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.     

Flicker Light�CInduced Retinal Vasodilation in Diabetes and Diabetic Retinopathy

OBJECTIVE

Flicker light–induced retinal vasodilation may reflect endothelial function in the retinal circulation. We investigated flicker light–induced vasodilation in individuals with diabetes and diabetic retinopathy.

RESEARCH DESIGN AND METHODS

Participants consisted of 224 individuals with diabetes and 103 nondiabetic control subjects. Flicker light–induced retinal vasodilation (percentage increase over baseline diameter) was measured using the Dynamic Vessel Analyzer. Diabetic retinopathy was graded from retinal photographs.

RESULTS

Mean ± SD age was 56.5 ± 11.8 years for those with diabetes and 48.0 ± 16.3 years for control subjects. Mean arteriolar and venular dilation after flicker light stimulation were reduced in participants with diabetes compared with those in control subjects (1.43 ± 2.10 vs. 3.46 ± 2.36%, P < 0.001 for arteriolar and 2.83 ± 2.10 vs. 3.98 ± 1.84%, P < 0.001 for venular dilation). After adjustment for age, sex, diabetes duration, fasting glucose, cholesterol and triglyceride levels, current smoking status, systolic blood pressure, and use of antihypertensive and lipid-lowering medications, participants with reduced flicker light–induced vasodilation were more likely to have diabetes (odds ratio 19.7 [95% CI 6.5–59.1], P < 0.001 and 8.14 [3.1–21.4], P < 0.001, comparing lowest vs. highest tertile of arteriolar and venular dilation, respectively). Diabetic participants with reduced flicker light–induced vasodilation were more likely to have diabetic retinopathy (2.2 [1.2–4.0], P = 0.01 for arteriolar dilation and 2.5 [1.3–4.5], P = 0.004 for venular dilation).

CONCLUSIONS

Reduced retinal vasodilation after flicker light stimulation is independently associated with diabetes status and, in individuals with diabetes, with diabetic retinopathy. Our findings may therefore support endothelial dysfunction as a pathophysiological mechanism underlying diabetes and its microvascular manifestations.Diabetes affects more than 240 million individuals worldwide, and diabetic retinopathy is the leading cause of blindness in the working-age population in most developed countries (1). There is increasing recognition that early endothelial dysfunction plays a key role in the pathogenesis of diabetes (2) and the development of subsequent microvascular complications (3). In support of endothelial dysfunction in diabetic retinopathy (4) are studies showing relationships of diabetic retinopathy with cardiovascular diseases, including stroke, coronary heart disease, and heart failure, independent of traditional risk factors (5–7). Diabetic retinopathy has also been linked with subclinical manifestations of vascular diseases such as coronary artery calcification and cardiac remodeling (5). However, clinical and epidemiological studies have not found consistent associations of serum markers of endothelial dysfunction (e.g., soluble vascular adhesion molecule-1) with diabetic retinopathy, with some reporting positive associations (8,9), but others not finding any (10,11).The response of retinal vessels to diffuse luminance flicker can be measured noninvasively (12) and may reflect endothelial function of the retinal circulation because it has been demonstrated that nitric oxide is released in the retinal vasculature when it is stimulated by flicker light (13). One recent study showed that individuals with diabetes and diabetic retinopathy have reduced flicker-induced retinal vasodilation but did not control for concomitant risk factors including hyperglycemia, hypertension, and diabetes duration (14). In our current study, we sought to clarify whether flicker light–induced vasodilation is impaired in patients with diabetes and in those with diabetic retinopathy, signs independent of major risk factors.     

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.     

Retinal Vascular Fractal Dimension and Risk of Early Diabetic Retinopathy: A prospective study of children and adolescents with type 1 diabetes

OBJECTIVE

To examine the prospective association of retinal vascular fractal dimension with diabetic retinopathy risk in young people with type 1 diabetes.

RESEARCH DESIGN AND METHODS

This was a hospital-based prospective study of 590 patients aged 12–20 years with type 1 diabetes free of retinopathy at baseline. All patients had seven-field retinal photographs taken of both eyes. Incident retinopathy was ascertained from retinal photographs taken at follow-up visits. Fractal dimension was measured from baseline photographs using a computer-based program following a standardized protocol.

RESULTS

Over a mean ± SD follow-up period of 2.9 ± 2.0 years, 262 participants developed mild nonproliferative diabetic retinopathy (15.0 per 100 person-years). After adjusting for age, sex, diabetes duration, A1C, and other risk factors, we found no association between retinal vascular fractal dimension and incident retinopathy.

CONCLUSIONS

Retinal vascular fractal dimension was not associated with incident early diabetic retinopathy in this sample of children and adolescents with type 1 diabetes.Fractal objects are self-similar structures that retain a similar level of complexity across all scales. For example, blood vessels repeatedly subdivide downstream into smaller blood vessels with similar network patterns. Fractal dimension (D_f) quantifies the degree of complexity into a single value and is particularly useful for quantifying non-Euclidean geometric shapes such as vascular networks. The retinal circulation is a fractal object (1–3), and fractal analysis has been used to study the embryological development of the retinal vasculature (2) and vascular changes associated with diabetic retinopathy (3–7). Variations in retinal vascular D_f may reflect geometric alterations in the vascular network in response to hypoxia (2,7).Earlier case-control studies showed that retinal vascular D_f was associated with proliferative diabetic retinopathy (5,6), suggesting that neovascularization increases the complexity of the retinal vascular branching pattern. More recently, using a computer-based program to reliably measure D_f of the retinal vasculature (8), we reported that retinal vascular D_f was cross-sectionally associated with the prevalence of early retinopathy in patients with type 1 diabetes (9). However, prospective data are needed to elucidate the significance of this interesting finding. We therefore aimed to determine whether retinal vascular D_f measured from baseline photographs of eyes without retinopathy is associated with subsequent risk of retinopathy development in a cohort of type 1 diabetic subjects.     

