Vincent M. Monnier

Bio: Vincent M. Monnier is an academic researcher from Case Western Reserve University. The author has contributed to research in topics: Glycation & Pentosidine. The author has an hindex of 69, co-authored 217 publications receiving 19390 citations. Previous affiliations of Vincent M. Monnier include University of Michigan & Rockefeller University.

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

Abstract: 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.

Advanced Maillard reaction end products are associated with Alzheimer disease pathology

Abstract: During aging long-lived proteins accumulate specific post-translational modifications. One family of modifications, termed Maillard reaction products, are initiated by the condensation between amino groups of proteins and reducing sugars. Protein modification by the Maillard reaction is associated with crosslink formation, decreased protein solubility, and increased protease resistance. Here, we present evidence that the characteristic pathological structures associated with Alzheimer disease contain modifications typical of advanced Maillard reaction end products. Specifically, antibodies against two Maillard end products, pyrraline and pentosidine, immunocytochemically label neurofibrillary tangles and senile plaques in brain tissue from patients with Alzheimer disease. In contrast, little or no staining is observed in apparently healthy neurons of the same brain. The Maillard-reaction-related modifications described herein could account for the biochemical and insolubility properties of the lesions of Alzheimer disease through the formation of protein crosslinks.

Accelerated age-related browning of human collagen in diabetes mellitus

Abstract: 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.

Relation between Complications of Type I Diabetes Mellitus and Collagen-Linked Fluorescence

Abstract: 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.

Biochemistry and molecular cell biology of diabetic complications

Abstract: Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.

Abstract: BACKGROUND Intensive diabetes therapy aimed at achieving near normoglycemia reduces the risk of microvascular and neurologic complications of type 1 diabetes. We studied whether the use of intensive therapy as compared with conventional therapy during the Diabetes Control and Complications Trial (DCCT) affected the long-term incidence of cardiovascular disease. METHODS The DCCT randomly assigned 1441 patients with type 1 diabetes to intensive or conventional therapy, treating them for a mean of 6.5 years between 1983 and 1993. Ninety-three percent were subsequently followed until February 1, 2005, during the observational Epidemiology of Diabetes Interventions and Complications study. Cardiovascular disease (defined as nonfatal myocardial infarction, stroke, death from cardiovascular disease, confirmed angina, or the need for coronary-artery revascularization) was assessed with standardized measures and classified by an independent committee. RESULTS During the mean 17 years of follow-up, 46 cardiovascular disease events occurred in 31 patients who had received intensive treatment in the DCCT, as compared with 98 events in 52 patients who had received conventional treatment. Intensive treatment reduced the risk of any cardiovascular disease event by 42 percent (95 percent confidence interval, 9 to 63 percent; P=0.02) and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57 percent (95 percent confidence interval, 12 to 79 percent; P=0.02). The decrease in glycosylated hemoglobin values during the DCCT was significantly associated with most of the positive effects of intensive treatment on the risk of cardiovascular disease. Microalbuminuria and albuminuria were associated with a significant increase in the risk of cardiovascular disease, but differences between treatment groups remained significant (P< or =0.05) after adjusting for these factors. CONCLUSIONS Intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes.

Role of Oxidative Stress in Development of Complications in Diabetes

Abstract: N epsilon-(carboxymethyl)lysine, N epsilon-(carboxymethyl)hydroxylysine, and the fluorescent cross-link pentosidine are formed by sequential glycation and oxidation reactions between reducing sugars and proteins. These compounds, termed glycoxidation products, accumulate in tissue collagen with age and at an accelerated rate in diabetes. Although glycoxidation products are present in only trace concentrations, even in diabetic collagen, studies on glycation and oxidation of model proteins in vitro suggest that these products are biomarkers of more extensive underlying glycative and oxidative damage to the protein. Possible sources of oxidative stress and damage to proteins in diabetes include free radicals generated by autoxidation reactions of sugars and sugar adducts to protein and by autoxidation of unsaturated lipids in plasma and membrane proteins. The oxidative stress may be amplified by a continuing cycle of metabolic stress, tissue damage, and cell death, leading to increased free radical production and compromised free radical inhibitory and scavenger systems, which further exacerbate the oxidative stress. Structural characterization of the cross-links and other products accumulating in collagen in diabetes is needed to gain a better understanding of the relationship between oxidative stress and the development of complications in diabetes. Such studies may lead to therapeutic approaches for limiting the damage from glycation and oxidation reactions and for complementing existing therapy for treatment of the complications of diabetes.