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1.  Consequences of Advanced Glycation End Products Accumulation in Chronic Kidney Disease and Clinical Usefulness of Their Assessment Using a Non-invasive Technique – Skin Autofluorescence 
Mædica  2011;6(4):298-307.
ABSTRACT
Accelerated formation and accumulation of advanced glycation end-products occur under circumstances of increased supply of substrates such as hyperglycaemic or oxidative stress and in age-related and chronic diseases like diabetes mellitus, chronic renal failure, neurodegenerative diseases, osteoarthritis and also non-diabetic atherosclerosis and chronic heart failure. Advanced glycation end-products accumulation occurs especially on long-lived proteins such as collagen in the skin and in vascular basement membranes leading to vascular damage. Adequate renal clearance capacity is an important factor in the effective removal of advanced glycation end-products. The Autofluorescence Reader was developed as a marker, representative for tissue advanced glycation end-products accumulation, easily applicable in a clinical setting, initially for predicting diabetes related complications. Studies have already shown a relationship between skin autofluorescence and diabetes complications, as well as its predictive value for total and cardiovascular mortality in type 2 diabetes. Moreover skin autofluorescence was demonstrated to be superior to Haemoglobin A1c and other conventional risk factors. Advanced glycation end-products have been proposed as a novel factor involved in the development and progression of chronic heart failure. Assessment of advanced glycation end-products accumulation in end-stage renal disease and undergoing renal replacement therapies patients has become of great importance. Cardiovascular and connective tissue disorders are very common in patients with end-stage renal disease, and the accumulation of advanced glycation end-products is significantly increased in these patients. Mortality is markedly increased in patients with decreased kidney function, particularly in patients with end-stage renal disease. Skin advanced glycation end-products levels are strong predictors of survival in haemodialysis patients independent of other established risk factors. The Autofluorescence Reader may be useful as a clinical tool for rapid assessment of risk for advanced glycation end-products related long-term complications, not only in diabetes, but in other conditions associated with advanced glycation end-products accumulation as well.
PMCID: PMC3391948  PMID: 22879845
advanced glycation end-products; skin autofluorescence; metabolic stess; chronic kidney disease
2.  Consequences of Aberrant Insulin Regulation in the Brain: Can Treating Diabetes be Effective for Alzheimer’s Disease 
Current Neuropharmacology  2011;9(4):693-705.
There is an urgent need for new ways to treat Alzheimer’s disease (AD), the most common cause of dementia in the elderly. Current therapies are modestly effective at treating the symptoms, and do not significantly alter the course of the disease. Over the years, a range of epidemiological and experimental studies have demonstrated interactions between diabetes mellitus and AD. As both diseases are leading causes of morbidity and mortality in the elderly and are frequent co-morbid conditions, it has raised the possibility that treating diabetes might be effective in slowing AD. This is currently being attempted with drugs such as the insulin sensitizer rosiglitazone. These two diseases share many clinical and biochemical features, such as elevated oxidative stress, vascular dysfunction, amyloidogenesis and impaired glucose metabolism suggesting common pathogenic mechanisms. The main thrust of this review will be to explore the evidence from a pathological point of view to determine whether diabetes can cause or exacerbate AD. This was supported by a number of animal models of AD that have been shown to have enhanced pathology when diabetic conditions were induced. The one drawback in linking diabetes and insulin to AD has been the postmortem studies of diabetic brains demonstrating that AD pathology was not increased; in fact decreased pathology has often been reported. In addition, diabetes induces its own distinct features of neuropathology different from AD. There are common pathological features to be considered including vascular abnormalities, a major feature arising from diabetes; there is increasing evidence that vascular abnormalities can contribute to AD. The most important common mechanism between insulin-resistant (type II) diabetes and AD could be impaired insulin signaling; a form of toxic amyloid can damage neuronal insulin receptors and affect insulin signaling and cell survival. It has even been suggested that AD could be considered as “type 3 diabetes” since insulin can be produced in brain. Another common feature of diabetes and AD are increased advanced glycation endproduct-modified proteins are found in diabetes and in the AD brain; the receptor for advanced glycation endproducts plays a prominent role in both diseases. In addition, a major role for insulin degrading enzyme in the degradation of Aβ peptide has been identified. Although clinical trials of certain types of diabetic medications for treatment of AD have been conducted, further understanding the common pathological processes of diabetes and AD are needed to determine whether these diseases share common therapeutic targets.
doi:10.2174/157015911798376334
PMCID: PMC3263463  PMID: 22654727
Alzheimer’s disease; pathology; neurodegeneration; glucose metabolism; amyloid beta.
3.  Skin Autofluorescence: A Pronounced Marker of Mortality in Hemodialysis Patients 
Nephron Extra  2012;2(1):184-191.
Background
Accelerated formation and tissue accumulation of advanced glycation endproducts (AGEs), reflecting cumulative glycemic and oxidative stress, occur in age-related and chronic diseases like diabetes mellitus (DM) and renal failure, and contribute to vascular damage. Skin autofluorescence (AF), a noninvasive measurement method, reflects tissue accumulation of AGEs. The aim of our study was to determine the predictive value of skin AF on overall and cardiovascular mortality in hemodialysis patients.
Methods
Baseline skin AF was measured in 105 patients on hemodialysis, 23 had DM. Survival status was assessed after a mean follow-up period of 4.9 years (interquartile range 2.3–6.9 years).
Results
Multivariate Cox regression analysis showed skin AF (hazard ratio (HR) 1.83; 95% confidence interval (CI) 1.32–2.54), preexisting cardiovascular disease (CVD) (HR 2.77; 95% CI 1.48–5.18), renal replacement therapy duration (HR 1.10; 95% CI 1.01–1.19), age (HR 1.03; 95% CI 1.01–1.06), serum albumin (HR 0.90; 95% CI 0.85–0.95), hematocrit (HR 0.92; 95% CI 0.86–0.98), phosphorus (HR 2.01; 95% CI 1.15–3.49), and parathyroid hormone (HR 0.99; 95% CI 0.98–0.996) to be predictors of mortality, whereas DM was not. Preexisting CVD and serum phosphorus were the only predictors of cardiovascular mortality.
Conclusion
Skin AF showed to be an independent predictor of overall mortality in hemodialysis patients, but it had no predictive value for cardiovascular mortality.
doi:10.1159/000339282
PMCID: PMC3398816  PMID: 22811692
Autofluorescence; Diabetes mellitus; Hemodialysis; Mortality
4.  Novel Association of HK1 with Glycated Hemoglobin in a Non-Diabetic Population: A Genome-Wide Evaluation of 14,618 Participants in the Women's Genome Health Study 
PLoS Genetics  2008;4(12):e1000312.
Type 2 diabetes is a leading cause of morbidity and mortality. While genetic variants have been found to influence the risk of type 2 diabetes mellitus, relatively few studies have focused on genes associated with glycated hemoglobin, an index of the mean blood glucose concentration of the preceding 8–12 weeks. Epidemiologic studies and randomized clinical trials have documented the relationship between glycated hemoglobin levels and the development of long-term complications in diabetes; moreover, higher glycated hemoglobin levels in the subdiabetic range have been shown to predict type 2 diabetes risk and cardiovascular disease. To examine the common genetic determinants of glycated hemoglobin levels, we performed a genome-wide association study that evaluated 337,343 SNPs in 14,618 apparently healthy Caucasian women. The results show that glycated hemoglobin levels are associated with genetic variation at the GCK (rs730497; P = 2.8×10−12), SLC30A8 (rs13266634; P = 9.8×10−8), G6PC2 (rs1402837; P = 6.8×10−10), and HK1 (rs7072268; P = 6.4×10−9) loci. While associations at the GCK, SLC30A8, and G6PC2 loci are confirmatory, the findings at HK1 are novel. We were able to replicate this novel association in an independent validation sample of 455 additional non-diabetic men and women. HK1 encodes the enzyme hexokinase, the first step in glycolysis and a likely candidate for the control of glucose metabolism. This observed genetic association between glycated hemoglobin levels and HK1 polymorphisms paves the way for further studies of the role of HK1 in hemoglobin glycation, glucose metabolism, and diabetes.
Author Summary
Type 2 diabetes is a leading cause of morbidity and mortality in both the developed and developing world. Because the main metabolic characteristic of diabetes is increased blood glucose concentration, we sought to uncover the genetic determinants of glycated hemoglobin, an index of the mean blood glucose concentration of the preceding 8–12 weeks. Taking advantage of new technologies allowing us to interrogate genetic variation on a whole-genome basis, we found that variations in the GCK, SLC30A8, G6PC2, and HK1 genes are important determinants of glycated hemoglobin concentrations. While associations with the GCK, SLC30A8, and G6PC2 genes have previously been identified in genetic studies of diabetes and blood glucose concentration, the findings at HK1 are novel. HK1 encodes the enzyme hexokinase, responsible for the first step in glucose utilization and a likely candidate for the control of glucose metabolism. This observed genetic association between glycated hemoglobin levels and HK1 genetic variants paves the way for further studies of the role of HK1 in glucose metabolism and diabetes.
doi:10.1371/journal.pgen.1000312
PMCID: PMC2596965  PMID: 19096518
5.  Skin Autofluorescence, a Non-Invasive Marker for AGE Accumulation, Is Associated with the Degree of Atherosclerosis 
PLoS ONE  2013;8(12):e83084.
Introduction
Advanced glycation endproducts (AGEs) may be involved in the development of atherosclerosis, beyond diabetes and renal disease. Skin autofluorescence (AF) is a non-invasive marker for AGEs. We examined whether skin AF is increased in (subclinical) atherosclerosis and associated with the degree of atherosclerosis independent of diabetes and renal function.
Methods
A cross-sectional study of 223 patients referred for primary (n = 163) or secondary (n = 60) prevention between 2006 and 2012 was performed. Skin AF was measured using the AGE-Reader. Ultrasonography was used to assess plaques in carotid and femoral arteries and computed tomography for the calculation of the coronary artery calcium score (CACS; in primary prevention only). Primary prevention patients were divided into a group with subclinical atherosclerosis defined as >1 plaque or CACS>100 (n = 67; age 53 year [interquartile range 48–56]; 49% male) and without (controls; 96; 43 [38–51]; 55%). Secondary prevention were patients with peripheral arterial disease (60; 64 [58–70]; 73%).
