Epidemiology of type 2 diabetes and cardiovascular disease: translation from population to prevention: the Kelly West award lecture 2009.
ABSTRACT: In the book Epidemiology of Diabetes and Its Vascular Lesions (1978), Kelly West summarized extant knowledge of the distribution and causes of diabetes. The 30 years of epidemiological research that followed have seen remarkable advances in the understanding of obesity as a risk factor for type 2 diabetes, and diabetes and pre-diabetes as risk factors for cardiovascular disease. Increasingly detailed understanding of these relationships has, unfortunately, been accompanied by an alarming increase in the prevalence of obesity, diabetes, and cardiovascular disease. West recognized that pre-diabetes is recognizable as what we now call metabolic syndrome. He predicted that novel insight into diabetes pathogenesis would come from biochemical and genetic epidemiology studies. He predicted that type 2 diabetes could be prevented by healthy lifestyle change. The challenge now is for us to translate these insights into effective strategies for the prevention of the modern epidemic of diabetes and vascular disease.
Project description:The Edwin Bierman Award Lecture is presented in honor of the memory of Edwin L. Bierman, MD, an exemplary scientist, mentor, and leader in the field of diabetes, obesity, hyperlipidemia, and atherosclerosis. The award and lecture recognizes a leading scientist in the field of macrovascular complications and contributing risk factors in diabetes. Clay F. Semenkovich, MD, the Irene E. and Michael M. Karl Professor and Chief of the Division of Endocrinology, Metabolism and Lipid Research at Washington University School of Medicine in St. Louis, St. Louis, MO, received the prestigious award at the American Diabetes Association's 76th Scientific Sessions, 10-14 June 2016, in New Orleans, LA. He presented the Edwin Bierman Award Lecture, "We Know More Than We Can Tell About Diabetes and Vascular Disease," on Sunday, 12 June 2016.Diabetes is a disorder of abnormal lipid metabolism, a notion strongly supported by the work of Edwin Bierman, for whom this eponymous lecture is named. This abnormal lipid environment continues to be associated with devastating vascular complications in diabetes despite current therapies, suggesting that our understanding of the pathophysiology of blood vessel disease in diabetes is limited. In this review, potential new insights into the nature of diabetic vasculopathy will be discussed. Recent observations suggest that while the concept of distinct macrovascular and microvascular complications of diabetes has been useful, vascular diseases in diabetes may be more interrelated than previously appreciated. Moreover, the intermediary metabolic pathway of de novo lipogenesis, which synthesizes lipids from simple precursors, is robustly sensitive to insulin and may contribute to these complications. De novo lipogenesis requires fatty acid synthase, and recent studies of this enzyme suggest that endogenously produced lipids are channeled to specific intracellular sites to affect physiology. These findings raise the possibility that novel approaches to treating diabetes and its complications could be based on altering the intracellular lipid milieu.
Project description:The past decade has witnessed an exponential increase in our ability to search the genome for genetic factors predisposing to cardiovascular disease (CVD) and in particular coronary heart disease (CHD). Identifying these genes could lead to the development of innovative strategies to prevent the cardiovascular complications of diabetes by allowing us to 1) create predictive algorithms for the identification of patients at especially high risk of CVD so that these individuals can undergo preventive interventions early in the natural history of the disease; 2) discover as yet unknown disease pathways linking diabetes to atherosclerosis, which can be used as targets for the development of new CVD-preventing drugs specifically directed at subjects with diabetes; and 3) devise personalized programs increasing the cost-effectiveness of preventive interventions by tailoring them to the genetic background of each patient. Substantial progress has been made in each of these three areas as exemplified by the recent development of a CHD genetic risk score improving CHD prediction among subjects with type 2 diabetes, the discovery of a diabetes-specific CHD locus on 1q25 pointing to glutamine synthase (GLUL) and the ?-glutamyl cycle as key regulators of CHD risk in diabetes, and the identification of two genetic loci allowing the selection of patients with type 2 diabetes who may especially benefit from intensive glycemic control. Translating these discoveries into clinical practice will not be without challenges, but the potential rewards, from the perspective of public health as well as that of persons with diabetes, make this goal worth pursuing.
