Clinical utility of creatinine- and cystatin C-based definition of renal function for risk prediction of primary cardiovascular events in patients with diabetes

OBJECTIVE

To assess the cardiovascular risk of diabetic subjects with chronic kidney disease (CKD) based on different estimated glomerular filtration rate (eGFR) equations and to evaluate which definition of CKD best improves cardiovascular risk prediction of the Framingham Cardiovascular Risk Score (Framingham-CV-RS).

RESEARCH DESIGN AND METHODS

CKD was defined as eGFR <60 mL/min/1.73 m², estimated by the creatinine-based Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations and a cystatin C–based equation (CKD-CysC). Cox regression was used to estimate hazard ratios (HRs) of subjects with CKD for incident cardiovascular events in a cohort of 1,153 individuals with diabetes (baseline age 50–74 years). Furthermore, the CKD definitions were added individually to a reference model comprising the Framingham-CV-RS variables and HbA_1c, and measures of model discrimination and reclassification were assessed.

RESULTS

During 5 years of follow-up, 95 individuals had a primary cardiovascular event. Crude HRs were increased for all CKD definitions. However, after adjusting for established cardiovascular risk factors, HRs for both creatinine-based CKD definitions were attenuated to point estimates of 1.03, whereas the HRs for the cystatin C–based CKD definition remained significantly increased (HR 1.75 [95% CI 1.07–2.87]). Extension of the reference model by the different CKD definitions resulted in an increase in the c statistic only when adding CKD-CysC (from 0.638 to 0.644) along with a net reclassification improvement of 8.9%.

CONCLUSIONS

Only the cystatin C–based CKD definition was an independent risk predictor for cardiovascular events in our diabetic study cohort and indicated a potentially better clinical utility for cardiovascular risk prediction than creatinine-based equations.Chronic kidney disease (CKD) is a frequent disease in the elderly, especially among older adults with diabetes (1,2). However, epidemiologic data about the prevalence of CKD in patients with diabetes remain sparse and the accuracy of the different estimating equations to assess renal function in clinical routine is still debated (1,3,4).CKD can be classified with an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m² (CKD stages 3–5) (5). The most commonly used equation to estimate glomerular filtration rate (GFR) is the serum creatinine–based abbreviated Modification of Diet in Renal Disease (MDRD) equation (6), although it is well known that it underestimates GFR in the normal and high-normal range (7). Recently, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation has been introduced as a better means of estimate eGFR in observational research (8). However, data from patients with diabetes comparing the CKD-EPI and MDRD equations are still limited (8). Performance of creatinine-based eGFR in patients with diabetes and nephropathy lacks accuracy to monitor kidney function (9), especially in the early phases of renal impairment, and it can take years until other signs of a glomerulopathy such as albuminuria appear (10). Therefore, cystatin C–based estimating equations are suggested to show better clinical utility compared with creatinine-based equations (11,12).Which formula is best to be used to classify CKD in subjects with diabetes is an important question, especially because effective interventions exist to reduce the risk for cardiovascular disease and progression to end-stage renal disease (13). However, no study thus far has compared the MDRD and CKD-EPI formulas with a cystatin C–based equation in patients with diabetes (14). An eligible end point to shed further light on this question is an estimated predictive value of each equation for cardiovascular disease because CKD is clearly associated with cardiovascular end points, independent of established cardiovascular risk factors (15,16).Therefore, the objective of this analysis is to estimate the prognostic utility of serum creatinine– and cystatin C–based CKD definitions for incident cardiovascular events in subjects with diabetes.     

Cardiovascular Risk Factors Are Associated With Increased Arterial Stiffness in Youth With Type 1 Diabetes: The SEARCH CVD study

OBJECTIVE

To evaluate if presence of cardiovascular (CV) risk factors and their clustering as metabolic syndrome (MetS) is associated with increased arterial stiffness and accelerated progression over time among youth with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Longitudinal study of 298 youth with type 1 diabetes (age 14.5 years; 46.3% female; duration 4.8 years), with two research visits conducted 5 years apart. CV factors included: waist circumference, blood pressure (BP), fasting lipids (HDL cholesterol, LDL cholesterol [LDL-c], triglycerides), albumin/creatinine ratio, and HbA_1c. MetS was based on Adult Treatment Panel III criteria modified for youth. Pulse wave velocity (PWV) in the carotid–femoral segment was measured by tonometry. Mixed models were used to assess the rate of progression in PWV and the association between CV factors and PWV over time.

RESULTS

PWV increased significantly over time (0.145 m/s/year; P < 0.0001). MetS (P = 0.0035), large waist (P < 0.0001), and elevated BP (P = 0.0003) at baseline were each associated with worse PWV over time. These baseline factors, however, did not significantly influence the rate of progression. Increases in waist circumference (P < 0.0001), LDL-c levels (P = 0.0156), and declining glucose control (HbA_1c; P = 0.0419) were independently associated with higher PWV over time.

