Circulation Research Thematic Synopsis Diabetes and Obesity

Abstract

HomeCirculation ResearchVol. 113, No. 7Circulation Research Thematic Synopsis Diabetes and Obesity Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCirculation Research Thematic Synopsis Diabetes and Obesity The Editors The Editors Search for more papers by this author Originally published13 Sep 2013https://doi.org/10.1161/CIRCRESAHA.113.302431Circulation Research. 2013;113:e62–e75IntroductionDiabetes and obesity have emerged as global epidemics. At present more than 150 million individuals worldwide are living with diabetes and this number is expected to increase by 30% by 2015 and double to 300 million by 2025. In the US alone, there are 18.2 million diabetics (6.3% of the total population) and an estimated 1.3 million new cases are expected to be diagnosed each year.1 Diabetes and insulin resistance, fueled by pandemic obesity, has emerged as an explosive worldwide epidemic that encompasses all ethnicities, economic classes, and age groups.2–4 While diabetes affects several organs systems and disease processes, heart disease is the leading cause of death in diabetics. Both diabetes and cardiovascular disease share a common set of risk factors, and therefore it has been suggested that the two diseases share a similar etiology (the “common soil” hypothesis) and that diabetes and cardiovascular disease share overlapping, if not identical, molecular and cellular mechanisms. Not only does insulin resistance originate from cardiovascular dysfunction, but cardiovascular tissues are the primary targets of diabetes and obesity. Patients with both type 1 and type 2 diabetes are at high risk for developing cardiovascular disease and nearly 70% of diabetics die of heart disease.5 Nevertheless, diabetes and its cardiovascular complications remain poorly understood. The processes that cause insulin resistance remain unknown and the mechanisms by which diabetes accelerates cardiovascular disease are unclear.6It is currently believed that diabetes and obesity are metabolic states that lead to chronic low-grade inflammation.7 Although the origins of such inflammation remain unknown, it is becoming increasingly clear that metabolism is inextricably linked to immunity and that the two regulate each other. Because energy is required to fight infection, starvation suppresses immune responses. Inflammation and infection, in turn, favor catabolism and down-regulate anabolic signals such as those triggered by insulin. The emerging paradigm is that metabolic imbalance leads to immune imbalance. Obesity and other insulin-resistant states are characterized by a broad spectrum of inflammatory responses involving several cytokines, chemokines and inflammatory mediators.8 It has also become evident that metabolic mediators regulate immune function (leptin for instance is responsible for immunosuppression during starvation) and that lipids themselves regulate immunity. Both saturated lipids and products derived from the oxidation of unsaturated lipids have been shown to be potent regulators of immune responses. The documented ability of lipids to trigger and sustain inflammation is consistent both with a critical role of hyperlipidemia in inducing peripheral insulin resistance in obesity and diabetes and with the contribution of dyslipidemia and LDL oxidation to vascular inflammation and arterial lesion formation during atherogenesis.Accumulating suggests that endothelial dysfunction may be another critical feature of the injury induced by nutrient excess that leads to metabolic changes resulting in an increase in adiposity and systemic insulin resistance. Endothelial dysfunction is robustly and positively linked to a decrease in nitric oxide (NO) production. When mice are fed a high fat diet, the endothelium becomes resistant to insulin before any other tissue.9 Similarly, studies with human diabetics demonstrate that loss of NO precedes the development of T2D.5 In addition, it has been reported that deletion of endothelial NO synthase (eNOS) in mice is associated with adiposity and insulin resistance.10 Recent work published in Circulation Research indicates that overexpression of endothelial nitric oxide synthase (eNOS) prevents diet-induced obesity in mice11 and that mitochondrial uncoupling in the endothelium, by decreasing the production of reactive oxygen species, increases NO availability and prevents endothelial dysfunction in diet-induced obesity.12 Therefore, therapies that increase NO production might be useful in preventing obesity as well as endothelial dysfunction in diabetes and obesity.In addition to the endothelium, diabetes also affects the heart. While under normal conditions, the heart is an omnivore, and utilizes both carbohydrates and lipids during diabetes increased free fatty acids in the heart exceed the oxidative capacity of the myocytes resulting lipid accumulation and lipotoxicity.8 Cardiac dysfunction in diabetes