Predicting Development of Proliferative Diabetic Retinopathy

OBJECTIVE

Identifying individuals most at risk for diabetic retinopathy progression and intervening early can limit vision loss and reduce the costs associated with managing more advanced disease. The purpose of this study was to identify factors associated with progression from nonproliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR).

RESEARCH DESIGN AND METHODS

This was a retrospective cohort analysis using a claims database of all eye care recipients age ≥30 years enrolled in a large managed-care network from 2001 to 2009. Individuals with newly diagnosed NPDR were followed longitudinally. Multivariable Cox regression analyses identified factors associated with progression to PDR. Three- and five-year probabilities of retinopathy progression were determined.

RESULTS

Among the 4,617 enrollees with incident NPDR, 307 (6.6%) developed PDR. After adjustment for confounders, every 1-point increase in HbA_1c was associated with a 14% (adjusted hazard ratio 1.14 [95% CI 1.07–1.21]) increased hazard of developing PDR. Those with nonhealing ulcers had a 54% (1.54 [1.15–2.07]) increased hazard of progressing to PDR, and enrollees with nephropathy had a marginally significant increased hazard of progressing to PDR (1.29 [0.99–1.67]) relative to those without these conditions. The 5-year probability of progression for low-risk individuals with NPDR was 5% (range 2–8) and for high-risk patients was 38% (14–55).

CONCLUSIONS

Along with glycemic control, nonophthalmologic manifestations of diabetes mellitus (e.g., nephropathy and nonhealing ulcers) are associated with an increased risk of diabetic retinopathy progression. Our retinopathy progression risk score can help clinicians stratify patients who are most at risk for disease progression.Diabetic retinopathy is the leading cause of new cases of legal blindness in the U.S. (1), affecting 4.2 million Americans, 655,000 of whom have sight-threatening retinopathy (1,2). Identifying patients who are at increased risk of progression from nonproliferative (NPDR) to proliferative diabetic retinopathy (PDR) is important for many reasons. From the patient’s perspective, individuals who progress from NPDR to PDR frequently experience a decline in best-corrected visual acuity, which can have a profound impact on health-related quality of life (3). In addition, those who develop PDR are at substantially increased risk of serious complications that can result in permanent vision loss such as tractional retinal detachment, vitreous hemorrhage, and neovascular glaucoma (4,5). From a societal perspective, the costs of caring for patients with PDR are four times greater than the costs of managing patients with NPDR. One study found the average cost of caring for patients with NPDR to be 292 USD, while it cost 1,207 USD to manage patients who develop PDR (6). Another study conducted by the National Health Services in Taiwan found that individuals who progressed from NPDR to PDR were noted to have an increase in expenditures of 3,482 USD (7). The ability for clinicians to identify and treat patients early in the disease process, before they experience progression to PDR, may result in considerable cost savings, especially in light of the growing number of individuals with diabetes mellitus (DM) in the U.S. population.In patients with DM, metabolic control as measured by HbA_1c and disease duration account for only 11% of the risk of retinopathy, leaving 89% to other factors (8). Several large population-based studies including the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), the UK Prospective Diabetes Study (UKPDS), and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study have identified other risk factors associated with the development or progression of diabetic retinopathy (9–11). From the results of these studies, age, sex, socioeconomic status, and comorbid systemic arterial hypertension are considered important determinants of retinopathy risk. We are unaware of any studies in the literature that have integrated these and other factors into a comprehensive diabetic retinopathy risk score that can help clinicians identify individuals who are at increased risk of progression from NPDR to PDR. Risk calculators such as the Framingham Risk Score for Atrial Fibrillation (12) and the Ocular Hypertension Treatment Study risk calculator (13) have been found to be useful in aiding clinicians with patient decision making.The purpose of this analysis was to assess risk factors associated with progression of diabetic retinopathy among a diverse group of individuals with DM enrolled in a large managed-care network. By following beneficiaries longitudinally, we sought to confirm previously identified risk factors and to define additional risk factors that may be associated with progression from NPDR to PDR. Finally, using the risk factors identified from our regression models, we developed a risk score that clinicians can use to identify groups of individuals who are at low and high risk of retinopathy progression.     

Can the Retinal Screening Interval Be Safely Increased to 2 Years for Type 2 Diabetic Patients Without Retinopathy?

OBJECTIVE

In the U.K., people with diabetes are typically screened for retinopathy annually. However, diabetic retinopathy sometimes has a slow progression rate. We developed a simulation model to predict the likely impact of screening patients with type 2 diabetes, who have not been diagnosed with diabetic retinopathy, every 2 years rather than annually. We aimed to assess whether or not such a policy would increase the proportion of patients who developed retinopathy-mediated vision loss compared with the current policy, along with the potential cost savings that could be achieved.

RESEARCH DESIGN AND METHODS

We developed a model that simulates the progression of retinopathy in type 2 diabetic patients, and the screening of these patients, to predict rates of retinopathy-mediated vision loss. We populated the model with data obtained from a National Health Service Foundation Trust. We generated comparative 15-year forecasts to assess the differences between the current and proposed screening policies.

RESULTS

The simulation model predicts that implementing a 2-year screening interval for type 2 diabetic patients without evidence of diabetic retinopathy does not increase their risk of vision loss. Furthermore, we predict that this policy could reduce screening costs by ∼25%.

