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).     

Plasma 25-Hydroxyvitamin D Concentration and Metabolic Syndrome Among Middle-Aged and Elderly Chinese Individuals

OBJECTIVE

To evaluate the association between 25-hydroxyvitamin D [25(OH)D] and metabolic syndrome in the Chinese population.

RESEARCH DESIGN AND METHODS

Plasma 25(OH)D was measured in a cross-sectional sample of 1,443 men and 1,819 women aged 50–70 years from Beijing and Shanghai. Metabolic syndrome was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans. Fasting plasma glucose, insulin, lipid profile, A1C, and inflammatory markers were measured.

RESULTS

The geometric mean of plasma 25(OH)D was 40.4 nmol/l, and percentages of vitamin D deficiency [25(OH)D <50 nmol/l] and insufficiency [50 ≤ 25(OH)D <75 nmol/l] were 69.2 and 24.4%, respectively. Compared with the highest 25(OH)D quintile (≥57.7 nmol/l), the odds ratio for metabolic syndrome in the lowest quintile (≤28.7 nmol/l) was 1.52 (95% CI 1.17–1.98, P_trend = 0.0002) after multiple adjustment. Significant inverse associations also existed between 25(OH)D and individual metabolic syndrome components plus A1C. Moreover, we observed significant inverse associations of 25(OH)D with fasting insulin and the insulin resistance index (homeostasis model assessment of insulin resistance [HOMA-IR]) in overweight and obese individuals (BMI ≥24 kg/m²) but not in their normal-weight counterparts (test for interaction: P = 0.0363 and 0.0187 for insulin and HOMA-IR, respectively).

CONCLUSIONS

Vitamin D deficiency is common in the middle-aged and elderly Chinese population, and a low 25(OH)D level is significantly associated with an increased risk of having metabolic syndrome and insulin resistance. Prospective studies and randomized clinical trials are warranted to determine the role of 25(OH)D in the development of metabolic syndrome and related metabolic diseases.Vitamin D deficiency is now recognized as a worldwide concern (1). A growing body of evidence suggests that 25-hydroxyvitamin D [25(OH)D], a generally accepted indicator of vitamin D status, is inversely associated with adiposity, glucose homeostasis, lipid profiles, and blood pressure along with its classic role in calcium homeostasis and bone metabolism (1–6). Even though the underlying mechanism has not been well understood, vitamin D appears to exert effects through direct modulation of gene expression via vitamin D receptors (VDRs) (1) and through regulation of extra- and intracellular calcium (1,7).Metabolic syndrome, a constellation of cardiometabolic disease risk factors, has become a global epidemic (8). Several epidemiologic studies (5,6,9,10) have suggested that 25(OH)D status is inversely associated with metabolic syndrome in western populations, although data for morbidly obese individuals are inconsistent (11,12). Nevertheless, evidence from the Asian population is limited. Because of ethnic differences in vitamin D metabolism and its nutritional status indicated by previous studies (3,13), it is not clear whether the findings from western populations could be extrapolated directly to Asian individuals. With rapid nutrition and lifestyle transitions in the last 20 years, metabolic syndrome has become one of the most widespread health problems in Asian countries (8). However, little is known regarding whether vitamin D deficiency plays an important role in the heightened prevalence of metabolic syndrome and other metabolic disorders among Asian individuals. Therefore, the aim of our study was to evaluate the plasma 25(OH)D concentration and its association with metabolic syndrome among Chinese individuals aged 50–70 years.     

Cardiovascular risk prediction is improved by adding asymptomatic coronary status to routine risk assessment in type 2 diabetic patients

OBJECTIVE

To evaluate if silent myocardial ischemia (SMI) and silent coronary artery disease (CAD) provide significant additional value to routine cardiovascular risk assessment in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

We followed up to a first cardiovascular event 688 subjects (322 men, aged 59 ± 8 years) out of 731 consecutive asymptomatic type 2 diabetic patients with ≥1 additional risk factor who had been prospectively screened between 1992 and 2006 for SMI by stress myocardial scintigraphy and for silent CAD by coronary angiography.

