Paul Beisswenger

Journey Bioscience

Aims: We aimed to determine whether plasma advanced glycation end products or oxidation products (AGE/oxidation-P) predict altered renal function and/or preeclampsia (PE) in pregnant women with type 1 diabetes. Methods: Prospectively, using a nested case-control design, we studied 47 pregnant women with type 1 diabetes, of whom 23 developed PE a...

Objective: To evaluate the association of a multicomponent advanced glycation end product (AGE) panel with decline in kidney function and its utility in predicting renal function loss (RFL) when added to routine clinical measures in type 2 diabetes. Research design and methods: Carboxymethyl and carboxyethyl lysine and methylglyoxal, 3-deoxygluc...

Objective The goal of this investigation was to evaluate circulating and skeletal muscle inflammatory biomarkers between MHD and demographic-matched control subjects (CON) before and after ingestion of a protein rich meal. Design and Methods CON (n=8; 50±2 y; 31±1 kg/m²) and MHD patients (n=8; 56±5 y; 32±2 kg/m²) underwent a basal blood draw and m...

Background Despite advances in ART, people living with HIV (PLWH)continue to be at increased risk of cardiometabolic complications compared to HIV-uninfected individuals. Advanced glycation end products (AGEs) are implicated in the development and progression of cardiometabolic complications in the general population. Their role in HIV remains uncl...

Individual advanced glycation end products (AGEs) have been implicated in the development of chronic kidney disease (CKD). We evaluated the prognostic utility of a comprehensive multicomponent AGE panel in predicting long-term renal function loss and CKD when added to routine clinical measures in persons with type 2 diabetes (T2D) followed for 12.5...

Objective: To compare levels of advanced glycation end products (AGEs) between HIV-infected patients and uninfected controls and assess the relationship between AGEs, HIV, inflammation, and endothelial dysfunction. Design: Cross-sectional study involving 90 individuals (68 HIV+ and 22 healthy controls matched by age and sex). Methods: AGE leve...

Preeclampsia (PE) occurs four times more frequently in pregnant women with type 1 diabetes (T1D) than in nondiabetic women. We hypothesized that elevated plasma advanced glycoxidation products (AGEs) predict PE in T1D women. In a prospective T1D pregnancy cohort (study visits at 12, 22, 32 weeks' gestation), we used liquid chromatography/mass spect...

The purpose of this investigation was to evaluate the effects of experimental hyperglycemia on oxidative damage (OX), advanced glycation end products (AGEs), and the receptor for AGEs (RAGE) through an in vivo approach. Obese subjects (n = 10; 31.2 ± 1.2 kg·m−2; 56 ± 3 years) underwent 24 h of hyperglycemic clamp (+5.4 mM above basal), where plasma...

Advanced glycation end products (AGEs) promote the development of diabetic complications through activation of their receptor (RAGE). Isoforms of soluble RAGE (sRAGE) sequester AGEs and protect against RAGE-mediated diabetic complications. We investigated the effect of an overnight fast on circulating metabolic substrates, hormones, AGEs, and sRAGE...

Chronic hyperglycemia promotes oxidative stress and advanced glycation end product (AGE) formation, leading to recognition by the AGE receptor (RAGE). AGE-RAGE binding and inflammation perpetuates diabetic complications, however the study of these phenomenon present inherent challenges in vivo. Therefore, our purpose was to evaluate the effects of...

Context and Objectives: Advanced glycation end products (AGEs) promote the development of diabetic complications through activation of their receptor (RAGE). Isoforms of soluble RAGE (sRAGE) sequester AGEs and thus protect against RAGE-mediated diabetic complications. Low cellular energy, such as during fasting, activates sRAGE production. We inves...

Introduction: Early diagnostic measures that predict development of complications in individuals with type 1 diabetes would be clinically relevant. Our goal was to determine if glycative and oxidative stress biomarker levels are independent risk factors in the development of advanced diabetic kidney disease (DKD) prior to detection of overt disease...

