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R P Eaton

Publications and source records attributed to R P Eaton.

At least 19 recordsLinked to original sources
PubMed1992

Noninvasive glucose monitoring in diabetic patients: a preliminary evaluation.

Noninvasive monitoring of blood/tissue glucose concentrations has been successfully accomplished in individual diabetic subjects by using near-infrared (NIR) spectroscopy coupled with chemometric methods. Three different spectrometer configurations were tested: a) a Fourier-transform infrared spectrometer with an indium antimonide detector; b) a grating monochromator equipped with a silicon (Si) array detector, without fiber optics; and c) a grating monochromator equipped with an Si detector, with fiber-optic sampling. NIR spectra were obtained from diabetic subjects by transmission through the finger during a meal-tolerance test. The maximum range of observed plasma glucose concentrations obtained from the blood samples was 2.5-27 mmol/L. The NIR spectra were processed by using the chemometric multivariate calibration methods of partial least squares and principal component regression. The best calibration yielded a cross-validated average absolute error in glucose concentration of 1.1 mmol/L. This predictive ability suggests that noninvasive glucose determinations by NIR/chemometrics is a viable analytical method.

Blood Glucose↗
PubMed1989

Increased urinary prostaglandin excretion in galactose-fed rats.

Increased renal production of prostaglandins (PG) may contribute to the hyperfiltration that accompanies early diabetes. It was postulated that a putative metabolic abnormality of diabetes, ie, increased flux through the polyol pathway, stimulates renal PG production and that this phenomenon can be prevented by aldose-reductase inhibition. To test this hypothesis, the effects of polyol accumulation on urinary excretion rates (UER) of PGE2 and 6-keto-PGF1 alpha were studied, using the galactose-fed rat model. UER of PGE2 and 6-keto-PGF1 alpha were measured in three groups of weanling Wistar male rats. Group 1 was maintained on normal chow (n = 6), group 2 was fed chow supplemented with 30% galactose (n = 6), and group 3 received chow supplemented with 30% galactose and 0.7% sorbinil (n = 6). Ten 24-hour urine samples were obtained from each group between 151 and 240 days on the respective diets. UER of PGE2 (P less than .001) and 6-keto-PGF1 alpha (P less than .01) were higher in group 2 than in group 1. UER of PGE2 (NS) and 6-keto-PGF1 alpha (NS), respectively, were similar in groups 1 and 3. These data indicate that flux through the polyol pathway modulates the UER of PGE2 and 6-keto-PGF1 alpha. This phenomenon may contribute to the glomerular hyperfiltration of early diabetes.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Glucose inhibition of human fibroblast proliferation and response to growth factors is prevented by inhibitors of aldose reductase.

Diabetes mellitus is associated with premature senescence of cultured dermal fibroblasts. The present study investigated the effect of elevated glucose concentrations on cultured human fibroblasts from normal donors. Mean population doubling times, population doublings until senescence, saturation density at confluence (cells/cm2), tritiated thymidine incorporation, and response to platelet-derived growth factor (PDGF) were inhibited with the increasing glucose concentrations (11.0, 22, 44, or 55 mM glucose) (P less than 0.05). Replicative life span was markedly diminished by multiple passages in high glucose medium (5.5 mM glucose: 62.4 +/- 7.9 population doublings; 22 mM glucose: 22.8 +/- 3.4 population doublings: P less than 0.05). Aldose reductase activity was present in the cultured fibroblasts (3.9 +/- 0.5 nmol/min per mg protein), and inhibitors of aldose reductase, including sorbinil (10(-4) M--10(-6) M) and tolrestat (10(-6) M--10(-8) M), completely prevented glucose-mediated inhibition of fibroblast proliferation, restored the response to PDGF, and allowed a normal replicative life span. Myo-inositol (11 microM--5.5 mM) also reversed the adverse effects of glucose. These in vitro data demonstrate that elevated concentrations of glucose inhibit cell growth and promote premature senescence, effects which can be prevented with inhibitors of aldose reductase or supplemental myo-inositol. These aldose reductase-related effects may explain the impaired growth and premature senescence of cultured connective tissue from diabetic patients.

Aldehyde Reductase↗
PubMed1988

Diabetic neuropathy. Structural analysis of nerve hydration by magnetic resonance spectroscopy.

The water content of the sural nerve of diabetic patients was quantitatively defined by magnetic resonance proton imaging as a putative reflection of activity of the aldose-reductase pathway. Thirty-nine patients were evaluated, comparing group A, symptomatic diabetic men with sensory neuropathy; group B, similarly symptomatic diabetic men treated with aldose-reductase inhibition; group C, neurologically asymptomatic diabetic men; and group D, control nondiabetic men. Marked increase in hydration of the sural nerve was seen in more than half of the symptomatic diabetic patients. Two of 11 neurologically asymptomatic diabetics had increased nerve hydration, suggesting a presymptomatic alteration of the nerve. Symptomatic diabetics treated with aldose-reductase inhibitors had normal nerve water levels. Increased level of peripheral nerve water represents a new finding in diabetes mellitus. It seems to be related to aldose-reductase activity, involved in the development of neuropathy, and similar to events that occur in other target tissue in human diabetes.