CONCLUSIONS

Presence, clustering, and worsening of CV risk factors are associated with increased arterial stiffness over time in youth with type 1 diabetes. Whether improvement in CV risk factors early in life will slow the progression of arterial stiffness and reduce the burden of CV disease in this population requires further study.Adults with childhood-onset type 1 diabetes are at increased risk of premature cardiovascular disease (CVD) morbidity and mortality (1,2). Increased arterial stiffness independently predicts all-cause and CVD mortality (3), and higher pulse pressure predicts CVD mortality, incidence, and end-stage renal disease development among adults with type 1 diabetes (1,4,5). Several reports have shown that youth and adults with type 1 diabetes have elevated arterial stiffness, though the mechanisms are largely unknown (6). The etiology of advanced atherosclerosis in type 1 diabetes is likely multifactorial, involving metabolic, behavioral, and diabetes-specific cardiovascular (CV) risk factors. Aging, high blood pressure (BP), obesity, the metabolic syndrome (MetS), and type 2 diabetes are the main contributors of sustained increased arterial stiffness in adults (7,8). However, the natural history, the age-related progression, and the possible determinants of increased arterial stiffness in youth with type 1 diabetes have not been studied systematically.Childhood obesity has been shown to be related to CV risk factors in young adulthood, and adult obesity is also a risk factor for CVD (9). Central adiposity is considered an even more accurate indicator of CVD risk in adults, and it was shown to predict coronary artery disease risk even among young people (10). Unfortunately, children with type 1 diabetes, who previously were not overweight, are no longer immune to obesity. Data from the SEARCH for Diabetes in Youth Study showed that 31.5% of non-Hispanic white (NHW), 46.6% of African Americans, and 45% of Hispanic youth with type 1 diabetes had a BMI ≥85th percentile (11). A sizeable proportion of such youth have also been shown to have elevated BP (12), dyslipidemia (13), and elevated albumin/creatinine ratio (ACR) (14). Moreover, a clustering of CV risk factors (i.e., at least two, in addition to hyperglycemia) were present in 14% of SEARCH youth with type 1 diabetes (12), clearly an excess compared with the general population.There are currently no data examining the impact of CV risk factors and their clustering in youth with type 1 diabetes on subsequent CVD morbidity and mortality, though childhood and young adult MetS have been shown to predict arterial stiffness in adults (15,16). Thus, the aims of this report were: 1) to describe the progression of arterial stiffness, as measured by pulse wave velocity (PWV), over time, among youth with type 1 diabetes, and 2) to explore the association of CV risk factors and their clustering as MetS with PWV in this cohort.     

Short-Term Aerobic Exercise Reduces Arterial Stiffness in Older Adults With Type 2 Diabetes, Hypertension, and Hypercholesterolemia

OBJECTIVE

The relationship between increased arterial stiffness and cardiovascular mortality is well established in type 2 diabetes. We examined whether aerobic exercise could reduce arterial stiffness in older adults with type 2 diabetes complicated by comorbid hypertension and hyperlipidemia.

RESEARCH DESIGN AND METHODS

A total of 36 older adults (mean age 71.4 ± 0.7 years) with diet-controlled or oral hypoglycemic–controlled type 2 diabetes, hypertension, and hypercholesterolemia were recruited. Subjects were randomly assigned to one of two groups: an aerobic group (3 months vigorous aerobic exercise) and a nonaerobic group (no aerobic exercise). Exercise sessions were supervised by a certified exercise trainer three times per week, and a combination of cycle ergometers and treadmills was used. Arterial stiffness was measured using the Complior device.

RESULTS

When the two groups were compared, aerobic training resulted in a decrease in measures of both radial (−20.7 ± 6.3 vs. +8.5 ± 6.6%, P = 0.005) and femoral (−13.9 ± 6.7 vs. +4.4 ± 3.3%, P = 0.015) pulse-wave velocity despite the fact that aerobic fitness as assessed by Vo_2max did not demonstrate an improvement with training (P = 0.026).

CONCLUSIONS

Our findings indicate that a relatively short aerobic exercise intervention in older adults can reduce multifactorial arterial stiffness (type 2 diabetes, aging, hypertension, and hypercholesterolemia).The normal aging process is associated with an increase in vascular stiffness (1), a process that is accelerated by the presence of type 2 diabetes (2), hypercholesterolemia (3), and hypertension (4). The relationship between increased arterial stiffness and cardiovascular mortality is well established (5). Exercise has successfully reduced vascular stiffness in young populations (6), suggesting that it could be used in older adults with type 2 diabetes complicated by other cardiovascular risk factors.Previous cross-sectional studies have shown that older adults who engage in regular aerobic exercise training have lower arterial stiffness than sedentary older adults (7). Prospective examinations of a moderate aerobic exercise program in middle-aged subjects with type 2 diabetes (6) and normal older adults (7) have demonstrated a decrease in arterial stiffness. In fact, even brief aerobic interventions in healthy middle-aged men have demonstrated a direct impact on arterial compliance without any effect on cholesterol, blood pressure, body weight, or resting heart rate (7). It has been hypothesized that mechanical distension during aerobic exercise sessions results in pulsatile “stretching” of the collagen fibers that reverses the glycation-related collagen cross-linking that is responsible for reduced arterial compliance in diabetes (8). The impact of aerobic exercise on arterial stiffness in older adults with extensive vascular damage due to multiple etiologies (type 2 diabetes, hypercholesterolemia, and hypertension) has not been examined previously.In the current study, we examined whether aerobic exercise can reverse arterial stiffness in adults at very high cardiovascular risk (long-standing diabetes, geriatric age-group, hypercholesterolemia, and hypertension). We hypothesized that despite these multifactorial reasons for reduced arterial compliance, aerobic exercise would be an effective nonpharmacological therapy for increased arterial stiffness.     