RESULTS

SMI was found in 207 (30.1%) patients and CAD in 76 of those with SMI. Of the patients, 98 had a first cardiovascular event during a 5.4 ± 3.5 (range: 0.1–19.2) year follow-up period. Cox regression analysis considering parameters predicting events but not SMI and CAD (“routine assessment”) showed in univariate analyses that macroproteinuria (hazard ratio [HR] 3.33 [95% CI 1.74–6.35]; P < 0.001), current multifactorial care (0.27 [0.15–0.47]; P < 0.001), and peripheral/carotid occlusive arterial disease (PCOAD; 4.33 [2.15–8.71]; P < 0.001) independently predicted cardiovascular events. When added into the model, SMI (HR 1.76 [1.00–3.12]; P = 0.05) and CAD (2.28 [1.24–4.57]; P < 0.01) were also independently associated with events. SMI added to the prediction of an event in the following 5 years above and beyond routine assessment risk prediction (c statistic with or without SMI 0.788 [0.720–0.855] and 0.705 [0.616–0.794], respectively).

CONCLUSIONS

Although screening for SMI and silent CAD should not be systematic, these complications are predictive of cardiovascular events in type 2 diabetic patients in addition to routine risk predictors, especially represented by PCOAD, macroproteinuria, and nonintensive management.Type 2 diabetes is associated with a high prevalence of coronary artery disease (CAD) and cardiovascular events (1,2). Other cardiovascular risk factors are common in this population and must be taken into account for the estimation of the cardiovascular risk, such as in the United Kingdom Prospective Diabetes Study (UKPDS) risk engine (3) or the Framingham equation (4). However, since these models have been created, cardiovascular risk factors have been better controlled in accordance with guidelines. Therefore, the performances of these models have recently been discussed (5,6). It has been suggested that markers of subclinical organ damage (7) and some specific markers, such as nephropathy (8) or retinopathy (9), could be considered for cardiovascular risk stratification.Silent myocardial ischemia (SMI) is two- to fourfold more frequent in type 2 diabetic patients as compared with the nondiabetic population (1,2). SMI has been reported in 10–65% of the diabetic population (10) and is a strong predictor for incident coronary events and premature death (11,12), especially when it is associated with silent CAD (i.e., angiography-diagnosed coronary stenoses) (13). We raised the hypothesis that the prognostic value of SMI and silent CAD was better than routine cardiovascular risk assessment. Therefore, the aim of the current study was to evaluate if ischemic and coronary status (SMI and silent CAD) provided significant additional value to routine cardiovascular risk assessment in asymptomatic type 2 diabetic patients with at least one other cardiovascular risk factor.     

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

Long-Term 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 25-hydroxyvitamin D, calcium intake, and risk of type 2 diabetes after 5 years: results from a national, population-based prospective study (the Australian Diabetes, Obesity and Lifestyle study)

OBJECTIVE

To examine whether serum 25-hydroxyvitamin D (25OHD) and dietary calcium predict incident type 2 diabetes and insulin sensitivity.

RESEARCH DESIGN AND METHODS

A total of 6,537 of the 11,247 adults evaluated in 1999–2000 in the Australian Diabetes, Obesity and Lifestyle (AusDiab) study, returned for oral glucose tolerance test (OGTT) in 2004–2005. We studied those without diabetes who had complete data at baseline (n = 5,200; mean age 51 years; 55% were women; 92% were Europids). Serum 25OHD and energy-adjusted calcium intake (food frequency questionnaire) were assessed at baseline. Logistic regression was used to evaluate associations between serum 25OHD and dietary calcium on 5-year incidence of diabetes (diagnosed by OGTT) and insulin sensitivity (homeostasis model assessment of insulin sensitivity [HOMA-S]), adjusted for multiple potential confounders, including fasting plasma glucose (FPG).