Adult↗
PubMed1988

Purification of aldose reductase from human placenta and stabilization of the inhibitor binding site.

Aldose reductase from human placenta was purified to homogeneity by a rapid (2 day) and efficient purification scheme involving Red Sepharose affinity chromatography, chromatofocusing and high performance liquid chromatography on a size-exclusion column. Addition of NADP+ at all steps in the purification of aldose reductase and during storage of the enzyme at -20 degrees stabilized both the enzyme active site and the major site for binding of aldose reductase inhibitors such as sorbinil and tolrestat. Aldose reductase is a monomer with a molecular mass of 38 kD by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, apparent pI 5.9. Placenta aldose reductase exhibited no cross-reactivity with aldehyde reductase from human liver in an ELISA assay. Aldose reductase showed broad specificity for aldehydes, was specific for NADPH, and was activated by sulfate.

Alcohol Dehydrogenase↗
PubMed1988

Characterization of the carbamino adducts of insulin.

Carbon-13 (13C) nuclear magnetic resonance spectroscopy (NMR) is performed to characterize the formation of carbamino adducts between insulin and (13C) carbon dioxide over a range of pH values in the presence of a physiological concentration (23 mM) of sodium bicarbonate. The peaks from two of the carbamino adducts resonate at higher frequencies than the signal from bicarbonate, at 164.6 and 165.3 ppm, and are attributed to the adducts with the terminal amino groups of phenylalanine B1 and glycine A1. The intensities of these signals vary with the pH, with unique patterns. Over 6% of each terminal amino group exists as the carbamino adduct at the optimum pH values of 7.8 and 8.3. A unique third adduct resonates at 159.3 ppm, and is attributed to lysine B29. This adduct is present on 2% of the insulin molecules at pH 8.2, but has minimal intensity at pH 7.4. No signals from adducts are detected below pH 6.2, where the amino groups exist predominantly in the protonated form. Creation of the adducts is rapid and they are stable for over 4 wk at 37 degrees C. The narrow bandwidth of the resonance of the adduct (4.0-4.5 Hz) relative to the irreversible cyanate adduct is consistent with molecular forms of the carbamino adduct smaller than the 2-Zn-hexamer which is the preponderate form of clinically utilized U-100 insulin (i.e., 100 U/ml).

Animals↗
PubMed1987

Underestimation of hepatic glucose production by radioactive and stable tracers.

Although negative hepatic glucose production rates are physiologically impossible, they have been observed when hepatic glucose production is measured with the tracer-dilution technique during the hyperinsulinemic, euglycemic glucose clamp. Because hepatic glucose production is determined from the difference between tracer-derived glucose disposal and the known exogenous glucose infusion rate, the negative values for hepatic glucose production must result from an underestimation of glucose disposal by the tracer technique. In the current investigation, tracer-derived glucose disposal was measured in 25 subjects undergoing hyperinsulinemic, euglycemic clamps. Glucose disposal was measured with both radioactive and stable isotopes that utilize different methodologies, to determine whether discriminant metabolism of the isotopes versus methodological error leads to underestimation of tracer-derived glucose disposal. Both the radioactive and stable methodologies underestimated the exogenous glucose infusion rate during the hyperinsulinemic euglycemic clamp by 27 and 17%, respectively. Mean hepatic glucose production was -2.1 +/- 0.2 and -1.3 +/- 0.2 mg X kg-1 X min-1 as determined by the radioactive and stable isotope methodologies, respectively. Methodological error was an unlikely cause of this underestimation because it occurred with two different methodologies. The most likely explanation for underestimated rates of glucose disposal determined by the two types of isotope methodologies is discrepant metabolism of glucose tracers in comparison with unlabeled glucose.

Adult↗
PubMed1987

Galactose neuropathy. Structural changes evaluated by nuclear magnetic resonance spectroscopy.

We examined the hypothesis that the polyol accumulation resulting from chronic galactose supplementation in the diet produces endoneurial edema that can be prevented by inhibition of aldose reductase. We explored the potential of nuclear magnetic resonance (NMR) spectroscopy to quantitate and characterize the water accumulation in the sciatic nerve in this "galactose neuropathy." The data demonstrate a 16% increase in gravimetrically determined total water content of nerve in the galactose-fed rat after 8 mo of this diet and a 50% increase in the T1 relaxation time for nerve water as determined by NMR spectroscopy. Prolongation of the T1 relaxation time reflects increased rotation of water in a magnetic field, consistent with an extracellular site of the additional water. Simultaneous feeding of sorbinil to inhibit aldose reductase resulted in normalization of both total nerve water and of the prolongation of T1 relaxation time. These data define the NMR-spectroscopic state of endoneurial edema in the galactose-fed rat and suggest specific application to the investigation of the role of aldose reductase in human diabetic neuropathy.

Animals↗
PubMed1987

Insulin suppresses its own secretion in vivo.