Results
Skin AF was higher in subclinical and clinical atherosclerosis compared with controls (skin AF 2.11 [interquartile range 1.83–2.46] and 2.71 [2.15–3.27] vs. 1.87 [1.68–2.12] respectively; P = 0.005 and <0.001). In a multivariate analysis, the association of skin AF with the atherosclerosis categories was independent of age, sex, diabetes, presence of the metabolic syndrome, Framingham Risk Score, and renal function. Skin AF correlated with most cardiovascular risk factors, Framingham risk score, and IMT and CACS.
Conclusions
Skin AF is increased in documented subclinical and clinical atherosclerosis, independent of known risk factors such as diabetes and renal disease. These data suggest that AGEs may be associated with the burden of atherosclerosis and warrant a prospective study to investigate its clinical usability as a risk assessment tool for primary prevention.
doi:10.1371/journal.pone.0083084
PMCID: PMC3871581  PMID: 24376641
6.  Effect of dietary prebiotic supplementation on advanced glycation, insulin resistance and inflammatory biomarkers in adults with pre-diabetes: a study protocol for a double-blind placebo-controlled randomised crossover clinical trial 
Background
Advanced glycation endproducts (AGEs) contribute to the development of vascular complications of diabetes and have been recently implicated in the pathogenesis of diabetes. Since AGEs are generated within foodstuffs upon food processing, it is increasingly recognised that the modern diet is replete with AGEs. AGEs are thought to stimulate chronic low-grade inflammation and promote oxidative stress and have been linked to the development of insulin resistance. Simple therapeutic strategies targeted at attenuating the progression of chronic low-grade inflammation and insulin resistance are urgently required to prevent or slow the development of type 2 diabetes in susceptible individuals. Dietary modulation of the human colonic microbiota has been shown to confer a number of health benefits to the host, but its effect on advanced glycation is unknown. The aim of this article is to describe the methodology of a double-blind placebo-controlled randomised crossover trial designed to determine the effect of 12 week consumption of a prebiotic dietary supplement on the advanced glycation pathway, insulin sensitivity and chronic low-grade inflammation in adults with pre-diabetes.
Methods/Design
Thirty adults with pre-diabetes (Impaired Glucose Tolerance or Impaired Fasting Glucose) aged between 40–60 years will be randomly assigned to receive either 10 grams of prebiotic (inulin/oligofructose) daily or 10 grams placebo (maltodextrin) daily for 12 weeks. After a 2-week washout period, study subjects will crossover to receive the alternative dietary treatment for 12 weeks. The primary outcome is the difference in markers of the advanced glycation pathway carboxymethyllysine (CML) and methylglyoxal (MG) between experimental and control treatments. Secondary outcomes include HbA1c, insulin sensitivity, lipid levels, blood pressure, serum glutathione, adiponectin, IL-6, E-selectin, myeloperoxidase, C-reactive protein, Toll-like Receptor 4 (TLR4), soluble receptor for AGE (sRAGE), urinary 8-isoprostanes, faecal bacterial composition and short chain fatty acid profile. Anthropometric measures including BMI and waist circumference will be collected in addition to comprehensive dietary and lifestyle data.
Discussion
Prebiotics which selectively stimulate the growth of beneficial bacteria in the human colon might offer protection against AGE-related pathology in people at risk of developing type 2 diabetes.
Trial registration
Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12613000130763.
doi:10.1186/1472-6823-14-55
PMCID: PMC4099169  PMID: 25011647
Advanced glycation end products; Maillard reaction; Prebiotics; Gut microbiota; Type 2 diabetes mellitus; Insulin resistance; Inflammation
7.  Event Rates, Hospital Utilization, and Costs Associated with Major Complications of Diabetes: A Multicountry Comparative Analysis 
PLoS Medicine  2010;7(2):e1000236.
Philip Clarke and colleagues examined patient-level data for over 11,000 participants with type 2 diabetes from 20 countries and find that major complications of diabetes significantly increased hospital use and costs across settings.
Background
Diabetes imposes a substantial burden globally in terms of premature mortality, morbidity, and health care costs. Estimates of economic outcomes associated with diabetes are essential inputs to policy analyses aimed at prevention and treatment of diabetes. Our objective was to estimate and compare event rates, hospital utilization, and costs associated with major diabetes-related complications in high-, middle-, and low-income countries.
Methods and Findings
Incidence and history of diabetes-related complications, hospital admissions, and length of stay were recorded in 11,140 patients with type 2 diabetes participating in the Action in Diabetes and Vascular Disease (ADVANCE) study (mean age at entry 66 y). The probability of hospital utilization and number of days in hospital for major events associated with coronary disease, cerebrovascular disease, congestive heart failure, peripheral vascular disease, and nephropathy were estimated for three regions (Asia, Eastern Europe, and Established Market Economies) using multiple regression analysis. The resulting estimates of days spent in hospital were multiplied by regional estimates of the costs per hospital bed-day from the World Health Organization to compute annual acute and long-term costs associated with the different types of complications. To assist, comparability, costs are reported in international dollars (Int$), which represent a hypothetical currency that allows for the same quantities of goods or services to be purchased regardless of country, standardized on purchasing power in the United States. A cost calculator accompanying this paper enables the estimation of costs for individual countries and translation of these costs into local currency units. The probability of attending a hospital following an event was highest for heart failure (93%–96% across regions) and lowest for nephropathy (15%–26%). The average numbers of days in hospital given at least one admission were greatest for stroke (17–32 d across region) and heart failure (16–31 d) and lowest for nephropathy (12–23 d). Considering regional differences, probabilities of hospitalization were lowest in Asia and highest in Established Market Economies; on the other hand, lengths of stay were highest in Asia and lowest in Established Market Economies. Overall estimated annual hospital costs for patients with none of the specified events or event histories ranged from Int$76 in Asia to Int$296 in Established Market Economies. All complications included in this analysis led to significant increases in hospital costs; coronary events, cerebrovascular events, and heart failure were the most costly, at more than Int$1,800, Int$3,000, and Int$4,000 in Asia, Eastern Europe, and Established Market Economies, respectively.
Conclusions
Major complications of diabetes significantly increase hospital use and costs across various settings and are likely to impose a high economic burden on health care systems.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, nearly 250 million people have diabetes, and this number is increasing rapidly. Diabetes is characterized by dangerous amounts of sugar (glucose) in the blood. Blood sugar levels are normally controlled by insulin, a hormone produced by the pancreas. Blood sugar control fails in people with diabetes because they make no insulin (type 1 diabetes) or, more commonly, because the fat and muscle cells that usually respond to insulin by removing excess sugar from the blood have become insulin insensitive (type 2 diabetes). Type 2 diabetes can be prevented and controlled by eating a healthy diet and exercising regularly. It can also be treated with drugs that help the pancreas make more insulin or that increase insulin sensitivity. Major long-term complications of diabetes include kidney failure and an increased risk of cardiovascular problems such as heart attacks, heart failure, stroke, and problems with the blood vessels in the arms and legs. Because of these complications, the life expectancy of people with diabetes is about ten years shorter than that of people without diabetes.
Why Was This Study Done?
Diabetes imposes considerable demands on health care systems but little is known about the direct medical costs associated with treating this chronic disease in low- and middle-income countries where more than three-quarters of affected people live. In particular, although estimates have been made of the overall resources devoted to the treatment of diabetes, very little is known about how the different long-term complications of diabetes contribute to health care costs in different countries. Public-health experts and governments need this information to help them design effective and sustainable policies for the prevention and treatment of diabetes. In this study, the researchers estimate the resource use associated with diabetes-related complications in three economic regions using information collected in the Action in Diabetes and Vascular Disease (ADVANCE) study. This multinational clinical trial is investigating how drugs that control blood pressure and blood sugar levels affect the long-term complications of diabetes.
What Did the Researchers Do and Find?
The researchers recorded diabetes-related complications, hospital admissions for these complications, and length of hospital stays in 11,140 patients with severe diabetes from 20 countries who participated in the ADVANCE study. They used “multiple regression analysis” to estimate the number of days spent in hospital for diabetes-related complications in Asia, Eastern Europe, and the Established Market Economies (Canada, Australia, New Zealand, and several Western European countries). Finally, they calculated the economic costs of each complication using regional estimates of the costs per bed-day from the World Health Organization's CHOICE project (CHOosing Interventions that are Cost Effective). Nearly everyone in the study who developed heart failure attended a hospital, but only 15%–26% of people attended a hospital for kidney problems. The chances of hospitalization for any complication were lowest in Asia and highest in the Established Market Economies; conversely, lengths of stay were longest in Asia and shortest in the Established Market Economies. Finally, the estimated annual hospital costs for patients who had a coronary event, stroke, or heart failure were more than Int$1,800, Int$3,000, and Int$4,000 in Asia, Eastern Europe, and the Established Market Economies, respectively (the international dollar, Int$, is a hypothetical currency that has the same purchasing power in all countries), compared to Int$76, Int$156, and Int$296 for patients who experienced none of these events.
What Do These Findings Mean?
Because the ADVANCE trial had strict entry criteria, the findings of this study may not be generalizable to the broader population of people with diabetes. Nevertheless, given the lack of information about the costs associated with diabetes-related complications in low- and middle-income countries, these findings provide important new information about the patterns of hospital resource use and costs in these countries. Specifically, these findings show that the major complications of diabetes greatly increase hospital use and costs in all three economic regions considered and impose a high economic burden on health care systems that is likely to increase as the diabetes epidemic develops. Importantly, these findings should help policy makers anticipate the future health care costs associated with diabetes and should help them evaluate which therapies aimed at preventing diabetes-related complications will reduce these costs most effectively.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000236.
The International Diabetes Federation provides information about all aspects of diabetes
The US National Diabetes Information Clearinghouse provides detailed information about diabetes for patients, health care professionals, and the general public (in English and Spanish)
The UK National Health Service also provides information for patients and caregivers about type 2 diabetes (in several languages)
Information about the ADVANCE study is available
The World Health Organization's CHOICE Web site provides information about the analysis of the cost effectiveness of health care interventions
doi:10.1371/journal.pmed.1000236
PMCID: PMC2826379  PMID: 20186272
8.  Early- and advanced non-enzymatic glycation in diabetic vascular complications: the search for therapeutics 
Amino Acids  2010;42(4):1193-1204.
