Long-Term Cardiovascular Risk in Type 2 Diabetic Compared With Nondiabetic First Acute Myocardial Infarction Patients: A population-based cohort study in southern Europe

OBJECTIVE

The aim of this study was to determine whether long-term cardiovascular risk differs in type 2 diabetic patients compared with first acute myocardial infarction patients in a Mediterranean region, considering therapy, diabetes duration, and glycemic control.

RESEARCH DESIGN AND METHODS

A prospective population-based cohort study with 10-year follow-up was performed in 4,410 patients aged 30–74 years: 2,260 with type 2 diabetes without coronary heart disease recruited in 53 primary health care centers and 2,150 with first acute myocardial infarction without diabetes recruited in 10 hospitals. We compared coronary heart disease incidence and cardiovascular mortality rates in myocardial infarction patients and diabetic patients, including subgroups by diabetes treatment, duration, and A1C.

RESULTS

The adjusted hazard ratios (HRs) for 10-year coronary heart disease incidence and for cardiovascular mortality were significantly lower in men and women with diabetes than in myocardial infarction patients: HR 0.54 (95% CI 0.45–0.66) and 0.28 (0.21–0.37) and 0.26 (0.19–0.36) and 0.16 (0.10–0.26), respectively. All diabetic patient subgroups had significantly fewer events than myocardial infarction patients: the HR of cardiovascular mortality ranged from 0.15 (0.09–0.26) to 0.36 (0.24–0.54) and that of coronary heart disease incidence ranged from 0.34 (0.26–0.46) to 0.56 (0.43–0.72).

CONCLUSIONS

Lower long-term cardiovascular risk was found in type 2 diabetic and all subgroups analyzed compared with myocardial infarction patients. These results do not support equivalence in coronary disease risk for diabetic and myocardial infarction patients.The prevalence of diabetes is reaching epidemic proportions in developed countries (1). For example, the U.S. has 18 million diabetic patients, Spain has >2 million diabetic patients, and management of the disease costs >$132 and >$3.3 billion per year, respectively (2).Some studies (3–5), several of them with great influence on important guidelines for cardiovascular prevention (3), suggest that the cardiovascular risk of diabetic patients is similar to that of coronary heart disease secondary prevention patients. Other reports, however, do not confirm these observations (6–10).Part of the discrepancy may stem from differences in the duration of diabetes, type of treatment, and baseline glucose control of diabetic patients included in the studies (3–5). These limit comparability, given the fact that time of evolution and treatment required to attain appropriate glycemic control are key determinants of prognosis (10–16).Among population-based cohort studies that compared the prognosis of diabetic patients with that of myocardial infarction patients without diabetes (3–10), only two analyzed the role of diabetes duration (11,12). Even these studies did not include unstable angina among the end points and risk was not stratified by type of treatment. To our knowledge, the effect of type 2 diabetes on coronary heart disease incidence has barely been studied in southern Europe, a region known for low cardiovascular mortality (17). The aim of this study was to determine whether long-term cardiovascular risk differed between type 2 diabetic patients and first acute myocardial infarction patients and to assess the influence of diabetes duration, type of treatment, and glycemic control at baseline.     

Elevated Serum Uric Acid Concentrations Independently Predict Cardiovascular Mortality in Type 2 Diabetic Patients

OBJECTIVE

There is limited information on whether increased serum uric acid levels are independently associated with cardiovascular mortality in type 2 diabetes. We assessed the predictive role of serum uric acid levels on all-cause and cardiovascular mortality in a large cohort of type 2 diabetic individuals.

RESEARCH DESIGN AND METHODS

The cohort included 2,726 type 2 diabetic outpatients, who were followed for a mean period of 4.7 years. The independent association of serum uric acid levels with all-cause and cardiovascular mortality was assessed by Cox proportional hazards models and adjusted for conventional risk factors and several potential confounders.

RESULTS

During follow-up, 329 (12.1%) patients died, 44.1% (n = 145) of whom from cardiovascular causes. In univariate analysis, higher serum uric acid levels were significantly associated with increased risk of all-cause (hazard ratio 19 [95% CI 1.12–1.27], P < 0.001) and cardiovascular (1.25 [1.16–1.34], P < 0.001) mortality. After adjustment for age, sex, BMI, smoking, hypertension, dyslipidemia, diabetes duration, A1C, medication use (allopurinol or hypoglycemic, antihypertensive, lipid-lowering, and antiplatelet drugs), estimated glomerular filtration rate, and albuminuria, the association of serum uric acid with cardiovascular mortality remained statistically significant (1.27 [1.01–1.61], P = 0.046), whereas the association of serum uric acid with all-cause mortality did not.

CONCLUSIONS

Higher serum uric acid levels are associated with increased risk of cardiovascular mortality in type 2 diabetic patients, independent of several potential confounders, including renal function measures.Cardiovascular disease (CVD) represents the most common cause of morbidity and mortality in the type 2 diabetic population (1,2). Several biochemical parameters have been associated with increased risk for CVD in type 2 diabetes (3–5). Increased levels of serum uric acid are quite common in type 2 diabetic patients (6), and they might represent an additional CVD risk factor in these patients (7,8).Whereas several prospective studies have consistently demonstrated that elevated serum uric acid levels are an independent risk factor for CVD mortality in the general population (9–13), there is currently a paucity of available data on the association between serum uric acid levels and CVD mortality in the type 2 diabetic population. In a small retrospective study of 535 type 2 diabetic patients, it was found that higher serum uric acid levels were significantly associated with an increased risk of all-cause mortality (14). However, no information was available on specific causes of mortality in such studies, and no adjustment was made for important risk factors, such as diabetes duration and albuminuria. In another small study of 581 elderly type 2 diabetic patients, it was found that higher serum uric acid levels independently predicted cardiovascular mortality, but the authors did not adjust for glycemic control, use of medications, and albuminuria (15). In this respect, it is important to emphasize that the progressive decline in kidney function, which frequently occurs with aging and the course of type 2 diabetes, is also generally paralleled by progressive increases in serum uric acid levels (16). Thus, the presence of renal dysfunction, as assessed by glomerular filtration rate and albuminuria, should be always taken into account when the association of serum uric acid levels with mortality is explored, especially in the type 2 diabetic population.The aim of this prospective study was to investigate whether an association does exist between serum uric acid concentrations and all-cause and cardiovascular mortality in a large cohort of type 2 diabetic individuals, independent of several baseline confounding factors, including markers of kidney function.     

Osteoprotegerin Is an Independent Predictor of Vascular Events in Finnish Adults With Type 1 Diabetes

OBJECTIVEOsteoprotegerin (OPG) is involved in the process of vascular calcification. We investigated whether OPG is associated with the development and progression of diabetes complications in adults with type 1 diabetes (T1D).RESULTSOnly patients with macroalbuminuria and/or renal impairment had elevated OPG concentrations, when compared with participants without overt kidney disease. Patients with retinopathy or CV disease also had higher OPG concentrations, but this was attributable to their higher frequency of chronic kidney disease. OPG predicted an incident CV event (hazard ratio 1.21 [95% CI 1.01–1.45]; P = 0.035) and peripheral vascular disease/amputation events (1.46 [1.13–1.88]; P = 0.004) during follow-up.CONCLUSIONSWe showed that serum OPG is an independent predictor of CV complications. OPG may be directly involved in extraosseous calcification, resulting in stiffening of the arteries and subsequent vascular insufficiency in patients with T1D.Arterial calcification is strongly associated with the development and progression of vascular stiffening and arteriosclerosis leading to cardiovascular disease (CVD). This process is accelerated in patients with diabetes or chronic kidney disease (CKD) and especially in those with both (1). Many of the key regulators of bone mineralization also appear to be key mediators of osteogenic transformation of vascular smooth muscle cells and arterial calcification in diabetes (2,3). One of the most well known is osteoprotegerin (OPG) (4,5). OPG concentrations are positively correlated with coronary calcification (6), vascular stiffness (7), and the presence of unstable plaque (8) in nondiabetic individuals and an increased risk of cardiovascular (CV) mortality in patients with diabetes (9,10). In this study, we further explore the association between circulating concentrations of OPG and CV outcomes in a large well-characterized cohort of patients with type 1 diabetes (T1D) exploring mortality, coronary, stroke, and amputation events.     

Rates of Progression in Diabetic Retinopathy During Different Time Periods: A systematic review and meta-analysis

OBJECTIVE

This meta-analysis reviews rates of progression of diabetic retinopathy to proliferative diabetic retinopathy (PDR) and/or severe visual loss (SVL) and temporal trends.

RESEARCH DESIGN AND METHODS

This systematic literature review and meta-analysis of prospective studies assesses progression of retinopathy among diabetic patients without treatment for retinopathy at baseline. Studies published between 1975 to February 2008 were identified. Outcomes of interest were rates of progression to PDR and/or SVL. Pooled baseline characteristics and outcome measures were summarized using weighted averages of counts and means. Baseline characteristics and outcomes were compared between two periods: 1975–1985 and 1986–2008.

