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139 results on '"Leslie, R. David G."'

17. Age-dependent influences on the origins of autoimmune diabetes: evidence and implications

Author

Leslie, R. David G. and Castelli, Michela Delli

Subjects
Care and treatment, Research, Causes of, Pancreatic beta cells -- Research, Type 1 diabetes -- Causes of -- Care and treatment -- Research
Abstract

A decade ago we proposed that environmental factors operating in early life lead to type 1 diabetes, outlining the evidence and the implications if the hypothesis was true (1). Today [...]

Published
2004

19. Level of an advanced glycated end product is genetically determined: a study of normal twins

Author

Leslie, R. David G., Beyan, Huriya, Sawtell, Pam, Boehm, Bernard O., Spector, Tim D., and Snieder, Harold

Subjects
Physiological aspects, Development and progression, Genetic aspects, Diabetes mellitus -- Physiological aspects -- Development and progression -- Genetic aspects, Diabetes -- Physiological aspects -- Development and progression -- Genetic aspects
Abstract

The formation of advanced glycation end products (AGEs) by glycation and oxidation alters the functional property of matrix proteins and mediates sustained cellular changes by binding to AGE ligands (1). [...], Reducing sugars react with amino groups in proteins, lipids, and nucleic acids to produce advanced glycation end products (AGEs), including [N.sup.∈]-carboxymethyl lysine (CML), which have been implicated in oxidative stress and vascular damage. The aim of this study was to determine whether genetic factors influence serum CML levels in normal subjects. We performed a classical twin study of CML in healthy nondiabetic female twins, 39 monozygotic and 45 dizygotic pairs, aged 21-74 years. Serum CML levels were estimated by enzymelinked immunosorbent assay. Twin correlations (r) for serum CML levels were higher in monozygotic (r = 0.71) compared with dizygotic (r = 0.50) twin pairs, suggesting a substantial genetic effect and confirmed by quantitative genetic model fitting. Additive genetic effects (heritability) explained 74% (95% CI 58-84) of population variance in CML. Heritability (%) of fasting glucose (51%) and Hb[A.sub.1c] (62%) could not explain CML heritability, which was not associated with them. CML levels are, therefore, predominantly genetically determined and independent of genes influencing fasting glucose or Hb[A.sub.1c]. Thus familial, largely genetic factors influence AGE implicating these glycoxidation products in the genetic contribution to macro- and microvascular disease.

Published
2003

31. Early environmental events as a cause of IDDM: evidence and implications

Author

Leslie, R. David G. and Elliott, Bob

Subjects
Physiological aspects, Causes of, Environmental illness -- Physiological aspects, Type 1 diabetes -- Causes of -- Physiological aspects, Environmentally induced diseases -- Physiological aspects
Abstract

Insulin-depdent diabetes mellitus (IDDM) is caused by destruction of the insulin-secreting β-cells of the islets of Langerhans. It is proposed that the disease is caused by nongenetic, probably environmental, factors [...]

Published
1994

32. Risk factors for cardiovascular disease in IDDM: a study of identical twins

Author

Dubrey, Simon W., Reaveley, David R., Seed, Mary, Lane, David A., Ireland, Helen, O'Donnell, Martina, O'Connor, Bernadette, Noble, Mark I., and Leslie, R. David G.

Subjects
Diseases, Complications and side effects, Research, Risk factors, Twins -- Research -- Diseases, Cardiovascular diseases -- Risk factors -- Research -- Complications and side effects, Twin studies -- Research, Type 1 diabetes -- Complications and side effects -- Risk factors -- Research
Abstract

A Study of Identical Twins Patients with insulin-dependent diabetes mellitus (IDDM) have an excess mortality, predominantly attributable to cardiovascular disease. To determine the effect of IDDM on potential risk factors [...]

Published
1994

33. Increased expression of T-cell markers of immunological memory associated with protection from type I diabetes: a study of identical twins

Author

Peakman, Mark, Alviggi, Lorenzo, Hussain, Munther J., Lo, Simon S.S., Hawa, Mohammed, Leslie, R. David G., and Vergani, Diego

Subjects
Diseases, Research, Genetic aspects, Twins -- Research -- Diseases -- Genetic aspects, Type 1 diabetes -- Genetic aspects -- Research, Twin studies -- Research, T cells -- Genetic aspects -- Research
Abstract

A Study of Identical Twins Disturbances in the balance of [CD4.sup.+] helper T-lymphocytes expressing the surface molecules CD45RA and CD45R0, which define naive and memory populations, respectively, are present at [...]

Published
1994

34. Information on type 1 diabetes mellitus and QT interval from identical twins

Author

Lo, Simon S.S., Sutton, Martin St. John, and Leslie, R. David G.

