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Biomedical subjects

V M Monnier

Publications and source records attributed to V M Monnier.

At least 91 records · Page 5Linked to original sources
PubMed1987

Detection of D-glucose-derived pyrrole compounds during Maillard reaction under physiological conditions.

5-Hydroxyl-1-neopentylpyrrole-2-carbaldehyde, 2-(2-hydroxyacetyl)-1-neopentylpyrrole, in decreasing order or abundance, have been isolated and the structures characterized. These compounds were obtained from the reaction of a mixture of D-glucose and neopentylamine under physiological conditions of pH and temperature. In addition, 4H-dihydropyran-4-one, a known intermediate product of the Maillard reaction, was detected. The neopentylamine adducts were already detectable after one week of incubation, but rapid acid and alkaline degradation explains the lack of detection in body proteins.

Chemical Phenomena↗
PubMed1986

Relation between complications of type I diabetes mellitus and collagen-linked fluorescence.

Nonenzymatically glycosylated proteins gradually form fluorescent cross-linked protein adducts--a process termed "browning." The rate of this reaction increases with the glucose concentration. Assaying for the presence of browning products in long-lived proteins should therefore provide information on long-term metabolic control. We measured collagen-linked fluorescence typical for nonenzymatic browning in skin-biopsy specimens from 41 subjects with longstanding Type I diabetes and from 25 controls. Fluorescence correlated with age and (weakly) with the duration of diabetes. Mean age-adjusted fluorescence values were twice as high in diabetic subjects as in control subjects (P less than 0.0001) and increased with the severity of retinopathy, nephropathy, and arterial and joint stiffness. The correlation was significant for retinopathy (r = 0.42; P less than 0.01), arterial stiffness (r = 0.41; P less than 0.01), joint stiffness (r = 0.34; P less than 0.05), and the sum of all complications (r = 0.47; P less than 0.01). Fluorescence also correlated with systolic (r = 0.42; P less than 0.01) and diastolic (r = 0.36; P less than 0.05) blood pressures. If one can assume that the fluorescence results from a browning product of glucose, our data suggest that there is an overall correlation between the severity of diabetic complications and cumulative glycemia over many years.

Adult↗
PubMed1986

Age-related normalization of the browning rate of collagen in diabetic subjects without retinopathy.

The age-related changes in collagen-linked fluorescence (browning) were investigated in skin from subjects with long-standing type I diabetes. Overall browning rates were 2.4 times higher in diabetics than in controls (P less than 0.02) and slope intercept accurately reflected the mean age of onset of diabetes (11.6 vs. 11.2 yr), suggesting that the browning process has the attributes of a biological clock. Browning rates were not different in controls and diabetics without retinopathy (P greater than 0.05) but were 2.4 (P less than 0.05) and 2.7 (P less than 0.01) times increased in the presence of background and proliferative retinopathy, respectively. Compared with subjects with retinopathy, individual browning rates since onset of diabetes decreased with advancing age in subjects free of retinopathy (P less than 0.001). Extrapolation revealed that they would become identical to that of nondiabetic subjects by the age of 66.4 yr. These results suggest the presence of a mechanism that controls the browning rate of collagen in diabetics who do not develop retinopathy.

Adult↗
PubMed1986

Glycation of skin collagen in type I diabetes mellitus. Correlation with long-term complications.

Nonenzymatic glycosylation (glycation) of collagen was measured by boronate affinity chromatography in skin biopsies from 41 type I diabetics with mean duration of diabetes of 25 yr (range 20-40 yr) and from 25 age-matched controls. Mean level of Amadori products was significantly increased in diabetic [7.85 +/- 1.78 (SD) nmol/mg collagen] versus control subjects [3.34 +/- 1.06 (SD) nmol/mg collagen, P less than .001] but did not correlate with age, diabetes duration, or severity of retinopathy, nephropathy, arterial stiffness, and joint stiffness. Similarly, mean collagen content per biopsies was 42% increased in diabetic versus control subjects (P less than .001) but did not correlate with age, diabetes duration, or severity of complications. A weak but positive correlation between glycohemoglobin level and glycation of skin collagen was observed. These results indicate that Amadori products cannot explain by themselves the pathogenesis of diabetic complications unless individual tissue response to glycation is different in subjects with and without complication. They do not exclude a role for the late stages of the Maillard reaction, nonenzymatic browning, in the formation of some of these complications.

Adult↗
PubMed1984

Accelerated age-related browning of human collagen in diabetes mellitus.

