The Experts below are selected from a list of 222 Experts worldwide ranked by ideXlab platform

Paul J. Thornalley - One of the best experts on this subject based on the ideXlab platform.

  • The Critical Role of
    2016
    Co-Authors: Naila Rabbani, Paul J. Thornalley
    Abstract:

    The discovery of increased formation of methylglyoxal (MG) by cell metabolism in high glucose concentration in vitro suggested possible relevance to Diabetes and di-abetes complications (1,2). MG is the precursor of quantitatively important advanced glycation end prod-ucts (AGEs) of protein and DNA- and MG-derived AGEs increase in experimental and Clinical Diabetes (3,4). In-creased MG and its metabolism by glyoxalase 1 (Glo1) was linked to Clinical microvascular complications (ne-phropathy, retinopathy, and neuropathy) (5). Current Clinical treatment decreasing MG and MG-derived AGEs, such as insulin lispro (6,7), has some Clinical benefit in diabetic nephropathy (8), although the decrease in MG-derived AGE exposure is minor—;17 % (7). Greater benefits may be achieved with specific and effective anti

  • glucose induced down regulation of thiamine transporters in the kidney proximal tubular epithelium produces thiamine insufficiency in Diabetes
    PLOS ONE, 2012
    Co-Authors: James R Larkin, Naila Rabbani, Fang Zhang, Lisa Godfrey, Guerman Molostvov, Daniel Zehnder, Paul J. Thornalley
    Abstract:

    Increased renal clearance of thiamine (vitamin B1) occurs in experimental and Clinical Diabetes producing thiamine insufficiency mediated by impaired tubular re-uptake and linked to the development of diabetic nephropathy. We studied the mechanism of impaired renal re-uptake of thiamine in Diabetes. Expression of thiamine transporter proteins THTR-1 and THTR-2 in normal human kidney sections examined by immunohistochemistry showed intense polarised staining of the apical, luminal membranes in proximal tubules for THTR-1 and THTR-2 of the cortex and uniform, diffuse staining throughout cells of the collecting duct for THTR-1 and THTR-2 of the medulla. Human primary proximal tubule epithelial cells were incubated with low and high glucose concentration, 5 and 26 mmol/l, respectively. In high glucose concentration there was decreased expression of THTR-1 and THTR-2 (transporter mRNA: −76% and −53% respectively, p<0.001; transporter protein −77% and −83% respectively, p<0.05), concomitant with decreased expression of transcription factor specificity protein-1. High glucose concentration also produced a 37% decrease in apical to basolateral transport of thiamine transport across cell monolayers. Intensification of glycemic control corrected increased fractional excretion of thiamine in experimental Diabetes. We conclude that glucose-induced decreased expression of thiamine transporters in the tubular epithelium may mediate renal mishandling of thiamine in Diabetes. This is a novel mechanism of thiamine insufficiency linked to diabetic nephropathy.

  • the potential role of thiamine vitamin b1 in diabetic complications
    Current Diabetes Reviews, 2005
    Co-Authors: Paul J. Thornalley
    Abstract:

    Accumulation of triosephosphates arising from high cytosolic glucose concentrations in hyperglycemia is one likely or potential trigger for biochemical dysfunction leading to the development of diabetic complications. This may be prevented by disposal of excess triosephosphates via the reductive pentosephosphate pathway. This pathway is impaired in experimental and Clinical Diabetes by mild thiamine deficiency. The expression and activity of the thiamine-dependent enzyme, transketolase--the pacemaking enzyme of the reductive pentosephosphate pathway, is consequently decreased. Correction of thiamine deficiency in experimental Diabetes by high dose therapy with thiamine and the thiamine monophosphate prodrug, Benfotiamine, restores disposal of triosephosphates by the reductive pentosephosphate pathway in hyperglycemia. This prevented multiple mechanisms of biochemical dysfunction: activation of protein kinase C, activation of the hexosamine pathway, increased glycation and oxidative stress. Consequently, the development of incipient diabetic nephropathy, neuropathy and retinopathy were prevented. Both thiamine and Benfotiamine produced other remarkable effects in experimental Diabetes: marked reversals of increased diuresis and glucosuria without change in glycemic status. High dose thiamine also corrected dyslipidemia in experimental Diabetes--normalizing cholesterol and triglycerides. Dysfunction of beta-cells and impaired glucose tolerance in thiamine deficiency and suggestion of a link of impaired glucose tolerance with dietary thiamine indicates that thiamine therapy may have a future role in prevention of type 2 Diabetes. More immediately, given the emerging multiple benefits of thiamine repletion, even mild thiamine deficiency in Diabetes should be avoided and thiamine supplementation to high dose should be considered as adjunct nutritional therapy to prevent dyslipidemia and the development of vascular complications in Clinical Diabetes.