Objective: The goal of this study was to determine whether plasma levels of advanced glycation end products (AGE) and oxidation products (OP) predict the incidence of cardiovascular disease (CVD) in type 2 diabetes. Research design and methods: Five specific AGE (methylglyoxal hydroimidazolone, carboxymethyl lysine, carboxyethyl lysine, 3-deoxyg...

Advanced glycation end-products (AGEs) have been associated with poorer outcomes after myocardial infarction (MI), and linked with heart failure. Methylglyoxal (MG) is considered the most important AGE precursor, but its role in MI is unknown. In this study, we investigated the involvement of MG-derived AGEs (MG-AGEs) in MI using transgenic mice th...

Objective: To determine whether plasma levels of advanced glycation end products and oxidation products play a role in the development of atherosclerosis in patients with type 2 diabetes (T2D) over nearly 10 years of the VA Diabetes Trial and Follow-up Study. Research design and methods: Baseline plasma levels of methylglyoxal hydroimidazolone,...

We examined associations of advanced glycation end-products (AGEs) with renal function loss (RFL) and its structural determinants in American Indians with type 2 diabetes. Data were from a 6-year clinical trial which assessed renoprotective efficacy of losartan. Participants remained under observation after the trial concluded. Glomerular filtratio...

Diabetic complications are major health problems worldwide, with the cost of caring for diabetes rising to US$245 billion in 2012 in the U.S.A. alone. It is widely recognized that non-enzymatic glycation in diabetes is a major cause of damage and dysfunction of key vascular cells. MG (methylglyoxal) is directly toxic to tissues, and is a major prec...

Detection of diabetic nephropathy from advanced glycation endproducts (AGEs) differs in plasma and urine, and is dependent on the method of preparation

Increased advanced glycation endproducts (AGEs) and oxidation products (OPs) have been proposed as pathogenic for diabetic nephropathy (DN). We investigated the relationship between AGEs and OPs measured in different plasma and urine preparations, and progression of DN in 103 young, normoalbuminuric, normotensive participants with type 1 diabetes i...

OBJECTIVE Increased advanced glycation end products (AGEs) and oxidation products (OPs) are proposed to lead to progression of diabetic nephropathy (DN). We investigated the relationship between AGEs, OPs, and progression of DN in 103 subjects with type 1 diabetes participating in the Natural History of Diabetic Nephropathy Study.RESEARCH DESIGN AN...

Progressive β-cell dysfunction in Type 2 diabetes results in the need for insulin therapy in many patients. Yet the best regimen to prescribe to patients transitioning from oral anti-hyperglycemic drugs (OADs) is not clear. We sought to compare the effects of two standard initial insulin strategies (basal insulin alone versus premixed insulin) on p...

Advanced glycation end products (AGEs) and oxidation products (OPs) play an important role in diabetes complications, aging, and damage from sun exposure. Measurement of skin autofluorescence (SAF) has been promoted as a noninvasive technique to measure skin AGEs, but the actual products quantified are uncertain. We have compared specific SAF measu...

To determine if a regimen with prandial + basal insulin compared with basal insulin attenuates post-meal inflammatory and glycative biomarkers in patients with Type 2 diabetes. This test-meal sub-study in the USA is from a previously reported clinical trial comparing the effect on glycaemic control of 24 weeks of thrice-daily pre-meal insulin lispr...

Propensity to diabetic nephropathy (DN), retinopathy (DR), and cardiovascular disease (CVD) varies between individuals. Current biomarkers such as indicators of glycemia (HbA1c), retinal examinations, and albuminuria, cannot detect early tissue damage. HbAIc also doesn't reflect most glycative and oxidative chemical pathways that cause complication...