is also associated with amylin deposition, which disrupts cardiac structure and function.13 Most surprisingly, recent work has shown that the heart regulates systemic energy homeostasis and that cardiac-specific expression of MED13, which controls gene transcription by the thyroid hormone and other nuclear hormone receptors, improves insulin sensitivity and confers protection against diet-induced obesity.14 These findings completely revise our view of systemic energy homeostasis and could lead to the development of new therapeutic interventions to prevent diabetes and obesity and their devastating cardiovascular complications.Circulation Research is leading the way in disseminating diabetes and obesity research by publishing original manuscripts, review articles, editorial and commentaries in this field.The following represents a selection of recently published Circulation Research articles on diabetes and obesity, presented in their reverse order of publication. Articles highlighted in yellow represent the top 10 most read original research articles selected based on the number of Full Text/PDF downloads, adjusted to compensate for differences in the length of time since online publication.Adipose Tissue Biology and Cardiomyopathy: Translational Implications [Review]; Turer et al8AbstractIt is epidemiologically established that obesity is frequently associated with the metabolic syndrome and poses an increased risk for the development of type 2 diabetes mellitus and cardiovascular disease. The molecular links that connect the phenomenon of obesity, per se, with insulin resistance and cardiovascular disease are still not fully elucidated. It is increasingly apparent that fully functional adipose tissue can be cardioprotective by reducing lipotoxic effects in other peripheral tissues and by maintaining a healthy balance of critical adipokines, thereby allowing the heart to maintain its full metabolic flexibility. The present review highlights both basic and clinical findings that emphasize the complex interplay of adipose tissue physiology and adipokine-mediated effects on the heart exerted by either direct effects on cardiac myocytes or indirect actions via central mechanisms through sympathetic outflow to the heart.Acute Psychological Stress Accelerates Reverse Cholesterol Transport via Corticosterone-Dependent Inhibition of Intestinal Cholesterol Absorption; Silvennoinen et al15What Is Known?Stress in humans is considered a risk factor of atherosclerosis, but its effects on experimental atherogenesis are model dependent.Reverse cholesterol transport (RCT) is a multistep pathway for elimination of cholesterol in feces, but only the RCT fraction that originates in macrophages (macrophage-RCT) is relevant for atherosclerosis.Peroxisome proliferator–activated receptors and liver X receptors regulate intestinal cholesterol homeostasis via several target genes, particularly the gene encoding Niemann Pick C1–like 1 protein, the major transporter facilitating cholesterol influx into the enterocyte.What New Information Does This Article Contribute?Restraint stress in mice, a model of psychological stress in humans, accelerates the rate of macrophage-RCT by suppressing cholesterol absorption in small intestine.Administration of corticosterone, the stress hormone in rodents, to nonstressed mice upregulates the peroxisome proliferator–activated receptors-α gene and downregulates Niemann-Pick C1–like 1 protein in the small intestine, and fully reproduced the effect of stress on macrophage-RCT.The mechanism of the stress-induced RCT response of the intestine appears to involve a complex cross-talk among corticosterone, peroxisome proliferator–activated receptor (PPAR)α, and liver X receptor (LXR)α.ConclusionsAcute psychological stress accelerated RCT by compromising intestinal cholesterol absorption. The present results uncover a novel functional connection between the hypothalamic-pituitary-adrenal axis and RCT that can be triggered by a stress-induced increase in circulating CORT.Myeloid Cell−Specific ABCA1 Deletion Protects Mice From Bacterial Infection; Zhu et al16What Is Known?ATP-binding cassette transporter AI (ABCA1) is a plasma membrane protein that transports cellular free cholesterol and phospholipids to lipid-free apolipoprotein AI, forming nascent high-density lipoprotein particles and eliminating excess free cholesterol from tissues.ABCA1 attenuates macrophage inflammation by downregulating toll-like receptor signaling via reducing free cholesterol enrichment in membrane lipid rafts and the trafficking of toll-like receptors into rafts.What New Information Does This Article Contribute?Myeloid cell–specific ABCA1 knockout (MSKO) mice are more resistance to acute infection with intracellular bacteria Listeria monocytogenes (Lm) compared with wild-type mice.MSKO mice infected with Lm have enhanced macrophage chemotaxis and increased hepatic chemokine expression, resulting in more rapid