CONCLUSIONS

Screening people with type 2 diabetes, who have not yet developed retinopathy, every 2 years, rather than annually, is a safe and cost-effective strategy. Our findings support those of other studies, and we therefore recommend a review of the current National Institute for Health and Clinical Excellence (NICE) guidelines for diabetic retinopathy screening implemented in the U.K.Diabetic retinopathy is a serious complication for people with diabetes that can lead to blindness or severe vision loss (1). Although retinopathy cannot be cured, its progression can be slowed or halted, and laser treatment can prevent visual loss if offered promptly at the proliferative stage (2). Diabetic digital retinal photography is an effective method of detecting the onset of treatable retinopathy (3). National Institute for Health and Clinical Excellence (NICE) guidelines in the U.K. currently recommend that people with diabetes are screened for retinopathy annually, or every 3–6 months for those patients who have developed beyond mild background retinopathy or who are at higher risk of progression (4). This also forms part of the National Screening Committee’s policy of a national screening program for diabetes in the U.K. (5).The development of retinopathy may take decades (6), and the annual screening of all diabetic patients may therefore incur considerable cumulative health service cost and patient inconvenience that, for some, may be unjustified (7). With a significant increase in diabetes incidence forecast in the U.K. (8), it is imperative that screening policies for diabetes complications are cost-effective and practicable. It is therefore prudent to ask whether it would be cost-effective and safe to screen diabetic patients for retinopathy less frequently (7), particularly in light of more recent evidence that suggests an overall decline in the rates at which people with diabetes are developing vision-threatening retinopathy (9,10).We undertook a collaborative project with the Royal Devon and Exeter National Health Service (NHS) Foundation Trust (henceforth referred to simply as Royal Devon and Exeter), which carries out annual retinopathy screening for a population of ∼20,000 patients across Devon. Using simulation modeling, we assessed the potential impact of implementing a 2-year retinopathy screening interval for those patients without retinopathy and who have type 2 diabetes. Diabetic retinopathy may progress more quickly in patients with type 1 diabetes (1,11–13), and although it has been shown that less frequent screening may be feasible for type 1 patients (14), we focus on the lower-risk type 2 diabetic patient group in this study. Previous studies have looked at the cost-effectiveness of longer screening intervals for diabetic retinopathy screening across all patients in a population (7,15,16), but we assessed an increased screening interval solely for those patients who have not yet been diagnosed with diabetic retinopathy. These patients represent ∼40% of the type 1 and type 2 diabetic population screened by Royal Devon and Exeter, and reductions in the frequency with which they are screened could therefore lead to large potential cost and resource savings.     

Age at Onset and the Risk of Proliferative Retinopathy in Type 1 Diabetes

OBJECTIVE

Age at onset of type 1 diabetes influences the risk of microvascular complications. However, the long-term risk of proliferative retinopathy within the wide spectrum of age at onset of type 1 diabetes is less well known.

RESEARCH DESIGN AND METHODS

A sample of 1,117 consecutively recruited patients was drawn from the FinnDiane Study population (4,800 patients). Type 1 diabetes was defined as age at onset ≤40 years, insulin treatment initiated within 1 year, and C-peptide ≤0.3 nmol/l. Retinopathy status was graded based on ophthalmic records and/or fundus photographs. The risk of proliferative retinopathy was studied in age-at-onset groups 0–4, 5–14, and 15–40 years.

RESULTS

The mean durations to proliferative retinopathy were 24.3 (22.7–25.9) years in the 0–4 years group, 20.1 (19.2–21.1) years in the 5–14 years group, and 21.6 (19.8–23.3) years in the 15–40 years group (P < 0.001). In a Cox regression model, with A1C, blood pressure, sex, and BMI as covariates, the highest risk of proliferative retinopathy was observed in the 5–14 years group (hazard ratio 1.90 [95% CI 1.45–2.48], P < 0.001). Diabetes onset 0–4 vs. 5–14 years made no difference in the long-term risk of proliferative retinopathy (P = 0.2). When split into two groups, age at onset <15 years was associated with a higher long-term risk than age at onset ≥15 years (1.82 [1.40–2.36], P < 0.001).

CONCLUSIONS

Age at onset significantly modifies the long-term risk of proliferative retinopathy. The highest risk is in age-at-onset group 5–14 years, whereas the lowest risk is in age-at-onset group 15–40 years.Proliferative retinopathy is a severe microvascular complication in patients with type 1 diabetes. After 20 years of diabetes, almost all patients with type 1 diabetes and 58% of patients with type 2 diabetes show signs of retinopathy. When retinopathy worsens, severe visual loss eventually threatens 5–10% of the patients (1). The most severe form of retinopathy is proliferative retinopathy, and most of the patients with this complication will become blind after 5–10 years without treatment (2). The prevalence of proliferative retinopathy varies between 13 and 50% after 15–25 years of diabetes in patients who need insulin (3,4).Several risk factors for diabetic retinopathy have already been identified. The prevalence of any retinopathy is strongly related to duration of diabetes and glycemic control (1,4). Poor glycemic control increases both the incidence and the progression of retinopathy (5). Male sex and high blood pressure further increase the risk of retinopathy (3). Genetic factors are also likely to play a major role (6). It is of note that the age at onset of diabetes may modify the metabolic phenotype of the patients and thus predispose certain patients to diabetic retinopathy. In particular, diabetes onset at age <5 years may have a protective effect on the development of retinopathy (7,8). Thus, it can be hypothesized that because the incidence of type 1 diabetes is on the rise and the increase has been greatest in children aged 0–4 years (9), there may possibly be a decrease in the overall risk of retinopathy. The studies so far have not focused on the onset of type 1 diabetes in adulthood, and therefore the number of patients with late-onset diabetes has been rather small and not large enough to study the effect of late age at onset on the risk of proliferative retinopathy. Furthermore, it is not yet known whether young age at onset is a protective factor in the long term or whether it only delays the onset of proliferative retinopathy. Therefore, the aim of this study was to elucidate how the age at onset of type 1 diabetes influences the long-term risk of proliferative retinopathy in patients with type 1 diabetes.     

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.     

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.     

��-Cell�CMediated Signaling Predominates Over Direct ��-Cell Signaling in the Regulation of Glucagon Secretion in Humans

OBJECTIVE

Given evidence of both indirect and direct signaling, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans.

RESEARCH DESIGN AND METHODS

We measured plasma glucagon concentrations before and after ingestion of a formula mixed meal and, on a separate occasion, ingestion of the sulfonylurea glimepiride in 24 basal insulin-infused, demonstrably β-cell–deficient patients with type 1 diabetes and 20 nondiabetic, demonstrably β-cell–sufficient individuals; the latter were infused with glucose to prevent hypoglycemia after glimepiride.

