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.     

Serum uric acid levels and incident chronic kidney disease in patients with type 2 diabetes and preserved kidney function

OBJECTIVE

Recent studies have suggested an association between hyperuricemia and adverse renal outcomes in nondiabetic populations. Data on the relationship between hyperuricemia and the risk of incident chronic kidney disease (CKD) in type 2 diabetic patients with normal or near-normal kidney function are lacking. We determined whether baseline serum uric acid levels predict the subsequent development of CKD in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

We followed 1,449 type 2 diabetic patients with normal kidney function and without overt proteinuria for 5 years for the occurrence of incident CKD (defined as overt proteinuria or estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m²).

RESULTS

During a 5-year follow-up period, 194 (13.4%) patients developed incident CKD. The cumulative incidence of CKD was significantly greater in patients with hyperuricemia than in those without hyperuricemia (29.5 vs. 11.4%, P < 0.001). In univariate logistic regression analysis, the presence of hyperuricemia roughly doubled the risk of developing CKD (odds ratio [OR] 2.55 [95% CI 1.71–3.85], P < 0.001). After adjusting for age, sex, BMI, smoking status, diabetes duration, systolic blood pressure, antihypertensive treatment, insulin therapy, HbA_1c, eGFR, and albuminuria, hyperuricemia was associated with an increased risk of incident CKD (adjusted OR 2.10 [1.16–3.76], P < 0.01). In continuous analyses, a 1-SD increment in the serum uric acid level was significantly associated with a 21% increased risk of CKD.

CONCLUSIONS

In type 2 diabetic individuals with preserved kidney function, hyperuricemia seems to be an independent risk factor for the development of incident CKD.The tide of type 2 diabetes is rising in the U.S. and all over the world, thereby becoming an increasingly powerful threat to global health (1). Type 2 diabetes also has become the leading cause of end-stage renal disease in the world, and the number of patients diagnosed each year with end-stage renal disease attributed to type 2 diabetes is rising (2).The pathophysiology of diabetic nephropathy is complex and still not fully elucidated (3). Several prospective studies have suggested that hyperuricemia is associated with an increased risk of incident cardiovascular events and death in both nondiabetic and type 2 diabetic individuals (4–9). Hyperuricemia also is largely prevalent in patients with chronic kidney disease (CKD) (10,11). However, hyperuricemia might have a pathogenic role in the development and progression of CKD, rather than solely reflecting decreased renal uric acid excretion. Indeed, several (12–17), but not all (18–20), prospective studies recently have shown a significant association between hyperuricemia and adverse renal outcomes in both the general population and other nondiabetic high-risk patient populations. However, epidemiologic data are limited about the relationship between hyperuricemia and adverse renal outcomes in patients with type 1 (21,22) or type 2 (23) diabetes.In a post hoc analysis of 1,342 patients with type 2 diabetes and nephropathy participating in the Reduction of End Points in Non–Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) Trial, the investigators reported that the risk of adverse renal outcomes was decreased by 6% per 0.5 mg/dL decrement in serum uric acid levels during the first 6 months of treatment with losartan (23). These findings support the view that serum uric acid may be a modifiable risk factor for renal disease in type 2 diabetic patients (23).To our knowledge, however, no large prospective studies are available on the relationship between hyperuricemia and incident CKD in patients with type 2 diabetes and normal or near-normal kidney function. Thus, the purpose of this prospective, observational study was to determine whether baseline serum uric acid levels are associated with an increased incidence of CKD in a large cohort of type 2 diabetic patients with preserved kidney function at baseline and without a previous history of cardiovascular disease.     

High-Normal Serum Uric Acid Increases Risk of Early Progressive Renal Function Loss in Type 1 Diabetes: Results of a 6-year follow-up

OBJECTIVE

We previously described a cross-sectional association between serum uric acid and reduced glomerular filtration rate (GFR) in nonproteinuric patients with type 1 diabetes. Here, we prospectively investigated whether baseline uric acid impacts the risk of early progressive renal function loss (early GFR loss) in these patients.

RESEARCH DESIGN AND METHODS

Patients with elevated urinary albumin excretion (n = 355) were followed for 4–6 years for changes in urinary albumin excretion and GFR. The changes were estimated by multiple determinations of albumin-to-creatinine ratios (ACRs) and serum cystatin C (GFRcystatin).

RESULTS

At baseline, the medians (25th–75th percentiles) for uric acid, ACR, and GFRcystatin values were 4.6 mg/dl (3.8–5.4), 26.2 mg/g (15.1–56.0), and 129 ml/min per 1.73 m² (111–145), respectively. During the 6-year follow-up, significant association (P < 0.0002) was observed between serum uric acid and development of early GFR loss, defined as GFRcystatin decline exceeding 3.3% per year. In baseline uric acid concentration categories (in mg/dl: <3.0, 3.0–3.9, 4.0–4.9, 5.0–5.9, and ≥6), the risk of early GFR loss increased linearly (9, 13, 20, 29, and 36%, respectively). This linear increase corresponds to odds ratio 1.4 (95% CI 1.1–1.8) per 1 mg/dl increase of uric acid. The progression and regression of urinary albumin excretion were not associated with uric acid.