and efficient clearance and killing of Lm.Lm infection reduces expression of macrophage cholesterol export proteins, suggesting that diminished myeloid cholesterol efflux enhances macrophage innate immune function.ConclusionsMyeloid-specific ABCA1 deletion favors host response to and clearance of Lm. Macrophage Lm infection reduces expression of cholesterol export proteins, suggesting that diminished cholesterol efflux enhances innate immune function of macrophages.Restraint Stress Restrains Cholesterol in the Intestine [Editorial]; von Eckardstein17AbstractEpidemiological studies have observed that psychosocial stress, for example, by unemployment, low socioeconomic status, or work stress, increases the risk of cardiovascular events.1 The pathophysiological basis of this association is poorly understood. Restraint stress, which is an experimental model for psychosocial stress, is characterized by the activation of the sympathetic nervous system involving the fast release of epinephrine and norepinephrine and the hypothalamic-pituitary-adrenal axis, resulting in a slow but sustained increase in circulating glucocorticoids.2 Both neuroendocrine axes elicit multiple and complex responses, aiming to protect the threatened organism. As yet, there is little and mixed epidemiological evidence about which of these pathways is relevant for the pathogenesis of cardiovascular diseases.3 to 6 Diurnal and other intraindividual variation of cortisol and catecholamine plasma concentrations make the design of meaningful observational studies difficult. More recently, measurements of cortisol in saliva or urine found positive associations between cortisol and risk of incident coronary events.5,6 Elevated cortisol levels in plasma or saliva have also been associated with increased blood pressure, diabetes mellitus, hyperglycemia, hypertriglyceridemia, and central adiposity. However, these associations have been questioned by 2 recent population studies that did not find any significant association of cortisol awakening response, evening cortisol, cortisol decline across the waking day, total cortisol output, and cortisol after dexamethasone suppression with metabolic syndrome or its individual componentsOverexpression of Endothelial Nitric Oxide Synthase Prevents Diet-Induced Obesity and Regulates Adipocyte Phenotype; Sansbury et al11What Is Known?Obesity is positively and robustly associated with the risk of development of cardiovascular disease and diabetes.Vascular dysfunction and, in particular, deficits in endothelial-derived nitric oxide (NO) production and bioavailability are associated with insulin resistance, adiposity, and deleterious changes in metabolism.What New Information Does This Article Contribute?The expression of endothelial NO synthase (eNOS) in adipose tissue is decreased in mouse models of obesity and type 2 diabetes.Transgenic overexpression of eNOS in mice decreases circulating fatty acids and prevents obesity and hyperinsulinemia induced by a high-fat diet.Overexpression of eNOS prevents adipocyte hypertrophy, increases mitochondrial abundance and activity, and regulates branched chain amino acid metabolism.ConclusionsThese findings demonstrate that increased eNOS activity prevents the obesogenic effects of high-fat diet without affecting systemic insulin resistance, in part, by stimulating metabolic activity in adipose tissue.STIM1 Restores Coronary Endothelial Function in Type 1 Diabetic Mice; Estrada et al18What Is Known?Coronary vascular endothelial dysfunction is implicated in the development and progression of cardiac ischemia and heart failure due to a decrease in coronary blood flow.The Ca2+ concentration in the endoplasmic reticulum (ER) is important for generating critical Ca2+ signals to mediate endothelium-dependent vasodilation.Stromal interaction molecule (STIM) protein (eg, STIM1) is an important regulator that activates Ca2+-permeable channels in the plasma membrane after depletion of Ca2+ from the ER and refill Ca2+ into the ER.What New Information Does This Article Contribute?Protein expression of STIM1 is significantly downregulated and the Ca2+ concentration in the ER is markedly decreased in coronary endothelial cells in diabetes in comparison to coronary endothelial cells isolated from controls.Downregulated STIM1 in diabetic coronary endothelial cells contributes to the decreased Ca2+ concentration in the ER and results in significant inhibition of endothelium-dependent coronary vasodilation.Restoration of STIM1 protein expression in coronary endothelial cells has a beneficial effect on coronary endothelial dysfunction in diabetes.ConclusionsImpaired ER Ca2+ refilling in diabetic MCECs, due to the decrease in STIM1 protein expression, attenuates endothelium-dependent relaxation in diabetic coronary arteries, while STIM1 overexpression has a beneficial and therapeutic effect on coronary endothelial dysfunction in diabetes.HDL and Cardiovascular Risk: Time to