RESULTS

After the mixed meal, plasma glucagon concentrations increased from 22 ± 1 pmol/l (78 ± 4 pg/ml) to 30 ± 2 pmol/l (103 ± 7 pg/ml) in the patients with type 1 diabetes but were unchanged from 27 ± 1 pmol/l (93 ± 3 pg/ml) to 26 ± 1 pmol/l (89 ± 3 pg/ml) in the nondiabetic individuals (P < 0.0001). After glimepiride, plasma glucagon concentrations increased from 24 ± 1 pmol/l (83 ± 4 pg/ml) to 26 ± 1 pmol/l (91 ± 4 pg/ml) in the patients with type 1 diabetes and decreased from 28 ± 1 pmol/l (97 ± 5 pg/ml) to 24 ± 1 pmol/l (82 ± 4 pg/ml) in the nondiabetic individuals (P < 0.0001). Thus, in the presence of both β-cell and α-cell secretory stimuli (increased amino acid and glucose levels, a sulfonylurea) glucagon secretion was prevented when β-cell secretion was sufficient but not when β-cell secretion was deficient.

CONCLUSIONS

These data indicate that, among the array of signals, indirect reciprocal β-cell–mediated signaling predominates over direct α-cell signaling in the regulation of glucagon secretion in humans.The regulation of pancreatic islet α-cell glucagon secretion is complex (1–10). It involves direct signaling of α-cells (1) and indirect signaling of α-cells by β-cell (2–6) and δ-cell (7) secretory products, the autonomic nervous system (8,9), and gut incretins (10).Appropriate glucagon secretory responses occur from the perfused pancreas (3,5) and perifused islets (2). Low plasma glucose concentrations stimulate glucagon secretion from the transplanted (i.e., denervated) human pancreas (11) and the denervated dog pancreas (12). Therefore, we have focused on the intraislet regulation of glucagon secretion. Furthermore, because selective destruction of β-cells results in loss of the glucagon response to hypoglycemia in type 1 diabetes (13), and partial reduction of the β-cell mass in minipigs results in impaired postprandial suppression of glucagon secretion (14), we have focused on the role of β-cell–mediated signaling in the regulation of glucagon secretion.Findings from studies of the perfused rat (3,4) and human (5) pancreas, rats in vivo (6), rat islets (2), isolated rat α-cells (2), and humans (15–18) have been interpreted to indicate that a β-cell secretory product or products tonically restrains basal α-cell glucagon secretion during euglycemia and that a decrease in β-cell secretion, coupled with low glucose concentrations at the α-cells, signals an increase in glucagon secretion in response to hypoglycemia. Parenthetically, the relative roles of the candidate β-cell secretory products (insulin, zinc, γ-aminobutyric acid, and amylin, among others) (2) that normally restrain α-cell glucagon secretion remain to be determined. However, that interpretation rests, in part, on results of studies in isolated rat α-cells (2), which are debated (1), and on the evidence that the islet microcirculation flows from β-cells to α-cells to δ-cells (4), which is also debated (19). Furthermore, it does not address the plausible possibility that a decrease in intraislet δ-cell somatostatin secretion might also signal an increase in α-cell glucagon secretion during hypoglycemia (7).Given that interpretation, it follows that an increase in β-cell secretion would signal a decrease in glucagon secretion in the postprandial state (14). The concept is an interplay of indirect reciprocal β-cell–mediated signaling of α-cells and of direct α-cell signaling in the regulation of glucagon secretion.There is, in our view, compelling evidence that, among other mechanisms, both indirect reciprocal β-cell–mediated signaling of α-cells (2–6) and direct α-cell signaling (1) are involved in the regulation of glucagon secretion by nutrients, hormones, neurotransmitters, and drugs. Given that premise, we posed the question: Which of these predominates in humans? Accordingly, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans. To do so, we measured plasma glucagon responses to ingestion of a mixed meal and, on a separate occasion, to ingestion of the sulfonylurea glimepiride in patients with type 1 diabetes and in nondiabetic individuals. We conceptualized patients with type 1 diabetes as a model of α-cells isolated from β-cells because their β-cells had been destroyed but they have functioning α-cells. (Their α-cells are not, of course, isolated from other islet cells, including δ-cells.) Increased plasma amino acid and glucose levels after a mixed meal and sulfonylureas normally stimulate β-cell secretion; increased plasma amino acid and perhaps glucose (2) levels after a mixed meal and sulfonylureas (1) stimulate α-cell secretion. Our hypothesis predicts that such factors that normally stimulate both β-cells and α-cells would stimulate glucagon secretion in patients with type 1 diabetes but not in nondiabetic individuals, i.e., in the virtual absence and the presence of β-cell function, respectively. Indeed, a mixed meal (20,21) and the secretagogues tolbutamide (22), glyburide (23), and repaglinide (23) have been reported to raise plasma glucagon concentrations in patients with type 1 diabetes, but all of those studies lacked nondiabetic control subjects.     

More impact of microalbuminuria on retinopathy than moderately reduced GFR among type 2 diabetic patients

OBJECTIVE

The current study aimed to investigate whether microalbuminuria or moderately decreased glomerular filtration rate (GFR) is a better predictor for the development and progression of retinopathy in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

Type 2 diabetic patients without cardiovascular diseases, malignancy, pregnancy, and acute intercurrent illness were enrolled between 1 August 2001 and 31 December 2002. All participants provided their detailed medical history and underwent an eye fundus examination. They were followed up in outpatient clinics, and serum creatinine, urinary albumin-to-creatinine ratio (UACR), and retinal photographs were followed up annually until 31 December 2009. The primary outcomes were development and progression of diabetic retinopathy and nephropathy. The secondary outcomes were cardiovascular events and all-cause mortality.