CONCLUSIONS

We found a clear dose-response relation between serum uric acid and risk of early GFR loss in patients with type 1 diabetes. Clinical trials are warranted to determine whether uric acid–lowering drugs can halt renal function decline before it becomes clinically significant.The paradigm of early diabetic nephropathy in type 1 diabetes has changed during the past few years. Previously, it focused on urinary leakage of small amounts of albumin, designated microalbuminuria, which was believed to predict progression to overt proteinuria and ultimately end-stage renal disease (ESRD) (1). However, recent studies (2,3) documented that rather than progression, regression to normoalbuminuria is the fate of microalbuminuria in the majority of patients. Progression to proteinuria is the fate in a minority only. At the same time, the onset of progressive renal function loss was observed in a subset of these patients well before the onset of proteinuria (4). Because this decline occurs while renal function is still normal, we label it “early” progressive renal function loss (early GFR loss). Whereas microalbuminuria may regress, remain stable, or progress during the course of diabetes, early GFR loss progresses to chronic kidney disease (CKD) and ESRD (4–6).Because early GFR loss is detectable while renal function is normal or elevated, an opportunity may exist for effective intervention many years before the occurrence of meaningful loss of renal function. However, our knowledge of early GFR loss determinants is limited (4). Discovery of these determinants, especially modifiable ones, may enable the design of more effective programs for the prevention of CKD and ESRD.A body of evidence suggests that elevated serum uric acid may cause kidney injury in animal models (7). Also, mounting evidence points to a role of elevated serum uric acid in the development of kidney disease in humans. In cohort studies of subjects without diabetes, hyperuricemia predicted the development of CKD stage 3 (8) and ESRD (9,10), and in community-based cohorts moderately elevated serum uric acid concentrations were associated with the development of CKD stage 3 (11,12). Recently, in a type 1 diabetic cohort in Denmark, moderately elevated uric acid concentrations were found to be associated with risk of proteinuria during an 18-year follow-up (13). However, changes in renal function were not examined.The Second Joslin Study on the Natural History of Microalbuminuria in Type 1 Diabetes (Second Joslin Study) is a follow-up study designed to determine the natural history of early diabetic nephropathy in nonproteinuric patients with type 1 diabetes. In baseline data, high-normal serum uric acid concentration was strongly associated with reduced glomerular filtration rate (GFR), as estimated by serum cystatin C (GFRcystatin) (14). Whether elevated serum uric acid preceded or followed reduced GFR could not be determined in that cross-sectional data. Therefore, we prospectively measured GFRcystatin during 4–6 years of follow-up and investigated the association between baseline serum uric acid concentration and changes in renal function. A secondary aim was to explore the role of serum uric acid in the progression and regression of urinary albumin excretion.     

Transthyretin Predicts Cardiovascular Outcome in Hemodialysis Patients With Type 2 Diabetes

OBJECTIVE

BMI and albumin are commonly accepted parameters to recognize wasting in dialysis patients and are powerful predictors of morbidity and mortality. However, both parameters reveal limitations and may not cover the entire range of patients with wasting. The visceral protein transthyretin (TTR) may be helpful in overcoming the diagnostic and prognostic gap. Therefore, the aim of this study was to assess the association of TTR with morbidity and mortality in hemodialysis patients.

RESEARCH DESIGN AND METHODS

The TTR concentration was determined in plasma samples of 1,177 hemodialysis patients with type 2 diabetes. Cox regression analyses were used to determine hazard ratios (HRs) for the risk of cardiovascular end points (CVEs) and mortality according to quartiles of TTR concentration for the total study cohort and the subgroups BMI ≥23 kg/m², albumin concentration ≥3.8 g/dL, and a combination of both.

RESULTS

A low TTR concentration was associated with an increased risk for CVE for the total study cohort (HR 1.65 [95% CI 1.27–2.14]), patients with BMI ≥23 kg/m² (1.70 [1.22–2.37]), albumin ≥3.8 g/dL (1.68 [1.17–2.42]), and the combination of both (1.69 [1.13–2.53]). Additionally, a low TTR concentration predicted mortality for the total study cohort (1.79 [1.43–2.24]) and patients with BMI ≥23 kg/m² (1.46 [1.09–1.95]).

CONCLUSIONS

The current study demonstrated that TTR is a useful predictor for cardiovascular outcome and mortality in diabetic hemodialysis patients. TTR was particularly useful in patients who were not identified to be at risk by BMI or albumin status.Transthyretin (TTR), formerly referred to as prealbumin, is known as a sensitive indicator of inflammation and malnutrition (1,2) and has also been described as a marker of body composition (3,4). With regard to hemodialysis patients, TTR is a well-accepted marker of protein-energy wasting (PEW), which is highly prevalent in patients with end-stage renal disease (5,6). PEW represents a syndrome characterized by depletion of body energy and protein stores, inflammation, and development of comorbidities (7) and is highly associated with the risk of death as well as fatal and nonfatal cardiovascular disease (CVD) in hemodialysis patients (8,9). An expert panel suggested a combination of several parameters for the diagnosis of PEW (7); among these, the most frequently and routinely applied are BMI and serum albumin concentration. Both parameters are known to be inversely associated with mortality and morbidity in hemodialysis patients (10–12).However, BMI and serum albumin concentration have several limitations in diagnosing PEW and subsequently the risk for all-cause mortality and CVD. Among other things, it has been criticized that BMI is not able to discriminate between fat and lean body mass, and a high body mass might be misinterpreted as an appropriate nutritional status. Consequently, patients may be misclassified and wasting may not be recognized. On the other hand, the detrimental effects of being overweight and obesity may also not be recognized or underestimated (13–15). Furthermore, the importance of serum albumin concentration is probably limited since it is more sensitive to inflammation than to nutrition (16), and thus nutrition-related complications are insufficiently considered (13). Additionally, serum albumin is sensitive to hydration status (17,18), and in diabetic patients, the capillary permeability of serum albumin is increased, which might adulterate the serum levels (19).In this context, the analysis of TTR might be useful in overcoming the resulting diagnostic and prognostic gap since TTR is known to be very sensitive to changes in visceral protein stores, correlated with muscle mass, and not affected by hydration status (3,20). Therefore, we hypothesized that TTR may likewise be a potent predictor of mortality and morbidity in hemodialysis patients beyond BMI and serum albumin concentration. Furthermore, since diabetes is a major risk factor for chronic kidney disease, aggravates PEW, and unequivocally increases the risk for cardiovascular events and mortality (6,21,22), the current study was particularly focused on hemodialysis patients with type 2 diabetes using data from the German Diabetes and Dialysis (4D) study.     