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

Renal Hyperfiltration and Arterial Stiffness in Humans With Uncomplicated Type 1 Diabetes

OBJECTIVE

We have reported that renal hyperfiltration is associated with endothelial dysfunction in early type 1 diabetes. However, the relationship between renal hyperfiltration and arterial stiffness is unknown. Accordingly, we measured arterial stiffness in type 1 diabetic subjects with hyperfiltering (n = 20) or normofiltering (n = 18).

RESEARCH DESIGN AND METHODS

Augmentation index (AIx), aortic pulse wave velocity (PWV), renal hemodynamic function (inulin and paraaminohippurate clearances), and urinary and circulating plasma cGMP were measured in normoalbuminuric subjects with type 1 diabetes during clamped euglycemia (glucose 4–6 mmol/l) and hyperglycemia (glucose 9–11 mmol/l).

RESULTS

During clamped euglycemia, hyperfiltering subjects (glomerular filtration rate ≥135 ml/min/1.73 m²) exhibited lower AIx values (−6.1 ± 2.9 vs. 13.9 ± 2.7%, P = 0.001) and higher cGMP levels in urine and plasma compared with normofiltering subjects. These differences were maintained during clamped hyperglycemia. As expected, renal hemodynamic responses to clamped hyperglycemia were exaggerated in normofilterers, but values for AIx remained unchanged.

CONCLUSIONS

Renal hyperfiltration is associated with reduced arterial stiffness in subjects with uncomplicated type 1 diabetes.Early type 1 diabetes is associated with renal hemodynamic function changes characterized by arteriolar vasodilation and hyperfiltration (1). In addition to renal microvascular vasodilation, previous work has suggested the presence of macrovascular arterial dysfunction in diabetic subjects with renal hyperfiltration, which may reflect generalized endothelial dysfunction (2). In addition to effects on endothelial function, diabetes is associated with increased arterial stiffness, which is correlated with progression of diabetic nephropathy and increased systemic vascular risk (3–7). The relationship between arterial stiffness and renal hyperfiltration, which is the earliest preclinical manifestation of diabetic renal microvascular dysfunction, is currently unknown.Accordingly, we studied arterial stiffness in subjects based on renal filtration status to further elucidate the relationship between early renal and systemic abnormalities in diabetes (3,8). We hypothesized that arterial stiffness would be lower in hyperfiltering subjects (glomerular filtration rate [GFR] ≥135 ml/min/1.73 m²) than in individuals with normofiltration (GFR <135 ml/min/1.73 m²). Furthermore, we hypothesized that hyperfiltering subjects would exhibit higher levels of vasodilators.     

Aortic Distensibility in Type 1 Diabetes

OBJECTIVE

To evaluate the relationship between long-term glycemia, traditional cardiovascular disease (CVD) risk factors, and ascending aortic stiffness in type 1 diabetes.

RESEARCH DESIGN AND METHODS

Eight hundred seventy-nine subjects in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study were evaluated. The stiffness/distensibility of the ascending thoracic aorta (AA) was measured with magnetic resonance imaging. Associations of AA distensibility and CVD risk factors, mean HbA_1c, and cardiovascular complications including macroalbuminuria were assessed using multivariate linear regression models.

RESULTS

The mean age of the subjects was 50 ± 7 years (47% women, mean diabetes duration of 28 years). Over 22 years of follow-up, 27% of participants had cardiovascular complications. After adjusting for gender and cohort, AA distensibility was lower with increasing age, mean systolic blood pressure, LDL, and HbA_1c measured over an average of 22 years (−26.3% per 10 years, −11.0% per 10 mmHg SBP, −1.8% per 10 mg/dL of LDL, and −9.3% per unit mean HbA_1c [%], respectively). Patients with macroalbuminuria had 25% lower AA distensibility compared with those without (P < 0.0001). Lower AA distensibility also was associated with greater ratio of left ventricular mass to volume (−3.4% per 0.1 g/mL; P < 0.0001).

CONCLUSIONS

Our findings indicate strong adverse effects of hypertension, chronic hyperglycemia and macroalbuminuria on AA stiffness in type 1 diabetes in the DCCT/EDIC cohort.Increased arterial stiffness is an important marker of increased left ventricular load and an independent predictor of cardiovascular morbidity and mortality both in asymptomatic humans (1) and in disease including renal failure (2), hypertension (3), and diabetes (4). Increased aortic stiffness has been shown to be an independent predictor of 10-year mortality in diabetic patients (5).Aortic stiffness is a marker of vascular age and is notably greater after the fifth decade of life in healthy men and women (6,7). The main mechanism for age-related aortic stiffening is fracture and fragmentation of elastin fibers with repetitive stretch, leading to the transfer of stress to less extensible collagenous fibers in the arterial wall (8). Arterial–ventricular coupling is an important determinant of circulatory function (9). Aortic stiffness corresponds to a chronic increased afterload leading to concentric left ventricular remodeling and hypertrophy and potentially heart failure (10). Age-related aortic changes are accelerated by cardiovascular disease (CVD) and potentially modifiable cardiovascular risk factors including hypertension (11) and glucose status (12). Age and diabetes have been shown to lead to aortic stiffness through arterial wall glycation processes (13) that potentiate accelerated aortic alterations in younger individuals (12).The adverse impact of type 1 diabetes on the stiffness/distensibility of large arteries may depend on a number of factors, such as concurrent CVD risk factors, the presence of macrovascular or microvascular complications, and duration of diabetes (5). Whether the degree of chronic glycemic control also affects distensibility is not known. A better understanding of factors that contribute to the development of a less distensible aorta in type 1 diabetes may provide a useful start point to formulate strategies designed to improve arterial health. In this study, we used magnetic resonance imaging (MRI) to characterize aortic distensibility (14) in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) cohort of patients with type 1 diabetes (15). The DCCT/EDIC cohort is uniquely suited to evaluate risk factors that contribute to decreased aortic distensibility in type 1 diabetes because of its large sample size and long period of close patient follow-up.     