RESULTS

A total of 28 studies comprising 27,120 diabetic patients (mean age 49.8 years) were included. After 4 years, pooled incidence rates for PDR and SVL were 11.0 and 7.2%, respectively. Rates were lower among participants in 1986–2008 than in 1975–1985. After 10 years, similar patterns were observed. Participants in 1986–2008 studies had lower proportions of PDR and non-PDR at all time points than participants in 1975–1985 studies.

CONCLUSIONS

Since 1985, diabetic patients have lower rates of progression to PDR and SVL. These findings may reflect an increased awareness of retinopathy risk factors; earlier identification and initiation of care for patients with retinopathy; and improved medical management of glucose, blood pressure, and serum lipids. Differences in baseline characteristics, particularly in the prevalence and severity of retinopathy, could also have contributed to these temporal differences.Diabetes affects more than 170 million individuals worldwide (1,2), and diabetic retinopathy is the most frequent cause of visual impairment among working-age individuals (3,4). In the last 3 decades, a relative decline in rates of diabetic retinopathy has been suggested by some studies, (5–8) possibly reflecting improved patient and physician awareness, screening, and prevention, as well as better management of diabetes (9). In 1985, the Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated the effectiveness of laser photocoagulation (10,11). Systemic control of both hyperglycemia and hypertension was shown to be important in the Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS) in the 1990s (12,13). Findings from these trials, other studies, and clinical practice guidelines may have led to increased public awareness to diabetes risk factors and a shorter time from onset to diagnosis, potentially altering the rates of diabetic retinopathy progression (9,14).Understanding the natural history of diabetic retinopathy is also important for estimating sample size for testing new interventions in clinical trials. Already, inadequate sample size estimations may have resulted in underpowered trials (15). Traditionally, progression rates from the ETDRS and the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) were used for sample size calculations (16–22). However, these studies were conducted almost 30 years ago. Contemporary estimates for diabetic retinopathy progression are clearly needed, some of which may, in part, be provided by more recent studies, such as the Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy (DIRECT) trial (23,24).In this systematic review and meta-analysis, we summarized the best available evidence to provide contemporary data on the clinical course of diabetic retinopathy and to examine potential differences in rates of diabetic retinopathy progression over time.     

Automated Ankle-Brachial Pressure Index Measurement by Clinical Staff for Peripheral Arterial Disease Diagnosis in Nondiabetic and Diabetic Patients

OBJECTIVE

Peripheral arterial disease (PAD) is a prognostic marker in cardiovascular disease. The use of Doppler-measured ankle-brachial pressure index (Dop-ABI) for PAD diagnosis is limited because of time, required training, and costs. We assessed automated oscillometric measurement of the ankle-brachial pressure index (Osc-ABI) by nurses and clinical staff.

RESEARCH DESIGN AND METHODS

Clinical staff obtained Osc-ABI with an automated oscillometric device in 146 patients (83 with diabetes) at the time of Dop-ABI measurement and ultrasound evaluation.

RESULTS

Measurements were obtained in most legs (Dop-ABI 98%; Osc-ABI 95.5%). Dop- and Osc-ABI were significantly related in diabetic and nondiabetic patients with good agreement over a wide range of values. When Dop-ABI ≤0.90 was used as the gold standard for PAD, receiver operating characteristic curve analysis showed that PAD was accurately diagnosed with Osc-ABI in diabetic patients. When ultrasound was used to define PAD, Dop-ABI had better diagnostic performance than Osc-ABI in the whole population and in diabetic patients (P = 0.026). Both methods gave similar results in nondiabetic patients. The cutoff values for the highest sensitivity and specificity for PAD screening were between 1.0 and 1.1. Estimation of cost with the French medical care system fees showed a potential reduction by three of the screening procedures.

CONCLUSIONS

PAD screening could be improved by using Osc-ABI measured by clinical staff with the benefit of greater cost-effectiveness but at the risk of lower diagnostic performance in diabetic patients.Peripheral arterial disease (PAD) is a frequent manifestation of atherosclerosis in the general population and is two to four times more prevalent in diabetic patients (1). A continuous wave Doppler-measured ankle-brachial pressure index (Dop-ABI) ≤0.90 is commonly used for diagnosing PAD (2,3). Ankle-brachial pressure index (ABI) sensitivity is 79% and specificity is 96% for detection of ≥50% reduction in vascular lumina (4). Moreover, Dop-ABI has prognostic value for cardiovascular morbidity and mortality and for coronary heart disease in particular (5). Despite the apparent simplicity of Dop-ABI measurements, they are time consuming and require technical skill and a dedicated device (2,6,7), which preclude routine use of ABI measurements in general practice (6). PAD remains largely underdiagnosed (1), particularly in diabetic patients in whom it is frequently associated with lower limb complications (8).Automated oscillometric determination of blood pressure is commonly used for screening for hypertension (9). Devices are widely available and reliable (9,10). Several studies reported automated oscillometric ankle-brachial pressure index measurement (Osc-ABI) with good agreement with Dop-ABI results (11,12), suggesting that it might be used for PAD screening.In this study, we evaluated Osc-ABI and Dop-ABI for PAD screening with ultrasound as a reference diagnostic procedure in diabetic and nondiabetic patients. Furthermore, we assessed the possible utility of involving nurses and clinical staff in PAD screening.     

Comparison of Two Creatinine-Based Estimating Equations in Predicting All-Cause and Cardiovascular Mortality in Patients With Type 2 Diabetes

OBJECTIVE

To compare the performance of two glomerular filtration rate (GFR)-estimating equations in predicting the risk of all-cause and cardiovascular mortality in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

We followed 2,823 type 2 diabetic outpatients for a period of 6 years for the occurrence of all-cause and cardiovascular mortality. GFR was estimated using the four-variable Modification of Diet in Renal Disease (MDRD) study equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.

RESULTS

At baseline, an estimated GFR (eGFR) <60 mL/min/1.73 m² was present in 22.0 and 20.2% of patients using the MDRD study equation and the CKD-EPI equation, respectively. A total of 309 patients died during the follow-up (152 patients from cardiovascular causes). Both creatinine-based equations were associated with an increased risk of all-cause and cardiovascular mortality. However, the CKD-EPI equation provided a more accurate risk prediction of mortality than the MDRD study equation. Receiving operating characteristic curves showed that the areas under the curve (AUCs) for all-cause mortality (AUC 0.712 [95% CI 0.682–0.741]) and cardiovascular mortality (0.771 [0.734–0.808]) using eGFR_CKD-EPI were significantly greater (P < 0.0001 by the z statistic) than those obtained by using eGFR_MDRD (0.679 [0.647–0.711] for all-cause mortality and 0.739 [0.698–0.783] for cardiovascular mortality).

CONCLUSIONS

Our findings suggest that the estimation of GFR using the CKD-EPI equation more appropriately stratifies patients with type 2 diabetes according to the risk of all-cause and cardiovascular mortality compared with the MDRD study equation.Chronic kidney disease (CKD) is a major public health problem because its prevalence is rapidly increasing worldwide and it is strongly associated with increased risks of end-stage renal disease, death, cardiovascular disease (CVD), and hospitalization (1–5). Glomerular filtration rate (GFR) is the best overall measure of kidney function. Current diagnosis, evaluation, and management of CKD routinely rely on estimates of GFR (eGFRs) usually derived from creatinine-based equations such as the Modification of Diet in Renal Disease (MDRD) study equation, which incorporates information on serum creatinine concentration, age, sex, and race (1,6,7). This equation is the most commonly used method for estimating kidney function in routine clinical practice. Its prognostic value has been validated in several studies and populations (1,6,7). Decreased eGFR_MDRD has been shown to be an important risk factor for death, CVD events, and other adverse clinical outcomes, specifically in patients with a GFR level <60 mL/min/1.73 m² (1–5). However, despite its widespread use, it is known that the major limitations of the MDRD study equation are imprecision and systematic underestimation of measured GFR (bias) at higher values (1,6,7).The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) investigators recently developed and validated a new equation to improve the estimation of GFR (eGFR_CKD-EPI) by using a large database pooled from 10 studies (8). This equation, which uses the same four variables as the MDRD study equation (i.e., serum creatinine level, age, sex, and race), has been shown to be more precise and accurate than the MDRD study equation in estimating measured GFR, especially at higher GFR values (8). Improved accuracy of the CKD-EPI equation could have important implications for public health and clinical practice (8). In addition, some large population-based cohort studies have recently shown that the CKD-EPI equation also has superior accuracy in classifying individuals at risk for CVD events and death compared with the MDRD study equation (9–11).However, the CKD-EPI equation might not work equally well in people at high CVD risk, such as type 2 diabetic individuals. Whether the use of the CKD-EPI equation provides more accurate prognostic information than the MDRD study equation with respect to the risk of all-cause and CVD mortality in patients with type 2 diabetes is currently unknown. Thus, the aim of this prospective, longitudinal study was to compare the performance of the MDRD study equation and the CKD-EPI equation in predicting all-cause and CVD mortality in a large sample of type 2 diabetic individuals during a follow-up period of 6 years.     