Introduction and Background Synthetic Pathways for Glycation ProductsEnzymatic Deglycation PathwaysSusceptibility to Diabetic Complications Varies Widely among IndividualsOverproduction of α-Dicarbonyls is Characteristic of Individuals Who are Prone to Diabetic ComplicationsOxidative Stress and Propensity to Diabetic NephropathyConclusions Referenc...

Background: In people without diabetes, approximately 50% of daily insulin secretion is basal and the remainder is postprandial. Hence, it would be expected that insulin replacement therapy in a 50/50 ratio with each meal would mimic physiologic insulin secretion better than treatment with once-daily basal insulin in patients with diabetes mellitu...

To address the role of 3-deoxyglucosone (3DG) and the activity of its major degradative pathways in diabetic nephropathy and retinopathy we have measured 3DG and its degradation products [3-deoxyfructose (3DF) and 3-deoxy-2-keto-gluconic acid (DGA)] in plasma and RBCs. In addition to these compounds, we have quantified HbAlc, renal dysfunction [glo...

3-deoxyglucosone (3DG), a reactive dicarbonyl sugar involved in nonenzymatic glycation of proteins is found in elevated concentrations in diabetic patients and has been implicated in the pathogenesis of diabetic complications. In this study, we provide ex-vivo and in-vivo evidence for production of 3DG via the fructose-3-phosphokinase pathway. Evid...

To assess the relative importance of fasting and postprandial hyperglycemia to vascular dysfunction in diabetes, we have measured indicators of glycation, oxidative and nitrosative stress in subjects with type 1 diabetes, and different postprandial glucose patterns. Plasma and urinary levels of specific arginine- and lysine-derived advanced glycati...

Dicarbonyl and oxidative stress may play important roles in the development of diabetes complications, and their response to hyperglycemia could determine individual susceptibility to diabetic nephropathy. This study examines the relationship of methylglyoxal, 3-deoxyglucosone (3DG), and oxidative stress levels to diabetic nephropathy risk in three...

Hyperglycaemia in diabetes is associated with increased glycation, oxidative stress and nitrosative stress. Proteins modified consequently contain glycation, oxidation and nitration adduct residues, and undergo cellular proteolysis with release of corresponding free adducts. These free adducts leak into blood plasma for eventual renal excretion. Th...

The activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) can play an important role in regulating multiple upstream pathways relating to the development of diabetic complications. GAPDH can be modified by a number of metabolic factors, including oxidative and glycation products. To study the effect of glycation on GAPDH we have measured GAP...

In the popular and widely used Atkins diet, the body burns fat as its main fuel. This process produces ketosis and hence increased levels of beta-hydroxybutyrate (BOB) acetoacetate (AcAc) and its by-products acetone and acetol. These products are potential precursors of the glycotoxin methylglyoxal. Since methylglyoxal and its byproducts are recogn...

Fructosamine-3-kinase (FN3K) and the more recently discovered fructosamine-3-kinase-related protein (FN3KRP) appear to protect proteins from nonenzymatic glycation. To gain a better understanding of these enzymes we performed a series of investigations including (1) in silico comparisons of their promoters; (2) real-time PCR analysis of their expre...

Nonenzymatic glycation is believed to play a major role in the development of diabetic complications. Over the past several years we and others have shown that in cells this nonenzymatic process can be reversed by an ATP-dependent reaction catalyzed by fructosamine-3-kinase (FN3K) and possibly by its isozyme, fructosamine-3-kinase-related protein (...

OBJECTIVE — To assess the relative importance of fasting and postprandial hyperglycemia to vascular dysfunction in diabetes, we have measured indicators of glycation, oxidative and nitrosative stress in subjects with type 1 diabetes, and different postprandial glucose patterns. RESEARCH DESIGN AND METHODS — Plasma and urinary levels of specific arg...

While it is well established that overall glycemic control reduces the complications of diabetes, the role of fasting glycemia versus postprandial glycemia in the pathophysiology of diabetes and its complications, and the relative importance of these parameters as specific targets of therapy, remain controversial. Evidence that postprandial glucose...