Project description:OBJECTIVE:Early initiation of intensive diabetes therapy aimed at achieving near-normal glycemia reduces the early development of vascular complications in type 1 diabetes. We now assess whether intensive therapy compared with conventional therapy during the Diabetes Control and Complications Trial (DCCT) affected the incidence of cardiovascular disease over 30 years of follow-up. RESEARCH DESIGN AND METHODS:The DCCT randomly assigned 1,441 patients with type 1 diabetes to intensive versus conventional therapy for a mean of 6.5 years, after which 93% were subsequently monitored during the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. Cardiovascular disease (nonfatal myocardial infarction and stroke, cardiovascular death, confirmed angina, congestive heart failure, and coronary artery revascularization) was adjudicated using standardized measures. RESULTS:During 30 years of follow-up in DCCT and EDIC, 149 cardiovascular disease events occurred in 82 former intensive treatment group subjects versus 217 events in 102 former conventional treatment group subjects. Intensive therapy reduced the incidence of any cardiovascular disease by 30% (95% CI 7, 48; P = 0.016), and the incidence of major cardiovascular events (nonfatal myocardial infarction, stroke, or cardiovascular death) by 32% (95% CI -3, 56; P = 0.07). The lower HbA1c levels during the DCCT/EDIC statistically account for all of the observed treatment effect on cardiovascular disease risk. Increased albuminuria was also independently associated with cardiovascular disease risk. CONCLUSIONS:Intensive diabetes therapy during the DCCT (6.5 years) has long-term beneficial effects on the incidence of cardiovascular disease in type 1 diabetes that persist for up to 30 years.
Project description:Our genetic background provides limited information on individual risk of developing vascular complications overtime. New biological layers, namely epigenetic modifications, are now emerging as potent regulators of gene expression thus leading to altered transcriptional programs and vascular disease phenotypes. Such epigenetic modifications, defined as changes to the genome that do not involve changes in DNA sequence, are generally induced by environmental factors and poor lifestyle habits. Of note, adverse epigenetic signals acquired during life can be transmitted to the offspring thus leading to premature alterations of the epigenetic and transcriptional landscape eventually leading to early endothelial dysfunction and vascular senescence. Modifications of the epigenome play a pivotal role in the pathophysiology of cardiometabolic disturbances such as obesity and type 2 diabetes. In these patients, changes of DNA methylation and chromatin structure contribute to alter pathways regulating insulin sensitivity, glucose homeostasis, adipogenesis and vascular function. In this perspective, unveiling the 'epigenetic landscape' in cardiometabolic patients may help to identify new players implicated in obesity and diabetes-related vascular dysfunction and may pave the way for personalized therapies in this setting. In the present review, we discuss current knowledge of the epigenetic routes implicated in vascular damage and cardiovascular disease in patients with metabolic alterations.
Project description:The genus Tsitsikamma Samaai & Kelly, 2002 is to date exclusively reported from South Africa. Three species are known from the southern coast: Tsitsikamma favus Samaai & Kelly, 2002, from the Garden Route National Park Tsitsikamma Marine Protected Area (MPA) and Algoa Bay; T. pedunculata Samaai, Gibbons, Kelly and Davies-Coleman, 2003, collected from Cape Recife in St. Francis Bay, and T. scurra Samaai, Gibbons, Kelly and Davies-Coleman, 2003, collected from a wreck site in a small bay west of Hout Bay on the west coast of South Africa. Here two new species are described: Tsitsikamma michaeli Parker-Nance, sp. nov., a small green purse-like species, collected from Algoa Bay, and Tsitsikamma nguni Parker-Nance, sp. nov., from The Garden Route National Park, Tsitsikamma MPA. Additional morphological characteristics, spicule morphology, and distribution records are provided for T. favus and T. pedunculata from Algoa Bay. The phylogenetic relationship of these five Tsitsikamma species is investigated.