Effect of diabetes on severity and hospital mortality in patients with acute pancreatitis: a national population-based study

OBJECTIVE

Diabetes may increase the risk of acute pancreatitis (AP). We aimed to further investigate whether diabetes may also adversely affect outcomes of patients with AP.

RESEARCH DESIGN AND METHODS

In this retrospective cohort study, we compared 18,990 first-attack AP with diabetes to 37,980 matched control subjects from Taiwan’s National Health Insurance Research Database between 2000 and 2009. Primary outcomes were development of severe AP, defined by a modified Atlanta classification scheme, and hospital mortality. Analyses were performed using univariable and multivariable logistic regression model with generalized estimating equations accounting for hospital clustering effect.

RESULTS

After baseline characteristics were adjusted, AP patients with diabetes had a higher risk of a severe attack than their nondiabetic counterparts (adjusted odds ratio [OR] 1.21, 95% CI 1.16–1.26). When severity criteria were analyzed individually, diabetic AP patients had a 58% higher risk of intensive care unit admission and a 30% higher risk of local complications, but a 16% lower risk of gastrointestinal bleeding, than AP patients without diabetes. The risk of organ failure at least one system) was similar between the two groups. Conversely, AP patients with diabetes were associated with a lower risk of hospital mortality (adjusted OR 0.77, 95% CI 0.65–0.91).

CONCLUSIONS

Although diabetes may adversely affect the disease process of AP, it seems to protect patients from AP-related mortality.Acute pancreatitis (AP) is an acute inflammatory disease of the pancreas. The local inflammation is usually self-limited within a few days, but it can be destructive and cause a severe local complication and/or systemic reaction leading to organ failures and death. Although the case-fatality rate has been decreasing over the decades (1,2), severe cases still carry a high mortality (20–50%) and consume nearly half of the resources and costs incurred by all patients with AP (3). Accordingly, many efforts have been made to identify correlates of severity and predictors for mortality in patients with AP (4–6).In addition to older people (7), patients with certain comorbidities, such as obesity (8), hypertriglyceridemia (9), chronic renal failure (10), and systemic lupus erythematosus (11), are shown to be associated with greater risk of not only the incidence but also the severity and mortality of AP. Among various comorbidities, diabetes mellitus is relatively common in patients with AP; the prevalence was 11% in Japan (12), 17.7% in California (U.S.), (13) and 19.3% in Taiwan (3). These figures are expected to continuously increase in the future because diabetic patients not only are at risk for developing AP (14–16) but also are growing in prevalence worldwide (17). Nonetheless, the effect of diabetes on outcomes of patients with AP has not been adequately studied, and the results of available reports are inconsistent (13,18). For example, Frey and colleagues examined the effect of comorbidities on patients with AP and found that diabetes was not associated with early mortality (13), whereas Graham and coworkers assessed the effect of diabetes on critically ill patients and showed a reduced risk of hospital mortality in a subgroup patients with AP (18). In both studies, however, the effect of diabetes was not specifically examined and detailed analyses were not performed (13,18).In a recent national population-based study on Taiwanese patients with first-attack AP, we found that the prevalence of diabetes increased from 15.6% in 2000 to 2001 to 19.7% in 2008 to 2009 (1). In this study, we used the same cohort (1) to further investigate the effect of diabetes on outcomes of these patients. Because diabetic patients are likely to have a higher comorbid burden and hence a poorer reserve for acute illnesses, we hypothesized that diabetes is associated with a higher risk of severe attacks and hospital mortality in adult patients with first-attack AP.     

Diabetes and risk of prostate cancer: a study using the National Health Insurance

OBJECTIVE

The link between diabetes and prostate cancer is rarely studied in Asians.

RESEARCH DESIGN AND METHODS

The trend of age-standardized prostate cancer incidence in 1995–2006 in the Taiwanese general population was calculated. A random sample of 1,000,000 subjects covered by the National Health Insurance in 2005 was recruited. A total of 494,630 men for all ages and 204,741 men ≥40 years old and without prostate cancer at the beginning of 2003 were followed to the end of 2005. Cumulative incidence and risk ratio between diabetic and nondiabetic men were calculated. Logistic regression estimated the adjusted odds ratios for risk factors.

RESULTS

The trend of prostate cancer incidence increased significantly (P < 0.0001). The cumulative incidence markedly increased with age in either the diabetic or nondiabetic men. The respective risk ratio (95% CI) for all ages and age 40–64, 65–74, and ≥75 years was 5.83 (5.10–6.66), 2.09 (1.60–2.74), 1.35 (1.07–1.71), and 1.39 (1.12–1.71). In logistic regression for all ages or for age ≥40 years, age, diabetes, nephropathy, ischemic heart disease, dyslipidemia, living region, and occupation were significantly associated with increased risk, but medications including insulin and oral antidiabetic agents were not.

CONCLUSIONS

Prostate cancer incidence is increasing in Taiwan. A positive link between diabetes and prostate cancer is observed, which is more remarkable in the youngest age of 40–64 years. The association between prostate cancer and comorbidities commonly seen in diabetic patients suggests a more complicated scenario in the link between prostate cancer and diabetes at different disease stages.The association between diabetes and prostate cancer has been inconsistently reported, even though two meta-analyses suggested that diabetic patients have a lower risk of prostate cancer of 9% (1) and 16% (2), respectively.While the two meta-analyses were examined, many studies were case-control and only three focused on the follow-up of cohorts of diabetic patients (3–5). Among the three cohorts, the cases of prostate cancer were 9 (3), 498 (4), and 2,455 (5), respectively; and only the last (5) showed a significant 9% risk reduction in diabetic patients. Except for the first study being conducted in residents with diabetes in Rochester, Minnesota (3), the diabetic patients in the other two were from hospitalized patients in Denmark (4) and Sweden (5), respectively. The meta-analyses have limitations including a mixture of case-control and cohort designs, a mixture of incident and dead cases, a small number of prostate cancer in most studies, and different sources of subjects with potential selection bias. Although the contamination of type 1 diabetes is possibly minimal because >90% of overall patients have type 2 diabetes, residual confounding could not be excluded if the two types of diabetes are not differentiated.Although some recent studies still suggested a lower risk of prostate cancer in diabetic patients including Caucasians (6,7), Iranians (8), Israelis (9), African Americans, Native Hawaiians, and Japanese Americans (6), the lower risk in African Americans and Native Hawaiians (6) was not significant. Two Japanese studies did not find any significant association (10,11). The Ohsaki Cohort Study suggested that diabetes was not predictive for total prostate cancer, but diabetic patients did show a higher risk of advanced cancer (11).Because diabetic patients are prone to develop cancer involving pancreas, liver, breast, colorectum, bladder, and endometrium (12–15) and the protective effect of diabetes on prostate cancer requires confirmation, this study evaluated the possible link between diabetes and prostate cancer, and the potential risk factors, by using the reimbursement database of the National Health Insurance (NHI) in Taiwan.     

Inflammatory, Hemostatic, and Other Novel Biomarkers for Diabetic Retinopathy: The Multi-Ethnic Study of Atherosclerosis

OBJECTIVE

There are conflicting data regarding relationships of systemic biomarkers of inflammation, hemostasis, and homocysteine with diabetic retinopathy. We examined these relationships in the Multi-Ethnic Study of Atherosclerosis.

RESEARCH DESIGN AND METHODS

A total of 921 participants with diabetes were included. Diabetic retinopathy was graded from retinal photographs. We defined two outcomes: any diabetic retinopathy and vision-threatening diabetic retinopathy (severe nonproliferative diabetic retinopathy or worse). Systemic markers analyzed were C-reactive protein, homocysteine, fibrinogen, plasmin-α₂-antiplasmin complex (PAP), interleukin-6, d-dimer, factor VIII, serum creatinine, and urinary albumin-to-creatinine (UAC) ratio.

RESULTS

Prevalence of diabetic retinopathy was 33.2% and vision-threatening diabetic retinopathy 7.1%. After adjusting for established risk factors (diabetes duration, A1C, systolic blood pressure, waist-to-hip ratio, and use of diabetes medications), fibrinogen (odds ratio 1.14 [95% CI 1.01–1.32], P = 0.05) and PAP (1.25 [1.05–1.50], P = 0.01) were associated with any diabetic retinopathy, while PAP (1.54 [1.13–2.11], P = 0.007) and homocysteine (1.57 [1.16–2.11], P = 0.003) were associated with vision-threatening diabetic retinopathy. Only PAP remained significant after additional adjustment for serum creatinine and UAC ratio. Area under receiver-operator characteristic curve (AUROC) for diabetic retinopathy was constructed for established and novel risk factors. Established risk factors accounted for a 39.2% increase of the AUROC, whereas novel markers (fibrinogen, PAP, homocysteine, serum creatinine, and UAC ratio) only accounted for an additional 2.2%.