Call the Plumber? [Commentary]; Hewing et al19AbstractHigh-density lipoprotein cholesterol (HDL-C) has been dubbed the good cholesterol because it is thought to reflect the ability of HDL particles to remove excess cholesterol molecules from peripheral cells (including those in atherosclerotic plaques) for return to the liver. Not surprisingly, then, HDL-C has frequently been assumed to be a biomarker of HDL function, consistent with the inverse relationship in observational studies between plasma levels of HDL-C and risk of coronary artery disease. Recently, Voight et al have challenged this assumption by showing that genetically elevated HDL-C did not protect against myocardial infarction. This finding has fueled a lively discussion in the lay, scientific, and medical press about the relationship between HDL-C and HDL function, and the potential effectiveness of various HDL-C raising strategies.A New Approach to Weight Loss: Just Activate Endothelial NO Synthase! [Editorial]; Sessa20AbstractSustained consumption of dietary fats induces endothelial dysfunction and insulin resistance in experimental models and humans. Endothelial dysfunction, manifested by reduced endothelium-dependent dilation, is a hallmark of several cardiovascular diseases and obesity. Indeed, exercise training and caloric restriction attenuate endothelial dysfunction and delay the onset or reduce the magnitude of vascular diseases and insulin resistance.RTEF-1 Attenuates Blood Glucose Levels by Regulating Insulin-Like Growth Factor Binding Protein-1 in the Endothelium; Messmer-Blust et al21What Is Known?Related transcriptional enhancer factor-1 (RTEF-1) plays an important role in cardiac and endothelial cell function.Insulin-like growth factor binding proteins (IGFBPs) are key regulators of insulin-like growth factor at the cellular level.Low levels of IGFBP-1 are associated with metabolic syndrome and cardiovascular diseases.What New Information Does This Article Contribute?RTEF-1 increases IGFBP-1 gene expression by interacting with its insulin response element.RTEF-1 deficiency in endothelial cells exhibited increased blood glucose and insulin sensitivity in vivo.The increased blood glucose and insulin sensitivity shown in RTEF-1 deficiency in vivo was exacerbated in a high-fat diet, correlating with decreasing IGFBP-1 levels.ConclusionsTo the best of our knowledge, this is the first report demonstrating that RTEF-1 stimulates promoter activity through an insulin response element and also mediates the effects of insulin on gene expression. These results show that RTEF-1–stimulated IGFBP-1 expression may be central to the mechanism by which RTEF-1 attenuates blood glucose levels. These findings provide the basis for novel insights into the transcriptional regulation of IGFBP-1 and contribute to our understanding of the role of vascular endothelial cells in metabolism.Microvascular Management of Systemic Insulin Sensitivity [Editorial]; Rubinow & Bornfeldt22AbstractMicrovascular disease is a well-recognized complication of long-standing diabetes mellitus and is preceded by impaired vasoreactivity, a consequence largely of decreased endothelial cell (EC) generation of NO. This loss of normal vasodilation is evident particularly in EC responses to insulin and may arise early in states of obesity and insulin resistance.1 to 3 In addition, ECs serve as purveyors of other paracrine signals, with targets beyond vascular cells. Thus, a broader scope of endothelial function is being recognized, with increased attention now focused on the dynamic interactions between the microvasculature and surrounding tissues. Indeed, recent findings suggest that ECs might be critical metabolic mediators, obscuring a clear boundary between vascular biology and metabolism. Accordingly, dysregulated EC function may prove to be not only a sequela of diabetes mellitus but also a contributing factor to the pathogenesis and progression of metabolic disease.Novel Biological Functions of High-Density Lipoprotein Cholesterol [Review]; Mineo & Shaul23AbstractIn addition to its role in reverse cholesterol transport, high-density lipoprotein (HDL) cholesterol has direct action on numerous cell types that influence cardiovascular and metabolic health. Cellular responses to HDL entail its capacity to invoke cholesterol efflux that causes signal initiation via scavenger receptor class B, type I, and plasma membrane receptor activation by HDL cargo molecules. In endothelial cells and their progenitors, HDL attenuates apoptosis and stimulates proliferation and migration. HDL also has diverse anti-inflammatory actions in both endothelial cells and leukocytes. In vascular smooth muscles, HDL tempers proinflammatory, promigratory, and degradative processes, and through actions on endothelium and platelets HDL is antithrombotic. There are additional actions of HDL of potential cardiovascular consequence that are indirect, including the capacities to promote