RESULTS

During the 5-year follow-up, 199 incident cases of diabetes were diagnosed. Those who developed diabetes had lower serum 25OHD (mean 58 vs. 65 nmol/L; P < 0.001) and calcium intake (mean 881 vs. 923 mg/day; P = 0.03) compared with those who remained free of diabetes. Each 25 nmol/L increment in serum 25OHD was associated with a 24% reduced risk of diabetes (odds ratio 0.76 [95% CI 0.63–0.92]) after adjusting for age, waist circumference, ethnicity, season, latitude, smoking, physical activity, family history of diabetes, dietary magnesium, hypertension, serum triglycerides, and FPG. Dietary calcium intake was not associated with reduced diabetes risk. Only serum 25OHD was positively and independently associated with HOMA-S at 5 years.

CONCLUSIONS

Higher serum 25OHD levels, but not higher dietary calcium, were associated with a significantly reduced risk of diabetes in Australian adult men and women.Accumulating evidence suggests that vitamin D deficiency is associated with an increased risk of developing type 2 diabetes (1–3). Animal and human studies indicate that vitamin D can have a direct (via activation of the vitamin D receptor on pancreatic β-cells and insulin-sensitive organs) and indirect (via regulation of calcium homeostasis) positive effect on insulin secretion and sensitivity (3,4). Several prospective studies also support the hypothesis that low vitamin D status is a risk factor for the development of type 2 diabetes (1–3,5,6); however, these studies were limited by small study sample sizes (3), indirect measures of vitamin D status as a surrogate marker (6,7), and incomplete identification of incident diabetes cases (1,2,5). In addition, most did not include an assessment of dietary calcium, which may have an independent or synergistic effect with vitamin D on lowering type 2 diabetes risk (7). The aim of this study was to examine the relationship between serum 25-hydroxyvitamin D (25OHD), dietary calcium, and risk of developing type 2 diabetes as assessed by an oral glucose tolerance test (OGTT) in a large national, population-based prospective study: the Australian Diabetes, Obesity and Lifestyle (AusDiab) 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.     

Serum carotenoids and fat-soluble vitamins in women with type 1 diabetes and preeclampsia: a longitudinal study

OBJECTIVE

Increased oxidative stress and immune dysfunction are implicated in preeclampsia (PE) and may contribute to the two- to fourfold increase in PE prevalence among women with type 1 diabetes. Prospective measures of fat-soluble vitamins in diabetic pregnancy are therefore of interest.

RESEARCH DESIGN AND METHODS

Maternal serum carotenoids (α- and β-carotene, lycopene, and lutein) and vitamins A, D, and E (α- and γ-tocopherols) were measured at first (12.2 ± 1.9 weeks [mean ± SD], visit 1), second (21.6 ± 1.5 weeks, visit 2), and third (31.5 ± 1.7 weeks, visit 3) trimesters of pregnancy in 23 women with type 1 diabetes who subsequently developed PE (DM PE+) and 24 women with type 1 diabetes, matched for age, diabetes duration, HbA_1c, and parity, who did not develop PE (DM PE−). Data were analyzed without and with adjustment for baseline differences in BMI, HDL cholesterol, and prandial status.

RESULTS

In unadjusted analysis, in DM PE+ versus DM PE−, α-carotene and β-carotene were 45 and 53% lower, respectively, at visit 3 (P < 0.05), before PE onset. In adjusted analyses, the difference in β-carotene at visit 3 remained significant. Most participants were vitamin D deficient (<20 ng/mL), and vitamin D levels were lower in DM PE+ versus DM PE− throughout the pregnancy, although this did not reach statistical significance.

