Professor and Division Director
Division of Endocrinology, Diabetes & Metabolic Diseases
The Lyons lab has more than 25 years of experience in translational diabetes research. The primary focus of the research is the role of oxidation, glycation, glycoxidation, and lipoxidation in the promotion of micro- and macro-vascular damage as a complication of diabetes. Much of the work has focused on mechanisms driving the vascular complications of diabetes, with specific interests in retinopathy, atherogenesis, and pre-eclampsia.
The following is a summary of the work:
Some of the labs early work began in the 1980s, studying the effects of stresses present in the diabetic environment on long-lived connective tissue proteins. It was at this time that HbA1c was a novel marker of glycemic control, when the realization was dawning that post-translational modification of proteins was a general feature of the diabetic state, and could be an important ‘driver’ of complications. The simple hypothesis that ‘non-enzymatic glycosylation’, later termed ‘glycation’, of proteins might lead to functional damage was extended to encompass advanced glycation, which usually involved free-radical-mediated oxidative damage (‘glycoxidation’), and to modification of proteins by carbonyl-containing products derived from lipids (‘lipoxidation’). Also, it became evident that in addition to proteins (both extra- and intra-cellular), other large bio-molecules, including phospholipids and nucleic acids, could be modified by the same stresses. Dr. Lyons’ studies involved collagen isolated from skin biopsies from people without and with diabetes and, among the latter, either prone or resistant to its complications. Skin collagen was employed as a surrogate for collagens in other less accessible locations in the body. Here he demonstrated the relationships between collagen modification and complication status, the reversibility of early vs. late glycation, and the amplification of the oxidative component of ‘glycoxidation’ of collagen in people who were prone vs. resistant to complications. He was first to use the unifying term ‘carbonyl stress’ to provide a simple, comprehensible and unifying term for the immensely complex biochemistry involved in these processes.
Another area of study was of the effects of carbonyl stress on species with a short half-life in plasma, but a prolonged existence if trapped in ectopic extra-vascular locations. Diabetes-related modifications of complex biological systems, in which proteins, lipids, and carbohydrates are closely associated and functionally interdependent (e.g. in cell membranes, tight junctions etc.), yield an immense variety of products. To dissect and simplify the system, Dr. Lyons employed LDL as a model target, focusing on controlled, in vitro, modifications of the lipoprotein, and their consequences for cells exposed in cell culture. Mildly-modified glycated LDL simulated effects of hyperglycemia in the circulation (an anti-oxidant plasma environment); ‘heavily-oxidized glycated LDL’ simulated effects of prolonged exposure to glucose and oxidative stress that follow extravasation and sequestration. Initial work focused on atherogenesis, and showed that even mildly modified LDL could induce foam cell formation, and thus that lipoprotein ‘quality’, not just quantity, was important.
The work above was extended to show that the effects of extravasated, modified plasma lipoproteins are not confined to atherogenesis. Noting that in diabetic patients, retinal vascular leakage is an early feature (the result of diabetes-related compromise of the blood retinal barrier) I hypothesized that extravasated and modified plasma lipoproteins might play a crucial but unrecognized role in propagating diabetic retinopathy. Dr. Lyons showed that modified LDL was toxic to retinal pericytes in culture, later demonstrating that ectopic oxidized and ‘immune-complexed, modified’ LDL is indeed present in the diabetic retina, and then that it may injure many different types of retinal cell. He developed a new animal model of DR employing modified LDL to accelerate retinal injury.
Ongoing Studies in the Lab
Markers and Mechanisms of Preeclampsia in Type I Diabetes (MAMPED) is a study Dr. Lyons initiated with the realization that pre-eclampsia (PE) is a complication of diabetes that develops within months, during pregnancy – thus an accelerated ‘model’ for prospective study. It was initiated in 2001 and was the first of its kind. The causes of PE are poorly understood. Most studies have been performed late in pregnancy when the condition has already become established. PE has been associated with oxidative stress, abnormal blood lipids (cholesterol and triglycerides) and altered function of cells which line blood vessels suggesting that PE is a disease of blood vessels, likely beginning in the placenta. However, it was not clear what is cause and what is effect. The complications of diabetes are also diseases of blood vessels, and exhibit associations similar to those for PE. Moreover, as with the eye and kidney complications of diabetes, the risk of PE in pregnant diabetic women is related to blood sugar control. There were few studies investigating risk factors for PE in the general population from early pregnancy through to term, and almost none investigating PE in diabetic women.
Pre-eclampsia in American Indian Women with Type 2 Diabetes: As in Type 1 diabetes, PE is increased in women with Type 2 diabetes and American Indians are experiencing a particularly severe “epidemic” of Type 2 diabetes. Again, many studies of PE have excluded women with Type 2 diabetes, particularly those from minority groups. To address these issues, Dr. Lyons, partnering with the Choctaw and Chickasaw Nations, in conjunction with colleagues, initiated this multi-center prospective study of pregnant women with Type 2 diabetes.
The ‘Diabetes Control and Complications Trial’ (DCCT) and its follow up study, ‘Epidemiology of Diabetes and Complications’ (EDIC): DCCT/EDIC has followed 1,441 people with Type 1 diabetes since the mid-1980s. Over 95% of the 1,200 surviving participants remain under follow-up, and the information gained is widely considered to have revolutionized diabetes care, driving an on-going (and very challenging) effort to normalize blood glucose levels to prevent complications. Importantly, Charleston-based investigators collaborated closely with the DCCT since its outset, bringing new ideas and gaining their own major program funding for laboratory-based work. The DCCT/EDIC sample collection is the result of decades of work by thousands of researchers and study subjects, with millions of dollars invested by many agencies, primarily the NIH. Work is likely to continue for the rest of the lives of the study participants, i.e. for another 20+ years.