This study addressed the controversial question of whether a negative-insulin-feedback loop exists in vivo. We utilized prehepatic insulin production, calculated by computerized deconvolution analysis of peripheral C-peptide concentration, as a measure of endogenous insulin secretion. Prehepatic insulin production was determined in 10 normal men who randomly underwent a control study and two additional studies involving different insulin infusion rates that achieved circulating insulin concentrations within the physiologic range during euglycemic clamps. The results demonstrate a dose-dependent suppression of prehepatic insulin production from 5.8 +/- 1.4 mU/min during the control study to 4.0 +/- 1.2 and 3.2 +/- 0.9 mU/min during plasma insulin levels of 34 +/- 4 and 61 +/- 6 microU/ml, respectively (P less than .05). Therefore, in contrast to recently reported results in vitro, insulin inhibits its own secretion in humans.

Adult↗
PubMed1986

Aldose reductase inhibition and the diabetic syndrome of limited joint mobility: implications for altered collagen hydration.

Improvement in the range of motion and strength of digital flexion and extension is reported in three diabetic subjects with the syndrome of limited joint mobility. Therapy was accomplished with sorbinil, an inhibitor of the enzyme aldose reductase, which inhibits the polyol pathway. We propose that reduction in collagen hydration secondary to reduced tissue content of polyols may play a role in the clinical response.

Aldehyde Reductase↗
PubMed1986

Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses.

Integrated insulin secretion rates calculated from peripheral venous C-peptide measurements by two-compartment kinetic analysis were measured in six young normal subjects after increasing oral glucose loads of 25, 50, and 100 g and respective isoglycemic glucose infusions. The differences in B-cell secretory responses between oral and iv glucose challenges were attributed to factors other than glycemia itself (incretin effect). Both insulin and C-peptide concentrations as well as calculated integrated insulin secretion rates increased with increasing oral glucose loads. Due to the similarity in the glucose profiles after all oral loads, almost identical amounts of iv glucose (approximately 20 g) were infused in all "isoglycemic" infusion experiments, with resulting similar hormone profiles and insulin secretion rates. The percent contribution of incretin factors to total immunoreactive insulin responses after 25, 50, and 100 g glucose (85.6%, 74.9%, and 93.0%; response to oral load, 100%) was significantly higher than their contribution to integrated C-peptide responses (27.6-62.9%) or calculated integrated insulin secretion rates (19.2-61.0%). These findings indicate that the degree of incretin stimulation of insulin secretion depends on the amount of glucose ingested. A discrepancy between the estimates of the incretin effect derived from peripheral venous insulin responses, on the one hand, and C-peptide responses or calculated insulin secretion rates, on the other hand, exists. Inasmuch as peripheral insulin values reflect both insulin secretion and hepatic insulin removal, this discrepancy suggests that elimination kinetics of insulin differ between oral and iv glucose administration. This difference can be related to a significantly reduced fractional hepatic insulin extraction after oral (46.9-54.6%) compared to iv (63.4-76.5%) glucose administration when calculated by a three-compartment kinetic model. This reduction in fractional hepatic insulin extraction could be caused by gastrointestinal factors (hormones or nerves) stimulated in the course of glucose ingestion.

Administration, Oral↗
PubMed1985

The effect of an aldose reductase inhibiting agent on limited joint mobility in diabetic patients.

Improvement in range of motion and in strength of digital flexion and extension is reported in three diabetic subjects with the syndrome of limited joint mobility. Therapy was accomplished with sorbinil, an inhibitor of the enzyme aldose reductase, which inhibits the polyol pathway. We propose that reduction in collagen hydration secondary to reduced tissue content of polyols may participate in the clinical response.

Adult↗
PubMed1985

Factitious brittle diabetes mellitus.

Five patients are described in whom factitious disease was the cause of brittle type I diabetes mellitus. The patients were referred from throughout the United States because their physicians had been unable to establish the reason for recurrent hospitalizations for diabetic ketoacidosis or coma. In three of the patients, unexplainable signs, symptoms, and/or laboratory results lead to the diagnosis of factitious disease. In the two remaining patients, long-term follow-up was necessary before a factitious cause was established. These five patients exemplify the extraordinary measures that some patients will utilize to continue as a "patient" rather than return to a normal lifestyle.

Adult↗
PubMed1984

Insulin removal in man: in vivo evidence for a receptor-mediated process.

To evaluate the in vivo participation of insulin receptors in both hepatic and extrahepatic removal of insulin, compartmental kinetic analysis of insulin behavior was performed in a patient with blocked receptors due to endogenous antiinsulin receptor antibodies. Using the standard three-compartment simulation of insulin behavior, the responses to both a 5-U injection of exogenous insulin and a 4.2-U secretion of endogenous insulin subsequent to tolbutamide injection were examined. In response to both exogenous and endogenous insulin, hepatic removal of insulin was reduced to less than 18% of the insulin exposure (normal, 40-60%). The metabolic clearance of insulin was reduced from the normal level of 520 ml/min to less than 120 ml/min, consistent with a reduction in receptor-mediated removal of insulin from the blood. These studies propose quantitative parameters for insulin receptor function in hepatic and extrahepatic removal of insulin in man.

Adult↗