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

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

Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials

OBJECTIVE

Thiazolidinediones and insulin are associated with a higher risk of fractures in type 2 diabetic patients. Incretin hormones increase bone density in experimental models, but the effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on bone fractures has not been reported so far.

RESEARCH DESIGN AND METHODS

A meta-analysis was performed including all randomized clinical trials with a duration of at least 24 weeks, enrolling patients with type 2 diabetes, comparing DPP-4 inhibitors with placebo or active drugs.

RESULTS

Twenty-eight trials enrolling 11,880 and 9,175 patients for DPP-4 inhibitors and comparators, respectively, were included, reporting 63 fractures. DPP-4 inhibitors, compared with placebo or other treatments, were associated with a reduced risk of fractures (Mantel–Haenszel odds ratio [MH-OR] 0.60, 95% CI 0.37–0.99, P = 0.045), even after the exclusion of comparisons with thiazolidinediones or sulfonylureas (MH-OR 0.56, 0.33–0.93, P = 0.026).

CONCLUSIONS

The present meta-analysis suggests that treatment with DPP-4 inhibitors could be associated with a reduced risk of bone fractures.Type 2 diabetes is associated with an increased risk for bone fractures (1–3). The higher risk could be determined by several factors, including falls, diabetes complications, and comorbidities (2). Moreover, glucose-lowering agents such as thiazolidinediones have been reported to reduce bone density (4,5) and to increase the incidence of fractures in longer-term trials (6,7) and in epidemiologic studies (8). Insulin therapy is also associated with an increased fracture risk (9–11) despite its neutral effect on bone density (12). The increased risk of falls, due to hypoglycemia, could lead to higher fracture risk (10).Glucagon-like peptide-1 (GLP-1) has been reported to induce osteoblast differentiation (13) and inhibit osteoclastic activity (14); GLP-1 receptor agonists stimulate bone formation in rodents (15). Experimental data in animal models suggest that gastric intestinal polypeptide is also capable of increasing bone density (16,17). Drugs capable of increasing incretin levels, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, could therefore exert beneficial effects on the bone.     

Arterial Stiffness Is Associated With Cardiovascular,Renal, Retinal,and Autonomic Disease in Type 1 Diabetes

OBJECTIVE

In patients with type 1 diabetes, we investigated the association between arterial stiffness and diabetes complications.

RESEARCH DESIGN AND METHODS

This was a cross-sectional study including 676 Caucasian patients with type 1 diabetes (374 [55%] men, aged 54 ± 13 years [mean ± SD]) and 51 nondiabetic controls (28 [55%] men, aged 47 ± 13 years). Aortic pulse wave velocity (PWV) was measured with SphygmoCor (AtCor Medical, Sydney, Australia) for 635 patients and all 51 controls.

RESULTS

PWVs (mean ± SD) in patients and controls were 10.4 ± 3.4 and 7.6 ± 1.9 m/s, respectively (P < 0.001). After multivariate adjustment, PWV correlated with age, diabetes duration, urinary albumin excretion rate, heart rate, and blood pressure (P < 0.05 for all). ANCOVA was used for comparisons between groups and adjusted for gender, age, estimated glomerular filtration rate, heart rate, HbA_1c, and 24-h mean arterial pressure. PWVs in normoalbuminuric, microalbuminuric, and macroalbuminuric patients were 9.5 ± 3.2, 11.0 ± 3.6, and 11.4 ± 3.0 m/s, respectively (adjusted P < 0.001). PWV in patients with previous cardiovascular disease, versus patients without, was 12.1 ± 3.5 vs. 10.0 ± 3.2 m/s, respectively (adjusted P < 0.001). PWVs in patients with high (≥140/90 mmHg) versus intermediate (130–40/80–89 mmHg) and low (<130/80 mmHg) blood pressure were 11.8 ± 3.6, 10.0 ± 3.0, and 9.8 ± 3.3 m/s, respectively (adjusted P < 0.001). Furthermore, PWV increased with increasing degree of retinopathy: 8.0 ± 2.5 m/s (nil), 10.0 ± 2.8 m/s (simplex), 12.1 ± 3.5 m/s (proliferative), and 12.7 ± 2.4 m/s (blind), respectively (adjusted P < 0.001). Finally, PWV increased with abnormal heart rate variability: 11.5 ± 3.3 m/s vs. 10.1 ± 3.1 m/s (borderline) and 8.1 ± 2.1 m/s (normal) (adjusted P = 0.027).