Cardiovascular disease is a common complication of diabetes and the leading cause of death among people with diabetes. Because of the huge premature morbidity and mortality associated with diabetes, prevention of vascular complications is a key issue. Although the exact mechanism by which vascular damage occurs in diabetes in not fully understood, numerous studies support the hypothesis of a causal relationship of non-enzymatic glycation with vascular complications. In this review, data which point to an important role of Amadori-modified glycated proteins and advanced glycation endproducts in vascular disease are surveyed. Because of the potential role of early- and advanced non-enzymatic glycation in vascular complications, we also described recent developments of pharmacological inhibitors that inhibit the formation of these glycated products or the biological consequences of glycation and thereby retard the development of vascular complications in diabetes.
doi:10.1007/s00726-010-0779-9
PMCID: PMC3296013  PMID: 20960212
Diabetes; Non-enzymatic glycation; AGEs; Amadori-albumin; Vascular complications
9.  Increased levels of advanced glycation endproducts in the lenses and blood vessels of cigarette smokers. 
Molecular Medicine  1998;4(9):594-601.
BACKGROUND: Advanced glycation endproducts (AGEs) arise from the spontaneous reaction of reducing sugars with the amino groups of macromolecules. AGEs accumulate in tissue as a consequence of diabetes and aging and have been causally implicated in the pathogenesis of several of the end-organ complications of diabetes and aging, including cataract, atherosclerosis, and renal insufficiency. It has been recently proposed that components in mainstream cigarette smoke can react with plasma and extracellular matrix proteins to form covalent adducts with many of the properties of AGEs. We wished to ascertain whether AGEs or immunochemically related molecules are present at higher levels in the tissues of smokers. MATERIALS AND METHODS: Lens and coronary artery specimens from nondiabetic smokers and nondiabetic nonsmokers were examined by immunohistochemistry, immunoelectron microscopy, and ELISA employing several distinct anti-AGE antibodies. In addition, lenticular extracts were tested for AGE-associated fluorescence by fluorescence spectroscopy. RESULTS: Immunoreactive AGEs were present at significantly higher levels in the lenses and lenticular extracts of nondiabetic smokers (p < 0.003). Anti-AGE immunogold staining was diffusely distributed throughout lens fiber cells. AGE-associated fluorescence was significantly increased in the lenticular extracts of nondiabetic smokers (p = 0.005). AGE-immunoreactivity was significantly elevated in coronary arteries from nondiabetic smokers compared with nondiabetic nonsmokers (p = 0.015). CONCLUSIONS: AGEs or immunochemically related molecules are present at higher levels in the tissues of smokers than in nonsmokers, irrespective of diabetes. In view of previous reports implicating AGEs in a causal association with numerous pathologies, these findings have significant ramifications for understanding the etiopathology of diseases associated with smoking, the single greatest preventable cause of morbidity and mortality in the United States.
Images
PMCID: PMC2230315  PMID: 9848076
10.  Skin Autofluorescence Based Decision Tree in Detection of Impaired Glucose Tolerance and Diabetes 
PLoS ONE  2013;8(6):e65592.
Aim
Diabetes (DM) and impaired glucose tolerance (IGT) detection are conventionally based on glycemic criteria. Skin autofluorescence (SAF) is a noninvasive proxy of tissue accumulation of advanced glycation endproducts (AGE) which are considered to be a carrier of glycometabolic memory. We compared SAF and a SAF-based decision tree (SAF-DM) with fasting plasma glucose (FPG) and HbA1c, and additionally with the Finnish Diabetes Risk Score (FINDRISC) questionnaire±FPG for detection of oral glucose tolerance test (OGTT)- or HbA1c-defined IGT and diabetes in intermediate risk persons.
Methods
Participants had ≥1 metabolic syndrome criteria. They underwent an OGTT, HbA1c, SAF and FINDRISC, in adition to SAF-DM which includes SAF, age, BMI, and conditional questions on DM family history, antihypertensives, renal or cardiovascular disease events (CVE).
Results
218 persons, age 56 yr, 128M/90F, 97 with previous CVE, participated. With OGTT 28 had DM, 46 IGT, 41 impaired fasting glucose, 103 normal glucose tolerance. SAF alone revealed 23 false positives (FP), 34 false negatives (FN) (sensitivity (S) 68%; specificity (SP) 86%). With SAF-DM, FP were reduced to 18, FN to 16 (5 with DM) (S 82%; SP 89%). HbA1c scored 48 FP, 18 FN (S 80%; SP 75%). Using HbA1c-defined DM-IGT/suspicion ≥6%/42 mmol/mol, SAF-DM scored 33 FP, 24 FN (4 DM) (S76%; SP72%), FPG 29 FP, 41 FN (S71%; SP80%). FINDRISC≥10 points as detection of HbA1c-based diabetes/suspicion scored 79 FP, 23 FN (S 69%; SP 45%).
Conclusion
SAF-DM is superior to FPG and non-inferior to HbA1c to detect diabetes/IGT in intermediate-risk persons. SAF-DM’s value for diabetes/IGT screening is further supported by its established performance in predicting diabetic complications.
doi:10.1371/journal.pone.0065592
PMCID: PMC3672176  PMID: 23750268
11.  Vascular effects of advanced glycation endproducts: Clinical effects and molecular mechanisms☆ 
Molecular Metabolism  2013;3(2):94-108.
The enhanced generation and accumulation of advanced glycation endproducts (AGEs) have been linked to increased risk for macrovascular and microvascular complications associated with diabetes mellitus. AGEs result from the nonenzymatic reaction of reducing sugars with proteins, lipids, and nucleic acids, potentially altering their function by disrupting molecular conformation, promoting cross-linking, altering enzyme activity, reducing their clearance, and impairing receptor recognition. AGEs may also activate specific receptors, like the receptor for AGEs (RAGE), which is present on the surface of all cells relevant to atherosclerotic processes, triggering oxidative stress, inflammation and apoptosis. Understanding the pathogenic mechanisms of AGEs is paramount to develop strategies against diabetic and cardiovascular complications.
doi:10.1016/j.molmet.2013.11.006
PMCID: PMC3953708  PMID: 24634815
Advanced glycation endproducts; Endothelium; Vascular
12.  Ethnic Disparities in Diabetes Management and Pay-for-Performance in the UK: The Wandsworth Prospective Diabetes Study 
PLoS Medicine  2007;4(6):e191.
Background
Pay-for-performance rewards health-care providers by paying them more if they succeed in meeting performance targets. A new contract for general practitioners in the United Kingdom represents the most radical shift towards pay-for-performance seen in any health-care system. The contract provides an important opportunity to address disparities in chronic disease management between ethnic and socioeconomic groups. We examined disparities in management of people with diabetes and intermediate clinical outcomes within a multiethnic population in primary care before and after the introduction of the new contract in April 2004.
Methods and Findings
We conducted a population-based longitudinal survey, using electronic general practice records, in an ethnically diverse part of southwest London. Outcome measures were prescribing levels and achievement of national treatment targets (HbA1c ≤ 7.0%; blood pressure [BP] < 140/80 mm Hg; total cholesterol ≤ 5 mmol/l or 193 mg/dl). The proportion of patients reaching treatment targets for HbA1c, BP, and total cholesterol increased significantly after the implementation of the new contract. The extents of these increases were broadly uniform across ethnic groups, with the exception of the black Caribbean patient group, which had a significantly lower improvement in HbA1c (adjusted odds ratio [AOR] 0.75, 95% confidence interval [CI] 0.57–0.97) and BP control (AOR 0.65, 95% CI 0.53–0.81) relative to the white British patient group. Variations in prescribing and achievement of treatment targets between ethnic groups present in 2003 were not attenuated in 2005.
Conclusions
Pay-for-performance incentives have not addressed disparities in the management and control of diabetes between ethnic groups. Quality improvement initiatives must place greater emphasis on minority communities to avoid continued disparities in mortality from cardiovascular disease and the other major complications of diabetes.
Based on a population-based longitudinal survey, Christopher Millett and colleagues concluded that pay-for-performance incentives for UK general practitioners had not addressed disparities in the management and control of diabetes between ethnic groups.
Editors' Summary
Background.
When used in health care, the term “pay-for-performance” means rewarding health-care providers by paying them more if they succeed in meeting performance targets set by the government and other commissioners of health care. It is an approach to health service management that is becoming common, particularly in the US and the UK. For example, the UK's general practitioners (family doctors) agreed with the government in 2004 that they would receive increases to their income that would depend on how well they were judged to be performing according to 146 quality indicators that cover clinical care for ten chronic diseases, as well as “organization of care,” and “patient experience.” One of the chronic diseases is diabetes, a condition that has reached epidemic proportions in the UK, as it has also in many other countries.
  Ethnic minorities often suffer more from health problems than the majority population of the country they live in. They are also likely to be served less well by the health services. Diabetes is a case in point; in many countries—including the US and UK—the condition is much more common in minority groups. In addition, their diabetes is usually less well “managed”—i.e., it becomes more severe more rapidly and there are more complications. In the UK, the government recognizes the need to ensure that its health policies are applied to all sectors of the population, including minority ethnic communities. Nevertheless, the advances that have been made in the management of diabetes have not benefited the UK's ethnic minorities to the same extent as they have the majority population. It is hoped that the use of pay-for-performance management by the UK National Health Service will lead to more efficient delivery of health care, and that one consequence will be that different communities will be more equally served.
Why Was This Study Done?
The researchers wanted to find out whether the introduction of pay-for-performance management in general medical practice in the UK was leading to a reduction in the gap in the quality of care provided to people with diabetes who belonged to ethnic minorities and other people with diabetes.
What Did the Researchers Do and Find?
The research was carried out in Wandsworth, an area of southwest London that is considered to be “ethnically diverse.” Over 4,200 people with diabetes are registered with general practitioners in this area. The researchers used the electronic records kept by these doctors and they focused on diabetes “treatment targets” set by the government, according to which the blood pressure and cholesterol levels of people with diabetes should be kept below defined levels. There is also a target level for glycated hemoglobin (HbA1c), which is a substance that can be used to measure the extent to which a patient's diabetes is under control. The researchers calculated the percentage of patients who were meeting these treatment targets. Overall, more patients met their treatment targets after the introduction of pay-for-performance management than were doing so before. All ethnic groups seemed to have benefited, but the black Caribbean group did not benefit as much as the other groups; the number of these patients who met the targets did improve, but the gap between them and patients with diabetes from other ethnic groups remained about the same.
What Do These Findings Mean?
