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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

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.     

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).     

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.     

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

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.     

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.     

Prediabetes and prehypertension in healthy adults are associated with low vitamin D levels

OBJECTIVE

To determine whether modest elevations of fasting serum glucose (FSG) and resting blood pressure (BP) in healthy adults are associated with differential serum vitamin D concentrations.

RESEARCH DESIGN AND METHODS

Disease-free adults in the National Health and Nutrition Examination Survey 2001–2006 were assessed. Prediabetes (PreDM) and prehypertension (PreHTN) were diagnosed using American Diabetes Association and Seventh Report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure criteria: FSG 100–125 mg/dL and systolic BP 120–139 mmHg and/or diastolic BP 80–89 mmHg. Logistic regression was used to assess the effects of low vitamin D levels on the odds for PreDM and PreHTN in asymptomatic adults (n = 1,711).

RESULTS

The odds ratio for comorbid PreDM and PreHTN in Caucasian men (n = 898) and women (n = 813) was 2.41 (P < 0.0001) with vitamin D levels ≤76.3 versus >76.3 nmol/L after adjusting for age, sex, and BMI.

CONCLUSIONS

This study strengthens the plausibility that low serum vitamin D levels elevate the risk for early-stage diabetes (PreDM) and hypertension (PreHTN).The link between low serum vitamin D concentrations and abnormal bone and calcium metabolism has been known for many years. The adverse associations between low vitamin D concentrations and metabolic syndrome (1), diabetes mellitus (2), hypertension (3), cardiovascular health (4), cardiovascular, and all-cause mortality (5) have also been identified. Vitamin D concentrations have an inverse relationship with circulating renin and angiotensin II, suggesting a mechanism for elevation of blood pressure (BP) (6). Moreover, dietary supplementation with vitamin D seems to reduce blood glucose and BP. The relationship between serum vitamin D and fasting serum glucose (FSG) and resting BP, specifically prediabetes (PreDM) and prehypertension (PreHTN), in healthy disease-free adults, however, is unknown.     

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.     

Sex and Racial/Ethnic Differences in Cardiovascular Disease Risk Factor Treatment and Control Among Individuals With Diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA)

OBJECTIVE

To examine sex and racial/ethnic differences in cardiovascular risk factor treatment and control among individuals with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA).

RESEARCH DESIGN AND METHODS

This study was an observational study examining mean levels of cardiovascular risk factors and proportion of subjects achieving treatment goals.

RESULTS

The sample included 926 individuals with diabetes. Compared with men, women were 9% less likely to achieve LDL cholesterol <130 mg/dl (adjusted prevalence ratio 0.91 [0.83–0.99]) and systolic blood pressure (SBP) <130 mmHg (adjusted prevalence ratio 0.91 [0.85–0.98]). These differences diminished over time. A lower percentage of women used aspirin (23 vs. 33%; P < 0.001). African American and Hispanic women had higher mean levels of SBP and lower prevalence of aspirin use than non-Hispanic white women.

CONCLUSIONS

Women with diabetes had unfavorable cardiovascular risk factor profiles compared with men. African American and Hispanic women had less favorable profiles than non-Hispanic white women.Population-based health survey data suggest that sex and racial/ethnic disparities are present in diabetes process of care measures and cardiovascular risk factor control (1–9). Available data also indicate that sex-specific race/ethnicity differences are present in cardiovascular risk factor control, but these data are limited to Medicare and Veterans'' Hospital patient populations (5,10–13). We therefore performed analyses of participants with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA) to examine sex and sex-specific racial/ethnic differences in cardiovascular risk factor treatment and control.     

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.     

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.     

Fetuin-A levels are increased in patients with type 2 diabetes and peripheral arterial disease

OBJECTIVE

Low levels of fetuin-A, a systemic calcification inhibitor, are linked to mortality in patients on dialysis. In contrast, elevated fetuin-A is associated with cardiovascular events in non-renal patients. We investigated fetuin-A in patients with type 2 diabetes and peripheral arterial disease (PAD).