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.     

Osteoprotegerin and mortality in type 2 diabetic patients

OBJECTIVE

Plasma osteoprotegerin (OPG) is an emerging strong and independent predictor of cardiovascular disease (CVD) in high-risk populations. OPG is a bone-related glycopeptide produced by vascular smooth muscle cells, and increased plasma OPG levels may reflect arterial vascular damage. We aimed to investigate the prognostic value of OPG in relation to all-cause and cardiovascular mortality in a cohort of type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

In a prospective observational follow-up study, 283 type 2 diabetic patients (172 men; aged 53.9 ± 8.8 years) were followed for a median of 16.8 years (range 0.2–23.0). Baseline plasma OPG concentrations were determined by immunoassay.

RESULTS

During follow-up, 193 (68%) patients died. High versus low levels of OPG predicted all-cause mortality (covariate-adjusted for urinary albumin excretion rate [UAER], estimated glomerular filtration rate, and conventional risk factors); hazard ratio (HR) 1.81 [95% CI 1.21–2.69]. The all-cause predictive effect of OPG was independent of NH₂-terminal pro-brain natriuretic peptide (NT-proBNP) and was also useful within groups divided according to level of UAER. In total, 103 (73%) patients died because of CVD. High and medium versus low levels of OPG predicted cardiovascular mortality (unadjusted HR 1.86 [95% CI 1.07–3.23] and 3.51 [2.10–5.85], respectively). However, after adjustment for the covariates, HRs were no longer significant.

CONCLUSIONS

Elevated plasma OPG is a strong predictor of all-cause mortality in type 2 diabetic patients. The effect of OPG on all-cause mortality was independent of conventional cardiovascular risk factors, UAER, and NT-proBNP levels.Plasma osteoprotegerin (OPG) is a promising strong and independent predictor of cardiovascular disease (CVD) in high-risk individuals, such as type 1 diabetic patients with nephropathy and nondiabetic patients after kidney transplantation or myocardial infarction (1–4). OPG is a member of the tumor necrosis factor receptor superfamily acting as a soluble decoy receptor for the receptor activator of nuclear factor-κβ ligand (RANKL) to prevent osteoclast activation and bone resorption (5). OPG mRNA has been detected in a variety of human tissues, including the lung, heart, and kidney (5). This bone-related glycoprotein is present in the arterial wall, and plasma OPG has been suggested to reflect the increased OPG content in arterial tissue observed in diabetic patients (6). OPG is upregulated in calcified coronary plaques (7) and associated with angiographic disease severity and cardiovascular events independent of conventional risk factors (8,9). Therefore, increased plasma OPG levels are suggested to be a marker of arterial vascular damage.CVD is the major determinant of morbidity and mortality in patients with type 2 diabetes and, in particular, patients with an elevated urinary albumin excretion rate (UAER) (10). Increased OPG levels are associated with diabetes (11). Recently, an elevated plasma OPG level was shown to predict increased mortality in patients with type 1 diabetes and diabetic nephropathy (4) and also to predict increased incidence of cardiovascular events among patients with uncomplicated type 2 diabetes who were followed for 18 months (12). However, the prognostic importance of OPG in type 2 diabetic patients with long follow-up and elevated UAER is unknown. Therefore, this study examines the predictive value of plasma OPG in relation to all-cause and cardiovascular mortality in a large cohort of type 2 diabetic patients followed prospectively for 17 years.     

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.     

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.     

Serum Uric Acid Predicts Progression of Subclinical Coronary Atherosclerosis in Individuals Without Renal Disease

OBJECTIVE

To examine uric acid (UA) as a possible predictor of the progression of coronary artery calcification (CAC) using data from the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study.

RESEARCH DESIGN AND METHODS

CAC was measured by electron beam tomography at the baseline and at a follow-up 6.0 ± 0.5 years later. The study population included 443 participants with type 1 diabetes and 526 control subjects who were free of diagnosed coronary artery disease at baseline. The presence of renal disease was defined by the presence of albuminuria and/or low glomerular filtration rate.

RESULTS

In subjects without renal disease, serum UA predicted CAC progression (odds ratio 1.30 [95% CI 1.07–1.58], P = 0.007) independent of conventional cardiovascular risk factors including diabetes and the presence of metabolic syndrome.