CONCLUSIONS

In pregnant women with type 1 diabetes, low serum α- and β-carotene were associated with subsequent development of PE, and vitamin D deficiency may also be implicated.Preeclampsia (PE) is defined as new-onset hypertension and proteinuria during pregnancy. PE is a major cause of maternal and infant morbidity and mortality, and its incidence is increased approximately fourfold by the presence of maternal type 1 diabetes (1,2). Placental oxidative stress is implicated in the pathogenesis of PE (3,4), and compared with the general population, women with type 1 diabetes may be particularly prone to and affected by impaired antioxidant status. Any alterations in maternal antioxidant status in pregnancy are therefore of interest. Risk for PE has also been associated with vitamin D deficiency, perhaps mediated through sequelae such as immune dysfunction, inflammation, and hypertension (5,6).Several cross-sectional PE studies have been performed, mostly in nondiabetic women. Altered levels of carotenoids (α- and β-carotene, lycopene, and lutein) have been reported (7). Mikhail et al. (8) found decreased maternal β-carotene levels in PE, but other studies were not confirmatory (9,10). Vitamin A, or retinol, is an essential fat-soluble vitamin with physiologic functions in mammalian reproduction (11). Cross-sectional studies in nondiabetic women with and without PE report both lower (9) and higher (10) vitamin A levels. Vitamin E or α-tocopherol, which has antioxidant functions, has been reported to be lower (8,12), higher (9,10), or similar (13) between PE and normotensive nondiabetic pregnancies.There are some longitudinal PE studies, although none in type 1 diabetes. Bodnar et al. (5) found that severe vitamin D deficiency [25(OH)D <15 ng/mL] in early pregnancy was associated with a fivefold increased risk of PE. Halhali et al. (14) showed that serum 1, 25(OH)₂D was not altered in pregnant women who subsequently developed PE. In a longitudinal study of nondiabetic women with a risk of high PE, Chappell et al. (15) found no significant differences in α-tocopherol concentrations.Thus, longitudinal studies are few, and cross-sectional studies are not informative on the temporal relationship between antioxidant status and subsequent PE. Furthermore, there are no prospective data relating serum carotenoids, fat-soluble vitamins, and PE in diabetes.We report a multicenter prospective study examining differences in serum carotenoids, vitamins A (retinol), D [25(OH)D], and E (tocopherols) between women with type 1 diabetes with and without subsequent PE. Levels were measured in each trimester of pregnancy and before PE onset. Our study evaluated the temporal association of vitamin and antioxidant provitamin levels with PE in type 1 diabetes.Because our major goal was to compare pregnant women with type 1 diabetes who subsequently developed PE with those who did not, our primary comparison is between these two groups. We also included healthy, normotensive, nondiabetic pregnant women to obtain reference values during pregnancy, and for illustrative purposes we report some secondary analyses using their data.     

Associations of Serum Concentrations of 25-Hydroxyvitamin D and Parathyroid Hormone With Surrogate Markers of Insulin Resistance Among U.S. Adults Without Physician-Diagnosed Diabetes: NHANES, 2003�C2006

OBJECTIVE

To examine whether concentrations of serum 25-hydroxyvitamin D (25[OH]D) and parathyroid hormone (PTH) are associated with surrogate markers of insulin resistance (IR) in U.S. adults without physician-diagnosed diabetes.

RESEARCH DESIGN AND METHODS

Cross-sectional data (n = 3,206) from the National Health and Nutrition Examination Survey (NHANES) 2003–2006 were analyzed.

RESULTS

The age-adjusted prevalence of hyperinsulinemia, high homeostasis model assessment-IR, high GHb, and fasting and 2-h hyperglycemia decreased linearly across quintiles of 25(OH)D but increased linearly across quintiles of PTH (except for a quadratic trend for fasting hyperglycemia). After extensive adjustment for potential confounders, the relationships between 25(OH)D and the markers of IR and 2-h hyperglycemia persisted. Only hyperinsulinemia was positively associated with PTH (P < 0.05).

CONCLUSIONS

Among U.S. adults without physician-diagnosed diabetes, low concentrations of serum 25(OH)D were associated with markers of IR. The role of PTH in IR deserves further investigation.The role of vitamin D and parathyroid hormone (PTH) in metabolic syndrome and diabetes is receiving increased attention. Insulin resistance (IR) may represent a potential mechanism linking vitamin D and PTH to these conditions. The inverse associations between vitamin D and fasting insulin concentrations or the homeostasis model assessment of IR (HOMA-IR) index have been reported in some (1–5) but not all studies (6). Moreover, evidence linking PTH to markers of IR is limited and inconsistent (7–9). This study examined whether serum 25-hydroxyvitamin D (25[OH]D) and PTH are associated with surrogate markers of IR in U.S. adults without physician-diagnosed diabetes.     