CONCLUSIONS

There were few associations of novel markers of inflammation, hemostasis, and homocysteine with diabetic retinopathy after controlling for established risk factors. These data suggest that there is limited clinical use of these biomarkers for prediction of diabetic retinopathy.Diabetic retinopathy is the leading cause of blindness in working-age individuals (1). There is increasing evidence that established risk factors for diabetic retinopathy (2,3), including duration of diabetes, hyperglycemia, and hypertension, only explain a limited amount of the variance in the risk of diabetic retinopathy (1). Furthermore, the underlying pathogenesis of diabetic retinopathy remains inadequately understood (4). This has resulted in examination of the relation of novel risk markers such as inflammation (e.g., C-reactive protein [CRP]), markers of hemostatic disturbances (e.g., fibrinogen levels), and hyperhomocysteinemia to diabetic retinopathy. However, to date, the relations of these factors to diabetic retinopathy have not been consistent (5–17). The reasons for these inconsistencies may be due, in part, to differences in study sample and definitions of diabetic retinopathy (e.g., clinical versus photograph grading) and failure in some studies to make adequate adjustments for traditional risk factors such as glycemic control and hypertension. Thus, it remains unclear if there is a role for the use of these systemic markers as additional clinical tests to identify individuals at high risk of diabetic retinopathy. In this study, we evaluated the relationship of a range of inflammatory, hemostatic, and novel vascular markers with diabetic retinopathy, while controlling for traditional risk factors, in a large multiethnic population.     

Inflammation and Cognitive Dysfunction in Type 2 Diabetic Carotid Endarterectomy Patients

OBJECTIVE

Type 2 diabetic patients have a high incidence of cerebrovascular disease, elevated inflammation, and high risk of developing cognitive dysfunction following carotid endarterectomy (CEA). To elucidate the relationship between inflammation and the risk of cognitive dysfunction in type 2 diabetic patients, we aim to determine whether elevated levels of systemic inflammatory markers are associated with cognitive dysfunction 1 day after CEA.

RESEARCH DESIGN AND METHODS

One hundred fifteen type 2 diabetic CEA patients and 156 reference surgical patients were recruited with written informed consent in this single-center cohort study. All patients were evaluated with an extensive battery of neuropsychometric tests. Preoperative monocyte counts, HbA_1c, C-reactive protein (CRP), intercellular adhesion molecule 1, and matrix metalloproteinase 9 activity levels were obtained.

RESULTS

In a multivariate logistic regression model constructed to identify predictors of cognitive dysfunction in type 2 diabetic CEA patients, each unit of monocyte counts (odds ratio [OR] 1.76 [95% CI 1.17–2.93]; P = 0.005) and CRP (OR 1.17 [1.10–1.29]; P < 0.001) was significantly associated with higher odds of developing cognitive dysfunction 1 day after CEA in type 2 diabetic patients.

CONCLUSIONS

Type 2 diabetic patients with elevated levels of preoperative systemic inflammatory markers exhibit more cognitive dysfunction 1 day after CEA. These observations have implications for the preoperative medical management of this high-risk group of surgical patients undergoing carotid revascularization with CEA.The incidence of ischemic stroke is significantly higher in type 2 diabetic patients (1,2), as type 2 diabetes is an independent risk factor for stroke and its recurrence (3,4). Carotid artery stenosis is a major cause of ischemic stroke and can be surgically treated with carotid endarterectomy (CEA). In previous work, we have demonstrated that ∼25% of CEA patients exhibit cognitive dysfunction, a subtle form of neurologic injury, within 1 day of CEA (5,6). Glial markers of neuronal injury (S100B) are elevated in patients who exhibit cognitive dysfunction within 1 day of CEA (7) and reflect opening of the blood–brain barrier (8). Additionally, we have data that demonstrate cognitive dysfunction exhibited within 1 day of CEA is associated with earlier mortality after CEA (9); patients who exhibit cognitive dysfunction within 1 day of CEA experience mortality 4 years earlier than those who do not exhibit cognitive dysfunction within 1 day of CEA. We have also demonstrated that type 2 diabetes is an independent risk factor for cognitive dysfunction (10). In this study, we will investigate factors that might contribute to the increased risk of type 2 diabetic patients undergoing CEA to exhibit the subtle, but significant, cognitive dysfunction.Type 2 diabetes has been associated with accelerated atherosclerosis (11) and elevated systemic inflammation (12–14). Inflammation may play a significant role in accounting for the increased risk of cognitive dysfunction in type 2 diabetic patients. Studies have shown that monocyte activation and infiltration are specifically implicated in the initiation of chronic inflammation and atherosclerosis (12). C-reactive protein (CRP) is a nonspecific marker of systemic inflammation that has been strongly associated with adverse cardiovascular outcomes in both healthy patients and those with coronary artery disease (15–18). Intercellular adhesion molecule-1 (ICAM-1) is a glycoprotein expressed on endothelial cells and cells of the immune system (19). Matrix metalloproteinase-9 (MMP-9) is secreted from macrophages (20), is involved in the breakdown of vasculature extracellular matrices, and has also been investigated for its various roles in inflammation (21–24). Many previous studies have demonstrated that CRP, ICAM-1, monocytes, and MMP-9 activity are all elevated in type 2 diabetic patients compared with nondiabetic patients. In our previous work, we have demonstrated that type 2 diabetes is a risk factor for cognitive dysfunction (10). We have also previously shown that elevated levels of ICAM-1 (25), monocyte counts (26), and MMP-9 activity (27) are associated with higher incidences of cognitive dysfunction in nondiabetic patients following CEA. We have yet to demonstrate a relationship between CRP and cognitive dysfunction. However, given the previous work done on CRP, we are inspired to do so in this study.Considering previous findings that 1) type 2 diabetes is a risk factor for cognitive dysfunction following CEA; 2) elevated ICAM-1, MMP-9, and monocyte counts are associated with more cognitive dysfunction in CEA patients; and 3) type 2 diabetic patients have elevated levels of CRP, ICAM-1, MMP-9 activity, and monocytes, we hypothesize that type 2 diabetic patients with elevated preoperative systemic inflammation are more likely to exhibit cognitive dysfunction following CEA than those with lower preoperative systemic inflammation. To date, there are no studies that investigate this relationship.We will evaluate preoperative systemic inflammation by measuring CRP, ICAM-1, MMP-9 activity, and monocytes and compare these levels between type 2 diabetic patients with and without cognitive dysfunction 1 day after CEA.     

Prognostic Impact of Aortic Stiffness in High-Risk Type 2 Diabetic Patients: The Rio de Janeiro Type 2 Diabetes Cohort Study

OBJECTIVE

The prognostic importance of carotid-femoral pulse wave velocity (PWV), the gold standard measure of aortic stiffness, has been scarcely investigated in type 2 diabetes and never after full adjustment for potential confounders. The aim was to evaluate the prognostic impact of carotid-femoral PWV for cardiovascular morbidity and all-cause mortality in a cohort of 565 high-risk type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

Clinical, laboratory, ambulatory blood pressure (BP) monitoring, and carotid-femoral PWV data were obtained at baseline. The primary end points were a composite of fatal and nonfatal cardiovascular events and all-cause mortality. Multiple Cox survival analysis was used to assess the associations between carotid-femoral PWV, as a continuous variable and categorized at 10 m/s, and the end points.

RESULTS

After a median follow-up of 5.75 years, 88 total cardiovascular events and 72 all-cause deaths occurred. After adjustments for potential cardiovascular risk factors, including micro- and macrovascular complications, ambulatory BP, and metabolic control, carotid-femoral PWV was predictive of the composite end point but not of all-cause mortality both as a continuous variable (hazard ratio 1.13 [95% CI 1.03–1.23], P = 0.009 for increments of 1 m/s) and as categorized at 10 m/s (1.92 [1.16–3.18], P = 0.012). On sensitivity analysis, carotid-femoral PWV was a better predictor of cardiovascular events in younger patients (<65 years), in those with microvascular complications, and in those with poorer glycemic control (HbA_1c ≥7.5% [58.5 mmol/mol]).