CONCLUSIONS

Serum UA levels predict the progression of coronary atherosclerosis and may be useful in identifying who is at risk for vascular disease in the absence of significant chronic kidney disease.Elevated serum uric acid (UA) is associated with kidney disease, but it has also been linked to endothelial dysfunction and development of hypertension irrespective of renal involvement (1). UA may contribute to the atherosclerotic process through induction of endothelial dysfunction (2) and inflammation (3).Serum UA levels have been correlated with negative cardiovascular outcomes in the general population (4) and type 2 diabetic subjects (5) and predict the progression of diabetic nephropathy (6) in type 1 diabetic subjects. The objective of this study was to evaluate UA levels as a predictor of subclinical atherosclerosis progression in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study.     

Adverse Outcomes After Noncardiac Surgery in Patients With Diabetes: A nationwide population-based retrospective cohort study

OBJECTIVE

To investigate whether diabetes affects perioperative complications or mortality and to gauge its impact on medical expenditures for noncardiac surgeries.

RESEARCH DESIGN AND METHODS

With the use of reimbursement claims from the Taiwan National Health Insurance system, we performed a population-based cohort study of patients with and without diabetes undergoing noncardiac surgeries. Outcomes of postoperative complications, mortality, hospital stay, and medical expenditures were compared between patients with and without diabetes.

RESULTS

Diabetes increased 30-day postoperative mortality (odds ratio 1.84 [95% CI 1.46–2.32]), particularly among patients with type 1 diabetes or uncontrolled diabetes and patients with preoperative diabetes-related comorbidities, such as eye involvement, peripheral circulatory disorders, ketoacidosis, renal manifestations, and coma. Compared with nondiabetic control patients, coexisting medical conditions, such as renal dialysis (5.17 [3.68–7.28]), liver cirrhosis (3.59 [2.19–5.88]), stroke (2.87 [1.95–4.22]), mental disorders (2.35 [1.71–3.24]), ischemic heart disease (2.08 [1.45–2.99]), chronic obstructive pulmonary disease (1.96 [1.29–2.97]), and hyperlipidemia (1.94 [1.01–3.76]) were associated with mortality for patients with diabetes undergoing noncardiac surgery. Patients with diabetes faced a higher risk of postoperative acute renal failure (3.59 [2.88–4.48]) and acute myocardial infarction (3.65 [2.43–5.49]). Furthermore, diabetes was associated with prolonged hospital stay (2.30 [2.16–2.44]) and increased medical expenditures (1.32 [1.25–1.40]).

CONCLUSIONS

Diabetes increases postoperative 30-day mortality, complications, and medical expenditures in patients undergoing in-hospital noncardiac surgeries.Diabetes is a common chronic disease that causes widespread disability and death, with a global prevalence of 2.8% in 2000 and an estimated prevalence of 4.4% in 2030 (1). In the U.S., the national burden of diabetes was estimated to be $245 billion in 2012 (2). The epidemiology, pathogenesis, prevention, and treatment of diabetes have been well established over the past 2 centuries (3).Diabetes is an independent determinant of increased risk of perioperative complications and mortality in cardiovascular surgeries (4,5), yet how extensively diabetes affects postoperative mortality and complications in noncardiac surgeries has not been determined. Some studies indicated that survival outcomes and perioperative complications in noncardiac surgeries do not differ between patients with and without diabetes (6,7), whereas other research showed conflicting data about whether diabetes increased perioperative complications, mortality, hospital stay, and health care expenditures (8–16).Previous studies were limited by several factors, including a focus on a single type of noncardiac surgery (6,8,10,12,14), small sample size (6,7,9,13), inappropriate selection of nondiabetes control subjects (6–16), inadequate adjustment for potential confounders (7,9–12,15), and reporting of a single outcome after surgery (10,16). It remains unclear whether coexisting medical conditions, types of diabetes, glycemic control, and diabetes-related comorbidities affect postoperative outcomes in patients with diabetes.This study used Taiwan National Health Insurance Program reimbursement claims to investigate postoperative complications, 30-day mortality, length of hospital stay, and medical expenditures after adjustment by propensity score-matched pair method in patients with diabetes undergoing noncardiac surgeries. We also investigated the impact of coexisting medical conditions and diabetes-related comorbidities on postoperative 30-day mortality among patients with diabetes.     

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.     

Postchallenge Glucose, A1C, and Fasting Glucose as Predictors of Type 2 Diabetes and Cardiovascular Disease: A 10-year prospective cohort study

OBJECTIVE

A1C has been proposed as a new indicator for high risk of type 2 diabetes. The long-term predictive power and comparability of elevated A1C with the currently used high-risk indicators remain unclear. We assessed A1C, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) as predictors of type 2 diabetes and cardiovascular disease (CVD) at 10 years.

RESEARCH DESIGN AND METHODS

This prospective population-based study of 593 inhabitants from northern Finland, born in 1935, was conducted between 1996 and 2008. An oral glucose tolerance test (OGTT) was conducted at baseline and follow-up, and A1C was determined at baseline. Those with a history of diabetes were excluded from the study. Elevated A1C was defined as 5.7–6.4%. Incident type 2 diabetes was confirmed by two OGTTs. Cardiovascular outcome was measured as incident CVD or CVD mortality. Multivariate log-binomial regression models were used to predict diabetes, CVD, and CVD mortality at 10 years. Receiver operating characteristic curves compared predictive values of A1C, IGT, and IFG.