RESULTS

Among 487 participants, 81 subjects had normoalbuminuria and moderate renal impairment (baseline eGFR 30–59.9 mL/min/1.73 m²), and 106 subjects had microalbuminuria and baseline eGFR ≥60 mL/min/1.73 m². Patients with microalbuminuria and eGFR ≥60 mL/min/1.73 m² had a significantly greater risk for development and progression of diabetic retinopathy (HR 3.34 [95% CI 1.04–10.70]) compared with those with moderate renal impairment and normoalbuminuria after multivariate adjustment. Risks for renal outcome, cardiovascular events, and all-cause mortality were not significantly different between the two groups.

CONCLUSIONS

Microalbuminuria has a greater impact on predicting the development and progression of diabetic retinopathy compared with moderate decline in GFR among type 2 diabetic patients.Diabetic retinopathy is a highly specific vascular complication and a sight-threatening problem related to diabetes. Diabetic retinopathy is characterized by gradually progressive alterations in the retinal microvasculature, leading to retinal nonperfusion, increased vascular permeability, and pathologically intraocular proliferation of retinal vessels. Both diabetic retinopathy and nephropathy are microvascular complications of diabetes. With the retina and glomerulus, diabetes-specific microvascular disease is characterized by similar pathophysiologic features. Chronic hyperglycemia is the central initiating factor for all types of diabetic microvascular disease. In exposure to high plasma glucose, hyperglycemic damage is limited to some cell types. Endothelial cells develop intracellular hyperglycemia, since they cannot downregulate glucose transport (1). The common pathologic trait of diabetic microvascular disease is progressive narrowing and eventual occlusion of vascular lumina, subsequently leading to inadequate perfusion of the affected tissues. In the retina, diabetes induces programmed cell death of Muller and ganglion cells (2) and pericytes and endothelial cells (3). In the glomerulus, urinary protein loss and renal function decline are associated with widespread capillary occlusion and podocyte loss.Elevated urinary albumin excretion has been found to increase the risk of proliferative diabetic retinopathy (PDR) and is associated with a higher prevalence of PDR (4–8). Diabetic retinopathy is present in virtually all type 1 diabetic patients with nephropathy, whereas only 50–60% of type 2 diabetic patients with nephropathy have retinopathy (5). Accordingly, nephropathy and retinopathy are not concurrent in type 2 diabetes. Although the prevalence and risk factors for diabetic retinopathy in type 2 diabetes have been extensively investigated (6–8), there are little data addressing the issue of whether microalbuminuria or moderate decline of estimated glomerular filtration rate (eGFR) (30–59.9 mL/min/1.73 m²) is a competing risk factor for the development and progression of diabetic retinopathy. Therefore, the current study strived to investigate whether microalbuminuria or moderately decreased eGFR is a better predictor for the retinal outcome in a type 2 diabetic cohort.     

No loss of chance of diabetic retinopathy screening by endocrinologists with a digital fundus camera

OBJECTIVE

To compare the efficacy of the diabetic retinopathy (DR) screening with digital camera by endocrinologists with that by specialist and resident ophthalmologists in terms of sensitivity, specificity, and level of “loss of chance.”

RESEARCH DESIGN AND METHODS

In a cross-sectional study, 500 adult diabetic patients (1,000 eyes) underwent three-field retinal photography with a digital fundus camera following pupillary dilatation. Five endocrinologists and two ophthalmology residents underwent 40 h of training on screening and grading of DR and detection of associated retinal findings. A κ test compared the accuracy of endocrinologist and ophthalmology resident screening with that performed by experienced ophthalmologists. Screening efficiency of endocrinologists was evaluated in terms of “loss of chance,” i.e., missed diagnoses that required ophthalmologist referrals.

RESULTS

The mean weighted κ of DR screening performed by endocronologists was similar to that of ophthalmology residents (0.65 vs. 0.73). Out of 456 DR eyes, both endocrinologists and ophthalmology residents misdiagnosed only stage 1 DR (36 and 14, respectively), which did not require ophthalmologist referral. There were no significant differences between endocrinologists and ophthalmology residents in terms of diabetic maculopathy and incidental findings except for papillary cupping and choroidal lesions, which were not the main purpose of the study or of the training.

CONCLUSIONS

The endocrinologist with specific training for DR detection using a three-field digital fundus camera with pupillary dilatation can perform a reliable DR screening without any loss of chance for the patients when compared with identical evaluation performed by experienced ophthalmologists.Diabetic retinopathy (DR) is one of the main causes of blindness in industrialized nations (1). The worldwide prevalence of diabetes in adults is estimated to rise to 7.7%, affecting 439 million adults by 2030 (2). In France, the increasing number of patients with diabetes, coupled with the lack of a national screening program, results in a steady rise in the visual handicaps related to the disease (3).Annual screening of DR is recommended as an effective approach to prevent visual loss related to diabetes (4,5). Currently, digital nonmydriatic fundus photography is increasingly used as a method of screening for ophthalmologists worldwide (5–7). According to consensus classifications (4,5), DR at a stage higher than 1 needs further ophthalmological management. Despite these recommendations, only 30% of the diabetic patients in France undergo DR screening each year. Partly, this is due to the lack of ophthalmologists and insufficient awareness about the visual consequences of the disease (3,8). The situation is slowly changing after implementation of telemedical screening networks using digital fundus photography (9–11). Further increase in screening coverage can be achieved with the involvement of allied medical professionals.Since the 1980s, the concept of “loss of chance” has emerged in medicine and law. The misdiagnosis during DR screening can lead to a loss of chance for patients requiring referral to an ophthalmologist for further examinations and management (12,13).Two studies have shown that screening performed by an endocrinologist using an ophthalmoscope (14) and a mydriatic camera (15), respectively, were reliable, although they didn’t evaluate the loss of chance. Furthermore, no endocrinologists’ team approach was evaluated so far.This clinical research trial has been designed to compare the efficacy of the DR screening with digital camera by a team of previously trained endocrinologists (7) with that of residents and specialist ophthalmologists, in terms of sensitivity, specificity and level of “loss of chance.”     