RESEARCH DESIGN AND METHODS

We studied fetuin-A in 76 patients with PAD and normal glucose metabolism (NGM-PAD) and in 129 patients with PAD and type 2 diabetes (type 2 diabetes–PAD). Additionally, 40 patients with diabetes without any complications (type 2 diabetes–non-PAD) were examined.

RESULTS

Type 2 diabetes–PAD subjects (399 ± 155 μg/ml) had significantly higher fetuin-A levels than type 2 diabetes–non-PAD subjects (247 ± 42; P < 0.001). In NGM-PAD subjects (376 ± 144), fetuin-A was significantly higher than in type 2 diabetes–non-PAD subjects (P < 0.001). Type 2 diabetes–PAD patients with mediasclerosis had lower fetuin-A than subjects without (P < 0.03). Regression analysis in type 2 diabetes–PAD subjects revealed that glycated A1C (P < 0.001) and mediasclerosis (P = 0.004) were the strongest predictors of fetuin-A. Multivariate regression revealed that a 1-SD increase in fetuin-A was associated with an odds ratio (OR) of 2.1 (95% CI 1.1–3.3; P < 0.001) for the prevalence of PAD and an OR of 1.4 (1.0–1.7, P = 0.039) for the prevalence of myocardial infarction.

CONCLUSIONS

In contrast to previous findings, fetuin-A was higher in type 2 diabetes–PAD patients than in type 2 diabetes–non-PAD patients. In NGM-PAD patients, fetuin-A was also higher than in type 2 diabetes–non-PAD patients. In type 2 diabetes–PAD patients, fetuin-A was inversely associated with mediasclerosis—the calcification process pathognomonic for diabetic PAD. This association persisted in multivariate regression, which is in line with the calcification inhibition in coronary heart or renal disease.Patients suffering from type 2 diabetes and peripheral artery disease (PAD) (type 2 diabetes–PAD) have a five times higher risk for cardiovascular mortality than patients with one disease alone (1–3). Furthermore, the risk of lower-extremity amputation is higher than in patients without diabetes (3).Fetuin-A, also known as α2-Schmid Heremans glycoprotein (ASHG), is a potent systemic calcification inhibitor (4). Fetuin-A knockout mice develop severe calcification of various organs (4). In a cross-sectional study, low levels of fetuin-A were associated with cardiovascular mortality in patients on dialysis (5). In addition, low fetuin-A has been linked to vascular calcification (6) and flow-limiting aortic stenosis (7).Fetuin-A interacts with the insulin receptor tyrosine kinase and induces insulin resistance in rodents (8,9). Stefan et al. (10) demonstrated in a prospective case-cohort study that elevated fetuin-A is an independent risk factor for developing diabetes. Contrariwise to renal (dialysis) patients, several studies showed that high levels of fetuin-A were associated with atherosclerosis and its manifestations in non-renal patients (11–13). Likewise, high levels of fetuin-A were linked to myocardial infarction and ischemic stroke (12). This possible involvement of fetuin-A in the pathogenesis of cardiovascular disease has been confirmed by a recent trans-European cohort study with 2,520 patients (13). Thus, it seems that high levels of fetuin-A are associated with atherosclerosis and its manifestations in non-renal patients.In contrast to the latter findings, a recent article (14) suggested that fetuin-A levels in a non-dialysis condition are lower in type 2 diabetes–PAD patients (n = 38) than in patients with diabetes alone.However, the role of fetuin-A and its involvement in atherosclerosis seems to be very complex and yet not understood. The situation is even more complex in patients with type 2 diabetes–PAD, who generally suffer from advanced/systemic atherosclerosis (1–3,15). In those high-risk patients, up to 30% show mediasclerosis (2,15). The aim of this study was to investigate fetuin-A levels in patients with type 2 diabetes with or without PAD in comparison with PAD patients with diabetes.     

Glycemic Control and Cardiovascular Disease in 7,454 Patients With Type 1 Diabetes: An observational study from the Swedish National Diabetes Register (NDR)

OBJECTIVE

We assessed the association between A1C and cardiovascular diseases (CVDs) in an observational study of patients with type 1 diabetes followed for 5 years.