RESULTS

Incidence of diabetes during the follow-up was 17.1%. Two of three of the cases of newly diagnosed diabetes were predicted by a raise in ≥1 of the markers. Elevated A1C, IGT, or IFG preceded diabetes in 32.8, 40.6, and 21.9%, respectively. CVD was predicted by an intermediate and diabetic range of 2-h glucose but only by diabetic A1C levels in women.

CONCLUSIONS

A1C predicted 10-year risk of type 2 diabetes at a range of A1C 5.7–6.4% but CVD only in women at A1C ≥6.5%.Early detection of high risk for type 2 diabetes is fundamental for prevention of diabetes and associated cardiovascular complications. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are currently used for diagnosis of high-risk glucose levels below the diabetic range. The International Expert Committee proposed A1C ≥6.5% as a diagnostic tool for diabetes in 2009 (1) and in January 2010 an intermediate range of A1C 5.7–6.4% (elevated A1C) was proposed by the American Diabetes Association (ADA) to detect individuals at high risk for developing type 2 diabetes (2).To date, however, limited data exist to support the use of A1C in predicting type 2 diabetes (3–8). Importantly, the long-term predictive power of elevated A1C as defined above has not yet been investigated. Previous data on the association between A1C and incident type 2 diabetes in unselected populations have relied on self-reporting, fasting glucose measurements, and use of antidiabetes medication to determine the outcomes. An oral glucose tolerance test (OGTT) has not been used to determine the outcome (3–8).Deterioration of glucose homeostasis reflects a continuum of glycemia, some of which is reversible if detected early (9,10). Importantly, the risk of cardiovascular disease is increased already before glycemia reaches the levels of diabetes, and 2-h glucose appears to be a better predictor of cardiovascular disease (CVD) than fasting glucose (11). Recently, A1C was shown to be a better predictor of CVD than fasting glucose (12).Data directly comparing 2-h glucose and A1C as long-term predictors of new-onset cardiovascular disease are scarce, and results are controversial (13,14). Therefore, we compared A1C, 2-h glucose, and fasting glucose as predictors of type 2 diabetes, CVD, and CVD mortality during a prospective population-based study with a 10-year follow-up.     

Vitamin D Levels in Subjects With and Without Type 1 Diabetes Residing in a Solar Rich Environment

OBJECTIVE

Previous studies, largely in northern Europe, have suggested an association between type 1 diabetes and reduced serum 25-hydroxy(OH) vitamin D levels, a concept we tested in individuals residing in a solar-rich region (Florida).

RESEARCH DESIGN AND METHODS

Serum samples from 415 individuals residing in Florida were cross-sectionally analyzed: 153 control subjects, 46 new-onset type 1 diabetic patients, 110 established type 1 diabetic patients (samples ≥5 months from diagnosis), and 106 first-degree relatives of the diabetic patients.

RESULTS

In this study, 25-OH vitamin D levels (median, range, interquartile range [IQR]) were similar among control subjects (20.1, below detection [bd]–163.5, 13.0–37.4 ng/ml), new-onset type 1 diabetic patients (21.2, bd–48.6, 12.2–30.2 ng/ml), established type 1 diabetic patients (23.2, bd–263.8, 13.8–33.9 ng/ml), and first-degree relatives (22.2, bd–59.9, 12.7–33.1 ng/ml) (P = 0.87). Mean 25-OH vitamin D levels were less than the optimal World Health Organization level of 30 ng/ml in all study groups.

CONCLUSIONS

Reduced serum 25-OH vitamin D levels were not specifically associated with type 1 diabetes. The uniform suboptimal 225-OH vitamin D levels, despite residence in a zone with abundant sunshine, support additional dietary vitamin D fortification practices.The role for environment in the development of type 1 diabetes has remained elusive, with multiple factors purported to modulate risk for this disease (e.g., viruses, breast-feeding, age for cereal introduction, and childhood immunizations) (1,2). Further to this list is vitamin D levels (3), with previous studies suggesting type 1 diabetic patients had lower serum concentrations of this metabolite than healthy control subjects (4–6) as well as disease-associated polymorphisms in a vitamin D metabolism gene (7). Although certainly intriguing, we note the aforementioned studies were largely undertaken in northern European countries (4,5), whereas the one study performed in the U.S. failed to provide values among healthy control subjects and, hence, did not identify disease specificity (6). Therefore, we measured serum 25-hydroxy (OH) vitamin D levels from type 1 diabetic patients, their first-degree relatives, and healthy control subjects all residing in a solar-rich region (Florida).     

Physical Activity, Adiposity, and Diabetes Risk in Middle-Aged and Older Chinese Population: The Guangzhou Biobank Cohort Study

OBJECTIVE

Physical activity may modify the association of adiposity with type 2 diabetes. We investigated the independent and joint association of adiposity and physical activity with fasting plasma glucose, impaired fasting glucose, and type 2 diabetes in a Chinese population.

RESEARCH DESIGN AND METHODS

Middle-aged and older Chinese (n = 28,946, ≥50 years, 72.4%women) from the Guangzhou Biobank Cohort Study were examined in 2003–2008. Multivariable regression was used in a cross-sectional analysis.