The researchers concluded that, while the introduction of pay-for-performance did seem to have been beneficial, it had not addressed disparities in the management and control of diabetes between ethnic groups. They say that, in all initiatives to improve the quality of health care, special efforts must be made to reduce such gaps. The UK's use of pay-for-performance in general practice is regarded internationally as a very bold step, but, as other countries are also considering moving in this direction, the lessons from the study will be relevant in many other parts of the world.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040191.
Wikipedia has an entry on pay-for-performance in health care (note: Wikipedia is a free online encyclopedia that anyone can edit)
Information about how the NHS works in England
Diabetes UK is the largest organization in the UK working for people with diabetes and its website includes a useful Guide to Diabetes
The London Health Observatory is one of nine health observatories set up by the NHS to monitor health and health care in England. There is a page devoted to “ethnic health intelligence”
Introductory information about diabetes as a medical condition may be found on the MedlinePlus website; there are several MedlinePlus pages on diabetes as well
doi:10.1371/journal.pmed.0040191
PMCID: PMC1891316  PMID: 17564486
13.  Stenting for Peripheral Artery Disease of the Lower Extremities 
Executive Summary
Background
Objective
In January 2010, the Medical Advisory Secretariat received an application from University Health Network to provide an evidentiary platform on stenting as a treatment management for peripheral artery disease. The purpose of this health technology assessment is to examine the effectiveness of primary stenting as a treatment management for peripheral artery disease of the lower extremities.
Clinical Need: Condition and Target Population
Peripheral artery disease (PAD) is a progressive disease occurring as a result of plaque accumulation (atherosclerosis) in the arterial system that carries blood to the extremities (arms and legs) as well as vital organs. The vessels that are most affected by PAD are the arteries of the lower extremities, the aorta, the visceral arterial branches, the carotid arteries and the arteries of the upper limbs. In the lower extremities, PAD affects three major arterial segments i) aortic-iliac, ii) femoro-popliteal (FP) and iii) infra-popliteal (primarily tibial) arteries. The disease is commonly classified clinically as asymptomatic claudication, rest pain and critical ischemia.
Although the prevalence of PAD in Canada is not known, it is estimated that 800,000 Canadians have PAD. The 2007 Trans Atlantic Intersociety Consensus (TASC) II Working Group for the Management of Peripheral Disease estimated that the prevalence of PAD in Europe and North America to be 27 million, of whom 88,000 are hospitalizations involving lower extremities. A higher prevalence of PAD among elderly individuals has been reported to range from 12% to 29%. The National Health and Nutrition Examination Survey (NHANES) estimated that the prevalence of PAD is 14.5% among individuals 70 years of age and over.
Modifiable and non-modifiable risk factors associated with PAD include advanced age, male gender, family history, smoking, diabetes, hypertension and hyperlipidemia. PAD is a strong predictor of myocardial infarction (MI), stroke and cardiovascular death. Annually, approximately 10% of ischemic cardiovascular and cerebrovascular events can be attributed to the progression of PAD. Compared with patients without PAD, the 10-year risk of all-cause mortality is 3-fold higher in patients with PAD with 4-5 times greater risk of dying from cardiovascular event. The risk of coronary heart disease is 6 times greater and increases 15-fold in patients with advanced or severe PAD. Among subjects with diabetes, the risk of PAD is often severe and associated with extensive arterial calcification. In these patients the risk of PAD increases two to four fold. The results of the Canadian public survey of knowledge of PAD demonstrated that Canadians are unaware of the morbidity and mortality associated with PAD. Despite its prevalence and cardiovascular risk implications, only 25% of PAD patients are undergoing treatment.
The diagnosis of PAD is difficult as most patients remain asymptomatic for many years. Symptoms do not present until there is at least 50% narrowing of an artery. In the general population, only 10% of persons with PAD have classic symptoms of claudication, 40% do not complain of leg pain, while the remaining 50% have a variety of leg symptoms different from classic claudication. The severity of symptoms depends on the degree of stenosis. The need to intervene is more urgent in patients with limb threatening ischemia as manifested by night pain, rest pain, ischemic ulcers or gangrene. Without successful revascularization those with critical ischemia have a limb loss (amputation) rate of 80-90% in one year.
Diagnosis of PAD is generally non-invasive and can be performed in the physician offices or on an outpatient basis in a hospital. Most common diagnostic procedure include: 1) Ankle Brachial Index (ABI), a ratio of the blood pressure readings between the highest ankle pressure and the highest brachial (arm) pressure; and 2) Doppler ultrasonography, a diagnostic imaging procedure that uses a combination of ultrasound and wave form recordings to evaluate arterial flow in blood vessels. The value of the ABI can provide an assessment of the severity of the disease. Other non invasive imaging techniques include: Computed Tomography (CT) and Magnetic Resonance Angiography (MRA). Definitive diagnosis of PAD can be made by an invasive catheter based angiography procedure which shows the roadmap of the arteries, depicting the exact location and length of the stenosis / occlusion. Angiography is the standard method against which all other imaging procedures are compared for accuracy.
More than 70% of the patients diagnosed with PAD remain stable or improve with conservative management of pharmacologic agents and life style modifications. Significant PAD symptoms are well known to negatively influence an individual quality of life. For those who do not improve, revascularization methods either invasive or non-invasive can be used to restore peripheral circulation.
Technology Under Review
A Stent is a wire mesh “scaffold” that is permanently implanted in the artery to keep the artery open and can be combined with angioplasty to treat PAD. There are two types of stents: i) balloon-expandable and ii) self expandable stents and are available in varying length. The former uses an angioplasty balloon to expand and set the stent within the arterial segment. Recently, drug-eluting stents have been developed and these types of stents release small amounts of medication intended to reduce neointimal hyperplasia, which can cause re-stenosis at the stent site. Endovascular stenting avoids the problem of early elastic recoil, residual stenosis and flow limiting dissection after balloon angioplasty.
Research Questions
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), is primary stenting more effective than percutaneous transluminal angioplasty (PTA) in improving patency?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), does primary stenting provide immediate success compared to PTA?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), is primary stenting associated with less complications compared to PTA?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), does primary stenting compared to PTA reduce the rate of re-intervention?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion) is primary stenting more effective than PTA in improving clinical and hemodynamic success?
Are drug eluting stents more effective than bare stents in improving patency, reducing rates of re-interventions or complications?
Research Methods
Literature Search
A literature search was performed on February 2, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA). Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language full-reports from 1950 to January Week 3, 2010
Comparative randomized controlled trials (RCTs), systematic reviews and meta-analyses of RCTs
Proven diagnosis of PAD of the lower extremities in all patients.
Adult patients at least 18 years of age.
Stent as at least one treatment arm.
Patency, re-stenosis, re-intervention, technical success, hemodynamic (ABI) and clinical improvement and complications as at least an outcome.
Exclusion Criteria
Non-randomized studies
Observational studies (cohort or retrospective studies) and case report
Feasibility studies
Studies that have evaluated stent but not as a primary intervention
Outcomes of Interest
The primary outcome measure was patency. Secondary measures included technical success, re-intervention, complications, hemodynamic (ankle brachial pressure index, treadmill walking distance) and clinical success or improvement according to Rutherford scale. It was anticipated, a priori, that there would be substantial differences among trials regarding the method of examination and definitions of patency or re-stenosis. Where studies reported only re-stenosis rates, patency rates were calculated as 1 minus re-stenosis rates.
Statistical Analysis
Odds ratios (for binary outcomes) or mean difference (for continuous outcomes) with 95% confidence intervals (CI) were calculated for each endpoint. An intention to treat principle (ITT) was used, with the total number of patients randomized to each study arm as the denominator for each proportion. Sensitivity analysis was performed using per protocol approach. A pooled odds ratio (POR) or mean difference for each endpoint was then calculated for all trials reporting that endpoint using a fixed effects model. PORs were calculated for comparisons of primary stenting versus PTA or other alternative procedures. Level of significance was set at alpha=0.05. Homogeneity was assessed using the chi-square test, I2 and by visual inspection of forest plots. If heterogeneity was encountered within groups (P < 0.10), a random effects model was used. All statistical analyses were performed using RevMan 5. Where sufficient data were available, these analyses were repeated within subgroups of patients defined by time of outcome assessment to evaluate sustainability of treatment benefit. Results were pooled based on the diseased artery and stent type.
Summary of Findings
Balloon-expandable stents vs PTA in superficial femoral artery disease
Based on a moderate quality of evidence, there is no significant difference in patency between primary stenting using balloon-expandable bare metal stents and PTA at 6, 12 and 24 months in patients with superficial femoral artery disease. The pooled OR for patency and their corresponding 95% CI are: 6 months 1.26 (0.74, 2.13); 12 months 0.95 (0.66, 1.38); and 24 months 0.72 (0.34. 1.55).
There is no significant difference in clinical improvement, re-interventions, peri and post operative complications, mortality and amputations between primary stenting using balloon-expandable bare stents and PTA in patients with superficial femoral artery. The pooled OR and their corresponding 95% CI are clinical improvement 0.85 (0.50, 1.42); ankle brachial index 0.01 (-0.02, 0.04) re-intervention 0.83 (0.26, 2.65); complications 0.73 (0.43, 1.22); all cause mortality 1.08 (0.59, 1.97) and amputation rates 0.41 (0.14, 1.18).
Self-expandable stents vs PTA in superficial femoral artery disease
Based on a moderate quality of evidence, primary stenting using self-expandable bare metal stents is associated with significant improvement in patency at 6, 12 and 24 months in patients with superficial femoral artery disease. The pooled OR for patency and their corresponding 95% CI are: 6 months 2.35 (1.06, 5.23); 12 months 1.54 (1.01, 2.35); and 24 months 2.18 (1.00. 4.78). However, the benefit of primary stenting is not observed for clinical improvement, re-interventions, peri and post operative complications, mortality and amputation in patients with superficial femoral artery disease. The pooled OR and their corresponding 95% CI are clinical improvement 0.61 (0.37, 1.01); ankle brachial index 0.01 (-0.06, 0.08) re-intervention 0.60 (0.36, 1.02); complications 1.60 (0.53, 4.85); all cause mortality 3.84 (0.74, 19.22) and amputation rates 1.96 (0.20, 18.86).