Project description:BACKGROUND:Obesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations that give rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined. Increasing evidence suggests that endothelial cells are not a population of uniform cells but are highly heterogeneous and are organized as a communicating multicellular network that controls vascular function. PURPOSE:To investigate the hypothesis that disrupted endothelial heterogeneity and network-level organization contribute to impaired vascular reactivity in obesity. METHODS AND RESULTS:To study obesity-related vascular function without complications associated with diabetes, a state of prediabetic obesity was induced in rats. Small artery diameter recordings confirmed nitric-oxide mediated vasodilator responses were dependent on increases in endothelial calcium levels and were impaired in obese animals. Single-photon imaging revealed a linear relationship between blood vessel relaxation and population-wide calcium responses. Obesity did not alter the slope of this relationship, but impaired calcium responses in the endothelial cell network. The network comprised structural and functional components. The structural architecture, a hexagonal lattice network of connected cells, was unchanged in obesity. The functional network contained sub-populations of clustered specialized agonist-sensing cells from which signals were communicated through the network. In obesity there were fewer but larger clusters of sensory cells and communication path lengths between clusters increased. Communication between neighboring cells was unaltered in obesity. Altered network organization resulted in impaired, population-level calcium signaling and deficient endothelial control of vascular tone. CONCLUSIONS:The distribution of cells in the endothelial network is critical in determining overall vascular response. Altered cell heterogeneity and arrangement in obesity decreases endothelial function and provides a novel framework for understanding compromised endothelial function in cardiovascular disease.
Project description:Cardiovascular disease (CVD) and type 2 diabetes remain significant public health concerns. Targeting of prevention efforts by geographical location has been suggested by the Institute of Medicine to coincide with the presence of area-based risk. The metabolic syndrome (MetS) is a stronger risk factor than is obesity for the prediction of future CVD and diabetes, yet its prevalence has not previously been described geographically. Our objective is to determine geographical variation in the prevalence of obesity, MetS, and diabetes among US adults. We assessed the prevalence of obesity, MetS, and diabetes by US census division, and the prevalence of obesity, MetS, and diabetes for each sex and racial/ethnic group by US region among 9826 US non-Hispanic white, non-Hispanic black, and Hispanic adults aged 20-65 years participating in the National Health and Nutrition Examination Survey 1999-2014. We also compared a sex- and race/ethnicity-specific MetS severity score by geographical area. The prevalence of obesity, MetS, and diabetes varied by US census division and region, with overall similarity by geographical area in the prevalence of each of these conditions. The prevalence of MetS was particularly high (?35%) in the West North Central, West South Central, and East South Central and low (30%) in the Pacific, New England, and Mid-Atlantic divisions. Some of the geographical variation appeared due to differences among non-Hispanic white females, who had a high prevalence of MetS (>32%) in the Midwest and South and a low prevalence of MetS (24%) in the West and Northeast. Geographical differences in MetS imply variation in the risk for future CVD and diabetes, with more elevated risk in the center of the United States. As MetS is a stronger risk factor for prediction of CVD and T2DM than is obesity, these differences are potentially important for prompting public health efforts toward surveillance and prevention in high-risk areas.
Project description:Syndrome X is a combination or co-occurrence of several known cardiovascular risk factors (including central obesity, dyslipidemias, fatty liver disease, hyperinsulinemia, insulin resistance, and hypertension) that affects at least one in five people in developed countries. Syndrome X shortens life and increases morbidity by contributing to the development of both diabetes and cardiovascular disease. Type 1 or 2 diabetes affects approximately 170 million people globally and these numbers are rapidly rising. In patients with diabetes, vascular diseases develop early and progress at an accelerated rate. It has recently become evident that glucose-6-phosphate dehydrogenase (G6PD), the rate limiting enzyme in the pentose-phosphate pathway and its reaction products play key roles in regulating vascular function. Epidemiological studies have also shown that G6PD deficiency markedly reduces retinopathy and mortality due to cardiovascular diseases in males from certain Mediterranean regions. Conversely, G6PD expression and activity are upregulated in rat and mouse models of obesity, hyperglycemia and hyperinsulinemia, and a role for G6PD in the development of insulin resistance in type 2 diabetes has been proposed. Unfortunately, there are no selective drugs available to validate the hypothesis that G6PD and its products are involved in the development of Syndrome X in humans. This review discusses the potential mechanisms by which G6PD could be implicated in vascular diseases in Syndrome X and the need to develop new approaches, including new drugs and molecular tools, to ameliorate diabetes-induced vascular dysfunction and vasculopathies.