  • glyoxalase system in Clinical Diabetes mellitus and correlation with diabetic complications
    Clinical Science, 1994
    Co-Authors: Antony C. Mclellan, Jonathan J Benn, Paul J. Thornalley, Peter H. Sönksen
    Abstract:

    1. The metabolism of methylglyoxal by the glyoxalase system may be linked to the development of diabetic complications. The glyoxalase system was characterized in blood samples from patients with insulin-dependent Diabetes mellitus (n=43), patients with non-insulin-dependent Diabetes mellitus (n=107) and 21 normal healthy control subjects

Joann E Manson - One of the best experts on this subject based on the ideXlab platform.

Aruna D Pradhan - One of the best experts on this subject based on the ideXlab platform.

Vilhelmiina Parikka - One of the best experts on this subject based on the ideXlab platform.

  • early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 Diabetes in children at genetic risk
    Diabetologia, 2012
    Co-Authors: Vilhelmiina Parikka, Kirsti Nantosalonen, Maiju Saarinen, Tuula Simell, Jorma Ilonen, Heikki Hyoty
    Abstract:

    Aims/hypothesis The aim of the study was to investigate the timing of the appearance of autoantibodies associated with type 1 Diabetes between birth and puberty, the natural fate of these autoantibodies and the predictive power of autoantibody concentrations for early progression to Clinical Diabetes.

  • dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 Diabetes
    Journal of Experimental Medicine, 2008
    Co-Authors: Matej Oresic, Vilhelmiina Parikka, Kirsti Nantosalonen, Satu Simell, Marko Sysiaho, Tuulikki Seppanenlaakso, Mikko Katajamaa, Anne Hekkala, Ismo Mattila, Paivi Keskinen
    Abstract:

    The risk determinants of type 1 Diabetes, initiators of autoimmune response, mechanisms regulating progress toward β cell failure, and factors determining time of presentation of Clinical Diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 Diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 Diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed Diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 Diabetes prevention strategies.

Graham A Colditz - One of the best experts on this subject based on the ideXlab platform.

  • weight gain as a risk factor for Clinical Diabetes mellitus in women
    Annals of Internal Medicine, 1995
    Co-Authors: Graham A Colditz, Walter C Willett, Andrea Rotnitzky, Joann E Manson
    Abstract:

    Objective: To examine the relation between adult weight change and the risk for Clinical Diabetes mellitus among middle-aged women. Design: Prospective cohort study with follow-up from 1976 to 1990...

  • obesity fat distribution and weight gain as risk factors for Clinical Diabetes in men
    Diabetes Care, 1994
    Co-Authors: June M Chan, Graham A Colditz, Eric B Rimm, Meir J Stampfer, Walter C Willett
    Abstract:

    OBJECTIVE To investigate the relation between obesity, fat distribution, and weight gain through adulthood and the risk of non-insulin-dependent Diabetes melli-tus (NIDDM). RESEARCH DESIGN AND METHODS We analyzed data from a cohort of 51,529 U.S. male health professionals, 40-75 years of age in 1986, who completed biennial questionnaires sent out in 1986, 1988, 1990, and 1992. During 5 years of follow-up (1987-1992), 272 cases of NIDDM were diagnosed among men without a history of Diabetes, heart disease, and cancer in 1986 and who provided complete health information. Relative risks (RRs) associated with different anthropometrie measures were calculated controlling for age, and multivariate RRs were calculated controlling for smoking, family history of Diabetes, and age. RESULTS We found a strong positive association between overall obesity as measured by body mass index (BMI) and risk of Diabetes. Men with a BMI of ≥35 kg/m 2 had a multivariate RR of 42.1 (95% confidence interval [CI] 22.0-80.6) compared with men with a BMI 2 . BMI at age 21 and absolute weight gain throughout adulthood were also significant independent risk factors for Diabetes. Fat distribution, measured by waist-to-hip ratio (WHR), was a good predictor of Diabetes only among the top 5%, while waist circumference was positively associated with the risk of Diabetes among the top 20% of the cohort. CONCLUSIONS These data suggest that waist circumference may be a better indicator than WHR of the relationship between abdominal adiposity and risk of Diabetes. Although early obesity, absolute weight gain throughout adulthood, and waist circumference were good predictors of Diabetes, attained BMI was the dominant risk factor for NIDDM; even men of average relative weight had significantly elevated RRs.