RESULTS

BMI, waist circumference, and waist-to-hip ratio (WHR) were positively associated with type 2 diabetes after multiple adjustment, most strongly for WHR with odds ratio (OR) of 3.99 (95% CI 3.60–4.42) for highest compared with lowest tertile. Lack of moderate-to-vigorous physical activity, but not walking, was associated with diabetes with an OR of 1.29 (1.17–1.41). The association of moderate-to-vigorous activity with fasting glucose varied with WHR tertiles (P = 0.01 for interaction). Within the high WHR tertile, participants who had a lack of moderate-to-vigorous activity had an OR of 3.87 (3.22–4.65) for diabetes, whereas those who were active had an OR of 2.94 (2.41–3.59).

CONCLUSIONS

In this population, WHR was a better measure of adiposity-related diabetes risk than BMI or waist circumference. Higher moderate-to-vigorous activity was associated with lower diabetes risk, especially in abdominally obese individuals.Type 2 diabetes is a worldwide cause of morbidity and mortality. Adiposity, especially abdominal adiposity, seems to be at the core of development of hyperglycemia and type 2 diabetes (1). Increased physical activity may mitigate some of the diabetogenic impact of adiposity (2–4). Individuals who are obese but fit could even have a lower risk of mortality than those who are normal weight but unfit (5,6). However, being physically active does not completely abolish the obesity-related risk for cardiovascular disease and associated mortality (7). Adiposity is still the main risk factor for the development of type 2 diabetes (2–4,8). Although increased physical activity has been shown to be associated with reduced type 2 diabetes risk independent of adiposity, the protective effects may differ by the level of adiposity. However, the group that could benefit most from physical activity for the prevention of diabetes is still unclear (2–4,8–10).Understanding the relationship between adiposity and physical activity is important to stratify risk groups for the development of effective diabetes prevention strategies from public health and clinical perspectives. Most of the studies relate to Caucasians (2–4,8–10), whereas Asians, including Chinese and Indians, are possibly more vulnerable to insulin resistance (11). The number of Chinese adults with type 2 diabetes was estimated to be ∼28.1 million in 2000 and may double by 2030, with China being second only to India (12). The purpose of this study was to investigate the independent and joint association of adiposity and physical activity with fasting plasma glucose, impaired fasting glucose (IFG), and type 2 diabetes in 28,946 middle-aged and older Chinese participants in the Guangzhou Biobank Cohort Study.     

Thoracoabdominal Calcifications Predict Cardiovascular Disease Mortality in Type 2 Diabetic and Nondiabetic Subjects: 18-year follow-up study

OBJECTIVE

To evaluate cardiovascular disease (CVD) and total mortality associated with thoracoabdominal calcifications.

RESEARCH DESIGN AND METHODS

Thoracoabdominal calcifications of native radiograms were evaluated in 833 subjects with type 2 diabetes and 1,292 subjects without diabetes, aged 45–64 years, without prior evidence of CVD. The type 2 diabetic and nondiabetic study cohorts were followed up for 18 years.

RESULTS

After adjustment for conventional risk factors, marked thoracoabdominal calcifications predicted CVD/total mortality with hazard ratio (HR) (95% CI) of 1.5 (0.8–3.0)/1.8 (1.1–2.9) in type 2 diabetic men, 3.0 (1.6–5.7)/3.1 (1.9–5.0) in type 2 diabetic women, 5.0 (2.2–12)/4.0 (2.2–7.4) in nondiabetic men, and 7.8 (1.8–34)/3.0 (1.3–7.0) in nondiabetic women and in the presence of C-reactive protein below/over 3 mg/l with HR of 2.4 (1.3–4.4)/3.0 (1.4–6.1) in type 2 diabetic subjects and 4.0 (1.5–10.8)/6.6 (2.7–16.0) in nondiabetic subjects.

CONCLUSIONS

Thoracoabdominal calcifications in native radiograms are significant predictors of CVD and total mortality, especially in type 2 diabetic and nondiabetic women with elevated high-sensitivity C-reactive protein level.Vascular calcification is initiated by metabolic, mechanical, infectious, or inflammatory injury to vasculature. Its progression is mainly determined by inflammatory response to vascular injury (1). It may precede cardiovascular disease (CVD) morbidity and mortality by years or decades in subjects with type 2 diabetes (2) and in the general population (3–6). Medial calcification has been associated with CVD morbidity and mortality in diabetic subjects (7) and in subjects with end-stage renal disease (8). Calcifications can be divided into intimal type, medial type of arterial calcification, cardiac valve calcification, and vascular calciphylaxis (9). These four entities of calcifications are consequences of distinct but overlapping pathophysiological mechanisms, which can occur simultaneously. Calcifications may function as a limiting factor for intimal plaque growth and represent a biological response to this process (10). A new perspective to the question of clinical significance of calcification has evolved from the practical need to evaluate CVD effects of medications targeted to bone formation and the bone density effects of medications targeted to vascular welfare (11,12).Although inflammation is involved in the initiation and progression of vascular calcification, inflammation and calcification may reflect partly independent processes. A combination of markers of calcification and inflammation might therefore be a good predictor CVD mortality. This study evaluates thoracoabdominal calcifications, and their combination with elevated high-sensitivity C-reactive protein (hs-CRP), in prediction of CVD mortality in a cohort of two diabetic and nondiabetic subjects without prior evidence of CVD during an 18-year follow-up.     