CONCLUSIONS

Carotid-femoral PWV provides cardiovascular risk prediction independent of standard risk factors, glycemic control, and ambulatory BPs and improves cardiovascular risk stratification in high-risk type 2 diabetes.In the past decade, knowledge of the importance of arterial stiffness in the pathogenesis of cardiovascular diseases grew (1,2). Arterial stiffness depends on the structural and geometric properties of the arterial wall and on the distending pressure, and aging and blood pressure (BP) are its main determinants (1,2). The measurement of carotid-femoral pulse wave velocity (PWV) is considered the gold standard evaluation of central aortic stiffness (1). Furthermore, aortic stiffness has been demonstrated to predict cardiovascular morbidity and mortality above and beyond other traditional cardiovascular risk factors in patients with end-stage renal disease (3) and hypertension (4), elderly individuals (5), and general population-based samples (6,7). This prognostic importance has also been recently confirmed in a meta-analysis (8).Type 2 diabetic patients have increased arterial stiffness (9–11) and are at particular risk for augmented cardiovascular morbidity and mortality. This high cardiovascular risk is not completely explained by clustering of traditional risk factors, and increased arterial stiffness may be one pathophysiological mechanism that links diabetes to increased cardiovascular morbidity and mortality (12). Nevertheless, only one previous study investigated the prognostic impact of increased aortic stiffness for cardiovascular outcomes in type 2 diabetes (13), but because of a smaller sample size (397 diabetic individuals), the study could not completely adjust for traditional cardiovascular risk factors, chronic diabetes complications, or metabolic control parameters. Therefore, we aimed to investigate in a prospective follow-up cohort of high-risk type 2 diabetic patients the prognostic impact of increased aortic stiffness for cardiovascular morbidity and mortality and for all-cause mortality. In particular, we evaluated whether aortic stiffness was able to add prognostic information beyond traditional cardiovascular risk markers and whether there were interactions between aortic stiffness and other important covariates, such as age, sex, presence of diabetes complications, and glycemic control.     

Maternal Family History of Diabetes Is Associated With a Reduced Risk of Cardiovascular Disease in Women With Type 2 Diabetes: The Fremantle Diabetes Study

OBJECTIVE

To investigate whether parental family history of diabetes influences cardiovascular outcomes in type 2 diabetes.

RESEARCH DESIGN AND METHODS

We studied 1,294 type 2 diabetic patients (mean age 64.1 years, 51.2% female) recruited to a community-based cohort study from 1993 to 1996 and followed until mid-2006. A data linkage system assessed all-cause and cardiac mortality, incident myocardial infarction, and stroke. Cox proportional hazards modeling was used to determine the influence of maternal or paternal family history on these outcomes.

RESULTS

A maternal family history of diabetes was reported by 20.4% of the cohort, 8.3% reported paternal family history, and 2.0% reported both parents affected. Maternal and paternal family history was associated with earlier age of diabetes onset, and maternal family history was associated with worse glycemic control. For all patients, maternal family history was significantly associated with reduced risk of all-cause mortality and cardiac mortality. When analyzed by sex, maternal family history had no effect on male patients, whereas female patients with diabetic mothers had significantly reduced hazard ratios for death from all causes (0.63 [95% CI 0.41–0.96]; P = 0.033), for death from cardiac causes (0.32 [0.14–0.72]; P = 0.006), and for first myocardial infarction (0.45 [0.26–0.76]; P = 0.003). Paternal family history status was not associated with these outcomes.

CONCLUSIONS

A maternal family history of diabetes confers relative protection against cardiovascular disease in female patients but not in male patients with type 2 diabetes. Paternal family history is associated with risks equivalent to those without a family history of diabetes. Some of the clinical heterogeneity of type 2 diabetes is related to maternal transmission effects with differential impact on male and female patients.The complex etiology of type 2 diabetes involves both genetic components and environmental exposures. In type 2 diabetes, there is a well documented association between a family history of the disease and its development (1,2). Maternal and paternal family histories of diabetes are both associated with an earlier age of onset (2–4), and this effect is more marked when multiple family members are affected (5). In addition, intrauterine exposure to diabetes increases the risk of diabetes in offspring (6), which may help explain the reported excess maternal transmission (7,8).Patients with familial diabetes have relatively poor glycemic control, but few other clinical differences have been reported (4,5,9,10). An early age of onset and poor glycemic control would both be expected to have a negative impact on the development of chronic complications, but no such longitudinal data have been published. In the present study, we examined relationships among parental diabetes and important clinical outcomes in type 2 diabetes, including incident coronary heart disease (CHD) and all-cause and cardiac mortality in a large community-based sample of patients with type 2 diabetes. We hypothesized that familial diabetes would indicate worse clinical outcomes. We investigated potential relationships in male and female patients separately, given the known differences in CHD incidence between men and women with diabetes (11).     

A New Mechanism of NK Cell Cytotoxicity Activation: The CD40–CD40 Ligand Interaction

NK recognition is regulated by a delicate balance between positive signals initiating their effector functions, and inhibitory signals preventing them from proceeding to cytolysis. Knowledge of the molecules responsible for positive signaling in NK cells is currently limited. We demonstrate that IL-2–activated human NK cells can express CD40 ligand (CD40L) and that recognition of CD40 on target cells can provide an activation pathway for such human NK cells. CD40-transfected P815 cells were killed by NK cell lines expressing CD40L, clones and PBLderived NK cells cultured for 18 h in the presence of IL-2, but not by CD40L-negative fresh NK cells. Cross-linking of CD40L on IL-2–activated NK cells induced redirected cytolysis of CD40-negative but Fc receptor-expressing P815 cells. The sensitivity of human TAP-deficient T2 cells could be blocked by anti-CD40 antibodies as well as by reconstitution of TAP/MHC class I expression, indicating that the CD40-dependent pathway for NK activation can be downregulated, at least in part, by MHC class I molecules on the target cells. NK cell recognition of CD40 may be important in immunoregulation as well as in immune responses against B cell malignancies.NK cells represent a distinct lineage of lymphocytes that are able to kill a variety of tumor (1), virus-infected (2), bone marrow transplanted (3), and allogeneic target cells (4). NK cells do not express T cell receptors or immunoglobulins and are apparently normal in mice with defects in the recombinase machinery (5, 6).Our knowledge about NK cell specificity has increased considerably in the last years. NK cells can probably interact with target cells by a variety of different cell surface molecules, some involved in cell adhesion, some activating the NK cytolytic program (7, 8), and other ones able to inhibit this activation by negative signaling (as reviewed in reference 9).A common feature of several inhibitory NK receptors is the capability to bind MHC class I molecules (10, 11), as predicted by the effector inhibition model within the missing self hypothesis of recognition by NK cells (12–14). Interestingly, the MHC class I receptors identified so far belong to different gene families in mouse and man; these are the p58/p70/NKAT or killer cell inhibitory receptors (KIR)¹ of the immunoglobulin superfamily in man and the Ly49 receptors of the C-type lectin family in the mouse. There is also evidence that MHC class I molecules can be recognized as triggering signals in NK cells of humans, rats as well as mice (13). The inhibitory receptors allow NK cells to kill tumor or normal cell targets with deficient MHC class I expression (12, 14). This does not exclude that other activating pathways can override inhibition by MHC class I molecules (15) and, even in their absence, there must be some activating target molecules that initiate the cytolytic program. Several surface molecules are able to mediate positive signals in NK cells. Some of these structures, like NKRP1 (16), CD69 (17), and NKG2 (18) map to the NK complex region (NKC) of chromosome 6 in mice and of chromosome 12 in humans (13). CD2 (19) and CD16 (20) molecules can also play a role in the activation pathway.NK cells resemble T cells in many respects, both may arise from an immediate common progenitor (21, 22), and share the expression of several surface molecules (23). NK cells produce cytokines resembling those secreted by some helper T cell subsets (24) and contain CD3 components in the cytoplasm (21). The expression of some surface structures, involved in TCR-dependent T cell costimulation, like CD28 in human (25), has been described on NK cells, but the functional relevance of these molecules for NK activation processes has not been fully established.Another T cell molecule of interest is CD40L, which interacts with CD40, a 50-kD membrane glycoprotein expressed on B cells (26), dendritic cells (27), and monocytes (28). CD40 is a member of the tumor necrosis factor/nerve growth factor receptor family (29) which includes CD27 (30), CD30 (31), and FAS antigen (32). Murine and human forms of CD40L had been cloned and found to be membrane glycoproteins with a molecular mass of ∼39 kD induced on T cells after activation (33). Also mast cells (34), eosinophils (35), and B cells (36) can be induced to express a functional CD40L. The CD40L–CD40 interaction has been demonstrated to be necessary for T cell–dependent B cell activation (33, 37). Mutations in the CD40L molecule cause a hyper-IgM immunodeficiency condition in man (38, 39, 40). On the other hand, CD40–CD40L interactions also orchestrate the response of regulatory T cells during both their development (41, 42) and their encounter with antigen (43, 44).NK cells have also been suggested to play a role in B cell differentiation and immunoglobulin production (45). Therefore, it was of interest to investigate whether NK cells could use a CD40-dependent pathway in their interactions with other cells. Therefore, we have investigated the ability of target cells expressing CD40 to induce activation of NK cytotoxicity.     