Prognostic Value of Coronary Computed Tomographic Angiography in Diabetic Patients Without Known Coronary Artery Disease

OBJECTIVE

Diabetic patients have a high prevalence of coronary artery disease (CAD), but timely diagnosis of CAD remains challenging. We assessed the ability of coronary computed tomography angiography (CCTA) to detect CAD in diabetic patients and to predict subsequent cardiac events.

RESEARCH DESIGN AND METHODS

We analyzed 140 diabetic patients without known CAD undergoing CCTA; 1,782 patients without diabetes were used as a control group. Besides calcium scoring and the degree of the most severe stenosis, the atherosclerotic burden score counting the number of segments having either a nonstenotic plaque or a stenosis was recorded. The primary end point was a composite of hard cardiac events defined as all-cause death, nonfatal myocardial infarction, or unstable angina requiring hospitalization.

RESULTS

During a mean follow-up of 33 months, there were seven events in the diabetic group and 24 events in the control group. The best predictor in diabetic patients was the atherosclerotic burden score: the annual event rate ranged from 0.5% for patients with <5 lesions to 9.6% for patients with >9 lesions, resulting in a hazard ratio (HR) of 1.3 (95% CI 1.1–1.7) for each additional lesion (P = 0.005). For comparison, in nondiabetic patients the annual event rate ranged from 0.3 to 2.2%, respectively, resulting in an HR of 1.2 (95% CI 1.1–1.3, P < 0.001). The atherosclerotic burden score improved the prognostic value of conventional risk factors significantly (P < 0.001).

CONCLUSIONS

In diabetic patients without known CAD, CCTA can identify a patient group at particularly high risk for subsequent hard cardiac events.Diabetes is associated with a markedly increased risk for coronary artery disease (CAD), and CAD is the most common cause of death in diabetic adults (1). Although primary prevention measures for CAD are recommended for all diabetic patients (2), additional therapies are indicated where known CAD is present, e.g., institution of β-blocker therapy, and goals for secondary prevention are more stringent, including an LDL cholesterol target <70 mg/dl (3). For an optimized prevention regimen, early detection of CAD is therefore of significant importance in diabetic patients. Unfortunately, the sensitivity of clinical risk assessment is limited, mainly because typical symptoms of ischemia are often absent, and cardiac stress imaging tests also have a limited negative predictive value in these patients (4). By virtue of its ability to detect both coronary stenoses and calcified and noncalcified plaques, coronary computed tomography angiography (CCTA) may be a reasonable option to close this diagnostic gap.During the last few years, CCTA has emerged as a widely used imaging modality for detection or exclusion of obstructive CAD, replacing invasive coronary angiography in certain conditions (5). In addition, several studies demonstrated the usefulness of CCTA as a prognostic tool for prediction of subsequent cardiac events (6–8).For diabetic patients undergoing CCTA, an increased prevalence of obstructive and nonobstructive CAD was recently demonstrated (9,10), but up to now, no data are available relating to how this observation influences further clinical outcome. Therefore, the aim of this study was twofold: to assess the prevalence of CAD by CCTA in diabetic patients without known CAD and to investigate the predictive value of CCTA on incident cardiac events.     

Vitamin D Levels and Mortality in Type 2 Diabetes

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

Association Between Urinary Type IV Collagen Level and Deterioration of Renal Function in Type 2 Diabetic Patients Without Overt Proteinuria

OBJECTIVE

Cross-sectional studies have reported increased levels of urinary type IV collagen in diabetic patients with progression of diabetic nephropathy. The aim of this study was to determine the role of urinary type IV collagen in predicting development and progression of early diabetic nephropathy and deterioration of renal function in a longitudinal study.