CONCLUSIONS

Arterial stiffness increased with presence and duration of type 1 diabetes. Furthermore, PWV increased with all the investigated diabetes complications (cardiovascular, renal, retinal, and autonomic disease) independently of other risk factors.Arterial stiffness predicts cardiovascular disease (CVD) events in the general population (1), in hypertension (2,3), and in diabetes (4,5). A recent meta-analysis by Vlachopoulos et al. (6) showed pulse wave velocity (PWV) to predict both CVD and all-cause mortality. The gold standard for measurement of arterial stiffness is aortic PWV measurements (7,8), which have shown to be reproducible in the general population (9) and in patients with chronic kidney disease (10).In hypertension, PWV is a marker of subclinical organ damage. Recent studies have shown PWV to be predictive of future changes in systolic blood pressure (SBP) development of hypertension (11) to potentially improve CVD risk scoring (12,13), and also to be higher among patients less responsive to antihypertensive medication (AHT) (14).Furthermore, in patients with end-stage renal disease, elevated PWV is an independent predictor of all-cause mortality (15), and lowering PWV by AHT reduces the mortality independently of the blood pressure (BP) reduction (16).In type 1 diabetes, PWV has been shown to be associated with cerebral microvascular disease, cardiac (17) and renal function (18), and in type 2 diabetes with microalbuminuria (19). These associations are suggestive of PWV being related to vascular dysfunction (20) and large artery alterations, thereby possibly engaging in the development of kidney impairment (21). Arterial stiffness also is associated with autonomic neuropathy in type 1 diabetes (22,23) and retinopathy in type 2 diabetes (24), further illustrating the association between arterial stiffness and microvascular disease.The current study is the first in a relatively large and diverse group of patients with type 1 diabetes to investigate the association between PWV and a range of diabetes complications, including albuminuria, CVD, elevated BP, retinopathy, and autonomic neuropathy.     

Arterial stiffness is increased in patients with type 1 diabetes without cardiovascular disease: a potential role of low-grade inflammation

OBJECTIVE

To investigate the relationship between arterial stiffness and low-grade inflammation in subjects with type 1 diabetes without clinical cardiovascular disease.

RESEARCH DESIGN AND METHODS

Sixty-eight patients with type 1 diabetes and 68 age- and sex-matched healthy subjects were evaluated. Arterial stiffness was assessed by aortic pulse wave velocity (aPWV). Serum concentrations of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, and soluble fractions of tumor necrosis factor-α receptors 1 and 2 (sTNFαR1 and sTNFαR2, respectively) were measured. All statistical analyses were stratified by sex.

RESULTS

Subjects with diabetes had a higher aPWV compared with healthy control subjects (men: 6.9 vs. 6.3 m/s, P < 0.001; women: 6.4 vs. 6.0 m/s, P = 0.023). These differences remained significant after adjusting for cardiovascular risk factors. Men with diabetes had higher concentrations of hsCRP (1.2 vs. 0.6 mg/L; P = 0.036), IL-6 (0.6 vs. 0.3 pg/mL; P = 0.002), sTNFαR1 (2,739 vs. 1,410 pg/mL; P < 0.001), and sTNFαR2 (2,774 vs. 2,060 pg/mL; P < 0.001). Women with diabetes only had higher concentrations of IL-6 (0.6 vs. 0.4 pg/mL; P = 0.039). In men with diabetes, aPWV correlated positively with hsCRP (r = 0.389; P = 0.031) and IL-6 (r = 0.447; P = 0.008), whereas in women with diabetes no significant correlation was found. In men, multiple linear regression analysis showed that the following variables were associated independently with aPWV: age, BMI, type 1 diabetes, and low-grade inflammation (R² = 0.543). In women, these variables were age, BMI, mean arterial pressure, and type 1 diabetes (R² = 0.550).