TRAF-interacting Protein (TRIP): A Novel Component of the Tumor Necrosis Factor Receptor (TNFR)- and CD30-TRAF Signaling Complexes That Inhibits TRAF2-mediated NF-κB Activation

Through their interaction with the TNF receptor–associated factor (TRAF) family, members of the tumor necrosis factor receptor (TNFR) superfamily elicit a wide range of biological effects including differentiation, proliferation, activation, or cell death. We have identified and characterized a novel component of the receptor–TRAF signaling complex, designated TRIP (TRAF-interacting protein), which contains a RING finger motif and an extended coiled-coil domain. TRIP associates with the TNFR2 or CD30 signaling complex through its interaction with TRAF proteins. When associated, TRIP inhibits the TRAF2-mediated NF-κB activation that is required for cell activation and also for protection against apoptosis. Thus, TRIP acts as a receptor–proximal regulator that may influence signals responsible for cell activation/proliferation and cell death induced by members of the TNFR superfamily.Members of the TNF receptor (TNFR)¹ superfamily play important roles in the induction of diverse signals leading to cell growth, activation, and apoptosis (1). Whether the signals induced by a given receptor leads to cell activation or death is, however, highly cell-type specific and tightly regulated during differentiation of cells. For example, the TNFRs can exert costimulatory signals for proliferation of naive lymphocytes but also induce death signals required for deletion of activated T lymphocytes (1). The cytoplasmic domains of these receptors lack intrinsic catalytic activity and also exhibit no significant homology to each other or to other known proteins. Exceptions to this include Fas(CD95) and TNFR1 that share a significant homology within an 80–amino acid region of their cytoplasmic tails (called the “death domain”; 2, 3). Therefore, it is suggested that the TNFR family members can initiate different signal transduction pathways by recruiting different types of intracellular signal transducers to the receptor complex (1).Indeed, several types of intracellular signal transducers have been identified that initiate distinct signal transduction pathways when recruited to the members of TNFR superfamily (4–19). Recent biochemical and molecular studies showed that a class of signal-transducing molecules are recruited to Fas(CD95) or TNFR1 via interaction of the death domains (2, 3, 6, 12, 17, 20). For example, Fas(CD95) and TNFR1 recruit FADD(MORT1)/RIP or TRADD/FADD (MORT1)/RIP through the interactions of their respective death domains (2, 3, 6, 12, 17, 20, 21). Clustering of these signal transducers leads to the recruitment of FLICE/ MACH, and subsequently, to cell death (13, 14).The TNFR family members can also recruit a second class of signal transducers called TRAFs (TNFR-associated factor), some of which are responsible for the activation of NF-κB or JNK (9, 20, 22). TRAF proteins were identified by their biochemical ability to interact with TNFR2, CD40, CD30, or LT-βR (4, 5, 10, 11, 15, 23–27). These receptors interact directly with TRAFs via a short stretch of amino acids within their cytoplasmic tails, but do not interact with the death domain containing proteins (4, 5, 15, 24–27). To date, five members of the TRAF family have been identified as signaling components of the TNFR family members. All TRAF members contain a conserved TRAF domain, ∼230 amino acids in length, that is used for either homo- or heterooligomerization among the TRAF family, for interactions with the cytoplasmic regions of the TNFR superfamily, or for interactions with downstream signal transducers (4, 5, 8, 10, 11, 19, 23–25, 28). In addition to the TRAF domain, most of the TRAF family members contain an NH₂-terminal RING finger and several zinc finger structures, which appear to be important for their effector functions (4, 5, 10, 11, 23–25).Several effector functions of TRAFs were revealed by recent experiments based on a transfection system. TRAF2, first identified by its interaction with TNFR2 (4), was subsequently shown to mediate NF-κB activation induced by two TNF receptors, CD40 and CD30 (9, 28–30). TRAF5 was also implicated in NF-κB activation mediated by LTβR (10), whereas TRAF3 (also known as CRAF1, CD40bp, or LAP1; references 5, 11, 24, and 25) was shown to be involved in the regulation of CD40-mediated CD23 upregulation in B cells (5). The role of other TRAF members in the TNFR family–mediated signal transduction is not clear. They may possess some effector functions as yet to be revealed, or work as adapter proteins to recruit different downstream signal transducers to the receptor complex. For example, TRAF1 is required for the recruitment of members of the cellular inhibitor of apoptosis protein (c-IAP) family to the TNFR2-signaling complex (7). In addition to the signal transduction by the TNFR family members, TRAFs may regulate other receptor-mediated signaling pathways. For example, TRAF6 is a component of IL-1 receptor (IL1R)–signaling complex, in which it mediates the activation of NF-κB by IL-1R (31). Since TRAFs form homo- or heterooligomers, it is suggested that the repertoire of TRAF members in a given cell type may differentially affect the intracellular signals triggered by these receptors. This may be accomplished by the selective interaction of TRAFs with a specific set of downstream signal transducers. Although many aspects of TRAF-mediated effector functions leading to cellular activation have been defined, it needs to be determined whether TRAF proteins will also mediate the apoptotic signals induced by the “death-domain-less” members of the TNFR superfamily (1, 27, 32–36).Here we report the isolation and characterization of a novel component of the TNFR superfamily/TRAFs signaling complex, named TRIP (TRAF-interacting protein). TRIP associates with the receptor/TRAF signaling complex, and inhibits the TRAF2-mediated NF-κB activation. Biochemical studies indicate that TRIP associates with the TNFR2 or CD30 receptor complex via its interaction with TRAF proteins, suggesting a model which can explain why the ligation of these receptors can promote different cell fates: proliferation or death.     

Aortic and mitral annular calcifications are predictive of all-cause and cardiovascular mortality in patients with type 2 diabetes

OBJECTIVE

To examine the association of aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) with all-cause and cardiovascular mortality in type 2 diabetic individuals.

RESEARCH DESIGN AND METHODS

We retrospectively analyzed the data from 902 type 2 diabetic outpatients, who had undergone a transthoracic echocardiography for clinical reasons during the years 1992–2007. AVS and MAC were diagnosed by echocardiography, and a heart valve calcium (HVC) score was calculated by summing up the AVS and MAC variables. The study outcomes were all-cause and cardiovascular mortality.

RESULTS

At baseline, 477 (52.9%) patients had no heart valves affected (HVC-0), 304 (33.7%) had one valve affected (HVC-1), and 121 (13.4%) had both valves affected (HVC-2). During a mean follow-up of 9 years, 137 (15.2%) patients died, 78 of them from cardiovascular causes. Compared with patients with HVC-0, those with HVC-2 had the highest risk of all-cause and cardiovascular mortality, whereas those with HVC-1 had an intermediate risk (P < 0.0001 by the log-rank test). After adjustment for sex, age, BMI, systolic blood pressure, diabetes duration, A1C, LDL cholesterol, estimated glomerular filtration rate, smoking, history of myocardial infarction, and use of antihypertensive and lipid-lowering drugs, the hazard ratio of all-cause mortality was 2.3 (95% CI 1.1–4.9; P < 0.01) for patients with HVC-1 and 9.3 (3.9–17.4; P < 0.001) for those with HVC-2. Similar results were found for cardiovascular mortality.

CONCLUSIONS

Our findings indicate that AVS and MAC, singly or in combination, are independently associated with all-cause and cardiovascular mortality in type 2 diabetic patients.Aortic valve sclerosis (AVS) is a common finding at echocardiography in the elderly population (1). AVS is defined as focal or diffuse calcification and thickening of a trileaflet aortic valve in the absence of obstruction of ventricular outflow. Approximately 30% of adults >65 years of age have AVS in Western countries. Until recently, AVS was considered an incidental echocardiographic finding of no clinical significance, as it does not significantly obstruct left ventricular outflow. However, AVS shows epidemiologic and histopathologic similarities to coronary atherosclerosis (2,3). In addition, recent large prospective studies have suggested a strong association between AVS and cardiovascular disease (CVD) outcomes both in the general population (1,4–6) and in nondiabetic high-risk patient populations such as patients with hypertension (7), coronary artery disease (8), and chronic kidney disease (9).Mitral annulus calcification (MAC) is also a common echocardiographic finding in the elderly (10). Similar to AVS, MAC is strongly associated with an increased risk of CVD morbidity and mortality, mainly in nondiabetic populations (11,12). Notably, a recent large community-based cohort study involving 2,081 German individuals aged ≥45 years (∼11% of patients with diabetes) showed that AVS and MAC were associated with a fourfold to fivefold increased risk of all-cause and CVD mortality and that the combination of AVS and MAC with a heart valve sclerosis score improved the predictability with respect to mortality (5). Similarly, patients with AVS were approximately four times more likely to develop incident coronary heart events than were those without AVS among the 2,279 middle-aged African American participants of the Jackson Atherosclerosis Risk in Community cohort (6), whereas AVS was found to be independently associated with an increase of ~50–60% in the risk of CVD events and death among the 5,621 elderly participants of the Cardiovascular Heart Study (1).To our knowledge, no large observational studies are available on the relationship of AVS and MAC with the risk of all-cause and CVD mortality in patients with type 2 diabetes. The aim of this observational study was to evaluate the association of AVS and MAC, singly or in combination, with the risk of all-cause and CVD mortality in a sample of type 2 diabetic individuals referred for clinically indicated echocardiograms.     