Fructosamine-3-kinase (FN3K) and the more recently discovered fructosamine-3-kinase related protein (FN3KRP) appear to protect proteins from nonenzymatic glycation. To elucidate the patterns of transcriptional regulation of these two genes, we performed in silico comparisons of their promoters along with real-time PCR assays of their expression in...

Following the discovery of FN3K (fructosamine 3-kinase), and more recently of FN3KRP (FN3K-related protein), research in our laboratory has been focused on testing the enzymatic deglycation hypothesis and investigating the roles of FN3K and FN3KRP. Thus far, using human erythrocytes as a model system, we have obtained the following evidence of enzy...

The factors responsible for variable susceptibility to diabetic nephropathy are not clear. According to the non-enzymatic glycation hypothesis, diabetes-related tissue damage occurs due to a complex mixture of toxic products, including α-oxoaldehydes, which are inherently toxic as well as serving as presursors for advanced glycation end-products. P...

A number of studies have shown that metformin is beneficial in reducing diabetes associated vascular risk beyond the benefits expected from its antihyperglycaemic effect. One of the main pathogenic mechanisms leading to chronic complications of diabetes is non-enzymatic glycation where damage is mediated through increased production of highly chemi...

Methylglyoxal (MG) may be an important cause of diabetic complications. Its primary source is dihydroxyacetone phosphate (DHAP) whose levels are partially controlled by glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Using a human red blood cell (RBC) culture, we examined the effect of modifying GAPDH activity on MG production. With the inhibitor...

Methylglyoxal (MG) may be an important cause of diabetic complications. Its primary source is dihydroxyacetone phosphate (DHAP) whose levels are partially controlled by glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Using a human red blood cell (RBC) culture, we examined the effect of modifying GAPDH activity on MG production. With the inhibitor...

Nonenzymatic glycation appears to play a major role in the development of diabetic complications. Key early intermediates in the nonenzymatic glycation cascade are glucoselysines (GL) and fructoselysines (FL).In 1997, we proposed that intracellular nonenzymatic glycation is controlled by an enzymatic deglycation process catalyzed by fructosamine-3-...

Nonenzymatic glycation appears to be an important factor in the pathogenesis of diabetic complications. Key early intermediates in this process are fructosamines, such as protein-bound fructoselysines. In this report, we describe the purification and characterization of a mammalian fructosamine-3-kinase (FN3K), which phosphorylates fructoselysine (...

The term nonenzymatic glycation (of protein) refers to a wide variety of spontaneous reactions between reducing sugars and protein-bound amines. This reaction has been documented in humans and plays a role in the development of diabetic complications and perhaps in some of the degenerative processes of aging. In addition to the monocarbonyl sugars...

Chronic hyperglycemia is known to increase tissue glycation and diabetic complications, but controversy exists regarding the independent role of increased postprandial glucose excursions. To address this question, we have studied the effect of postprandial glycemic excursions (PPGEs) on levels of methylglyoxal (MG) and 3-deoxyglucosone (3-DG), two...

Methylglyoxal (MG) is a reactive alpha-dicarbonyl that is thought to contribute to diabetic complications either as a direct toxin or as a precursor for advanced glycation end products. It is produced primarily from triose phosphates and is detoxified to D-lactate (DL) by the glyoxalase pathway. Because guanidino compounds can block dicarbonyl grou...

Methylglyoxal (MG), a dicarbonyl compound produced by the fragmentation of triose phosphates, forms advanced glycation endproducts (AGEs) in vitro. Glyoxalase-I catalyzes the conversion of MG to S-D-lactoylglutathione, which in turn is converted to D-lactate by glyoxalase-II. To evaluate directly the effect of glyoxalase-I activity on intracellular...