pancreatic β-cell insulin secretion, to protect pancreatic β cells from apoptosis, and to enhance glucose uptake by skeletal muscle myocytes. Furthermore, HDL decreases white adipose tissue mass, increases energy expenditure, and promotes the production of adipose-derived cytokine adiponectin that has its own vascular-protective properties. Many of these numerous actions of HDL have been observed not only in cell culture and animal models but also in human studies, and assessments of these functions are now being applied to patient populations to better-elucidate which actions of HDL may contribute to its cardioprotective potential and how they can be quantified and targeted. Further work on the many mechanisms of HDL action promises to reveal new prophylactic and therapeutic strategies to optimize both cardiovascular and metabolic health.IRF-1 and miRNA126 Modulate VCAM-1 Expression in Response to a High-Fat Meal; Sun et al24What Is Known?Diets high in fat are associated with hypertriglyceridemia and increased risk of cardiovascular disease.Cholesterol and fatty acids transported by lipoprotein particles exacerbate systemic inflammation and can initiate plaque formation in arteries.Genetics, diet, and lifestyle choices coalesce in determining the extent to which inflammation triggers atherosclerosis.What New Information Does This Article Contribute?Subjects consuming an identical high-fat meal produced and circulated lipoproteins that segregated into subsets eliciting either a proinflammatory or anti-inflammatory response in arterial endothelial cells.A direct correlation was found between an increase in particle density of triglycerides and expression of VCAM-1 receptors that supported monocyte adhesion to endothelium, a harbinger or atherosclerosis.We identified a molecular mechanism by which uptake of lipoproteins bias the inflammatory response of endothelium via transcriptional and posttranscriptional editing of VCAM-1.ConclusionsIn response to a high-fat meal, TGRL bias the inflammatory response of endothelium via transcriptional and posttranscriptional editing of VCAM-1. Subjects with an anti-inflammatory response to a meal produced TGRL that was enriched in nonesterified fatty acids, decreased IRF-1 expression, increased miR-126 activity, and diminished monocyte arrest.Structural Identification and Cardiovascular Activities of Oxidized Phospholipids [Review]; Salomon25AbstractFree radical–induced oxidation of membrane phospholipids generates complex mixtures of oxidized phospholipids (oxPLs). The combinatorial operation of a few dozen reaction types on a few dozen phospholipid structures results in the production of a dauntingly vast diversity of oxPL molecular species. Structural identification of the individual oxPL in these mixtures is a redoubtable challenge that is absolutely essential to allow determination of the biological activities of individual species. With an emphasis on cardiovascular consequences, this Review focuses on biological activities of oxPLs whose molecular structures are known and highlights 2 diametrically opposite approaches that were used to determine those structures, that is, (1) the classic approach from bioactivity of a complex mixture to isolation and structural characterization of the active molecule followed by confirmation of the structure by unambiguous chemical synthesis and (2) hypothesis of products that are likely to be generated by lipid oxidation, followed by synthesis, and then detection in vivo guided by the availability of authentic standards, and last, characterization of biological activities. Especially important for the application of the second paradigm is the capability of LC-MS/MS and derivatizations to selectively detect and quantify specific oxPL in complex mixtures, without the need for their isolation or complete separation. This technology can provide strong evidence for identity by comparisons with pure, well-characterized samples available by chemical syntheses. Those pure samples are critical for determining the biological activities attributable to specific molecular species of oxPLs in the complex mixtures generated in vivo as a consequence of oxidative stress.Leptin Signaling in Adipose Tissue: Role in Lipid Accumulation and Weight Gain; Singh et al26What Is Known?Increased cardiovascular risk in obesity is mediated, in part, by the expansion of adipose tissue and elevated levels of adipokines, including leptin.Although the central role of leptin in energy homeostasis is well-known, its effects on peripheral cells such as adipocytes are unclear.In cultured vascular endothelial cells, high levels of leptin increase caveolin-1 expression, which in turn impairs leptin signaling.What New Information Does This Article Contribute?Leptin decreases the accumulation of lipids in adipocytes.In humans, increases in leptin seen with modest weight gain could increase adipose tissue caveolin-1 expression.Increased caveolin-1 