Balloon expandable stents vs PTA in iliac artery occlusive disease
Based on moderate quality of evidence, despite immediate technical success, 12.23 (7.17, 20.88), primary stenting is not associated with significant improvement in patency, clinical status, treadmill walking distance and reduction in re-intervention, complications, cardiovascular events, all cause mortality, QoL and amputation rates in patients with intermittent claudication caused by iliac artery occlusive disease. The pooled OR and their corresponding 95% CI are: patency 1.03 (0.56, 1.87); clinical improvement 1.08 (0.60, 1.94); walking distance 3.00 (12.96, 18.96); re-intervention 1.16 (0.71, 1.90); complications 0.56 (0.20, 1.53); all cause mortality 0.89 (0.47, 1.71); QoL 0.40 (-4.42, 5.52); cardiovascular event 1.16 (0.56, 2.40) and amputation rates 0.37 (0.11, 1.23). To date no RCTs are available evaluating self-expandable stents in the common or external iliac artery stenosis or occlusion.
Drug-eluting stent vs balloon-expandable bare metal stents in crural arteries
Based on a very low quality of evidence, at 6 months of follow-up, sirolimus drug-eluting stents are associated with a reduction in target vessel revascularization and re-stenosis rates in patients with atherosclerotic lesions of crural (tibial) arteries compared with balloon-expandable bare metal stent. The OR and their corresponding 95% CI are: re-stenosis 0.09 (0.03, 0.28) and TVR 0.15 (0.05, 0.47) in patients with atherosclerotic lesions of the crural arteries at 6 months follow-up. Both types of stents offer similar immediate success. Limitations of this study include: short follow-up period, small sample and no assessment of mortality as an outcome. Further research is needed to confirm its effect and safety.
PMCID: PMC3377569  PMID: 23074395
14.  Value of serum glycated albumin and high-sensitivity C-reactive protein levels in the prediction of presence of coronary artery disease in patients with type 2 diabetes 
Background
Coronary artery disease (CAD) is a major vascular complication of diabetes mellitus and reveals high mortality. Up to 30% of diabetic patients with myocardial ischemia remain asymptomatic and are associated with worse prognosis compared to non-diabetic counterpart, which warrants routine screening for CAD in diabetic population. The purpose of this study was to evaluate the clinical value of serum glycated albumin and high-sensitivity C-reactive protein (hs-CRP) levels in predicting the presence of CAD in patients with type 2 diabetes.
Methods
Three hundred and twenty-four patients with type 2 diabetes were divided into two groups based on presence (CAD group, n = 241) or absence (control group, n = 83) of angiographically-documented CAD (lumen diameter narrowing ≥70%). Serum levels of glycated albumin and hs-CRP as well as serum concentrations of glucose, lipids, creatinine, blood urea nitrogen and uric acid were measured in both groups. Predictors of CAD were determined using multivariate logistic regression model and receiver-operating characteristic (ROC) curves.
Results
Serum glycated albumin and hs-CRP levels were significantly increased in diabetic patients with CAD. Multivariate regression analysis revealed that male gender, age, serum levels of glycated albumin, hs-CRP, creatinine and lipoprotein (a) were independent predictors for CAD. Areas under the curve of glycated albumin and hs-CRP and for regression model were 0.654 (95%CI 0.579–0.730, P < 0.001), 0.721 (95%CI 0.658–0.785, P < 0.001) and 0.824 (95% CI 0.768–0.879, P < 0.001), respectively. The optimal values of cut-off point were 18.7% (sensitivity 67.9%, specificity 60.0%) for glycated albumin and 5.2 mg/l (sensitivity 72.2%, specificity 60.0%) for hs-CRP to predict CAD. Logistic regression model was defined as: P/(1-P) = EXP(-1.5 + 1.265 gender + 0.812 age + 1.24 glycated albumin + 0.953 hs-CRP + 0.902 lipoprotein(a) + 1.918 creatinine). The optimal probability value for predicting CAD in type 2 diabetic patients was 0.648 (sensitivity 82.3%, specificity 68.6%).
Conclusion
Serum glycated albumin and hs-CRP levels were significantly elevated in patients with type 2 diabetes and CAD. The logistic regression model incorporating with glycated albumin, hs-CRP and other major risk factors of atherosclerosis may be useful for screening CAD in patients with type 2 diabetes.
doi:10.1186/1475-2840-5-27
PMCID: PMC1764721  PMID: 17178005
15.  Glycoxidative Stress and Cardiovascular Complications in Experimentally-Induced Diabetes: Effects of Antioxidant Treatment 
Diabetes mellitus (DM) is a common metabolic disease, representing a serious risk factor for the development of cardiovascular complications, such as coronary heart disease, peripheral arterial disease and hypertension. Oxidative stress (OS), a feature of DM, is defined as an increase in the steady-state levels of reactive oxygen species (ROS) and may occur as a result of increased free radical generation and/or decreased anti-oxidant defense mechanisms. Increasing evidence indicates that hyperglycemia is the initiating cause of the tissue damage in DM, either through repeated acute changes in cellular glucose metabolism, or through long-term accumulation of glycated biomolecules and advanced glycation end products (AGEs). AGEs are formed by the Maillard process, a non-enzymatic reaction between ketone group of the glucose molecule or aldehydes and the amino groups of proteins that contributes to the aging of proteins and to the pathological complications of DM. In the presence of uncontrolled hyperglycemia, the increased formation of AGEs and lipid peroxidation products exacerbate intracellular OS and results in a loss of molecular integrity, disruption in cellular signaling and homeostasis, followed by inflammation and tissue injury such as endothelium dysfunction, arterial stiffening and microvascular complications. In addition to increased AGE production, there is also evidence of multiple pathways elevating ROS generation in DM, including; enhanced glucose auto-oxidation, increased mitochondrial superoxide production, protein kinase C-dependent activation of NADPH oxidase, uncoupled endothelial nitric oxide synthase (eNOS) activity, increased substrate flux through the polyol pathway and stimulation of eicosanoid metabolism. It is, therefore, not surprising that the correction of these variables can result in amelioration of diabetic cardiovascular abnormalities. A linking element between these phenomena is cellular redox imbalance due to glycoxidative stress (GOS). Thus, recent interest has focused on strategies to prevent, reverse or retard GOS in order to modify the natural history of diabetic cardiovascular abnormalities. This review will discuss the links between GOS and diabetes-induced cardiovascular disorders and the effect of antioxidant therapy on altering the development of cardiovascular complications in diabetic animal models.
doi:10.2174/1874192401004010240
PMCID: PMC3026340  PMID: 21270942
Glycoxidative stress; glycation; diabetes mellitus; antioxidant; cardiovascular.
16.  Independent Associations of Fasting Insulin, Glucose, and Glycated Haemoglobin with Stroke and Coronary Heart Disease in Older Women 
PLoS Medicine  2007;4(8):e263.
Background
Evidence suggests that variations in fasting glucose and insulin amongst those without frank type 2 diabetes mellitus are important determinants of cardiovascular disease. However, the relative importance of variations in fasting insulin, glucose, and glycated haemoglobin as risk factors for cardiovascular disease in women without diabetes is unclear. Our aim was to determine the independent associations of fasting insulin, glucose, and glycated haemoglobin with coronary heart disease and stroke in older women.
Methods and Findings
We undertook a prospective cohort study of 3,246 British women aged 60–79 y, all of whom were free of baseline coronary heart disease, stroke, and diabetes, and all of whom had fasting glucose levels below 7 mmol/l. Fasting insulin and homeostasis model assessment for insulin sensitivity (HOMA-S) were linearly associated with a combined outcome of coronary heart disease or stroke (n = 219 events), but there was no association of fasting glucose or glycated haemoglobin with these outcomes. Results were similar for coronary heart disease and stroke as separate outcomes. The age, life-course socioeconomic position, smoking, and physical activity adjusted hazard ratio for a combined outcome of incident coronary heart disease or stroke per one standard deviation of fasting insulin was 1.14 (95% CI 1.02–1.33). Additional adjustment for other components of metabolic syndrome, low-density lipoprotein cholesterol, fasting glucose, and glycated haemoglobin had little effect on this result.
Conclusions
Our findings suggest that in women in the 60–79 y age range, insulin resistance, rather than insulin secretion or chronic hyperglycaemia, is a more important risk factor for coronary heart disease and stroke. Below currently used thresholds of fasting glucose for defining diabetes, neither fasting glucose nor glycated haemoglobin are associated with cardiovascular disease.
From a prospective study of women aged 60-79 years, Debbie Lawlor and colleagues conclude that insulin resistance is an important risk factor for coronary heart disease and stroke.
Editors' Summary
Background.
Narrowing of the vessels that take blood to the heart and brain is a common form of cardiovascular disease—i.e., a disorder of the heart and blood vessels. It is a major cause of illness and death. By starving the heart and brain of oxygen, this condition causes coronary heart disease (CHD; heart problems such as angina and heart attacks) and strokes. A major risk factor for CHD and strokes is diabetes, a common chronic disease characterized by high levels of sugar (glucose) in the blood. In people who don't have diabetes, the hormone insulin controls blood-sugar levels. Insulin, which is released by the pancreas after eating, “instructs” insulin-responsive muscle and fat cells to absorb the glucose (released from food) from the bloodstream. In the very early stages of type 2 diabetes (the commonest type of diabetes, also called “adult onset” or “noninsulin-dependent” diabetes”), muscle and fat cells become unresponsive to insulin, so blood-sugar levels increase. This is called “insulin resistance.” The pancreas responds by making more insulin. As a result, people with insulin resistance have high blood levels of both insulin (hyperinsulinemia) and glucose (hyperglycemia). Eventually, the insulin-producing cells in the pancreas start to malfunction, insulin secretion decreases, and type 2 diabetes is the result.
Why Was This Study Done?
It is not yet clear whether it is insulin resistance or reduced insulin secretion that is responsible for the association between diabetes and cardiovascular disease. Physicians would like to know this information to help them to prevent CHD and strokes in their patients. There is evidence that variations in fasting glucose levels (blood glucose measured more than 8 h after eating), which provide an indication of how well pancreatic cells are producing insulin, and in fasting insulin levels, which provide an indication of insulin resistance, determine cardiovascular disease risk among people without type 2 diabetes, but the relative importance of these risk factors is unclear. In this study, the researchers have investigated whether markers of insulin resistance (fasting hyperinsulinemia) and of altered insulin secretion (fasting hyperglycemia, and increased glycated hemoglobin, which indicates how much sugar has been in the blood over the past few months) are associated with CHD and strokes in elderly women without diabetes. Their aim is to gain new insights into how diabetes affects cardiovascular disease risk.