Subjects
Diabetes -- Complications, Diabetic neuropathies -- Genetic aspects, Diseases in twins -- Genetic aspects, Health
Abstract

To determine whether QT interval is influenced by genetic factors and whether QT-interval prolongation occurs in type 1 diabetes or is related to diabetic autonomic neuropathy, QT intervals were measured, and autonomic function was assessed in 44 pairs of identical twins who were discordant for type 1 diabetes. Twins were compared with 44 normal control subjects of similar age and sex. QT intervals were correct4d for heart rate (QTc). QTc in diabetic twins correlated with that in their nondiabetic twins had significantly longer QTc than din their nondiabetic co-twins and control subjects (416 [+ or -] 18 vs 407 [+ or -] 16 and 403 [+ or -] 19 ms, respectively; p 14 years (n + 22) had longer QTc than did their nondiabetic co-twins (420 [+ or -] 17 vs 402 [+ or -] 14 ms; p 14 years had a greater frequency of abnormal autonomic function tests than did those with diabetes

Published
1993

35. Increase in simultaneous coexpression of naive and memory lymphocyte markers at diagnosis of IDDM

Author

Smerdon, Rebecca A., Peakman, Mark, Hussain, Munther J., Alviggi, Lorenzo, Watkins, Peter J., Leslie, R. David G., and Vergani, Diego

Subjects
Diagnosis, Physiological aspects, Analysis, Development and progression, Autoimmune diseases -- Development and progression -- Diagnosis, Lymphocytes -- Analysis -- Physiological aspects, Type 1 diabetes -- Diagnosis -- Development and progression, T cells -- Physiological aspects -- Analysis
Abstract

The monoclonal antibodies 2H4 (anti-CD45RA) and UCHL1 (anti-CD45RO) were used to subdivide the CD4 and CD8 T-cell subsets into naive and memory cells. The peripheral blood lymphocytes of 34 patients [...]

Published
1993

36. Antibodies to GAD and tryptic fragments of islet 64K antigen as distinct markers for development of IDDM: studies with identical twins

Author

Christie, Michael R., Tun, Richard Y.M., Lo, Simon S.S., Cassidy, David, Brown, Thomas J., Hollands, Jacqueline, Shattock, Marion, Bottazzo, Gian Franco, and Leslie, R. David G.

Subjects
Physiological aspects, Development and progression, Pancreatic beta cells -- Physiological aspects, Antigen-antibody reactions -- Physiological aspects, Glutamate decarboxylase -- Physiological aspects, Type 1 diabetes -- Development and progression
Abstract

Insulin-dependent diabetes mellitus (IDDM) is associated with antibodies to a 64,000-[M.sub.r] islet cell protein, at least part of which is identified as glutamic acid decarboxylase (GAD). These antibodies are detected [...]

Published
1992

37. Decreased growth velocity before IDDM onset

Author

Leslie, R. David G., Lo, Simon, Millward, B. Anne, Honour, John, and Pyke, David A.

Subjects
Diagnosis, Diseases, Physiological aspects, Genetic aspects, Metabolic regulation -- Genetic aspects -- Physiological aspects, Growth (Physiology) -- Physiological aspects -- Genetic aspects, Twins -- Diagnosis -- Diseases -- Physiological aspects -- Genetic aspects, Juvenile diabetes -- Physiological aspects -- Diagnosis -- Genetic aspects, Growth regulators -- Physiological aspects -- Genetic aspects, Twin studies -- Physiological aspects, Type 1 diabetes -- Genetic aspects -- Diagnosis, Growth -- Physiological aspects -- Genetic aspects, Diabetes in children -- Physiological aspects -- Diagnosis -- Genetic aspects
Abstract

Decreased Growth Velocity Before IDDM Onset Growth is a sensitive indicator of health in childhood. Diabetes can retard growth, and before insulin was discovered, growth ceased entirely in children who [...]

Published
1991

39. Late Progression to Type 1 Diabetes of Discordant Twins of Patients with Type 1 Diabetes: Combined Analysis of Two Twin Series (United Kingdom and United States)

Author

REDONDO, MARIA J., YU, LIPING, HAWA, MOHAMMED, PYKE, DAVID A., and LESLIE, R. DAVID G

Subjects
Research, Diabetes research, Diabetes -- Research
Abstract

Two cohorts of non-diabetic monozygotic twins or triplets of patients with type 1 diabetes from Great Britain (n=134)and from the United States (n=53) were prospectively followed. Monozygosity was confirmed by [...]

Published
1999

41. Challenges in developing endpoints for type 1 diabetes intervention studies

Author

Cernea, Simona, primary, Raz, Itamar, additional, Herold, Kevan C., additional, Hirshberg, Boaz, additional, Roep, Bart O., additional, Schatz, Desmond A., additional, Fleming, G. Alexander, additional, Pozzilli, Paolo, additional, Little, Randie, additional, Schloot, Nanette C., additional, Leslie, R. David G., additional, Skyler, Jay S., additional, and Palmer, Jerry P., additional

Published
2009
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45. Type 1 Diabetes Mellitus.

Author

Conn, P. Michael, Weetman, Anthony P., Beyan, Huriya, and Leslie, R. David G.

