Modern-day clinical course of type 1 diabetes mellitus after 30 years' duration:the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983-2005)

Clinical treatment goals of type 1 diabetes mellitus (T1DM) have changed since the Diabetes Control and Complications Trial (DCCT) demonstrated reduced long-term complications with intensive diabetes therapy. There have been few longitudinal studies to describe the clinical course of T1DM in the age of intensive therapy. Our objective was to describe the current-day clinical course of T1DM.

Risk factors related to inflammation and endothelial dysfunction in the DCCT/EDIC cohort and their relationship with nephropathy and macrovascular complications

Because endothelial cell dysfunction and inflammation are key contributors to the development of complications in type 1 diabetes, we studied risk factors related to endothelial dysfunction and inflammation (C-reactive protein and fibrinogen, soluble vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and E-selectin, and fibrinolytic markers) in a subgroup of patients from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Intervention and Complications (EDIC) study cohort.

Cross-sectional associations of C-reactive protein with vascular risk factors and vascular complications in the DCCT/EDIC cohort

To determine the relationships between C-reactive protein (CRP) levels and features of Type 1 diabetes.

Increased serum pigment epithelium-derived factor is associated with microvascular complications, vascular stiffness and inflammation in Type 1 diabetes

To determine in Type 1 diabetes patients if levels of pigment epithelium-derived factor (PEDF), an anti-angiogenic, anti-inflammatory and antioxidant factor, are increased in individuals with complications and positively related to vascular and renal dysfunction, body mass index, glycated haemoglobin, lipids, inflammation and oxidative stress.

Glycation, carbonyl stress, EAGLEs, and the vascular complications of diabetes

The association between poor metabolic control and the microvascular complications of diabetes is now well established, but the relationship between long-term metabolic control and the accelerated atherosclerosis of diabetes is as yet poorly defined. Hyperglycemia is the standard benchmark by which metabolic control is assessed. One mechanism by which elevated glucose levels may mediate vascular injury is through early and advanced glycation reactions affecting a wide variety of target molecules. The "glycation hypothesis'' has developed over the past 30 years, evolving gradually into a "carbonyl stress hypothesis'' and taking into account not only the modification of proteins by glucose, but also the roles of oxidative stress, a wide range of reactive carbonyl-containing intermediates (derived not only from glucose but also from lipids), and a variety of extra- and intracellular target molecules. The final products of these reactions may now be termed "Either Advanced Glycation or Lipoxidation End-Products'' or "EAGLEs.'' The ubiquity of carbonyl stress within the body, the complexity of the reactions involved, the variety of potential carbonyl intermediates and target molecules and their differing half-lives, and the slow development of the complications of diabetes all pose major challenges in dissecting the significance of these processes. The extent of the reactions tends to correlate with overall metabolic control, creating pitfalls in the interpretation of associative data. Many animal and cell culture studies, while supporting the hypothesis, must be viewed with caution in terms of relevance to human diabetes. In this article, the development of the carbonyl stress hypothesis is reviewed, and implications for present and future treatments to prevent complications are discussed.

Effect of intensive glycemic control on levels of markers of inflammation in type 1 diabetes mellitus in the diabetes control and complications trial

Type 1 diabetes mellitus is associated with an increased risk of cardiovascular disease (CVD) that is not fully explained by conventional risk factors. The Diabetes Control and Complications Trial (DCCT) showed that intensive diabetes therapy reduced levels of LDL cholesterol and triglycerides but increased the risk of major weight gain, which might adversely affect CVD risk. The present study examined the effect of intensive therapy on levels of several markers of inflammation that have been linked to risk of CVD.

Apolipoprotein C-III protein concentrations and gene polymorphisms in Type 1 diabetes:associations with microvascular disease complications in the DCCT/EDIC cohort

We investigated the associations of apolipoprotein C-III (apoCIII) protein and apoCIII gene variation with microvascular disease complications in Type 1 diabetes.