The nonenzymatic glycosylation reaction that is accelerated in diabetes is the first step of the Maillard or nonenzymatic browning reaction that occurs in stored food. The glucose-protein adduct rearranges and dehydrates to form brown and fluorescent pigments, which can act as crosslinks, resulting in decreased protein solubility and altered mechanical properties. Evidence suggesting that this process occurs in vivo has been found in lens crystallins. The observation that nonenzymatic glycosylation and insolubility increases in collagen with age and diabetes led us to investigate the possible browning of human collagen. Insoluble human dura mater collagen was digested with collagenase. Absorbance at 350 nm and fluorescence at 440 nm (excitation at 370 nm) of the solubilized material was measured. A linear increase in the amounts of yellow and fluorescent material was observed with age. Samples obtained at autopsy from three type I diabetics and a young type II diabetic showed increased fluorescence and had absorbance values that corresponded to the amount of chromophore found in nondiabetics twice their age (P less than 0.025). The collagen adducts from aged and diabetic individuals had absorption and fluorescence spectra identical to those of collagen samples that underwent nonenzymatic browning with glucose in vitro. The structure of these collagen adducts is unknown. However, their likely occurrence throughout the body could explain the correlation between arterial stiffening, decreased joint mobility, and the severity of microvascular complications in type I diabetics.

Adult↗
PubMed1984

Collagen aging in vitro by nonenzymatic glycosylation and browning.

Aging and diabetes mellitus are associated with cross-linking and nonenzymatic glycosylation of collagen. Incubation of tendon fibers with reducing sugars results in increased breaking time in urea similar to that seen in aging, and in nonenzymatic glycosylation and browning. Effect of a sugar is proportional to the amount of sugar available in the open chain form. The increase in breaking time correlates with the appearance of chromophores characteristic of crosslinked browning products. Collagen altered by nonenzymatic browning may play a role in some age-like major complications of diabetes.

Aging↗
PubMed1983

Detection of nonenzymatic browning products in the human lens.

The nonenzymatic browning or Maillard reaction is an aging process in stored foods. The initial stage of this reaction, nonenzymatic glycosylation, has been shown to occur in the human lens. The possible occurrence of further steps of the Maillard reaction involving lysine residues and glucose has been investigated. A lipid-free protein extract from a pool of human cataractous lenses was reduced, alkylated, and digested with pronase. The digest was reduced with [3H]borohydride, acid hydrolyzed and fractionated by Sephadex G-15 chromatography. The fractions eluting ahead of epsilon-1-deoxyglucitolyllysine were pooled and separated with an amino acid analyzer. Four fluorescent, yellow, and radioactive peaks were obtained. One of these, which co-eluted with tyrosine, was isolated, acetylated, and further analyzed by reverse phase chromatography using HPLC. Two new peaks were separated which co-chromatographed with lysine derivatives isolated from the nonenzymatic browning reaction of alpha-tert-butyloxycarbonyllysine with glucose. Control experiments showed that they were not artifacts due to acid hydrolysis of epsilon-glucitolyllysine. These results suggest that dehydration and rearrangement of the Amadori product, epsilon-fructosyllysine, has occurred in vivo, thus leading to the formation of at least two nonenzymatic browning products.

Borohydrides↗
PubMed1981

Nonenzymatic browning in vivo: possible process for aging of long-lived proteins.

The incubation of lens proteins with reducing sugars leads to the formation of fluorescent yellow pigments and cross-like similar to those reported in aging and cataractous human lenses. Called nonenzymatic browning or the Maillard reaction, this aging process also occurs in stored foods. Reducing sugars condense with the free amino group of proteins, then rearrange and dehydrate to form unsaturated pigments and cross-linked products. Although most proteins in living systems turn over with sufficient rapidity to avoid nonenzymatic browning, some, such as lens crystallins and skin collagen, are exceptionally long-lived and may be vulnerable.

Aging↗
PubMed1979

Nonenzymatic glycosylation, sulfhydryl oxidation, and aggregation of lens proteins in experimental sugar cataracts.

The formation of sugar-cataracts has been hypothesized to involve the nonenzymatic glycosylation, sulfhydryl oxidation, and aggregation of lens proteins. Cataractous lenses of diabetic and galactosemic rats were analyzed for glycosylated lysine residues in crystallins. A five- and a ten-fold increase in glycosylated lysine residues was measured in galactose and diabetic cataracts, respectively. The modification was predominant in the insoluble fraction of the lens homogenate. The proteins were further examined for the presence of disulfide bonds and high molecular weight aggregates. After careful disruption of the lens in a nitrogen environment, a cloudy solution was obtained from cataractous lenses whereas a clear solution was obtained from normal lenses. The absorbance at 550 nm of the solution of both the galactosemic and the diabetic cataracts could be decreased by approximately 50% with the addition of dithioerythritol (50 mM). The presence of high molecular weight aggregates was ascertained by sucrose gradient centrifugation and gel filtration chromatography. The proteins were heterogenous in size and showed a mol wt range of 36 to greater than 176 million daltons. Treatment with dithioerythritol induced a marked decrease in the amount of high molecular weight proteins. These data suggest that sugar cataracts of experimental animals have, in common with human cataracts, the presence of high molecular weight aggregates which are in part linked by disulfide bonds.

Alloxan↗
PubMed1979

Role of nonenzymatic glycosylation in the development of the sequelae of diabetes mellitus.