What Did the Researchers Do and Find?
The researchers measured glucose, insulin, and glycated hemoglobulin in fasting blood samples taken from about 3,000 women aged 60–79 y when they enrolled in the British Women's Heart and Health Study. None of the women had CHD at enrollment, none had had a stroke, none had diagnosed diabetes, and all had a fasting blood glucose below 7 mmol/l (a higher reading indicates diabetes). After monitoring the women for nearly 5 y for CHD and strokes, the researchers looked for statistical associations between the occurrence of cardiovascular disease and markers of insulin resistance and reduced insulin secretion. They found that fasting insulin levels, but not fasting glucose or glycated hemoglobin levels, were associated with CHD and stroke, even after allowing for other factors that affect cardiovascular disease risk such as smoking and physical activity. In other words, raised fasting insulin levels increased the women's risk of developing cardiovascular disease.
What Do These Findings Mean?
These results indicate that in elderly women without diabetes, fasting insulin (a marker of insulin resistance) is a better predictor of future cardiovascular disease risk than fasting glucose or glycated hemoglobin (markers of reduced insulin secretion). This suggests that insulin resistance might be the main mechanism linking type 2 diabetes to CHD and stroke in elderly women. (Elderly women are known to run a high risk of developing these conditions, but they have been relatively neglected in previous studies of the risk factors for cardiovascular disease.) However, because relatively few women developed CHD during the study and even fewer had a stroke, this conclusion needs confirming in larger studies, preferably ones that include more rigorous tests of insulin resistance and secretion and also include women from more ethnic backgrounds than this study did. If the association between fasting insulin levels and cardiovascular disease risk is confirmed, therapeutic interventions or lifestyle interventions (for example, increased physical activity or weight loss) that prevent or reverse insulin resistance might reduce cardiovascular disease risk better than interventions that prevent chronic hyperglycemia.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040263.
MedlinePlus encyclopedia page on coronary heart disease, stroke, and diabetes (in English and Spanish)
Information for patients and caregivers from the US National Diabetes Information Clearinghouse on diabetes, including information on insulin resistance and on diabetes, heart disease, and stroke
Information on the British Women's Heart and Health Study
doi:10.1371/journal.pmed.0040263
PMCID: PMC1952205  PMID: 17760500
17.  Patterns of Obesity Development before the Diagnosis of Type 2 Diabetes: The Whitehall II Cohort Study 
PLoS Medicine  2014;11(2):e1001602.
Examining patterns of change in body mass index (BMI) and other cardiometabolic risk factors in individuals during the years before they were diagnosed with diabetes, Kristine Færch and colleagues report that few of them experienced dramatic BMI changes.
Please see later in the article for the Editors' Summary
Background
Patients with type 2 diabetes vary greatly with respect to degree of obesity at time of diagnosis. To address the heterogeneity of type 2 diabetes, we characterised patterns of change in body mass index (BMI) and other cardiometabolic risk factors before type 2 diabetes diagnosis.
Methods and Findings
We studied 6,705 participants from the Whitehall II study, an observational prospective cohort study of civil servants based in London. White men and women, initially free of diabetes, were followed with 5-yearly clinical examinations from 1991–2009 for a median of 14.1 years (interquartile range [IQR]: 8.7–16.2 years). Type 2 diabetes developed in 645 (1,209 person-examinations) and 6,060 remained free of diabetes during follow-up (14,060 person-examinations). Latent class trajectory analysis of incident diabetes cases was used to identify patterns of pre-disease BMI. Associated trajectories of cardiometabolic risk factors were studied using adjusted mixed-effects models. Three patterns of BMI changes were identified. Most participants belonged to the “stable overweight” group (n = 604, 94%) with a relatively constant BMI level within the overweight category throughout follow-up. They experienced slightly worsening of beta cell function and insulin sensitivity from 5 years prior to diagnosis. A small group of “progressive weight gainers” (n = 15) exhibited a pattern of consistent weight gain before diagnosis. Linear increases in blood pressure and an exponential increase in insulin resistance a few years before diagnosis accompanied the weight gain. The “persistently obese” (n = 26) were severely obese throughout the whole 18 years before diabetes diagnosis. They experienced an initial beta cell compensation followed by loss of beta cell function, whereas insulin sensitivity was relatively stable. Since the generalizability of these findings is limited, the results need confirmation in other study populations.
Conclusions
Three patterns of obesity changes prior to diabetes diagnosis were accompanied by distinct trajectories of insulin resistance and other cardiometabolic risk factors in a white, British population. While these results should be verified independently, the great majority of patients had modest weight gain prior to diagnosis. These results suggest that strategies focusing on small weight reductions for the entire population may be more beneficial than predominantly focusing on weight loss for high-risk individuals.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 350 million people have diabetes, a metabolic disorder characterized by high amounts of glucose (sugar) in the blood. Blood sugar levels are normally controlled by insulin, a hormone released by the pancreas after meals (digestion of food produces glucose). In people with type 2 diabetes (the commonest form of diabetes) blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing sugar from the blood become insulin resistant. Type 2 diabetes, which was previously called adult-onset diabetes, can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. Long-term complications, which include an increased risk of heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes. The number of people with diabetes is expected to increase dramatically over the next decades, coinciding with rising obesity rates in many countries. To better understand diabetes development, to identify people at risk, and to find ways to prevent the disease are urgent public health goals.
Why Was This Study Done?
It is known that people who are overweight or obese have a higher risk of developing diabetes. Because of this association, a common assumption is that people who experienced recent weight gain are more likely to be diagnosed with diabetes. In this prospective cohort study (an investigation that records the baseline characteristics of a group of people and then follows them to see who develops specific conditions), the researchers tested the hypothesis that substantial weight gain precedes a diagnosis of diabetes and explored more generally the patterns of body weight and composition in the years before people develop diabetes. They then examined whether changes in body weight corresponded with changes in other risk factors for diabetes (such as insulin resistance), lipid profiles and blood pressure.
What Did the Researchers Do and Find?
The researchers studied participants from the Whitehall II study, a prospective cohort study initiated in 1985 to investigate the socioeconomic inequalities in disease. Whitehall II enrolled more than 10,000 London-based government employees. Participants underwent regular health checks during which their weight and height were measured, blood tests were done, and they filled out questionnaires for other relevant information. From 1991 onwards, participants were tested every five years for diabetes. The 6,705 participants included in this study were initially free of diabetes, and most of them were followed for at least 14 years. During the follow-up, 645 participants developed diabetes, while 6,060 remained free of the disease.
The researchers used a statistical tool called “latent class trajectory analysis” to study patterns of changes in body mass index (BMI) in the years before people developed diabetes. BMI is a measure of human obesity based on a person's weight and height. Latent class trajectory analysis is an unbiased way to subdivide a number of people into groups that differ based on specified parameters. In this case, the researchers wanted to identify several groups among all the people who eventually developed diabetes each with a distinct pattern of BMI development. Having identified such groups, they also examined how a variety of tests associated with diabetes risk, and risks for heart disease and stroke changed in the identified groups over time.
They identified three different patterns of BMI changes in the 645 participants who developed diabetes. The vast majority (606 individuals, or 94%) belonged to a group they called “stable-overweight.” These people showed no dramatic change in their BMI in the years before they were diagnosed. They were overweight when they first entered the study and gained or lost little weight during the follow-up years. They showed only minor signs of insulin-resistance, starting five years before they developed diabetes. A second, much smaller group of 15 people gained weight consistently in the years before diagnosis. As they were gaining weight, these people also had raises in blood pressure and substantial gains in insulin resistance. The 26 remaining participants who formed the third group were persistently obese for the entire time they participated in the study, in some cases up to 18 years before they were diagnosed with diabetes. They had some signs of insulin resistance in the years before diagnosis, but not the substantial gain often seen as the hallmark of “pre-diabetes.”
What Do These Findings Mean?
These results suggest that diabetes development is a complicated process, and one that differs between individuals who end up with the disease. They call into question the common notion that most people who develop diabetes have recently gained a lot of weight or are obese. A substantial rise in insulin resistance, another established risk factor for diabetes, was only seen in the smallest of the groups, namely the people who gained weight consistently for years before they were diagnosed. When the scientists applied a commonly used predictor of diabetes called the “Framingham diabetes risk score” to their largest “stably overweight” group, they found that these people were not classified as having a particularly high risk, and that their risk scores actually declined in the last five years before their diabetes diagnosis. This suggests that predicting diabetes in this group might be difficult.
The researchers applied their methodology only to this one cohort of white civil servants in England. Before drawing more firm conclusions on the process of diabetes development, it will be important to test whether similar results are seen in other cohorts and among more diverse individuals. If the three groups identified here are found in other cohorts, another question is whether they are as unequal in size as in this example. And if they are, can the large group of stably overweight people be further subdivided in ways that suggest specific mechanisms of disease development? Even without knowing how generalizable the provocative findings of this study are, they should stimulate debate on how to identify people at risk for diabetes and how to prevent the disease or delay its onset.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001602.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health-care professionals, and the general public, including information on diabetes prevention (in English and Spanish)
The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes; it includes people's stories about diabetes
The charity Diabetes UK also provides detailed information about diabetes for patients and carers, including information on healthy lifestyles for people with diabetes, and has a further selection of stories from people with diabetes; the charity Healthtalkonline has interviews with people about their experiences of diabetes
MedlinePlus provides links to further resources and advice about diabetes (in English and Spanish)
More information about the Whitehall II study is available
doi:10.1371/journal.pmed.1001602
PMCID: PMC3921118  PMID: 24523667
18.  Cannabinoid 1 Receptor Promotes Cardiac Dysfunction, Oxidative Stress, Inflammation, and Fibrosis in Diabetic Cardiomyopathy 
Diabetes  2012;61(3):716-727.