Meta-analysis of the significance of asymptomatic bacteriuria in diabetes

OBJECTIVE

To evaluate whether asymptomatic bacteriuria (ASB) is more common in patients with diabetes than among control subjects. In addition, we wanted to clarify the clinical significance of ASB in patients with diabetes.

RESEARCH DESIGN AND METHODS

We conducted a systematic review and meta-analysis of published data since 1966. Twenty-two studies fulfilled the inclusion criteria of the meta-analysis.

RESULTS

ASB was present in 439 of 3,579 (12.2%) patients with diabetes and in 121 of 2,702 (4.5%) healthy control subjects. ASB was more common both in patients with type 1 diabetes (odds ratio 3.0 [95% CI 1.1–8.0]) and type 2 diabetes (3.2 [2.0–5.2]) than in control subjects. The point prevalence of ASB was higher in both women (14.2 vs. 5.1%; 2.6 [1.6–4.1]) and men (2.3 vs. 0.8%; 3.7 [1.3–10.2]) as well as in children and adolescents (12.9 vs. 2.7%; 5.4 [2.7–11.0]) with diabetes than in healthy control subjects. Albuminuria was more common in patients with diabetes and ASB than those without ASB (2.9 [1.7–4.8]). History of urinary tract infections was associated with ASB (1.6 [1.1–2.3]).

CONCLUSIONS

We were able to show that the prevalence of ASB is higher in all patients with diabetes compared with control subjects. We also found that diabetic subjects with ASB more often had albuminuria and symptomatic urinary tract infections.As the prevalence of both type 1 diabetes and type 2 diabetes increases world wide, factors associated with diabetes and its complications become more important (1,2). Asymptomatic bacteriuria (ASB) refers to the presence of bacteria in bladder urine in an asymptomatic individual. Usually, samples are collected indirectly by clean-voided midstream urine, and growth of the same uropathogen (≥10⁵ cfu/ml) in two consecutive specimens is considered to be a significant indication of the presence of bacteria in bladder urine (3). ASB is found in 2–5% of healthy adult women, is quite unusual in healthy men, and has been claimed to be three to four times more common in women with diabetes than in healthy women (3). A prevalence as high as 30% in diabetic women has been reported (4).ASB is considered clinically significant and worth treating during pregnancy because treatment effectively reduces the risk of pyelonephritis and preterm delivery (5,6). Although ASB has been found to associate with increased risk of hospitalization for urosepsis in a prospective observational study among women with diabetes (7), the treatment of ASB in one randomized controlled trial did not reduce the risk of symptomatic urinary tract infection (8). Associations between ASB, metabolic control of diabetes, and impaired renal function have been brought up repeatedly (9–15). To evaluate whether ASB is truly more common in patients with diabetes than among control subjects and to clarify the clinical significance of ASB in diabetic subjects we did a systematic literature search and performed a meta-analysis of the published data.     

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.     

High concentrations of AGE-LDL and oxidized LDL in circulating immune complexes are associated with progression of retinopathy in type 1 diabetes

OBJECTIVE

To determine whether immunocomplexes (ICs) containing advanced glycation end product (AGE)–LDL (AGE-LDL) and oxidized LDL (oxLDL) contribute to the development of retinopathy over a 16-year period in subjects with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Levels of AGE-LDL and oxLDL in ICs were measured in 517 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Retinopathy was assessed by stereoscopic fundus photography. Cox proportional hazards models were used to assess the effect of AGE-LDL-ICs and oxLDL-ICs on retinopathy progression.

RESULTS

In unadjusted models, higher baseline levels of AGE-LDL-ICs and oxLDL-ICs significantly predicted progression of diabetic retinopathy outcomes. After adjustment by study-design variables (treatment group, retinopathy cohort, duration of type 1 diabetes, and baseline albumin excretion rate [AER], hemoglobin A_1c (HbA_1c), and Early Treatment Diabetic Retinopathy Study [ETDRS] score), one SD increase in IC levels was associated with 47% (hazard ratio [HR] 1.47 [95% CI 1.19–1.81]; AGE-LDL-IC) and 45% (1.45 [1.17–1.80]; oxLDL-IC) increased risk of developing proliferative diabetic retinopathy (PDR) and 37% (1.37 [1.12–1.66]; to both ICs) increased risk of progressing to severe nonproliferative retinopathy. Analyses were stratified by retinopathy cohort because results differed between primary and secondary cohorts. For AGE-LDL-ICs, HR for progression to PDR was 2.38 (95% CI 1.30–4.34) in the primary cohort and attenuated in the secondary cohort (1.29 [1.03–1.62]). Similar results were observed for oxLDL-ICs.