CONCLUSIONS

Arterial stiffness assessed as aPWV is increased in patients with type 1 diabetes without clinical cardiovascular disease, independently of classical cardiovascular risk factors. In men with type 1 diabetes, low-grade inflammation is independently associated with arterial stiffness.It is well established that type 2 diabetes is a risk factor for cardiovascular disease. However, it is less well known that the relative risk of cardiovascular disease in type 1 diabetes can be as much as 10-fold greater than in the healthy population, especially in women (1), being even greater than in type 2 diabetes (2). Consequently, cardiovascular disease is the major cause of mortality in type 1 diabetes (2). Diabetes results in an accelerated arteriosclerotic process, which is not fully explained by classical cardiovascular risk factors. As a result, the pathophysiological mechanisms underlying cardiovascular events in type 1 diabetes are not completely understood.Arterial stiffness is an early sign of arteriosclerosis (3), and its study would be appropriate for investigating the arteriosclerotic mechanisms long before any cardiovascular event occurs. Arterial stiffness predicts cardiovascular events independently of classical cardiovascular risk factors in several populations (see below). Therefore, it can be assumed that it reflects the deleterious effect of all cardiovascular risk factors (known and unknown) on the arterial wall. The gold standard for measuring central arterial stiffness is aortic pulse wave velocity (aPWV), according to a recent consensus (4). aPWV independently predicts cardiovascular events and mortality in the general population, in the elderly, in hypertensive individuals, in subjects with end-stage renal failure, and in subjects with type 2 diabetes (5).Finally, little is known regarding factors involved in the pathophysiology of arterial stiffness in type 1 diabetes. One of these factors could be low-grade inflammation. High-sensitivity C-reactive protein (hsCRP) is the most established downstream marker of low-grade inflammation and has been reported to be a strong predictor of cardiovascular outcomes (6). The primary proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α are the main inducers for the hepatic synthesis of hsCRP (7). Although there is less evidence in comparison with hsCRP, both of them also have been associated with the prediction of cardiovascular outcomes (8–10). Low-grade inflammation also has been associated with the development of both micro- and macrovascular complications in type 1 diabetes (11). Indeed, low-grade inflammation impairs endothelial function and has been associated with an increase in aPWV in healthy subjects (12), in hypertensive individuals (13), and in subjects with chronic kidney disease (14) or with metabolic syndrome (15). No such evidence exists in type 1 diabetes; however, recently an activation of the TNFα system has been reported in association with an increase in brachial PP, a subrogate marker of arterial stiffness, in normotensive subjects with type 1 diabetes (16).Our main objective was to evaluate aPWV as a measure of arterial stiffness in a group of subjects with type 1 diabetes without clinical cardiovascular disease and to explore its relationship with biomarkers of low-grade inflammation. Because the role of low-grade inflammation in the atherosclerotic process seems to be different in men and women (17), our study was stratified by sex, and the sample size was calculated taking this stratification into account.     

Dietary Patterns and Risk for Diabetes: The Multiethnic Cohort

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

Variants of GCKR affect both β-cell and kidney function in patients with newly diagnosed type 2 diabetes: the Verona newly diagnosed type 2 diabetes study 2

OBJECTIVE

In genome-wide association studies, performed mostly in nondiabetic individuals, genetic variability of glucokinase regulatory protein (GCKR) affects type 2 diabetes-related phenotypes, kidney function, and risk of chronic kidney disease (CKD). We tested whether GCKR variability affects type 2 diabetes or kidney-related phenotypes in newly diagnosed type 2 diabetes.

RESEARCH DESIGN AND METHODS

In 509 GAD-negative patients with newly diagnosed type 2 diabetes, we 1) genotyped six single nucleotide polymorphisms in GCKR genomic region: rs6717980, rs1049817, rs6547626, rs780094, rs2384628, and rs8731; 2) assessed clinical phenotypes, insulin sensitivity by the euglycemic insulin clamp, and β-cell function by state-of-the-art modeling of glucose/C-peptide curves during an oral glucose tolerance test; and 3) estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease formula.

RESULTS

The major alleles of rs6717980 and rs2384628 were associated with reduced β-cell function (P < 0.05), with mutual additive effects of each variant (P < 0.01). The minor alleles of rs1049817 and rs6547626 and the major allele of rs780094 were associated with reduced eGFR according to a recessive model (P < 0.03), but with no mutual additive effects of the variants. Additional associations were found between rs780094 and 2-h plasma glucose (P < 0.05) and rs8731 and insulin sensitivity (P < 0.05) and triglycerides (P < 0.05).

CONCLUSIONS

Our findings are compatible with the idea that GCKR variability may play a pathogenetic role in both type 2 diabetes and CKD. Genotyping GCKR in patients with newly diagnosed type 2 diabetes might help in identifying patients at high risk for metabolic derangements or CKD.Glucokinase regulatory protein (GCKR) is expressed in liver and, to a lesser extent, in β-cells and exerts an inhibitory effect on glucokinase (GCK) by decreasing the affinity of the latter for glucose (1). Thus, it is in a key position to regulate liver glucose balance and, perhaps, glucose-stimulated insulin secretion.Allelic variability of two GCKR single nucleotide polymorphisms (SNPs), rs780094 and rs1260326, in strong linkage disequilibrium (LD) with each other, is associated with a number of human traits, including serum triglyceride (2–5), fasting glucose (2,5), C-reactive protein (6), coagulation protein C (7), uric acid (8), insulin levels (4), and susceptibility to type 2 diabetes (2,4,5,9,10). Moreover, the missense variant P446 L of rs1260326 is associated with reduced glomerular filtration rate (estimated glomerular filtration rate [eGFR]) and increased risk of chronic kidney disease (CKD) (11). On the whole, the major rs1260326 allele is associated with higher fasting glucose and insulin, lower eGFR, and increased CKD risk, but lower triglycerides. Thus, this single allele seems to be a multifaceted risk indicator of chronic diseases.Most studies reporting that GCKR variation is associated with diabetes-related intermediate phenotypes were performed in nondiabetic individuals, and surrogate markers, not state-of-art methods, were used to assess β-cell function or insulin sensitivity (2,4,5,9,10). Because both traits display a significant spread in patients with type 2 diabetes, the question arises whether GCKR variants may affect β-cell function in diabetic patients, thereby potentially being a determinant of type 2 diabetes heterogeneity, a marker of the metabolic phenotype, or a tool to select optimal therapy and to better define prognosis. Moreover, because GCKR is involved in the susceptibility to CKD, it might help to select subgroups of patients with higher risk of renal complications.We therefore undertook the present investigation to test whether the genetic variability of GCKR affects renal or β-cell function in patients with newly diagnosed type 2 diabetes. We used the database of the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS), an ongoing investigation of patients with newly diagnosed type 2 diabetes. This cohort was deemed useful for our purposes because of the absence of the potentially confounding effects of long-lasting antidiabetic treatments and of the limited impact of duration and severity of hyperglycemia per se on the metabolic phenotypes.     