RESEARCH DESIGN AND METHODS

A total of 7,454 patients were studied from the Swedish National Diabetes Register (aged 20–65 years, diabetes duration 1–35 years, followed from 2002 to 2007).

RESULTS

Hazard ratios (HRs) for fatal/nonfatal coronary heart disease (CHD) per 1% unit increase in baseline or updated mean A1C at Cox regression analysis were 1.31 and 1.34 and 1.26 and 1.32, respectively, for fatal/nonfatal CVD (all P < 0.001 after adjustment for age, sex, diabetes duration, blood pressure, total and LDL cholesterol, triglycerides, BMI, smoking, and history of CVD). HRs were only slightly lower for CHD (P = 0.002) and CVD (P = 0.002–0.007) after also adjusting for albuminuria. Adjusted 5-year event rates of CHD and CVD increased progressively with higher A1C, ranging from 5 to 12%, as well as when subgrouped by shorter (1–20 years) or longer (21–35 years) duration of diabetes. A group of 4,186 patients with A1C 5–7.9% (mean 7.2) at baseline showed risk reductions of 41% (95% confidence intervals: 15–60) (P = 0.005) for fatal/nonfatal CHD and 37% (12–55) (P = 0.008) for CVD, compared with 3,268 patients with A1C 8–11.9% (mean 9.0), fully adjusted also for albuminuria.

CONCLUSIONS

This observational study of patients in modern everyday clinical practice demonstrates progressively increasing risks for CHD and CVD with higher A1C, independently of traditional risk factors, with no J-shaped risk curves. A baseline mean A1C of 7.2% showed considerably reduced risks of CHD and CVD compared with A1C 9.0%, emphasizing A1C as a strong independent risk factor in type 1 diabetes.Patients with type 1 diabetes have long been considered to have increased risks of cardiovascular disease (CVD) and mortality (1,2), and this has recently been confirmed in two studies (3,4) from the General Practice Research Database in the U.K. Based on data from 1992 to 1999, risks of CVD and mortality were four to eight times higher in men and women with type 1 diabetes than nondiabetic individuals (3,4).While the association between glycemia and microvascular complications is established (5,6), there have been no long-term randomized clinical studies satisfactorily examining the relationship with macrovascular complications in type 1 diabetes, and epidemiological studies have shown conflicting results (7–14). The Epidemiology of Diabetes Interventions and Complications (EDIC) Study showed that patients who had previously been subjected to intensive glucose control during the Diabetes Control and Complications Trial (DCCT) had a considerably lower risk of CVD than patients receiving standard treatment (1983–1993) (7). A small study from Finland on late-onset type 1 diabetic patients without albuminuria showed increased risk of coronary heart disease (CHD) with poor glycemic control (9), but the EURODIAB Prospective Complications Study (PCS), the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study, and the Wisconsin Epidemiologic Study of Diabetic Retinopathy did not demonstrate a significant relationship between glycemia and CHD after controlling for other cardiovascular risk factors (10–13). However, a recent study (14) from the Pittsburgh EDC showed that change in A1C was related to coronary artery disease, whereas baseline A1C was not.With this background, we assessed the association between A1C and CHD, stroke, and CVD in a large cohort of patients with type 1 diabetes, aged 20–65 years, treated in everyday clinical practice from 2002 to 2007. Data were used from the Swedish National Diabetes register (NDR), a quality-assurance tool in diabetes care with nationwide coverage with recently published reports regarding type 1 and type 2 diabetes (15–17).     

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.     

Metabolic Syndrome as a Risk Factor for Cardiovascular Disease, Mortality, and Progression of Diabetic Nephropathy in Type 1 Diabetes

OBJECTIVE

To assess the predictive value of the metabolic syndrome in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Patients were from the prospective Finnish Diabetic Nephropathy (FinnDiane) Study (n = 3,783): mean age 37 ± 12 years and diabetes duration 23 ± 12 years. Metabolic syndrome was defined according to World Health Organization (WHO), National Cholesterol Education Program (NCEP), and International Diabetes Federation (IDF) definitions. Follow-up time was median 5.5 years (interquartile range 3.7–6.7). Mortality data were complete, whereas morbidity data were available in 69% of the patients.