The increased level of the glycosylated hemoglobin (hemoglobin A1c) in the diabetic patient has proved to be an interesting clue to understanding the biochemical basis of the sequelae of diabetes. This minor hemoglobin, which arises as nonenzymatic postsynthetic addition of glucose to hemoglobin A, acts as an indicator molecule for the glucose environment over a 3-5-wk period prior to measurement. Reasoning that a similar glycosylation reaction could be occurring with other body proteins, we have studied the ocular lens. The lens, like the erythrocyte, is not dependent on insulin for glucose concentration in the extracellular milieu that would be elevated in the diabetic state. These studies have revealed that a high glucose in vivo or an increased glucose or glucose-6-phosphate concentration in vitro leads to the glycosylation of epsilon-amino groups of lysine residues in bovine and rat lens crystallins. This glycosylation imparts an increased susceptibility of the crystallins to sulfhydryl oxidation. Disulfide crosslinks result in the formation of high molecular weight aggregates and an opalescence of the crystallin solutions.

Animals↗
PubMed1978

Diabetic cataract formation: potential role of glycosylation of lens crystallins.

A high glucose concentration in vivo or an increased glucose of glucose 6-phosphate concentration in vitro has been found to lead to the glycosylation of epsilon-amino groups of lysine residues in bovine and rat lens crystallins. In vitro, this glycosylation imparts an increased susceptibility of the crystallins to sulfhydryl oxidation. Disulfide crosslinks result in the formation of high molecular weight aggregates and an opalescence in the crystallin solutions. The addition of reducing agents prevents as well as reverses the formation of high molecular weight aggregates and the opalescence of the crystallins. These phenomena suggest a new interpretation of previous results on cataract formation and a new approach for development of drugs to prevent cataracts.

Animals↗
PubMed1978

Immunological studies in thymectomized and non-thymectomized patients with myasthenia gravis.

Eleven thymectomized and ten non-thymectomized patients with myasthenia gravis, matched with respect to sex, age, duration and severity of the disease were investigated with respect to routine clinical features, electrophysiological examination, HLA-typing, auto-antibodies, lymphocyte subpopulations in peripheral blood, Concanavalin A-induced release of leucocyte migration inhibitory factor (LIF), in vitro lymphocyte activation by mitogens and antigens and response to primary immunization with dinitrochlorobenzene measured in vivo and in vitro. The following conclusions could be drawn. The immune response to external antigens seems to be normal in myasthenia gravis and thymectomy is not followed by general defects in immune competence; at least as investigated by current techniques. The only reduction of responsiveness demonstrable in the thymectomized group was a decreased release of LIF by Concanavalin A-stimulated lymphocytes. Primary immune responses appear to be increased after adult thymectomy, which may be due to a decrease in suppressor T-lymphocyte activity. A hypothesis is formulated that Concanavalin A-induced release of LIF may reflect the competence of suppressor T-lymphocytes in man.

Adolescent↗
PubMed1977

A radioimmunoassay for the quantitative evaluation of anti-human acetylcholine receptor antibodies in myasthenia gravis.

A radioimmunoassay was developed for the quantitative evaluation of antibodies to the acetylcholine receptor in the serum of myasthenic patients. AcChR was extracted from human muscle. A detailed preparation of the 125I-labelled alpha-Bgt-AcChR complex used as antigen is reported. Usually, an average of 20 pmol were obtained form 100 g muscle. This preparation is stable for 1 month in presence of an inhibitor of proteolysis and sufficient for performing about fifteen assays. The labelled complex was incubated with increasing amounts of sera and precipitated with anti-human IgG serum. Titres were expressed in pmol 125I-labelled alpha-Bgt-AcChR complex precipitated per ml serum. Out of thirty-nine sera tested thirty-six had positive titres ranging from 0-1-46 pmol/ml. No anti-AcChR were detected in the sera from twenty-seven patients used as controls.

Antibodies↗
PubMed1977

Synthesis of the tripeptide L-Trp-L-Ser-L-Glu. Comparison of its biological activity with that of the delta-sleep-inducing-peptide (DSIP).

In order to test the specificity of the natural Delta-Sleep-Inducing-Peptide (DSIP), a tripeptide with the same N-terminal amino acid was synthesized. The synthesis of the new tripeptide L-Trp-L-Ser-L-Glu was carried out by the method of the mixed anhydride. Protecting groups were all oxygen-bound benzyl groups. The physical-chemical data of the newly synthesized peptides are reported. The biological activity of the tripeptide was assayed by intraventricular infusion in the rabbit under the same conditions as for the DSIP. The effects of the tripeptide on the EEG could not duplicate those of DSIP which induced a marked increase of delta activity, typical for orthodox 'Slow Wave Sleep' (SWS).

Animals↗
PubMedDate not supplied

Oxidative posttranslational modifications in Alzheimer disease. A possible pathogenic role in the formation of senile plaques and neurofibrillary tangles.

The distinctive pathological lesions of Alzheimer disease (AD), senile plaques, and neurofibrillary tangles comprise aggregates of insoluble fibrillar protein. We and other investigators recently demonstrated that several mechanisms related to oxidative stress and free-radical reactions could play a crucial role in the pathogenesis of AD and, specifically, in the formation of senile plaques and neurofibrillary tangles (NFT).

Alzheimer Disease↗