Endocannabinoids and cannabinoid 1 (CB1) receptors have been implicated in cardiac dysfunction, inflammation, and cell death associated with various forms of shock, heart failure, and atherosclerosis, in addition to their recognized role in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes. In this study, we explored the role of CB1 receptors in myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type 1 diabetic cardiomyopathy. Diabetic cardiomyopathy was characterized by increased myocardial endocannabinoid anandamide levels, oxidative/nitrative stress, activation of p38/Jun NH2-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs), enhanced inflammation (tumor necrosis factor-α, interleukin-1β, cyclooxygenase 2, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1), increased expression of CB1, advanced glycation end product (AGE) and angiotensin II type 1 receptors (receptor for advanced glycation end product [RAGE], angiotensin II receptor type 1 [AT1R]), p47(phox) NADPH oxidase subunit, β-myosin heavy chain isozyme switch, accumulation of AGE, fibrosis, and decreased expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a). Pharmacological inhibition or genetic deletion of CB1 receptors attenuated the diabetes-induced cardiac dysfunction and the above-mentioned pathological alterations. Activation of CB1 receptors by endocannabinoids may play an important role in the pathogenesis of diabetic cardiomyopathy by facilitating MAPK activation, AT1R expression/signaling, AGE accumulation, oxidative/nitrative stress, inflammation, and fibrosis. Conversely, CB1 receptor inhibition may be beneficial in the treatment of diabetic cardiovascular complications.
doi:10.2337/db11-0477
PMCID: PMC3282820  PMID: 22315315
19.  Oxidative stress and diabetic complications 
Circulation research  2010;107(9):1058-1070.
Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, and also in the myocardium. This increased superoxide production causes the activation of five major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of advanced glycation end-products (AGEs), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C (PKC) isoforms, and overactivity of the hexosamine pathway. It also directly inactivates two critical antiatherosclerotic enzymes, eNOS and prostacyclin synthase. Through these pathways, increased intracellular ROS cause defective angiogenesis in response to ischemia, activate a number of pro-inflammatory pathways, and cause long-lasting epigenetic changes which drive persistent expression of proinflammatory genes after glycemia is normalized (‘hyperglycemic memory’). Atherosclerosis and cardiomyopathy in type 2 diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of anti-atherosclerosis enzymes by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to highlight advances in understanding the role of metabolite-generated ROS in the development of diabetic complications.
doi:10.1161/CIRCRESAHA.110.223545
PMCID: PMC2996922  PMID: 21030723
Hyperglycemia; Mitochondria; Metabolic Memory; Epigenetic modifications; insulin resistance
20.  Cardiac Fibroblast-Dependent Extracellular Matrix Accumulation Is Associated with Diastolic Stiffness in Type 2 Diabetes 
PLoS ONE  2013;8(8):e72080.
Cardiovascular complications are a leading cause of death in patients with type 2 diabetes mellitus (T2DM). Diastolic dysfunction is one of the earliest manifestations of diabetes-induced changes in left ventricular (LV) function, and results from a reduced rate of relaxation and increased stiffness. The mechanisms responsible for increased stiffness are not completely understood. Chronic hyperglycemia, advanced glycation endproducts (AGEs), and increased levels of proinflammatory and profibrotic cytokines are molecular pathways known to be involved in regulating extracellular matrix (ECM) synthesis and accumulation resulting in increased LV diastolic stiffness. Experiments were conducted using a genetically-induced mouse model of T2DM generated by a point mutation in the leptin receptor resulting in nonfunctional leptin receptors (db/db murine model). This study correlated changes in LV ECM and stiffness with alterations in basal activation of signaling cascades and expression of profibrotic markers within primary cultures of cardiac fibroblasts from diabetic (db/db) mice with nondiabetic (db/wt) littermates as controls. Primary cultures of cardiac fibrobroblasts were maintained in 25 mM glucose (hyperglycemic-HG; diabetic db/db) media or 5 mM glucose (normoglycemic-NG, nondiabetic db/wt) media. The cells then underwent a 24-hour exposure to their opposite (NG; diabetic db/db) media or 5 mM glucose (HG, nondiabetic db/wt) media. Protein analysis demonstrated significantly increased expression of type I collagen, TIMP-2, TGF-β, PAI-1 and RAGE in diabetic db/db cells as compared to nondiabetic db/wt, independent of glucose media concentration. This pattern of protein expression was associated with increased LV collagen accumulation, myocardial stiffness and LV diastolic dysfunction. Isolated diabetic db/db fibroblasts were phenotypically distinct from nondiabetic db/wt fibroblasts and exhibited a profibrotic phenotype in normoglycemic conditions.
doi:10.1371/journal.pone.0072080
PMCID: PMC3749105  PMID: 23991045
21.  Community-Based Care for the Management of Type 2 Diabetes 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this report is to determine the efficacy of specialized multidisciplinary community care for the management of type 2 diabetes compared to usual care.
Clinical Need: Target Population and Condition
Diabetes (i.e. diabetes mellitus) is a highly prevalent chronic metabolic disorder that interferes with the body’s ability to produce or effectively use insulin. The majority (90%) of diabetes patients have type 2 diabetes. (1) Based on the United Kingdom Prospective Diabetes Study (UKPDS), intensive blood glucose and blood pressure control significantly reduce the risk of microvascular and macrovascular complications in type 2 diabetics. While many studies have documented that patients often do not meet the glycemic control targets specified by national and international guidelines, factors associated with glycemic control are less well studied, one of which is the provider(s) of care.
Multidisciplinary approaches to care may be particularly important for diabetes management. According guidelines from the Canadian Diabetes Association (CDA), the diabetes health care team should be multi-and interdisciplinary. Presently in Ontario, the core diabetes health care team consists of at least a family physician and/or diabetes specialist, and diabetes educators (registered nurse and registered dietician).
Increasing the role played by allied health care professionals in diabetes care and their collaboration with physicians may represent a more cost-effective option for diabetes management. Several systematic reviews and meta-analyses have examined multidisciplinary care programs, but these have either been limited to a specific component of multidisciplinary care (e.g. intensified education programs), or were conducted as part of a broader disease management program, of which not all were multidisciplinary in nature. Most reviews also do not clearly define the intervention(s) of interest, making the evaluation of such multidisciplinary community programs challenging.
Evidence-Based Analysis Methods
Research Questions
What is the evidence of efficacy of specialized multidisciplinary community care provided by at least a registered nurse, registered dietician and physician (primary care and/or specialist) for the management of type 2 diabetes compared to usual care? [Henceforth referred to as Model 1]
What is the evidence of efficacy of specialized multidisciplinary community care provided by at least a pharmacist and a primary care physician for the management of type 2 diabetes compared to usual care? [Henceforth referred to as Model 2]
Inclusion Criteria
English language full-reports
Published between January 1, 2000 and September 28, 2008
Randomized controlled trials (RCTs), systematic reviews and meta-analyses
Type 2 diabetic adult population (≥18 years of age)
Total sample size ≥30
Describe specialized multidisciplinary community care defined as ambulatory-based care provided by at least two health care disciplines (of which at least one must be a specialist in diabetes) with integrated communication between the care providers.
Compared to usual care (defined as health care provision by non-specialist(s) in diabetes, such as primary care providers; may include referral to other health care professionals/services as necessary)
≥6 months follow-up
Exclusion Criteria
Studies where discrete results on diabetes cannot be abstracted
Predominantly home-based interventions
Inpatient-based interventions
Outcomes of Interest
The primary outcomes for this review were glycosylated hemoglobin (rHbA1c) levels and systolic blood pressure (SBP).
Search Strategy
A literature search was performed on September 28, 2008 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1, 2000 and September 28, 2008. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Given the high clinical heterogeneity of the articles that met the inclusion criteria, specific models of specialized multidisciplinary community care were examined based on models of care that are currently being supported in Ontario, models of care that were commonly reported in the literature, as well as suggestions from an Expert Advisory Panel Meeting held on January 21, 2009.
Summary of Findings
The initial search yielded 2,116 unique citations, from which 22 RCTs trials and nine systematic reviews published were identified as meeting the eligibility criteria. Of these, five studies focused on care provided by at least a nurse, dietician, and physician (primary care and/or specialist) model of care (Model 1; see Table ES 1), while three studies focused on care provided by at least a pharmacist and primary care physician (Model 2; see Table ES 2).
Based on moderate quality evidence, specialized multidisciplinary community care Model 2 has demonstrated a statistically and clinically significant reduction in HbA1c of 1.0% compared with usual care. The effects of this model on SBP, however, are uncertain compared with usual care, based on very-low quality evidence. Specialized multidisciplinary community care Model 2 has demonstrated a statistically and clinically significant reduction in both HbA1c of 1.05% (based on high quality evidence) and SBP of 7.13 mm Hg (based on moderate quality evidence) compared to usual care. For both models, the evidence does not suggest a preferred setting of care delivery (i.e., primary care vs. hospital outpatient clinic vs. community clinic).
Summary of Results of Meta-Analyses of the Effects of Multidisciplinary Care Model 1
Mean change from baseline to follow-up between intervention and control groups
Summary of Results of Meta-Analyses of the Effects of Multidisciplinary Care Model 2
Mean change from baseline to follow-up between intervention and control groups
PMCID: PMC3377524  PMID: 23074528
22.  Managing Chronic Inflammation in the Aging Diabetic Patient With CKD by Diet or Sevelamer Carbonate: A Modern Paradigm Shift 
The maintenance of normal metabolism and body defenses depends on the balance between cellular antioxidant and anti-inflammatory factors. This balance can be disrupted by agents/mechanisms in the extracellular milieu that induce excess reactive oxygen species (ROS) and inflammation. Cytopathic advanced glycation endproducts, present in ever increasing amounts in the modern diet, are one of the major environmental factors that cause excess ROS and/or inflammation at all ages and induce complications in aging, such as chronic kidney disease (CKD) and type 2 diabetes. Increased ROS and/or inflammation are present in both aging and CKD, and are associated with reduced cellular defenses against ROS and/or inflammation. Affected individuals have reduced defenses against further stress and are predisposed to organ failure, now a well-known phenomenon in aging. Thus, new methods are urgently needed to safely reduce ROS and/or inflammation in the aging type 2 diabetes patient with CKD. Studies of both normal aging and diabetic patients with kidney disease underline the fact that increased ROS and/or inflammation can be managed in these conditions by economical, safe, and effective interventions that reduce the uptake of advanced glycation endproducts by either modifying preparation of food or an oral drug. This communication reviews these data and adds new information on the efficacy of a drug, sevelamer carbonate, required to reduce ROS and/or inflammation in the aging type 2 diabetes patient complicated by CKD. If larger and longer studies confirm the hypothesis that one or both of these interventions reduce progression of CKD, it could represent a new paradigm in the management of complications in the type 2 diabetes patient with CKD.
doi:10.1093/gerona/gls195
PMCID: PMC3636675  PMID: 23109677
Diabetes; Hemodialysis; AGEs; Diet; Inflammation; Aging
23.  Morphological Changes and Immunohistochemical Expression of RAGE and its Ligands in the Sciatic Nerve of Hyperglycemic Pig (Sus Scrofa) 
Biochemistry Insights (Online)  2010;2010(3):47-59.