expression in adipose tissue could impair leptin-dependent activation of signaling pathways and allow the storage of lipids in differentiating preadipocytes.ConclusionsIn healthy humans, increases in leptin, as seen with modest weight gain, may increase caveolin-1 expression in adipose tissue. Increased caveolin-1 expression in turn impairs leptin signaling and attenuates leptin-dependent lowering of intracellular lipid accumulation. Our study suggests a leptin-dependent feedback mechanism that may be essential to facilitate adipocyte lipid storage during weight gain.More Than Just an Engine: The Heart Regulates Body Weight [Commentary]; Taegtmeyer & Rodriguez27AbstractA recent study published in Cell may represent a paradigm shift in the way we look at cardiac metabolism: The study identifies the heart as an endocrine organ that regulates body weight. It raises two important questions: What would be the “slimming factor” released by the heart that regulates fuel homeostasis in distant organs? What are the possible mechanisms directing metabolic energy to either storage or dissipation?Gene Silencing of the Mitochondrial Adaptor p66Shc Suppresses Vascular Hyperglycemic Memory in Diabetes; Paneni et al28What Is Known?Recent prospective clinical trials have failed to confirm unequivocal benefits of glycemic control on cardiovascular outcomes.A long-term persistence of hyperglycemic stress even after blood glucose normalization has been recently defined as “hyperglycemic memory.”Reactive oxygen species (ROS) are likely involved in this phenomenon but the underlying molecular mechanisms remain unknown.What New Information Does This Article Contribute?Mitochondrial adaptor p66Shc is the key effector driving vascular hyperglycemic memory in diabetes.Persistent p66Shc upregulation is associated with continued ROS production, reduced nitric oxide (NO) availability, and apoptosis.p66Shc-derived ROS maintain protein kinase CβII (PKCβII) upregulation as well as inhibitory phosphorylation of endothelial NO synthase (eNOS) at Thr-495, leading to a detrimental vicious cycle despite restoration of normoglycemia.In vivo gene silencing of p66Shc, performed at the time of glucose normalization, suppresses persistent endothelial dysfunction and vascular apoptosis.Conclusionsp66Shc is the key effector driving vascular hyperglycemic memory in diabetes. Our study provides molecular insights for the progression of diabetic vascular complications despite glycemic control and may help to define novel therapeutic targets.Antibodies to PCSK9: A Superior Way to Lower LDL Cholesterol? [Commentary]; Maxwell & Breslow29AbstractLowering of LDL cholesterol, predominantly accomplished clinically by statins, is one of the key components of both the prevention and medical management of coronary atherosclerosis; however, additional or alternative cholesterol lowering agents are needed for patients who fail to achieve goals or have adverse effects on statins. Owing to relatively rapid translation of basic science research on a novel regulatory pathway of the LDL receptor by PCSK9, a new class of such drugs with a different mode of action, and potentially better tolerance and less off-target effects may be just over the horizon.Redox Mediating Epigenetic Changes Confer Metabolic Memories [Editorial]; El-Osta30AbstractIt’s not always the case that it’s easy to forgive and forget, particularly when it comes to past memories. The concept of the legacy effect or hyperglycemic memory describes the deferred consequence of antecedent glycemic status on the development of diabetic complications. Anyone researching chronic hyperglycemia appreciates that glucose is still considered the major risk factor implicated in the development and progression of diabetic vascular complications. Now, the same can be concluded for transient hyperglycemia. Large clinical studies have demonstrated that prior glycemic control has a sustained benefit in reducing subsequent diabetic complications.1 to 4 The Diabetes Control and Complications Trial (DCCT) and the follow-up study, Epidemiology of Diabetes Interventions and Complications (EDIC) have determined that episodes of poor glycemic control can lead many years later to the long-term complications of diabetes.5,6 The DCCT study was designed to compare intensive versus conventional approaches to improve glycemic control and determine the effects of these regimens on the development and progression of vascular complications in patients with type-1 diabetes. Because the development of diabetic microvascular complications and cardiovascular disease takes time, the follow-up EDIC study was designed to investigate the long-lasting effects of intensive and conventional therapies. The findings of these extended studies show that early intensive intervention was more effective in slowing the development of diabetic complications and this was clearly evidenced with the benefit of 6.5 years of intensive therapy duri