Evolution of renal hyperfiltration and arterial stiffness from adolescence into early adulthood in type 1 diabetes

OBJECTIVE

To determine, in a small but carefully physiologically characterized cohort of subjects with uncomplicated type 1 diabetes, the changes in renal hemodynamic function and arterial stiffness that occur over time as the participants transitioned from adolescence into early adulthood. The classical paradigm for type 1 diabetes suggests that glomerular filtration rate (GFR) declines in patients with renal hyperfiltration, but the natural history of peripheral vascular function abnormalities in uncomplicated type 1 diabetes is less well understood, particularly as patients transition from adolescence to early adulthood.

RESEARCH DESIGN AND METHODS

Renal hemodynamic function (inulin and p-aminohippuric acid clearance), blood pressure, arterial stiffness (radial augmentation index), albumin excretion, and circulating renin-angiotensin system measures were obtained during clamped euglycemia at baseline and at follow-up 6.8 ± 2.5 years later in 10 patients with hyperfiltration (GFR ≥135 mL/min/1.73 m²) and in 8 with normofiltration.

RESULTS

Compared with baseline values, GFR (171 ± 20 to 120 ± 15 mL/min/1.73 m²) and filtration fraction (FF, 0.24 ± 0.06 to 0.18 ± 0.03) declined in hyperfilterers (ANOVA P ≤ 0.033), and renal vascular resistance increased (0.0678 ± 0.0135 to 0.0783 ± 0.0121 mmHg/L/min, P = 0.017). GFR and FF did not change in normofiltering subjects. In contrast, the radial augmentation index decreased in hyperfiltering (1.2 ± 11.7 to −11.0 ± 7.8%) and normofiltering (14.3 ± 14.0 to 2.5 ± 14.6%) subjects (within-group changes, ANOVA P ≤ 0.030). The decline in circulating aldosterone levels was similar in both groups.

CONCLUSIONS

During the transition from adolescence to early adulthood, hyperfiltration is not sustained in subjects with type 1 diabetes, whereas GFR remains stable in normofiltering subjects. Our findings suggest early normofiltration may predict stable renal function. In contrast, arterial stiffness decreased in all patients regardless of filtration status, suggesting that age-related increases in arterial stiffness occur at older ages.Hyperfiltration is associated with the development of diabetic nephropathy, possibly because of high intraglomerular pressure that results in glomerular injury (1). A variety of hormonal factors influence hyperfiltration, including the renin-angiotensin system (RAS), cyclooxygenase 2, protein kinase C-β, and changes in hormones related to puberty (2–5). Blockade of these hormonal pathways partially reduces the glomerular filtration rate (GFR) in hyperfiltering subjects but has no effect in normofilterers, suggesting that individuals with hyperfiltration are physiologically distinct (2–4). More recently, hyperfiltration has been associated with peripheral vascular alterations, including low arterial stiffness and endothelial dysfunction (6,7). It has therefore been suggested that the hyperfiltration state reflects generalized microvascular and macrovascular functional changes (6–8).Although it is generally accepted that hyperfiltration represents a renal risk factor in diabetes, the natural history for changes in renal function in normofiltering subjects remains poorly defined. For example, normofilterers may represent a group of former hyperfiltering individuals who have had a decline in kidney function and were simply studied at a time when GFR was within the normal range. Alternatively, normofiltration may represent a subgroup that is protected against renal and vascular injury.Peripheral vascular function testing has suggested that normofiltration is associated with preserved endothelial function, which is important for two reasons (6). First, this observation suggests that normofiltration represents a “protective” vascular phenotype. Second, measures of peripheral vascular function, such as arterial stiffness, may offer additional, noninvasive insight into renal and vascular risk, before the onset of clinical end points such as declining renal function, hypertension, or microalbuminuria (9).Although renal hyperfiltration and changes in macrovascular function, such as low arterial stiffness, appear to be linked in cross-sectional studies of early type 1 diabetes, the interaction between these preclinical abnormalities over time, in the same individuals, is not known (7). This association is important, because hyperfiltration is associated with declining renal function (1). For example, if declining GFR in hyperfiltering subjects is also associated with a deleterious rise in arterial stiffness, this could yield important pathophysiologic insights into mechanisms of disease progression and clinical prognostic information (1,7). A more complete understanding of preclinical factors that may increase future renal risk is of particular importance during the transition from adolescence to early adulthood, which may represent a crucial period when renal injury is initiated (10).We initially measured GFR and arterial stiffness in a well-characterized adolescent cohort with uncomplicated type 1 diabetes (3,4). The same measures were repeated 6.8 ± 2.5 years later in a subgroup during the transition from adolescence to early adulthood. The goals of the present analysis were to 1) describe the relationship between changes in GFR and arterial compliance and 2) elucidate the natural history of arterial stiffness in patients with early type 1 diabetes renal hyperfiltration or normofiltration. Our hypotheses were that 1) renal hyperfiltration would decrease, in association with renal vasoconstriction and a concordant rise in arterial stiffness, as study participants transitioned from adolescence into early adulthood, and 2) normofiltration represents a state of preserved kidney function and stable macrovascular function that does not change significantly in early type 1 diabetes.     