Evaluation of Diabetic Foot Ulcer Healing With Hyperspectral Imaging of Oxyhemoglobin and Deoxyhemoglobin

OBJECTIVE

Foot ulceration remains a major health problem for diabetic patients and has a major impact on the cost of diabetes treatment. We tested a hyperspectral imaging technology that quantifies cutaneous tissue hemoglobin oxygenation and generated anatomically relevant tissue oxygenation maps to assess the healing potential of diabetic foot ulcers (DFUs).

RESEARCH DESIGN AND METHODS

A prospective single-arm blinded study was completed in which 66 patients with type 1 and type 2 diabetes were enrolled and followed over a 24-week period. Clinical, medical, and diabetes histories were collected. Transcutaneous oxygen tension was measured at the ankles. Superficial tissue oxyhemoglobin (oxy) and deoxyhemoglobin (deoxy) were measured with hyperspectral imaging from intact tissue bordering the ulcer. A healing index derived from oxy and deoxy values was used to assess the potential for healing.

RESULTS

Fifty-four patients with 73 ulcers completed the study; at 24 weeks, 54 ulcers healed while 19 ulcers did not heal. When using the healing index to predict healing, the sensitivity was 80% (43 of 54), the specificity was 74% (14 of 19), and the positive predictive value was 90% (43 of 48). The sensitivity, specificity, and positive predictive values increased to 86, 88, and 96%, respectively, when removing three false-positive osteomyelitis cases and four false-negative cases due to measurements on a callus. The results indicate that cutaneous tissue oxygenation correlates with wound healing in diabetic patients.

CONCLUSIONS

Hyperspectral imaging of tissue oxy and deoxy may predict the healing of DFUs with high sensitivity and specificity based on information obtained from a single visit.Diabetes is a major global disease that affects 194 million people worldwide and is expected to increase in prevalence to 344 million by the year 2030 (1). One major complication of diabetes is foot ulceration, which occurs in as many as 15–25% of type 1 and type 2 diabetic patients over their lifetimes (2–4). Studies show that between 2 and 6% of diabetic patients will develop a foot ulcer every year (5,6). The feet of patients with diabetes are at risk for ulceration due to a wide range of pathological conditions, the major three being peripheral neuropathy, foot deformity, and trauma, which may be exacerbated by comorbid peripheral vascular disease (4,7). If left untreated, foot ulcers lead to infection and deep-tissue necrosis (8).Foot pathology is a major source of morbidity in patients with diabetes and is a leading cause of hospitalization. Infected and/or ischemic diabetic foot ulcers (DFUs) account for about 25% of all hospital visits among patients with diabetes. Previous studies have shown that a DFU preceeds roughly 85% of all lower-extremity amputations in patients with diabetes (9,10), and more than 88,000 amputations are performed annually on diabetic patients (11). The cost to manage foot disorders is estimated at several billion dollars annually (5,12). Successful clinical management of DFUs not only has the potential to reduce the cost of caring for these patients but also to improve quality of life by reducing comorbidities.Current treatment options for DFUs include offloading to reduce pressure on the wound, wound care to prevent infections, and wound debridement to remove necrotic debris and restimulate the wound healing process (11,13,14). Even with these measures, some wounds fail to heal. Having a means to assess healing potential may help triage wounds earlier to more aggressive therapies, thereby avoiding infections and amputations.Clinical measurements of microvascular function may be an important part of DFU assessment (15–17). Hyperspectral imaging (HSI) was developed as a novel noninvasive diagnostic tool to quantify tissue oxygenation and generate anatomically relevant maps of microcirculatory changes seen in diabetic patients (18). HSI generates a map of regions of interest based on local molecular composition. With proper wavelength selection, spatial maps of molecules such as oxyhemoglobin (oxy) and deoxyhemoglobin (deoxy) can be acquired.A pilot study of 10 type 1 diabetic patients with 21 DFU sites showed that HSI identified changes in tissue oxygenation in the diabetic foot that were predictive of ulcer healing (18). The sensitivity, specificity, and positive predictive value of the healing index were 93, 86, and 93%, respectively. The goal of the current study was to test the accuracy of HSI in evaluating the healing potential of DFUs in a large number of type 1 and 2 diabetic patients.     

Corneal Confocal Microscopy: A novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy

OBJECTIVE

The accurate quantification of human diabetic neuropathy is important to define at-risk patients, anticipate deterioration, and assess new therapies.

RESEARCH DESIGN AND METHODS

A total of 101 diabetic patients and 17 age-matched control subjects underwent neurological evaluation, neurophysiology tests, quantitative sensory testing, and evaluation of corneal sensation and corneal nerve morphology using corneal confocal microscopy (CCM).

RESULTS

Corneal sensation decreased significantly (P = 0.0001) with increasing neuropathic severity and correlated with the neuropathy disability score (NDS) (r = 0.441, P < 0.0001). Corneal nerve fiber density (NFD) (P < 0.0001), nerve fiber length (NFL), (P < 0.0001), and nerve branch density (NBD) (P < 0.0001) decreased significantly with increasing neuropathic severity and correlated with NDS (NFD r = −0.475, P < 0.0001; NBD r = −0.511, P < 0.0001; and NFL r = −0.581, P < 0.0001). NBD and NFL demonstrated a significant and progressive reduction with worsening heat pain thresholds (P = 0.01). Receiver operating characteristic curve analysis for the diagnosis of neuropathy (NDS >3) defined an NFD of <27.8/mm² with a sensitivity of 0.82 (95% CI 0.68–0.92) and specificity of 0.52 (0.40–0.64) and for detecting patients at risk of foot ulceration (NDS >6) defined a NFD cutoff of <20.8/mm² with a sensitivity of 0.71 (0.42–0.92) and specificity of 0.64 (0.54–0.74).

CONCLUSIONS

CCM is a noninvasive clinical technique that may be used to detect early nerve damage and stratify diabetic patients with increasing neuropathic severity.Established diabetic neuropathy leads to pain and foot ulceration. Detecting neuropathy early may allow intervention with treatments to slow or reverse this condition (1). Recent studies suggested that small unmyelinated C-fibers are damaged early in diabetic neuropathy (2–4) but can only be detected using invasive procedures such as sural nerve biopsy (4,5) or skin-punch biopsy (6–8). Our studies have shown that corneal confocal microscopy (CCM) can identify early small nerve fiber damage and accurately quantify the severity of diabetic neuropathy (9–11). We have also shown that CCM relates to intraepidermal nerve fiber loss (12) and a reduction in corneal sensitivity (13) and detects early nerve fiber regeneration after pancreas transplantation (14). Recently we have also shown that CCM detects nerve fiber damage in patients with Fabry disease (15) and idiopathic small fiber neuropathy (16) when results of electrophysiology tests and quantitative sensory testing (QST) are normal.In this study we assessed corneal sensitivity and corneal nerve morphology using CCM in diabetic patients stratified for the severity of diabetic neuropathy using neurological evaluation, electrophysiology tests, and QST. This enabled us to compare CCM and corneal esthesiometry with established tests of diabetic neuropathy and define their sensitivity and specificity to detect diabetic patients with early neuropathy and those at risk of foot ulceration.     

Long-Term Outcomes of Japanese Type 2 Diabetic Patients With Biopsy-Proven Diabetic Nephropathy

OBJECTIVE

We evaluated the structural-functional relationships and the prognostic factors for renal events, cardiovascular events, and all-cause mortality in type 2 diabetic patients with biopsy-proven diabetic nephropathy.

RESEARCH DESIGN AND METHODS

Japanese type 2 diabetic patients with biopsy-proven diabetic nephropathy (n = 260) were enrolled. Patients were stratified by albuminuria (proteinuria) and estimated glomerular filtration rate (eGFR) at the time of renal biopsy. The outcomes were the first occurrence of renal events (requirement of dialysis or a 50% decline in eGFR from baseline), cardiovascular events (cardiovascular death, nonfatal myocardial infarction, coronary interventions, or nonfatal stroke), and all-cause mortality.

RESULTS

The factors associated with albuminuria (proteinuria) regardless of eGFR were hematuria, diabetic retinopathy, low hemoglobin, and glomerular lesions. The factors associated with low eGFR regardless of albuminuria (proteinuria) were age and diffuse, nodular, tubulointerstitial, and vascular lesions. The glomerular, tubulointerstitial, and vascular lesions in patients with normoalbuminuria (normal proteinuria) and low eGFR were more advanced compared to those in patients with normoalbuminuria (normal proteinuria) and maintained eGFR. In addition, compared to patients with micro-/macroalbuminuria (mild/severe proteinuria) and low eGFR, their tubulointerstitial and vascular lesions were similar or more advanced in contrast to glomerular lesions. The mean follow-up period was 8.1 years. There were 118 renal events, 62 cardiovascular events, and 45 deaths. The pathological determinants were glomerular lesions, interstitial fibrosis and tubular atrophy (IFTA), and arteriosclerosis for renal events, arteriosclerosis for cardiovascular events, and IFTA for all-cause mortality. The major clinical determinant for renal events and all-cause mortality was macroalbuminuria (severe proteinuria).