The aim of our project was to study the effect of streptozotocin (STZ)—induced hyperglycemia on sciatic nerve morphology, blood plasma markers and immunohistochemical expression of RAGE (the Receptor for Advanced Glycation End-products), and its ligands—S100B and Carboxymethyl Lysine (CML)-advanced glycation endproduct (AGE) in the laboratory pig. Six months after STZ—injections, blood plasma measurements, morphometric analysis of sciatic nerve fiber density, immunofluorescent distribution of potential molecular neuropathy contributors, ELISA measurement of plasma AGE level and HPLC analysis of sciatic nerve levels of one of the pre-AGE and the glycolysis intermediate products—methyl-glyoxal (MG) were performed. The results of our study revealed that STZ—injected animals displayed elevated levels of plasma glucose, gamma glutamyl transferase (GGT) and triglycerides. The sciatic nerve of STZ-injected pigs revealed significantly lower numbers of small-diameter myelinated fibers, higher immunoreactivity for RAGE and S100B and increased levels of MG as compared to control animals. Our results correspond to clinical findings in human patients with hyperglycemia/diabetes-evoked peripheral neuropathy and suggest that the domestic pig may be a suitable large animal model for the study of mechanisms underlying hyperglycemia-induced neurological complications in the peripheral nerve and may serve as a relevant model for the pre-clinical assessment of candidate drugs in neuropathy.
doi:10.4137/BCI.S5340
PMCID: PMC3156451  PMID: 21852897
pig; sciatic nerve; RAGE; AGE; S100B; CML
24.  Reappraisal of Metformin Efficacy in the Treatment of Type 2 Diabetes: A Meta-Analysis of Randomised Controlled Trials 
PLoS Medicine  2012;9(4):e1001204.
Catherine Cornu and colleagues performed a meta-analysis of randomised controlled trials of metformin efficacy on cardiovascular morbidity or mortality in patients with type 2 diabetes and showed that although metformin is considered the gold standard, its benefit/risk ratio remains uncertain.
Background
The UK Prospective Diabetes Study showed that metformin decreases mortality compared to diet alone in overweight patients with type 2 diabetes mellitus. Since then, it has been the first-line treatment in overweight patients with type 2 diabetes. However, metformin-sulphonylurea bitherapy may increase mortality.
Methods and Findings
This meta-analysis of randomised controlled trials evaluated metformin efficacy (in studies of metformin versus diet alone, versus placebo, and versus no treatment; metformin as an add-on therapy; and metformin withdrawal) against cardiovascular morbidity or mortality in patients with type 2 diabetes. We searched Medline, Embase, and the Cochrane database. Primary end points were all-cause mortality and cardiovascular death. Secondary end points included all myocardial infarctions, all strokes, congestive heart failure, peripheral vascular disease, leg amputations, and microvascular complications. Thirteen randomised controlled trials (13,110 patients) were retrieved; 9,560 patients were given metformin, and 3,550 patients were given conventional treatment or placebo. Metformin did not significantly affect the primary outcomes all-cause mortality, risk ratio (RR) = 0.99 (95% CI: 0.75 to 1.31), and cardiovascular mortality, RR = 1.05 (95% CI: 0.67 to 1.64). The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR = 0.90 (95% CI: 0.74 to 1.09); all strokes, RR = 0.76 (95% CI: 0.51 to 1.14); heart failure, RR = 1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR = 0.90 (95% CI: 0.46 to 1.78); leg amputations, RR = 1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR = 0.83 (95% CI: 0.59 to 1.17). For all-cause mortality and cardiovascular mortality, there was significant heterogeneity when including the UK Prospective Diabetes Study subgroups (I2 = 41% and 59%). There was significant interaction with sulphonylurea as a concomitant treatment for myocardial infarction (p = 0.10 and 0.02, respectively).
Conclusions
Although metformin is considered the gold standard, its benefit/risk ratio remains uncertain. We cannot exclude a 25% reduction or a 31% increase in all-cause mortality. We cannot exclude a 33% reduction or a 64% increase in cardiovascular mortality. Further studies are needed to clarify this situation.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 350 million people have diabetes, and this number is increasing rapidly. Diabetes is characterized by dangerous amounts of sugar (glucose) in the blood. Blood sugar levels are normally controlled by insulin, a hormone produced by the pancreas. In people with type 2 diabetes (the most common form of diabetes), blood sugar control fails because the fat and muscle cells that usually respond to insulin by removing excess sugar from the blood become less responsive to insulin. Type 2 diabetes can be controlled with diet and exercise and with antidiabetic pills, each of which works in a different way to maintain a healthy blood sugar level. Metformin, for example, stops the liver making glucose and increases the body's response to insulin, whereas sulfonylureas help the pancreas make more insulin. The long-term complications of diabetes, which include an increased risk of cardiovascular problems such as heart disease and stroke, reduce the life expectancy of people with diabetes by about ten years compared to people without diabetes.
Why Was This Study Done?
In 1998, a large randomized clinical trial called the UK Prospective Diabetes Study (UKPDS 34) reported that metformin in combination with dietary control reduced all-cause mortality in overweight patients with type 2 diabetes when compared to dietary control alone. Specifically, the risk of death from any cause among patients taking metformin was about a third lower than the risk of death among patients not taking metformin—a risk ratio (RR) of 0.64. This reduction in risk was significant (that is, it was unlikely to have occurred by chance) because its 95% confidence interval (95% CI; there is a 95% chance that the “true” RR lies within this interval) of 0.45–0.91 did not overlap 1.0. Given this finding, metformin is now recommended as the first-line treatment for type 2 diabetes. However, UKPDS 34 also reported an increase in death in non-overweight patients who took metformin plus sulfonylurea compared to those who took sulfonylurea alone (RR: 1.60; 95% CI: 1.02–2.52), a result considered non-significant by the UKPDS 34 researchers and largely ignored ever since. So do the benefits of metformin outweigh its risks? In this meta-analysis, the researchers re-evaluate the risk-to-benefit balance of metformin in the treatment of patients with type 2 diabetes. A meta-analysis is a statistical method that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 13 randomized controlled trials that evaluated the effect of metformin on cardiovascular morbidity (illness) and mortality in patients with type 2 diabetes. More than 13,000 patients participated in these studies, three-quarters of whom received metformin and a quarter of whom received other treatments or a placebo. Compared to other treatments, metformin treatment had no effect on the risk of all-cause mortality (RR: 0.99; 95% CI: 0.75–1.31) or cardiovascular mortality (RR: 1.05; 95% CI: 0.67–1.64), the primary end points of this study. However, the results of the individual trials varied more than would be expected by chance (“heterogeneity”). Exclusion of the UKPDS 34 trial from the meta-analysis had no effect on the estimated risk ratio for all-cause mortality or cardiovascular deaths, but the heterogeneity disappeared. Finally, metformin treatment had no significant effect on the risk of cardiovascular conditions such as heart attacks, strokes, and heart failure; there was no heterogeneity among the trials for these secondary end points.
What Do These Findings Mean?
These findings show no evidence that metformin has any beneficial effect on all-cause mortality, on cardiovascular mortality, or on cardiovascular morbidity among patients with type 2 diabetes. These findings must be cautiously interpreted because only a few randomized controlled trials were included in this study, and only a few patients died or developed any cardiovascular illnesses. Importantly, however, from these findings, it is impossible to exclude beyond reasonable doubt the possibility that metformin causes up to a 25% reduction or a 31% increase in all-cause mortality. Similarly, these findings cannot exclude the possibility that metformin causes up to a 33% reduction or a 64% increase in cardiovascular mortality. Given that a large number of patients take metformin for many years as a first-line treatment for diabetes, further studies are urgently needed to clarify this situation.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001204.
The International Diabetes Federation provides information about all aspects of diabetes
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health-care professionals, and the general public, including detailed information on diabetes medicines (in English and Spanish)
The UK National Health Service Choices web site provides information for patients and carers about type 2 diabetes and includes peoples stories about diabetes
The charity Diabetes UK also provides detailed information for patients and carers, including information on diabetes medications, and has a further selection of stories from people with diabetes
MedlinePlus provides links to further resources and advice about diabetes and about diabetes medicines; it also provides information about metformin (in English and Spanish)
The charity Healthtalkonline has interviews with people about their experiences of diabetes and of controlling diabetes with oral medications
doi:10.1371/journal.pmed.1001204
PMCID: PMC3323508  PMID: 22509138
25.  Covalent Binding Antibodies Suppress Advanced Glycation: On the Innate Tier of Adaptive Immunity 
Acta Naturae  2009;1(2):66-72.
Non-enzymatic protein glycation is a source of metabolic stress that contributes to cytotoxicity and tissue damage. Hyperglycemia has been linked to elevation of advanced glycation endproducts, which mediate much of the vascular pathology leading to diabetic complications. Enhanced glycation of immunoglobulins and their accelerated vascular clearance is proposed as a natural mechanism to intercept alternative advanced glycation endproducts, thereby mitigating microvascular disease. We reported that antibodies against the glycoprotein KLH have elevated reactivity for glycopeptides from diabetic serum. These reactions are mediated by covalent binding between antibody light chains and carbonyl groups of glycated peptides. Diabetic animals that were immunized to induce reactive antibodies had attenuated diabetic nephropathy, which correlated with reduced levels of circulating and kidney-bound glycation products. Molecular analysis of antibody glycation revealed the preferential modification of light chains bearing germline-encoded lambda V regions. We previously noted that antibody fragments carrying V regions in the germline configuration are selected from a human Fv library by covalent binding to a reactive organophosphorus ester. These Fv fragments were specifically modified at light chain V region residues, which map to the combining site at the interface between light and heavy chains. These findings suggest that covalent binding is an innate property of antibodies, which may be encoded in the genome for specific physiological purposes. This hypothesis is discussed in context with current knowledge of the natural antibodies that recognize altered self molecules and the catalytic autoantibodies found in autoimmune disease.
PMCID: PMC3347515  PMID: 22649604

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