Iron Status and Survival in Diabetic Patients With Coronary Artery Disease

OBJECTIVE

To investigate the impact of iron status on survival in patients with type 2 diabetes and coronary artery disease (CAD).

RESEARCH DESIGN AND METHODS

Serum ferritin, transferrin saturation (Tsat), and soluble transferrin receptor (sTfR) were measured in 287 patients with type 2 diabetes and stable CAD (65 ± 9 years of age, 78% men).

RESULTS

During a mean follow-up of 45 ± 19 months, there were 59 (21%) deaths and 60 (21%) cardiovascular hospitalizations. Both serum ferritin and sTfR strongly predicted 5-year all-cause mortality rates, independently of other variables (including hemoglobin, measures of renal function, inflammation, and neurohormonal activation). There was an exponential relationship between sTfR and mortality (adjusted hazard ratio [HR] per 1 log mg/L: 4.24 [95% CI 1.43–12.58], P = 0.01), whereas the relationship between ferritin and mortality was U-shaped (for the lowest and the highest quintiles vs. the middle quintile [reference group], respectively: adjusted HR 7.18 [95% CI 2.03–25.46], P = 0.002, and adjusted HR 5.12 [1.48–17.73], P = 0.01). Similar patterns were observed for the composite outcome of all-cause mortality or cardiovascular hospitalization, and in these multivariable models, low Tsat was related to unfavorable outcome.

CONCLUSIONS

Both low and high serum ferritin (possibly reflecting depleted and excessive iron stores, respectively) along with high serum sTfR (reflecting reduced metabolically available iron) identify patients with type 2 diabetes and CAD who have a poor prognosis.The clinical significance of deficiency and disordered metabolism of iron in patients with chronic diseases associated with aging (1), including obesity (2), metabolic syndrome (3), coronary artery disease (CAD) (4), and heart failure (HF) (5–7), has received much attention. Iron overload and associated oxidative stress have been reported to accelerate the development of atherosclerosis (8) and cause endocrine organ dysfunction (9). However, iron deficiency (ID) is the most common dietary deficiency and the predominant cause of anemia worldwide (10).The physiological significance of ID may be much broader than its role in erythropoiesis (1,7,11,12). Iron is also critical for cellular energy generation by mitochondria (13–15). ID will impair the function of cells with high energy demand whether due to mechanical work, high metabolic rate, or high rates of proliferation (11,12).Diabetes may cause profound derangements of energy metabolism due to insulin resistance and mitochondrial dysfunction (16,17), contributing to a high risk of fatal and nonfatal cardiovascular events, and acting as an adjuvant substrate for other factors interfering with energy metabolism, such as iron excess or depletion. Attention has focused, until now, on the unfavorable effects of iron overload in diabetes, including oxidative stress and hemochromatosis (9), with little attention being paid to ID other than in pregnancy (18).Accordingly, we investigated the impact of iron status assessed using circulating biomarkers on survival in patients with type 2 diabetes and CAD.     

Educational Disparities in Mortality Among Adults With Diabetes in the U.S.

OBJECTIVE

To measure relative and absolute educational disparities in mortality among U.S. adults with diabetes and to compare their magnitude with disparities observed within the nondiabetic population.

RESEARCH DESIGN AND METHODS

A total of 85,867 individuals (5,007 with diabetes), aged 35–84 years, who participated in the National Health Interview Survey from 1986 to 1996 were followed for mortality through 31 December 2002. Relative and absolute educational disparities in all-cause, cardiovascular disease (CVD), and non-CVD mortality were measured.

RESULTS

In relative terms, the risk of all-cause mortality was 28% higher in diabetic adults with the lowest versus the highest position on the educational scale (relative index of inequality 1.28 [95% CI 1.08–1.53]). This inverse relationship reflected marked disparities in CVD mortality and was found in all age, sex, and race/ethnicity groups except Hispanics. Although substantial, this relative educational gradient in mortality among adults with diabetes was smaller than in the nondiabetic population. In absolute terms, diabetic adults with the lowest position on the educational scale suffered 503 excess deaths per 10,000 person-years of follow-up compared with those with the highest position. These absolute disparities were stronger than in the nondiabetic population. The results were even more striking for CVD mortality.

CONCLUSIONS

The risk of mortality differs substantially according to educational level among individuals with diabetes in the U.S. Although relative educational disparities in mortality are weaker in adults with versus without diabetes, their absolute impact is greater and translates into a major mortality burden.In the U.S., >20 million adults have diabetes, and the prevalence is expected to rise substantially in the coming decades (1,2). Diabetes complications impose an enormous burden on public health, and people with diabetes have an age-adjusted mortality rate approximately twice as high as those without (3).The public health burden of diabetes is unevenly distributed across socioeconomic strata. First, diabetes is more common in ethnic minorities and people of low education and income level (4,5). Second, in people with diabetes, socioeconomic position (SEP) may influence major determinants of health, such as access to care, quality of care, and health behaviors (6). Correspondingly, SEP may have a profound impact on the morbidity and mortality associated with diabetes. In Europe, socioeconomic health disparities have been reported among people with diabetes in various settings (5,6); though, two large record linkage studies (7,8) found that the magnitude of socioeconomic differentials in survival was weaker in people with diabetes than in the general population, a result that has remained largely unexplained. In the U.S., only few studies have focused on SEP-related disparities among people with diabetes and then only in selected subpopulations (9–12), making it difficult to determine the impact of such disparities at the population level and their public health importance.To fully monitor health disparities, the general consensus is that both relative and absolute measures are required (13,14). The objective of this study was to quantify relative and absolute educational disparities in mortality within the U.S. diabetic population according to cause of death and across age, sex, and race/ethnicity strata and to compare the magnitude of these disparities to those found in the nondiabetic population.     