CONCLUSIONS

Our study suggests that the characteristic pathological lesions as well as macroalbuminuria (severe proteinuria) were closely related to the long-term outcomes of biopsy-proven diabetic nephropathy in type 2 diabetes.Diabetic nephropathy occurs in 20–40% of patients with diabetes (1). The prevalence of diabetic nephropathy is increasing in proportion to the increase in prevalence of diabetes, and it has been predicted to continue to increase in future (2). Diabetes is a risk factor of cardiovascular disease and death, and diabetic nephropathy further increases these risks (3). In addition, diabetic nephropathy is the leading cause of end-stage renal disease requiring dialysis or transplantation in developed countries (4–6).In recent years, many clinical studies have suggested strict glycemic control and blood pressure management by use of appropriate medication to suppress the onset and progression of diabetic nephropathy. Thus, it is important to identify patients at risk in the early stages to improve prognosis in patients with diabetic nephropathy (1). Albuminuria and glomerular filtration rate (GFR) are recommended for use as clinical markers of diabetic nephropathy (1,7–9). On the other hand, selection of pathological markers is complicated because a variety of renal lesions can be found in diabetic nephropathy in addition to factors such as obesity, hypertension, dyslipidemia, and aging, which are frequently complicated in type 2 diabetes, causing a wide variety of pathological changes (10).We previously reported on the clinical factors related to the development and progression of renal lesions in diabetic nephropathy by the evaluation of serial renal biopsies or autopsy (11). In this report, we demonstrated a significant relationship between the progression of diabetic glomerulosclerosis and clinical factors such as the control of blood glucose, type of diabetes, age at onset, type of treatment, and degree of obesity.After this study, we conducted a long-term retrospective study to evaluate the structural-functional relationships and the predictive impacts of clinicopathological parameters for renal events, cardiovascular events, and all-cause mortality among Japanese patients with biopsy-proven diabetic nephropathy in type 2 diabetes.     

Vitamin D Levels and Mortality in Type 2 Diabetes

OBJECTIVE

To evaluate vitamin D as a predictor of all-cause and cardiovascular mortality and risk of progression to micro- or macroalbuminuria in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

In a longitudinal observational follow-up study, 289 type 2 diabetic patients with normoalbuminuria (n = 172), microalbuminuria (n = 73), and macroalbuminuria (n = 44) at baseline were followed for a median (range) of 15.0 (0.2–23) years. Mean ± SD age was 54 ± 9 years. Plasma 25-hydroxyvitamin D₃ levels were determined by high-performance liquid chromatography/tandem mass spectrometry on baseline samples. Severe vitamin D deficiency was defined as the lower 10th percentile (<13.9 nmol/l).

RESULTS

Median (range) vitamin D level was 35.7 (5–136.7) nmol/l. Vitamin D levels were not associated with age, sex, estimated glomerular filtration rate, urinary albumin excretion rate (UAER), or A1C at baseline, but low levels were weakly associated with elevated systolic blood pressure (R = 0.13, P = 0.03). During follow-up, 196 (68%) patients died. All-cause mortality was increased in patients with severe vitamin D deficiency (hazard ratio 1.96 [95% CI 1.29–2.98]). The association persisted after adjustment for UAER, A1C, diabetes duration, and conventional cardiovascular risk factors (2.03 [1.31–3.13]). Severe vitamin D deficiency was associated with increased cardiovascular mortality (1.95 [1.11–3.44]), and the association persisted after adjustment (1.90 [1.15–3.10]). Severe vitamin D deficiency at baseline did not predict progression to micro- or macroalbuminuria.

CONCLUSIONS

In type 2 diabetic patients, severe vitamin D deficiency predicts increased risk of all-cause and cardiovascular mortality, independent of UAER and conventional cardiovascular risk factors. Whether vitamin D substitution improves prognosis remains to be investigated.Levels of vitamin D (25-hydroxyvitamin D₃ [25(OH)D₃]) vary considerably among individuals mainly because of differences in sun exposure and skin color and the presence of risk factors such as diabetes or other comorbidities. Hypovitaminosis is highly prevalent worldwide (1).The association between vitamin D and survival primarily originated from observational studies of dialysis cohorts receiving therapy with a vitamin D receptor analog (VDRA) (2). Recently, low levels of vitamin D have been associated with an increased risk of cardiovascular disease (CVD) (3) as well as all-cause (4) and cardiovascular mortality (5) in the general population.An observational study on patients with mainly nondiabetic chronic kidney disease (CKD) stage 2–5 showed that low levels of vitamin D independently predicted death from all-cause and cardiovascular causes (6). Findings from the same study support the hypothesis of vitamin D deficiency playing a role in progression to end-stage renal disease (ESRD).In the general population, an inverse association was found between vitamin D levels and the prevalence of albuminuria (7). Data from studies in experimental diabetic nephropathy and other kidney disease, as well as limited human evidence, indicate that vitamin D insufficiency may be involved in the pathogenesis of albuminuria (8,9).Diabetes is the leading cause of ESRD in the Western world, and many diabetic patients will die of cardiovascular complications. Early identification of increased renal as well as vascular risk paves the way for early intervention, thereby contributing to a desirable reduction in incidents of CVD and nephropathy among diabetic patients.Therefore, we aimed to investigate whether plasma vitamin D has a prognostic value in predicting increased risk of excess all-cause and cardiovascular mortality as well as in initiation and/or progression of diabetic kidney disease in type 2 diabetic patients.     

Vitamin D levels and asymptomatic coronary artery disease in type 2 diabetic patients with elevated urinary albumin excretion rate

OBJECTIVE

Coronary artery disease (CAD) is the major cause of morbidity and mortality in type 2 diabetic patients. Severe vitamin D deficiency has been shown to predict cardiovascular mortality in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

We investigated the association among severe vitamin D deficiency, coronary calcium score (CCS), and asymptomatic CAD in type 2 diabetic patients with elevated urinary albumin excretion rate (UAER) >30 mg/24 h. This was a cross-sectional study including 200 type 2 diabetic patients without a history of CAD. Severe vitamin D deficiency was defined as plasma 25-hydroxyvitamin D (p-25[OH]D3) <12.5 nmol/L. Patients with plasma N-terminal pro-brain natriuretic peptide >45.2 ng/L or CCS ≥400 were stratified as being high risk for CAD (n= 133). High-risk patients were examined by myocardial perfusion imaging (MPI; n = 109), computed tomography angiography (n = 20), or coronary angiography (CAG; n = 86). Patients’ p-25(OH)D3 levels were determined by high-performance liquid chromatography/tandem mass spectrometry.

RESULTS

The median (range) vitamin D level was 36.9 (3.8–118.6) nmol/L. The prevalence of severe vitamin D deficiency was 9.5% (19/200). MPI or CAG demonstrated significant CAD in 70 patients (35%). The prevalence of CCS ≥400 was 34% (68/200). Severe vitamin D deficiency was associated with CCS ≥400 (odds ratio [OR] 4.3, 95% CI [1.5–12.1], P = 0.005). This association persisted after adjusting for risk factors (4.6, 1.5–13.9, P = 0.007). Furthermore, severe vitamin D deficiency was associated with asymptomatic CAD (adjusted OR 2.9, 1.02–7.66, P = 0.047).

CONCLUSIONS

In high-risk type 2 diabetic patients with elevated UAER, low levels of vitamin D are associated with asymptomatic CAD.Coronary artery disease (CAD) is the major cause of morbidity and mortality in patients with type 2 diabetes. Diabetic patients have been shown to have an increased prevalence of subclinical CAD (1). Coronary calcium score (CCS), a noninvasive screening method quantifying the extent of coronary artery calcification (CAC), is generally accepted as a marker of increased cardiovascular risk. CCS has been shown to correlate strongly with histopathologic CAD (2,3) and the development of adverse coronary events (4,5).Results from cross-sectional studies examining the relation between low vitamin D levels and presence of CAD in the general population are conflicting (6,7). In type 1 diabetic patients, vitamin D deficiency has been shown to independently predict both prevalence and development of CAC (8). However, a study in type 2 diabetic patients with a history of cardiovascular disease (CVD) found a strong inverse association between low vitamin D levels and prevalent coronary, cerebrovascular, or peripheral CVD (9). Furthermore, low vitamin D levels have been associated with increased cardiovascular morbidity and mortality in the general population (10) and in patients with type 1 (8) and 2 (11) diabetes.To expand our knowledge on the increased all-cause and cardiovascular mortality seen in type 2 diabetic patients with low vitamin D levels, the current study investigated the association between severe vitamin D (plasma 25-hydroxyvitamin D [p-25(OH)D3]) deficiency and the presence of elevated CAC and asymptomatic CAD in type 2 diabetic patients with elevated urinary albumin excretion rate (UAER) >30 mg/24 h.