Project description:OBJECTIVES:To evaluate the prevalence and coprevalence of several chronic conditions in patients with type 2 diabetes in a Mediterranean region. DESIGN:A cross-sectional study. SETTING:Two hundred and eighty-six primary care teams of the Catalonian Health Institute (Catalonia, Spain). PARTICIPANTS:We included patients aged ?18 years with a diagnosis of type 2 diabetes by 31 December, 2016, who were registered in the Information System for the Development of Research in primary care (SIDIAP) database. We excluded patients with a diagnosis of type 1 diabetes, gestational diabetes mellitus and any other type of diabetes. PRIMARY AND SECONDARY OUTCOME MEASURES:We collected data on diabetes-related comorbidities (ie, chronic complications, associated cardiovascular risk factors and treatment complications). Diagnoses were based on the International Classification of Diseases, 10th Revision codes recorded in the database or, for some entities, on the cut-off points for a particular test result or a specific treatment indicated for that entity. The presence and stage of chronic kidney disease (CKD) were based on the glomerular filtration rate, the CKD Epidemiology Collaboration creatinine equation and the urine albumin-to-creatinine ratio. RESULTS:A total of 373?185 patients were analysed. 82% of patients exhibited ?2 comorbidities and 31% exhibited ?4 comorbidities. The most frequent comorbidities were hypertension (72%), hyperlipidaemia (60%), obesity (45%), CKD (33%), chronic renal failure (CRF)(28%) and cardiovascular disease (23%). The most frequently coprevalent pairs of chronic conditions were the combination of hypertension with hyperlipidaemia (45%), obesity (35%), CKD (28%), CRF (25%) or cardiovascular disease (19%), as well as the combination of hyperlipidaemia with obesity (28%), CKD (21%), CRF (18%) or cardiovascular disease (15%); other common pairs of comorbidities were obesity/CKD, obesity/CRF, hypertension/retinopathy, hypertension/albuminuria, hypertension/urinary tract infection, CVD/CRF and CVD/CKD, which were each present in more than 10% of patients. CONCLUSION:Patients with type 2 diabetes have a high frequency of coprevalence of metabolic risk factors, cardiovascular disease and CKD and thus require an integrated management approach.
Project description:Hypertension and type 2 diabetes are common comorbidities. Hypertension is twice as frequent in patients with diabetes compared with those who do not have diabetes. Moreover, patients with hypertension often exhibit insulin resistance and are at greater risk of diabetes developing than are normotensive individuals. The major cause of morbidity and mortality in diabetes is cardiovascular disease, which is exacerbated by hypertension. Accordingly, diabetes and hypertension are closely interlinked because of similar risk factors, such as endothelial dysfunction, vascular inflammation, arterial remodelling, atherosclerosis, dyslipidemia, and obesity. There is also substantial overlap in the cardiovascular complications of diabetes and hypertension related primarily to microvascular and macrovascular disease. Common mechanisms, such as upregulation of the renin-angiotensin-aldosterone system, oxidative stress, inflammation, and activation of the immune system likely contribute to the close relationship between diabetes and hypertension. In this article we discuss diabetes and hypertension as comorbidities and discuss the pathophysiological features of vascular complications associated with these conditions. We also highlight some vascular mechanisms that predispose to both conditions, focusing on advanced glycation end products, oxidative stress, inflammation, the immune system, and microRNAs. Finally, we provide some insights into current therapies targeting diabetes and cardiovascular complications and introduce some new agents that may have vasoprotective therapeutic potential in diabetes.