posterolateral wall, % FDG fractional uptake was not significantly different between the two groups. The % interregional coefficient of variation for both interventricular septum (10.6 +/- 1.6 vs. 4.1 +/- 0.5, p < 0.01) and posterolateral wall (5.9 +/- 0.7 vs. 3.8 +/- 0.5, p < 0.05) was significantly larger in patients with HCM than in HHD patients associated with asymmetrical septal hypertrophy. Echocardiography demonstrated that the degree of asymmetrical septal hypertrophy was similar between the two groups. These results suggest that myocardial glucose metabolism may be more heterogeneous in patients with HCM compared to HHD patients associated with asymmetrical septal hypertrophy, although the left ventricular shape is similar. The difference in the heterogeneity might have resulted from differences in the pathogeneses of the two diseases.     

Effects of methyltestosterone on insulin secretion and sensitivity in women

The frequent coexistence of hyperandrogenism and insulin resistance is well established; however, whether a cause and effect relationship exists remains to be established. In this study we tested the hypothesis that short-term androgen administered to women would induce insulin resistance. To test this hypothesis, regularly menstruating, nonobese women were studied before and during methyltestosterone administration (5 mg tid for 10-12 days) by the hyperglycemic (n=8) and euglycemic, hyperinsulinemic (n=7) clamp techniques. Short-term methyltestosterone administration had no significant effects on the fasting levels of glucose, insulin, c-peptide, glucagon, or glucose turnover. During the hyperglycemic clamp studies, the mean glucose level during the final hour was 203+/-2 and 201+/-1 mg/dL in the methyltestosterone and control studies, respectively. The insulin response to this hyperglycemic challenge was slightly but not significantly greater during methyltestosterone treatment (first phase 59+/-8 vs. 50+/-8 microU/mL in controls; second phase 74+/-9 vs. 67+/-9 microU/mL in controls; total insulin response 133+/-16 vs. 117+/-15 microU/mL in controls). In spite of this, glucose uptake was reduced from the control study value of 10.96+/-1.11 to 7.3+/-0.70 mg/kg/min by methyltestosterone (P < 0.05). The ratio of glucose uptake per unit of insulin was also significantly reduced from a control study value of 14.3+/-1.4 to 9.4+/-1.3 mg/kg/min per microU/mL x 100 during methyltestosterone administration. In the euglycemic hyperinsulinemic clamp studies, insulin was infused at rates of 0.25 and 1.0 mU/kg/min to achieve insulin levels of approximately 25 and 68 microU/mL, respectively. During low-dose insulin infusion, rates of endogenous hepatic glucose production were equivalently suppressed from basal values of 2.37+/-0.29 and 2.40+/-0.27 mg/kg/min to 0.88+/-0.25 and 0.77+/-0.26 mg/kg/min in the methyltestesterone and control studies respectively. Whole body glucose uptake during low-dose insulin infusion was minimally affected. During the high-dose insulin infusion, endogenous hepatic glucose production was nearly totally suppressed in both groups. However, whole body glucose uptake was reduced from the control value of 6.11+/-0.49 mg/kg/min to 4.93+/-0.44 mg/kg/min during methyltestosterone administration (P < 0.05). Our data demonstrate that androgen excess leads to the development of insulin resistance during both hyperglycemic and euglycemic hyperinsulinemia. These findings provide direct evidence for a relationship between hyperandrogenemia and insulin resistance, and its associated risk factors for cardiovascular disease.