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.     

Risk of Metabolic Syndrome and Diabetes Among Young Twins and Singletons in Guinea-Bissau

OBJECTIVE

Twins in Africa may be at increased risk of metabolic disorders due to strained conditions in utero, including high exposure to infections. We studied metabolic syndrome (MS) and diabetes mellitus (DM) among young twins and singletons in Guinea-Bissau.

RESEARCH DESIGN AND METHODS

The study was cross-sectional and occurred from October 2009 until August 2011 at the Bandim Health Project, a demographic surveillance site in the capital Bissau. Twins and singleton controls between 5 and 32 years were visited at home. Fasting blood samples for metabolic measurements were collected. Zygosity was established genetically for a subset. DM was defined as HbA_1c ≥6.5% (48 mmol/mol) and MS by the International Diabetes Federation criteria.

RESULTS

HbA_1c was available for 574 twins and 463 singletons. Mean age was 15.3 years versus 15.8 years, respectively. Eighteen percent of twins were monozygotic. There were no DM cases among twins but one among singletons. A total of 1.4% (8 of 574) of twins had elevated HbA_1c (6.0–6.4%, 42–46 mmol/mol) compared with 2.4% (11 of 463) of singletons (P = 0.28). Mean HbA_1c was 5.3% (34 mmol/mol) for both groups. MS data were available for 364 twins and 360 singletons. The MS prevalence was 3.0% (11 of 364) among twins and 3.6% (13 of 360) among singletons (P = 0.66). The prevalence of fasting blood glucose (F-glucose) ≥5.6 mmol/L was 34.9% (127 of 364) for twins versus 24.7% (89 of 360) for singletons (P = 0.003). Median homeostasis model assessment–insulin resistance did not differ (P = 0.34).

CONCLUSIONS

The MS and DM prevalences among young individuals in Guinea-Bissau were low. Twins did not have a higher MS and DM burden than singletons, though elevated F-glucose was more common among twins.Twins are born with substantially lower birth weight than singletons (1–3). This could reflect a more adverse intrauterine environment for twins (1,3), especially for monozygotic (MZ) twins due to frequently shared placenta.The intrauterine environment is now a well-established risk factor for metabolic disease later in life (4–7) (e.g., diabetes mellitus [DM] or metabolic syndrome [MS]). Twins may be at a higher risk of those conditions because of growth restriction in utero, as expressed by low birth weight (8). Currently, this remains unresolved, with studies pointing in different directions (8–11).In Sub-Saharan Africa, both twinning (2) and DM (12) are common, but no metabolic twin studies are available yet. This is problematic, as the DM pathogenesis may well be different here (12–14). Moreover, African twins have very high early mortality (2,15,16) and face an altogether different pre- and postnatal environment with frequent undernutrition (15) and increased risk of infections. Hence, conclusions drawn from twin studies in high-income countries may not necessarily apply in Sub-Saharan Africa, as adverse exposures vary widely.In this paper, we present results from a large-scale metabolic survey among twins and singletons from Guinea-Bissau. The study was conducted within the framework of a larger twin registry (17). The main objective was to determine the prevalence of MS and DM in a well-described urban population of young twins and singleton controls, as well as individual MS components.     

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.     

Trunk versus extremity adiposity and cardiometabolic risk factors in white and African American adults

OBJECTIVE

To determine contributions of trunk and extremity adiposity to cardiometabolic risk factors (blood pressure, fasting blood glucose, HDL cholesterol, and triglycerides) among white and African American adults.

RESEARCH DESIGN AND METHODS

The sample consisted of 1,129 white women, 779 African American women, 1,012 white men, and 300 African American men.

RESULTS

Higher trunk adiposity was significantly associated with an increased risk of having two or more cardiometabolic risk factors among African American and white men and women. After adjustment for trunk and arm adiposity, higher leg adiposity was significantly associated with a decreased risk of having two or more cardiometabolic risk factors among white men and women and African American women.

CONCLUSIONS

In contrast with adverse risk with high trunk adiposity, high leg adiposity is associated with a decreased risk of having two or more cardiometabolic risk factors in both African American and white adults.Obesity, a significant public health problem throughout the world (1), is strongly associated with cardiometabolic risk (2–5). There is growing recognition that adipose tissue stored in different body depots may have differential impacts on health. Several studies have assessed the associations of leg and trunk adiposity with cardiometabolic risk factors (6–12). Some, but not all, of these studies have found an inverse association of leg adiposity with blood pressure (11,12), glucose (7–12), dyslipidemia (6–8,11), and the metabolic syndrome (12). Moreover, these studies were carried out in white (6–10), Japanese (11), and Chinese (12) populations, and no studies included African Americans. Because African Americans have higher mortality rates from cardiovascular disease, diabetes, and cancer than white Americans (13), it is necessary to understand these differences and their clinical implications. The aim of this study is to determine the contribution of trunk and extremity adiposity to cardiometabolic risk factors among white and African American men and women.