3-Deoxyglucosone (3DG), a reactive dicarbonyl, is an important intermediate in the formation of advanced glycation end products (AGEs). The AGEs are particularly important in diabetes since they have been correlated with the development of diabetic complications. Consequently, measurements of 3DG are likely to provide valuable insights into the rol...

Elevated levels of advanced glycosylation end products (AGEs) have been found in multiple tissues in association with diabetic vascular complications and during the microalbuminuric phase of diabetic nephropathy. In this study, we have used an AGE-specific enzyme-linked immunosorbent assay (ELISA) to measure skin AGEs to determine whether elevated...

To compare the safety and efficacy of three doses of acarbose (100, 200, and 300 mg three times daily) with placebo for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) in patients maintained on dietary therapy alone. This multicenter double-blind placebo-controlled trial was 22 weeks in duration. The trial consisted of a 2-week scr...

To evaluate the relative value of glycosylated serum proteins (GSPs) versus glycosylated hemoglobin (HbA1c) in assessing glycemic control in diabetes mellitus, we performed regular monitoring of GSPs and HbA1c in 30 subjects with insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM) who performed frequent sel...

Advanced glycosylation end products (AGEs) may play an important role in the development of diabetic vascular sequelae. An AGE cross-link, pentosidine, is a sensitive and specific marker for tissue levels of AGEs. To evaluate the role of AGEs in the development of diabetic nephropathy and retinopathy, we studied pentosidine levels and the clinical...

To evaluate the relationship between glycemic control over a 3-yr period and tissue levels of advanced glycosylation end products. The development of renal failure, blindness, and generalized vascular occlusion continue to be the most serious ravages of diabetes. Tissue glycosylation and AGEs are felt to play an important role in the development of...

The current study examines the impact of glipizide, a second-generation sulfonylurea, on diabetes control in patients in whom adequate control was not achieved while receiving treatment with first-generation agents. The interim results of this multicenter study are presented in which patients in whom euglycemia was not achieved based on fasting and...

We have identified five kindreds with familial medullary carcinoma of the thyroid (MTC) or multiple endocrine neoplasia syndromes type 2 (MEN-2) in New Hampshire and Vermont during the past five years. These families have been followed by periodic calcitonin testing after stimulation by calcium and pentagastrin. Affected individuals have been treat...

To study the effect of streptozotocin induced diabetes on glomerular basement membrane (GBM) synthesis, an isolated rat glomerular preparation has been developed, and its metabolic properties have been defined. The chemical composition of normal rat GBM isolated from this preparation closely resembles human GBM. Incubation with [U-14C] lysine leads...

Vascular and neuropathic complications of diabetes are a significant cause of morbidity and mortality. Symmetric polyneuropathy is the most common diabetic neuropathy. Treatment of the mononeuropathies consists of pain control and physical therapy to maintain muscle tone. Prognosis for recovery is excellent. Renal and retinal microangiopathy produc...

A distinct chemical change has previously been described in the glomerular basement membrane (GMB) of patients with long standing diabetes mellitus. To assess the specificity of this lesion the chemical composition of the GMB was determined in a group of patients with nondiabetic renal disease associated with significant proteinuria and age matched...

The basement membrane has been isolated in purified form from pooled normal human glomeruli and shown by detailed analyses to be composed of glycoprotein material. The peptide portion was characterized by the presence of large amounts of glycine, as well as by the occurrence of a substantial number of hydroxyproline, hydroxylysine, and cystine resi...

The human glomerular basement membrane belongs to the collagen family of proteins. It contains about 7 percent carbohydrate, half of which occurs as glucosylgalactose disaccharide units linked to hydroxylysine. Glomeruli from diabetics contain increased amounts of basement membrane material. In addition, these membranes show a distict chemical alte...

The nature of the genetic defect in diabetes mellitus is unknown, and at present the data do not exclude its inheritance as a multifactorial trait. It is common knowledge that the experimental production of insulin deficiency in many mammalian species leads to gross abnormalities in glucose and lipid metabolism similar to those observed in patients...