Lipoproteins and diabetic microvascular complications

Risk factors for the microvascular complications (nephropathy and retinopathy) of Type 1 and Type 2 diabetes mellitus and the associated accelerated atherosclerosis include: age, diabetes duration, genetic factors, hyperglycaemia, hypertension, smoking, inflammation, glycation and oxidative stress and dyslipoproteinaemia. Hypertriglyceridaemia, low HDL and small dense LDL are common features of Type 2 diabetes and Type 1 diabetes with poor glycaemic control or renal complications. With the expansion of knowledge and of clinical and research laboratory tools, a broader definition of 'lipid' abnormalities in diabetes is appropriate. Dyslipoproteinaemia encompasses alterations in lipid levels, lipoprotein subclass distribution, composition (including modifications such as non-enzymatic glycation and oxidative damage), lipoprotein-related enzymes, and receptor interactions and subsequent cell signaling. Alterations occur in all lipoprotein classes; chylomicrons, VLDL, LDL, HDL, and Lp(a). There is also emerging evidence implicating lipoprotein related genotypes in the development of diabetic nephropathy and retinopathy. Lipoprotein related mechanisms associated with damage to the cardiovascular system may also be relevant to damage to the renal and ocular microvasculature. Adverse tissue effects are mediated by both alterations in lipoprotein function and adverse cellular responses. Recognition and treatment of lipoprotein-related risk factors, supported by an increasing array of assays and therapeutic agents, may facilitate early recognition and treatment of high complication risk diabetic patients. Further clinical and basic research, including intervention trials, is warranted to guide clinical practice. Optimal lipoprotein management, as part of a multi-faceted approach to diabetes care, may reduce the excessive personal and economic burden of microvascular complications and the related accelerated atherosclerosis.

Serum lipoproteins in the diabetes control and complications trial/epidemiology of diabetes intervention and complications cohort:associations with gender and glycemia

To relate the nuclear magnetic resonance (NMR)-determined lipoprotein profile, conventional lipid and apolipoprotein measures, and in vitro oxidizibility of LDL with gender and glycemia in type 1 diabetes.

Maillard reaction products and their relation to complications in insulin-dependent diabetes mellitus

Glycation, oxidation, and browning of proteins have all been implicated in the development of diabetic complications. We measured the initial Amadori adduct, fructoselysine (FL); two Maillard products, N epsilon-(carboxymethyl) lysine (CML) and pentosidine; and fluorescence (excitation = 328 nm, emission = 378 nm) in skin collagen from 39 type 1 diabetic patients (aged 41.5 +/- 15.3 [17-73] yr; duration of diabetes 17.9 +/- 11.5 [0-46] yr, [mean +/- SD, range]). The measurements were related to the presence of background (n = 9) or proliferative (n = 16) retinopathy; early nephropathy (24-h albumin excretion rate [AER24] > or = 20 micrograms/min; n = 9); and limited joint mobility (LJM; n = 20). FL, CML, pentosidine, and fluorescence increased progressively across diabetic retinopathy (P <0.05, P <0.001, P <0.05, P <0.01, respectively). FL, CML, pentosidine, and fluorescence were also elevated in patients with early nephropathy (P <0.05, P <0.001, P <0.01, P <0.01, respectively). There was no association with LJM. Controlling for age, sex, and duration of diabetes using logistic regression, FL and CML were independently associated with retinopathy (FL odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.01-1.12, P <0.05; CML OR = 6.77, 95% CI = 1.33-34.56, P <0.05) and with early nephropathy (FL OR = 1.05, 95% CI = 1.01-1.10, P <0.05; CML OR = 13.44, 95% CI = 2.00-93.30, P <0.01). The associations between fluorescence and retinopathy and between pentosidine and nephropathy approached significance (P = 0.05). These data show that FL and Maillard products in skin correlate with functional abnormalities in other tissues and suggest that protein glycation and oxidation (glycoxidation) may be implicated in the development of diabetic retinopathy and early nephropathy.

Glycation, oxidation, and lipoxidation in the development of the complications of diabetes: a carbonyl stress hypothesis

Modifications of extant plasma proteins, structural proteins,and other macromolecules are enhanced in diabetes because of increased glycation (secondary to increased glucose concentrations) and perhaps because of increased oxidative stress, Increased glycation is present from the time of onset of diabetes, but the relation between diabetes and oxidative stress is less clear: increased oxidative stress may occur later in the course of disease, as vascular damage becomes established, or it may be a feature of uncomplicated diabetes, The combined effects of protein modification by glycation and oxidation may contribute to the development of accelerated atherosclerosis in diabetes and to the development of microvascular complications, Thus, even if not increased by diabetes, variations in oxidative stress may modulate the consequences of hyperglycemia in individual diabetic patients, In this review, the close interaction between glycation and oxidative processes is discussed, and the theme is developed that the most significant modifications of proteins are the result of interactions with reactive carbonyl groups, While glucose itself contains a carbonyl group that is involved in the initial glycation reaction, the most important and reactive carbonyls are formed by free radical-oxidation reactions damaging either carbohydrates (including glucose itself) or lipids, The resulting carbonyl-containing intermediate products then modify proteins, yielding "glycoxidation" and "lipoxidation" products, respectively, This common pathway for glucose and lipid-mediated stress, which may contribute to diabetic complications, is the basis for the carbonyl stress hypothesis for the development of diabetic complications.