RESEARCH DESIGN AND METHODS

Japanese patients with type 2 diabetes (n = 254, 185 with normoalbuminuria and 69 with microalbuminuria) were enrolled in an observational follow-up study. The associations of urinary type IV collagen with progression of nephropathy and annual decline in estimated glomerular filtration rate (eGFR) were evaluated.

RESULTS

At baseline, urinary type IV collagen levels were higher in patients with microalbuminuria than in those with normoalbuminuria and correlated with urinary β₂-microglobulin (β = 0.57, P < 0.001), diastolic blood pressure (β = 0.15, P < 0.01), eGFR (β = 0.15, P < 0.01), and urinary albumin excretion rate (β = 0.13, P = 0.01) as determined by multivariate regression analysis. In the follow-up study (median duration 8 years), urinary type IV collagen level at baseline was not associated with progression to a higher stage of diabetic nephropathy. However, the level of urinary type IV collagen inversely correlated with the annual decline in eGFR (γ = −0.34, P < 0.001). Multivariate regression analysis identified urinary type IV collagen, eGFR at baseline, and hypertension as factors associated with the annual decline in eGFR.

CONCLUSIONS

Our results indicate that high urinary excretion of type IV collagen is associated with deterioration of renal function in type 2 diabetic patients without overt proteinuria.Diabetic nephropathy is characterized structurally by accumulation of mesangial matrix and thickening of the basement membrane in the glomeruli (1), as well as renal tubular hypertrophy and associated basement membrane alterations in the tubulointerstitium, which precede tubulointerstitial fibrosis (2). These abnormalities are associated with renal overproduction of the extracellular matrix proteins such as type IV collagen (3). We and others reported previously that the production of type IV collagen is enhanced in glomerular mesangial cells (4,5), podocytes (6), and proximal tubular cells (7,8) cultured under a high-glucose condition. Cross-sectional studies reported a stepwise increase in urinary type IV collagen excretion in diabetic patients, in parallel with increased levels of urinary albumin (9–14). Thus, a high level of urinary type IV collagen has been proposed as a marker of development and progression of early diabetic kidney disease. However, there is little information on whether the increase in type IV collagen excretion in urine is a predictor of progression of diabetic nephropathy or deterioration of renal function in type 2 diabetic patients.The aim of this study was to determine whether the urinary levels of type IV collagen can predict the progression of early diabetic kidney disease. For this purpose, we conducted a prospective observational follow-up study involving type 2 diabetic patients with normoalbuminuria and microalbuminuria and investigated the relationship between urinary levels of type IV collagen and the progression of diabetic nephropathy stage as well as the annual decline in estimated glomerular filtration rate (eGFR) during the follow-up period.     

��-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.     

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.     

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.     

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.     

Cognitive Function in Type 1 Diabetic Adults With Early Exposure to Severe Hypoglycemia: A 16-year follow-up study

OBJECTIVE

We assessed adulthood cognition in relation to early exposure to severe hypoglycemia (SH).

RESEARCH DESIGN AND METHODS

Sixteen years subsequent to a study of cognitive function in 28 diabetic children and 28 matched control subjects, we reexamined the same subjects with a 96% participation rate. Diabetic subjects were classified as with (n = 9) or without (n = 18) early (≤10 years of age) SH, which was defined as convulsions or loss of consciousness.

RESULTS

Overall, cognitive scores were 0.9 SDs lower in subjects with early SH compared with subjects without early SH (P = 0.003). The two diabetic groups particularly differed with respect to problem solving, verbal function, and psychomotor efficiency. Earlier age at first incident of SH was associated with poorer cognition (P for trend = 0.001).

CONCLUSIONS

The findings suggest that early exposure to SH may have lasting and clinically relevant effects on cognition.Early-onset diabetes is associated with reduced cognition (1), possibly due to the effects of severe hypoglycemia (SH) on the developing brain (2–5). Although moderate (1), this cognitive deficit seems to be enduring (5–7). We hypothesized that earlier age at SH occurrence would entail more pronounced effects on cognition. In this 16-year follow-up study of diabetic subjects, we investigated cognitive function in relation to early exposure to SH.     

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.