Abstract

Autoimmune diseases affect 10% or more of the North American and European populations. In organ-specific autoimmune diseases, an organ is targeted by an aggressive immune response, which can damage and even destroy it. Type 1 diabetes mellitus (T1DM), one such organ-specific autoimmune disease, is because of the destruction of the insulin-secreting beta cells in the islets of Langerhans of the pancreas. T1DM is because of the interaction of genetic and non-genetic factors thought to induce an immune response, which destroys insulin secretory cells over months, even years. We present the orthodox position regarding the cause of autoimmune T1DM but also emphasize where that orthodox is not based on a firm footing. We discuss the nature of the disease and how we can predict it with a degree of certainty and how we are now trying to modulate the disease process. Lessons learned from autoimmune diabetes could be relevant to other autoimmune diseases. [ABSTRACT FROM AUTHOR]

Published
2008
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48. Identical twins discordant for type 1 diabetes show a different pattern of in vitro CD56+ cell activation.

Author

Goodier, Martin R., Nawroly, Niga, Beyan, Huriya, Hawa, Mohammed, Leslie, R. David G., and Londei, Marco

Abstract

Background Recent studies in animal models indicate a role for natural killer (NK) cells in the protection against type 1 diabetes. In humans, a reduction of NK cell numbers has been reported in identical twins discordant for type 1 diabetes, irrespective of whether they have the disease. Here we have tested whether the activation and expansion of human NK cells with lipopolysaccharide (LPS) reveals differences between these twins. Methods Proportions of CD56+ NK cells and T-cells and Va24Vb11+ NK-T cells from diabetic and non-diabetic twins was assessed before and after activation using flow cytometry. NK receptor usage was monitored by PCR and flow cytometry. Results The profile of the expressed Killer Cell immunoglobulin-like receptor (KIR) repertoire (using mRNA) in freshly isolated NK cells was identical in pairs of identical twins, despite marked variation among individual twins as well as controls. Basal numbers of CD56+ and CD94+ (CD3− and CD3+) cells and Vα24+Vβ11+ NK-T cells were similarly strongly correlated between identical twins ( p < 0.006 for all correlations). Following LPS stimulation, the pattern of KIR mRNA expression remained unaltered in twins and the proportion of NK cells and Vα24+Vβ11+ NK-T cells remained correlated between pairs of twins. However, there was a significant reduction in the proportion of CD56+ cells and CD94+ cells (whether defined as CD3− or CD3+) responding to LPS in the diabetic compared to the non-diabetic twin ( p = 0.031 and 0.025, respectively). Conclusion: This reduction in NK cell expansion in response to LPS in patients with type 1 diabetes is consistent with a non-genetically determined alteration in the innate immune response either predisposing to or resulting from the disease. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Published
2006
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49. Evidence for Independent Heritability of the Glycation Gap (Glycosylation Gap) Fraction of HbA1c in Nondiabetic Twins.

Author

Cohen, Robert M., Lindsell, Christopher J., Snieder, Harold, Spector, Timothy D., Blinko, Stuart, Beyan, Huriya, Hawa, Mohammed I., Leslie, R. David G., and Edwards, Raymond

Subjects
GENETICS of diabetes, GLYCOSYLATION, GLYCOSYLATED hemoglobin, DIABETES, TWINS
Abstract

OBJECTIVE -- HbA1c (A1C) is substantially determined by genetic factors not shared in common with glucose. Fractions of the variance in A1C, the glycation gap (GG; previously called the glycosylation gap) and the hemoglobin glycosylation index, correlate with diabetes complications. We therefore tested whether GG (measured A1C -- A1C predicted from glycated serum proteins [GSPs]) was genetically determined and whether it accounted for the heritability of A1C. RESEARCH DESIGN AND METHODS -- We conducted a classic twin study on A1C and GSP collected in 40 and 46 pairs of monozygotic and dizygotic healthy female twins, respectively. The predicted A1C was based on the regression line between A1C and GSP in a separate population spanning the pathophysiologic range. RESULTS -- GG was more strongly correlated between monozygotic (r = 0.65) than dizygotic (r = 0.48) twins, adjusted for age and BMI. The best-fitting quantitative genetic model adjusted for age and BMI showed that 69% of population variance in GG is heritable, while the remaining 31% is due to unique environmental influences. In contrast, GSP was similarly correlated between monozygotic (r = 0.55) and dizygotic (r = 0.49) twins, hence not genetically determined. GG was strongly correlated to A1C (r = 0.48), attributable mostly to genetic factors. About one-third of the heritability of A1C is shared with GG; the remainder is specific to A1C. CONCLUSIONS -- Heritability of the GG accounts for about one-third of the heritability of A1C. By implication, there are gene(s) that preferentially affect erythrocyte lifespan or glucose and/or nonenzymatic glycation or deglycation in the intracellular, rather than extracellular, compartment. [ABSTRACT FROM AUTHOR]

Published
2006
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