RESULTS

The WHO definition was associated with a 2.1-fold increased risk of cardiovascular events and a 2.5-fold increased risk of cardiovascular- and diabetes-related mortality, after adjustment for traditional risk factors and diabetic nephropathy. The NCEP definition did not predict outcomes when adjusted for nephropathy but markedly added to the risk associated with elevated albuminuria alone (P < 0.001). The IDF definition did not predict outcomes.

CONCLUSIONS

The metabolic syndrome is a risk factor, beyond albuminuria, for cardiovascular morbidity and diabetes-related mortality in type 1 diabetes.Type 1 diabetes is associated with an increased risk of cardiovascular morbidity and mortality, which is largely, but not totally, explained by the presence of diabetic nephropathy (1). The metabolic syndrome, a cluster of cardiovascular risk factors, increases the risk of cardiovascular disease and chronic renal disease in the general population and in patients with type 2 diabetes (2–4). The metabolic syndrome is common in patients with type 1 diabetes (5–7), but its role as a predictor of cardiovascular disease and diabetic nephropathy is less clear (8,9). Therefore, the aim of this study was to assess the predictive value of the different definitions of the metabolic syndrome for cardiovascular events, cardiovascular- and diabetes-related mortality, and the progression of renal disease in type 1 diabetes.     

Vitamin D levels, microvascular complications, and mortality in type 1 diabetes

OBJECTIVE

To evaluate vitamin D as a predictor of all-cause mortality, progression from normoalbuminuria to micro- or macroalbuminuria, and the development of background or proliferative retinopathy in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS

A prospective observational follow-up study in which an inception cohort of type 1 diabetic patients was followed from onset of diabetes diagnosed between 1979 and 1984. Plasma vitamin D [25(OH)D3] levels were determined by high performance liquid chromatography/tandem mass spectrometry in 227 patients before the patients developed microalbuminuria. Values equal to or below the 10% percentile (15.5 nmol/L) were considered severe vitamin D deficiency.

RESULTS

Median (range) vitamin D was 44.6 (1.7–161.7) nmol/L. Vitamin D level was not associated with age, sex, urinary albumin excretion rate (UAER), or blood pressure. During follow-up, 44 (18%) patients died. In a Cox proportional hazards model, the hazard ratio for mortality in subjects with severe vitamin D deficiency was 2.7 (1.1–6.7), P = 0.03, after adjustment for UAER, HbA_1c, and conventional cardiovascular risk factors (age, sex, blood pressure, cholesterol, smoking). Of the 220 patients, 81 (37%) developed microalbuminuria and 27 (12%) of these progressed to macroalbuminuria. Furthermore, 192 (87%) patients developed background retinopathy, whereas 34 (15%) progressed to proliferative retinopathy. Severe vitamin D deficiency at baseline did not predict the development of these microvascular complications.