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.     

Sex Differences in the Association Between Serum Ferritin and Fasting Glucose in Type 2 Diabetes Among South Asian Surinamese,African Surinamese,and Ethnic Dutch: The population-based SUNSET study

OBJECTIVE

Moderately elevated iron stores below the levels commonly associated with hemochromatosis have been implicated in the etiology of diabetes. Studies suggest that iron status (measured by serum ferritin) differs significantly according to sex, but inconsistent findings have been reported. Our aim is to test the association between serum ferritin and the prevalence of type 2 diabetes and fasting glucose concentrations in a population-based, multiethnic, cross-sectional study including men and women of African Surinamese, South Asian Surinamese, and ethnic Dutch origin.

RESEARCH DESIGN AND METHODS

We analyzed data on 508 ethnic Dutch, 597 African Surinamese, and 339 South Asian Surinamese aged 35–60 years. Type 2 diabetes was defined as a fasting plasma glucose level ≥7.0 mmol/L or a self-reported diagnosis.

RESULTS

Serum ferritin was positively associated with type 2 diabetes and fasting glucose, but differences in the associations according to sex were observed. Serum ferritin concentration was positively associated with type 2 diabetes among women in all ethnic groups (odds ratio [OR] ethnic Dutch: 1.07 [95% CI 1.01–1.13]; OR South Asian Surinamese: 1.05 [1.00–1.10]; OR African Surinamese: 1.05 [1.01–1.10]), but not among men. Serum ferritin was also more strongly associated with fasting glucose in women than in men. Moreover, the magnitude of sex differences in the association between serum ferritin and fasting glucose, but not type 2 diabetes, was more pronounced in the African Surinamese group than in the other ethnic groups (P for interaction ≤0.0001).

CONCLUSIONS

We found a positive association between serum ferritin and type 2 diabetes and fasting glucose in our multiethnic population, which appeared stronger among women than men. Further evaluation of the variation in sex differences between ethnic groups is warranted, particularly among the African Surinamese, to understand the mechanisms behind these sex differences.Moderately elevated iron stores below the levels commonly associated with hemochromatosis have been implicated in the etiology of type 2 diabetes (1–3). Although a mechanism linking iron concentrations and diabetes is yet to be established, it is known that iron is a catalyst in the formation of hydroxyl radicals (4), which may contribute initially to insulin resistance, subsequently to decreased insulin secretion, and ultimately to the development of type 2 diabetes (5). Animal models suggest that iron excess may result in β-cell oxidative stress and decreased insulin secretion (6). Levels of serum ferritin, a predominant iron-storage protein and a biomarker of iron stores, are elevated in persons with prevalent diabetes as compared with nondiabetic controls (7) and correlate with impaired fasting glucose levels (8), an early marker of type 2 diabetes. In addition, several cross-sectional or case-control studies and two prospective studies have identified an independent association between baseline elevations in iron stores and the occurrence of type 2 diabetes (2,5,9–12). However, several questions remain unanswered.It is yet unclear whether the association between serum ferritin and diabetes differs among men and women. Some have found that differences in iron status exist according to sex (8,13–16), which might have implications for the association with the etiology of diabetes (13). Others have suggested that sex differences might exist due to differences in iron accumulation in the peripheral muscles, which may cause derangement of muscle glucose uptake because of muscle damage (17,18). However, robust studies on the influence of sex on the association between serum ferritin and diabetes are rather inconsistent. Some have reported sex differences in the association (9,18), whereas others have not demonstrated this (19–21). Moreover, in those studies in which different associations between serum ferritin and type 2 diabetes were found for men and women, it appeared that the direction of the differences varied across studies (7–9).These discrepancies might be the result of differences in the ethnic composition of study populations. A first argument to support this is a study reporting variations in the serum ferritin and type 2 diabetes associations across men and women from different ethnic populations, including white, black, Hispanic, Asian, and Pacific Islander populations (9). This study reported that the association between serum ferritin and type 2 diabetes differed significantly between the ethnic groups among women but not among men. Unfortunately, other multiethnic studies have not considered differential sex effects across ethnic groups (10,19,20). Another argument for the potential role of ethnicity is a difference in body composition that may occur between ethnic groups. For instance, in the Netherlands, differences in waist circumference or waist-to-height ratio have been reported among ethnic Dutch, South Asian Surinamese, and African Surinamese (22,23). This is relevant, as body composition is suggested to affect the association between serum ferritin and the insulin resistance syndrome (17,18).The aim of this exploratory study is: 1) to test whether the association between serum ferritin and diabetes and fasting glucose differs between men and women of African Surinamese, South Asian Surinamese, and ethnic Dutch origin, and 2) to test whether the differences in the association between serum ferritin between men and women varies between these populations.