CONCLUSIONS

Increased levels of AGE-LDL and oxLDL in ICs are associated with increased risk for progression to advanced retinopathy in patients with type 1 diabetes, indicating that the antibody response to modified LDL plays a significant role in retinopathy progression.Diabetic retinopathy is a major cause of vision loss in working-age adults (1) and affects the majority of people with type 1 diabetes at some stage of their lives (2). Established risk factors are long duration of diabetes, poor glycemic control, hypertension, dyslipidemia, smoking, and diabetic renal disease (3). In spite of this knowledge, diabetic retinopathy still occurs at an unacceptably high rate (4). Identification of novel markers and mechanisms for its onset and progression will facilitate new preventive and therapeutic strategies.In people both with and without diabetes, conventional “quantitative” measures of dyslipidemia (e.g., high LDL cholesterol or low HDL cholesterol) are associated with increased risk for atherosclerosis (5). Among subjects with diabetes, conventional lipid profiles are also associated with microvascular complications, including diabetic retinopathy (4). However the associations of plasma lipoprotein levels with diabetic retinopathy are less pronounced than for atherosclerosis, likely because in the retina specialized barrier functions must break down before lipoprotein-mediated effects become operative (6).In recent years, the importance of lipoprotein modification in the propagation of vascular damage has been recognized (7). Modifications including glycation, oxidation, and formation of advanced glycation end products (AGEs) are observed predominantly in extravasated lipoproteins and are enhanced in diabetes. These lipoprotein modifications are sufficient to elicit the synthesis of auto-antibodies that, in turn, lead to the formation of immunocomplexes (ICs) (8).Previous studies have focused on the effects of modified lipoproteins on atherosclerosis, but we have demonstrated that similar principles apply in diabetic retinopathy (6). Normally, the inner and outer blood retinal barriers prevent any extravasation of plasma lipoproteins, a special property of the retina; however, in diabetes, damage to these barriers enables extravasation and subsequent lipoprotein modification. High levels of modified forms of LDL in circulating ICs have been implicated as risk factors for atherosclerosis (9), but few studies have examined their associations with diabetic retinopathy. In this study, we have examined progression of retinopathy in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort of patients with type 1 diabetes, and we report a significant relationship between circulating levels of ICs containing AGE-LDL and oxidized LDL (oxLDL) and progression of diabetic retinopathy over a 16-year period.     

Dietary Patterns and Risk for Diabetes: The Multiethnic Cohort

OBJECTIVE

The high diabetes incidence among Japanese Americans and Native Hawaiians cannot be explained by BMI. Therefore, we examined the influence of three dietary patterns of “fat and meat,” “vegetables,” and “fruit and milk” on diabetes risk in the Hawaii component of the Multiethnic Cohort with 29,759 Caucasians, 35,244 Japanese Americans, and 10,509 Native Hawaiians.

RESEARCH DESIGN AND METHODS

Subjects aged 45–75 years completed a baseline food frequency questionnaire. After 14 years of follow-up, 8,587 subjects with incident diabetes were identified through self-reports or health plan linkages. Risk was assessed using Cox regression stratified by age and adjusted for ethnicity, BMI, physical activity, education, total energy, smoking, alcohol intake, marital status, and hypertension.

RESULTS

Fat and meat was significantly associated with diabetes risk in men (hazard ratio 1.40 [95% CI 1.23–1.60], P_trend < 0.0001) and women (1.22 [1.06–1.40], P_trend = 0.004) when extreme quintiles were compared. Except in Hawaiian women, the magnitude of the risk was similar across ethnic groups although not always significant. After stratification by BMI, fat and meat remained a predictor of disease primarily among overweight men and among overweight Japanese women. Vegetables lowered diabetes risk in men (0.86 [0.77–0.95], P_trend = 0.004) but not in women, whereas fruit and milk seemed to be more beneficial in women (0.85 [0.76–0.96], P_trend = 0.005) than in men (0.92 [0.83–1.02], P_trend = 0.04).

CONCLUSIONS

Foods high in meat and fat appear to confer a higher diabetes risk in all ethnic groups, whereas the effects of other dietary patterns vary by sex and ethnicity.Native Hawaiians have extremely high rates of obesity and diabetes, but despite their relatively low body weight, individuals with Japanese ancestry are also disproportionately affected by diabetes (1). Among the >44,000 Japanese Americans, 14,000 Native Hawaiians, and 35,000 Caucasians in the Hawaii component of the Multiethnic Cohort (MEC), a previous analysis had found diabetes incidence rates of 15.5, 12.5, and 5.8 per 1,000 person-years, respectively, that could not be explained by BMI (2). Dietary patterns have been identified as additional predictors of disease but have only rarely been investigated prospectively among non-Caucasian populations (3–5). The most commonly identified patterns are the so-called “western,” “unhealthy,” or “conservative” pattern (3–11), which is high in meat, high-fat foods, and sweets, and the “prudent” or “healthy” pattern, rich in fruit and vegetables (3–8,10,12,13). With the goal to contribute to the prevention of diabetes, we examined the effect of three dietary patterns, “fat and meat,” “vegetables,” and “fruit and milk,” which had been previously identified in the MEC, on diabetes risk (14).     

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.     

Hypoglycemia Unawareness in Older Compared With Middle-Aged Patients With Type 2 Diabetes

OBJECTIVE

Older patients with type 2 diabetes are at a particularly high risk for severe hypoglycemic episodes, and experimental studies in healthy subjects hint at a reduced awareness of hypoglycemia in aged humans. However, subjective responses to hypoglycemia have rarely been assessed in older type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

We tested hormonal, subjective, and cognitive responses (reaction time) to 30-min steady-state hypoglycemia at a level of 2.8 mmol/l in 13 older (≥65 years) and 13 middle-aged (39–64 years) type 2 diabetic patients.

RESULTS

Hormonal counterregulatory responses to hypoglycemia did not differ between older and middle-aged patients. In contrast, middle-aged patients showed a pronounced increase in autonomic and neuroglycopenic symptom scores at the end of the hypoglycemic plateau that was not observed in older patients (both P < 0.01). Also, seven middle-aged patients, but only one older participant, correctly estimated their blood glucose concentration to be <3.3 mmol/l during hypoglycemia (P = 0.011). A profound prolongation of reaction times induced by hypoglycemia in both groups persisted even after 30 min of subsequent euglycemia.