CONCLUSIONS

In patients with type 1 diabetes, severe vitamin D deficiency independently predicts all-cause mortality but not development of microvascular complications in the eye and kidney. Whether vitamin D substitution in type 1 diabetic patients can improve the prognosis remains to be investigated.Hypovitaminosis D is found to be highly prevalent worldwide (1). Recently, low levels of vitamin D have been associated with an increased risk of excess all-cause and cardiovascular mortality in the general population (2) as well as in type 2 diabetic patients (3). However, to our knowledge the association has never been investigated in type 1 diabetic subjects. The levels of plasma vitamin D (25-hydroxyvitamin D3 [25(OH)D3]) varies considerably among individuals mainly because of differences in sun exposure, skin color, and the presence of risk factors such as diabetes or other comorbidities.In patients with diabetes, an excess mortality in patients with diabetes complications has been established (4). Development and progression of diabetic microangiopathy in terms of retinopathy and nephropathy is known to be closely related to poor metabolic control, elevated arterial blood pressure, and other risk factors (5,6). Data from studies in experimental diabetic nephropathy indicate that vitamin D insufficiency may also be involved in the pathogenesis of albuminuria. In the general population, an inverse association is found between the level of vitamin D and the prevalence of albuminuria (7), and limited data from clinical trials in nondiabetic chronic kidney disease (CKD) patients suggest that treatment with paricalcitol (vitamin D receptor analog [VDRA]) may reduce proteinuria (8–10). Furthermore, recently published data suggest that administration of a VDRA on top of blockade of the rennin angiotensin aldosterone system (RAAS) in patients with type 2 diabetes and diabetic nephropathy lowers albuminuria (11). Diabetes is the leading cause of CKD and kidney failure in the Western world, but it is unclear if vitamin D insufficiency contributes to the risk of developing diabetic nephropathy or other microvascular complications. With this study we aimed to investigate whether very low levels of plasma 25(OH)D3 could predict increased risk of excess mortality as well as development of microvascular complications in type 1 diabetic patients.     

Pulse pressure predicts incident cardiovascular disease but not diabetic nephropathy in patients with type 1 diabetes (The FinnDiane Study)

OBJECTIVE

Pulse pressure (PP), an estimate of arterial stiffness, has been shown to be associated with incident cardiovascular disease (CVD) in patients with type 1 diabetes (T1D). However, diabetic kidney disease, a strong predictor of CVD, was not previously taken into account. Furthermore, the role of PP as a predictor of diabetic nephropathy is not known. Therefore, we prospectively investigated the associations between PP and these diabetes complications in patients with T1D.

RESEARCH DESIGN AND METHODS

A total of 4,509 patients from the FinnDiane Study participated. Follow-up data on incident CVD events and renal status (median 5.3 years) were available in 69 and 76% of the patients, respectively. Altogether, 269 patients (8.6%) had an incident CVD event and 370 patients (10.8%) progressed to a higher level of albuminuria or to end-stage renal disease.

RESULTS

PP was higher at baseline in patients who experienced a CVD event (66 ± 18 vs. 52 ± 14 mmHg; P < 0.001) or progressed in their renal status (58 ± 18 vs. 54 ± 15 mmHg; P < 0.01) during follow-up. In a Cox regression model, PP was independently associated with a first ever CVD event (hazard ratio per 10 mmHg 1.22 [95% CI 1.10–1.34]) but not progression of renal disease (1.00 [0.89–1.12]) after adjustments for traditional risk factors.

CONCLUSIONS

PP, a marker of arterial stiffness, is a risk factor for cardiovascular complications but not for diabetic nephropathy in patients with T1D.Whereas systolic blood pressure (SBP) increases with age in the western population, diastolic blood pressure (DBP) generally increases during adulthood, peaks at 55–60 years of age, and thereafter starts to decrease as the result of arterial stiffening (1). This results in an increased pulse pressure (PP) that is associated with cardiovascular disease (CVD) (2). We have shown a premature increase in PP in patients with type 1 diabetes (T1D) compared with nondiabetic subjects (3). The results indicated an accelerated arterial aging in patients with T1D that may contribute to a higher risk of CVD.PP has been shown to be a strong predictor of CVD in the general population, especially in elderly subjects aged >65 years (4,5). The EURODIAB Prospective Complications Study extended this finding to patients with T1D because PP was shown to be associated with incident CVD (6). However, diabetic nephropathy, a strong CVD risk factor (7), was not taken into account. Furthermore, Soedamah-Muthu et al. (8) reported that PP predicted all-cause but not cardiovascular mortality in the same cohort.Although PP was shown to be associated with diabetic nephropathy in a cross-sectional study (3), it is not known whether PP could be used as a predictor of progression of diabetic nephropathy. However, blood pressure per se has been shown to predict incipient and overt diabetic nephropathy, although the results have been conflicting (9–11).Therefore, the aim was to explore the role of PP in the development of CVD and progression of diabetic nephropathy in a large, homogeneous and nationwide cohort of patients with T1D.