CONCLUSIONS

Our data indicate marked subjective unawareness of hypoglycemia in older type 2 diabetic patients that does not depend on altered neuroendocrine counterregulation and may contribute to the increased probability of severe hypoglycemia frequently reported in these patients. The joint occurrence of hypoglycemia unawareness and deteriorated cognitive function is a critical factor to be carefully considered in the treatment of older patients.Hypoglycemia is the limiting factor in the glycemic management of diabetes (1). For a long time hypoglycemia was assumed a major problem only in patients suffering from type 1 diabetes (2); however, there is increasing evidence that hypoglycemic episodes are a critical factor also in type 2 diabetes (3,4). Older subjects aged >65 years, who represent the majority of type 2 diabetic patients, appear at a particularly high risk of experiencing severe hypoglycemia (3,4). Previous studies (5–7) have shown weakened perception of hypoglycemia-related symptoms in healthy older (i.e., nondiabetic older subjects, aged 65–80 years) as compared with younger subjects (aged 24–49 years). Of note, in aged humans, the perception of hypoglycemic symptoms was found to simultaneously occur with the impairment of cognitive functions during a stepwise reduction of blood glucose levels (7), contrasting the well-known hierarchical succession of central nervous responses to hypoglycemia in younger healthy adults who normally perceive hypoglycemic symptoms at higher glucose levels than cognitive dysfunction (4). The concurrence of glycemic thresholds for the onset of symptoms and of cognitive dysfunction may be expected to increase the risk for severe hypoglycemic episodes since it likely prevents behavioral counteractions (e.g., the intake of carbohydrates) (3).To date only one study (8) has assessed subjective responses to standardized hypoglycemia in older type 2 diabetic patients (aged 72 ± 1 years), revealing an impairment in the perception of hypoglycemic symptoms that was comparable to that of age-matched healthy control subjects. Although this finding points to a decrease in hypoglycemia awareness that develops in the course of aging also in type 2 diabetic patients, this assumption has not yet been experimentally elucidated. Moreover, in the previous studies in healthy subjects (5–7), the age gap between experimental groups was rather large, raising the question as to the perception of hypoglycemia in middle-aged subjects. On this background, we examined whether older (aged ≥65 years) as compared with middle-aged (aged 39–64 years) type 2 diabetic patients differ in their subjective response to hypoglycemia and how hypoglycemia awareness in these age-groups relates to hormonal and cognitive effects of hypoglycemia.     

Improved metabolic control in children and adolescents with type 1 diabetes: a trend analysis using prospective multicenter data from Germany and Austria

OBJECTIVE

To investigate the temporal trend of metabolic control and potential predictors in German and Austrian children and adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

This study is based on a large, multicenter database for prospective longitudinal documentation of diabetes care in Germany and Austria. Data from 30,708 patients documented in 305 diabetes centers between 1995 and 2009 were analyzed. Generalized linear mixed regression models were used to adjust trend analysis for relevant confounders.

RESULTS

Unadjusted mean HbA_1c decreased from 8.7 ± 1.8% in 1995 to 8.1 ± 1.5% in 2009. In multiple regression analysis, treatment year, age, sex, diabetes duration, migration background, BMI-SDS, and daily insulin dose were significant predictors of metabolic control (P < 0.001). After multiple adjustment, mean HbA_1c decreased significantly by 0.038% per year (95% CI 0.032–0.043%), average odds ratio (OR) per year for HbA_1c >7.5% (>9.0%) was 0.969 (95% CI 0.961–0.977) (0.948, 95% CI 0.941–0.956). Intensified insulin regimen was associated with lower frequency of poor metabolic control (HbA_1c >9%; P = 0.005) but not with average HbA_1c (P = 0.797). Rate of severe hypoglycemia and hypoglycemic coma decreased significantly (relative risk [RR] per year 0.948, 95% CI 0.918–0.979; RR 0.917, 95% CI 0.885–0.950) over the study period. Diabetic ketoacidosis rate showed no significant variation over time.

CONCLUSIONS

This study showed a significant improvement in metabolic control in children and adolescents with type 1 diabetes during the past decade and a simultaneous decrease in hypoglycemic events. The improvement was not completely explained by changes in the mode of insulin treatment. Other factors such as improved patient education may have accounted for the observed trend.The Diabetes Control and Complications Trial (DCCT) showed that improved metabolic control reduces the risk of long-term complications in both adult and adolescent patients with type 1 diabetes (1,2). The observational follow-up study of the DCCT (the Epidemiology of Diabetes Interventions and Complications [EDIC] study) further proved that good glycemic control had persistent beneficial effects on long-term complications (3). Based on the results of the DCCT/EDIC study, it was recommended to optimize glycemic control as early and close to normal as possible in all patients with type 1 diabetes in order to prevent development and progression of microvascular complications.Diabetes treatment has been intensified in pediatric and adolescent patients during the past 15 years. Insulin therapy has changed from twice-daily injection regimen to intensified therapy with multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII). This has been reported from single-center and multicenter studies (4–10). In the 1990s, mainly an increased use of MDI was observed, whereas since 2000, pump therapy increased considerably, paralleled by a decrease in MDI therapy (11). With the intensification of insulin regimen, the frequency of daily self-monitoring of blood glucose (SMBG) increased continuously (5,10–12), as close glucose monitoring is a precondition for intensified insulin therapy with an appropriate dose adjustment. Likewise, the use of short-acting insulin analogs has continuously increased since the mid-1990s and the use of long-acting analogs since 2000 (4,5,10).Despite these far-ranging changes in diabetes therapy, the anticipated improvement in metabolic control in children and adolescents with type 1 diabetes has not been achieved in all settings. The multicenter Hvidoere studies did not observe any improvement in glycemic control during 1995–2005 (6–8). Other studies, however, reported a significant decrease in average HbA_1c level over the past two decades (4,5,10,11,13). Concordantly, several studies indicated a notable increase in the proportion of children and adolescents with good metabolic control (HbA_1c <7.5 or <8%) over the past years (11,13).In the DCCT study, the tradeoff with intensified insulin therapy was a marked increase in episodes of severe hypoglycemia (2). Several studies reported a higher hypoglycemia risk with lower HbA_1c level (4,6,7,10,14), but others did not (15,16). Results on the trend of severe hypoglycemic events over the past 15 years are also inconsistent (4,5,8,9,11).The aim of this study was to give a current update on the temporal trend of metabolic control in German and Austrian children and adolescents over the past 15 years (1995–2009), to identify potential determinants of metabolic control, and to analyze the simultaneous trend of severe hypoglycemic and diabetic ketoacidotic events.