Association of Electrocardiographically Determined Left Ventricular Mass With Incident Diabetes, 1985–1986 to 2010–2011: Coronary Artery Risk Development in Young Adults (CARDIA) study

OBJECTIVE

Electrocardiographic indices reflecting left ventricular hypertrophy are associated with incident diabetes in clinical populations at risk for coronary heart disease. We tested whether electrocardiographically determined left ventricular mass was positively associated with incident diabetes in a population sample.

RESEARCH DESIGN AND METHODS

Coronary Artery Risk Development in Young Adults (CARDIA) study participants (n = 4,739) were followed from 1985–1986 to 2010–2011 for incident diabetes. Validated sex- and race-specific formulas were applied to standard electrocardiograms to determine left ventricular mass.

RESULTS

Over 25 years, 444 participants developed diabetes (9.4%). After adjustment for demographic, behavioral, and clinical covariates, participants in the highest quartile of left ventricular mass index (LVMI) were twice as likely to develop diabetes than participants in the lower three quartiles (hazard ratio 2.61 [95% CI 2.16–3.17]). Neither Cornell voltage nor Cornell voltage product was associated with incident diabetes in fully adjusted models.

CONCLUSIONS

Electrocardiographically determined LVMI may be a useful noninvasive marker for identifying adults at risk for diabetes.A post hoc analysis of the Losartan Intervention for Endpoint Reduction (LIFE) trial reported that improvements in electrocardiographically determined left ventricular hypertrophy over time were associated with lowered diabetes incidence (1,2). It was required that participants in the LIFE trial have hypertension, which could independently predispose to diabetes onset, and so it remains unknown whether electrocardiographically determined left ventricular mass is associated with diabetes incidence in healthy adults. We tested whether left ventricular mass, calculated from a single standard resting electrocardiogram in young adulthood (age 18–30 years), was positively associated with diabetes incidence over 25 years.     

Serum Uric Acid Levels Improve Prediction of Incident Type 2 Diabetes in Individuals With Impaired Fasting Glucose: The Rancho Bernardo Study

OBJECTIVE

To determine whether serum uric acid predicts incident type 2 diabetes by glucose tolerance status in older community-dwelling adults.

RESEARCH DESIGN AND METHODS

Participants without diabetes at baseline were evaluated for incident type 2 diabetes 13 years later. Baseline glucose tolerance status was defined as normoglycemia, impaired fasting glucose, and impaired postchallenge glucose tolerance.

RESULTS

A total of 566 participants were included (mean age 63.3 ± 8.6 years; 41% men). Regression models adjusted for age, sex, BMI, diuretic use, and estimated glomerular filtration rate showed that for each 1 mg/dl increment in uric acid levels, incident type 2 diabetes risk increased by ∼60%. When analyses were stratified by glucose status, uric acid levels independently predicted incident type 2 diabetes among participants who had impaired fasting glucose (odds ratio 1.75, 95% CI 1.1–2.9, P = 0.02).

CONCLUSIONS

Uric acid may be a useful predictor of type 2 diabetes in older adults with impaired fasting glucose.Increased levels of serum uric acid have been associated with insulin resistance (1) and with established type 2 diabetes (2). Previous studies demonstrated that uric acid is an independent predictor of incident type 2 diabetes in general populations (3,4), but whether uric acid predicts incident type 2 diabetes in individuals who have abnormal glucose tolerance is unknown. We examined whether baseline uric acid levels predict incident type 2 diabetes by glucose tolerance status in older adults.     

Plasma 25-Hydroxyvitamin D Concentration and Risk of Incident Type 2 Diabetes in Women

OBJECTIVE

To determine the association between 25-hydroxyvitamin D (25-OHD) concentration and risk of incident type 2 diabetes.

RESEARCH DESIGN AND METHODS

In a nested case-control study conducted among 608 women with newly diagnosed type 2 diabetes and 559 control subjects in the Nurses'' Health Study, we measured the association between baseline plasma 25-OHD concentration and risk of incident diabetes.

RESULTS

After adjusting for matching factors and diabetes risk factors, including BMI, higher levels of plasma 25-OHD were associated with a lower risk for type 2 diabetes. The odds ratio for incident type 2 diabetes in the top (median 25-OHD, 33.4 ng/ml) versus the bottom (median 25-OHD, 14.4 ng/ml) quartile was 0.52 (95% CI 0.33–0.83). The associations were consistent across subgroups of baseline BMI, age, and calcium intake.

CONCLUSIONS

Plasma 25-OHD concentration was associated with lower risk of incident type 2 diabetes in women.Growing evidence indicates that suboptimal vitamin D status may play a role in the development of type 2 diabetes (1). Results from longitudinal observational studies support the hypothesis that low vitamin D status is associated with development of type 2 diabetes; however, only one study has examined the association between blood 25-hydroxyvitamin D (25-OHD) concentration and incident type 2 diabetes, and there was no significant association among women (2,3). We examined prospectively the association between plasma 25-OHD concentration and risk of incident type 2 diabetes among women in a case-control study nested within the Nurses'' Health Study (NHS).     

Angiopoietin-Like Protein 2 and Risk of Type 2 Diabetes in a General Japanese Population: The Hisayama Study

OBJECTIVE

To examine, for the first time, the association between a novel inflammatory cytokine, angiopoietin-like protein (ANGPTL) 2, and the development of type 2 diabetes (T2DM).

RESEARCH DESIGN AND METHODS

A total of 2,164 community-dwelling Japanese individuals aged 40 to 79 years without diabetes were followed up for 7 years. Serum ANGPTL2 levels were divided into quartile categories at baseline: <2.15, 2.16–2.71, 2.72–3.40, and ≥3.41 ng/mL. During follow-up, 221 participants developed T2DM.

RESULTS

In multivariate analyses, after adjusting for comprehensive risk factors and high-sensitivity C-reactive protein (hs-CRP) levels, the risk of developing T2DM was significantly higher in the highest ANGPTL2 quartile than in the lowest quartile (hazard ratio, 1.80; 95% CI, 1.14–2.85; P = 0.01).

CONCLUSIONS

Elevated serum ANGPTL2 levels were positively associated with the development of T2DM in a general population, independent of other risk factors including hs-CRP levels.Angiopoietin-like proteins (ANGPTLs), which are structurally similar to angiopoietins, are characterized by a coiled-coil domain in the N-terminus and a fibrinogen-like domain in the C-terminus. Seven ANGPTLs have been identified to date (1–3); one of them, ANGPTL2, has been shown to be expressed abundantly in adipose tissues and to be a key mediator linking obesity to adipose tissue inflammation and systemic insulin resistance in mice (4,5). In humans, ANGPTL2 is also closely related to adiposity and inflammation (4). However, the association of serum ANGPTL2 levels with the risk of developing type 2 diabetes (T2DM) has not been investigated to date. The objective of this study was to examine this issue in a cohort of the general Japanese population, taking into account a comprehensive range of confounders.     

Inflammation and the Incidence of Type 2 Diabetes: The Multi-Ethnic Study of Atherosclerosis (MESA)

OBJECTIVE

Many studies have documented associations between inflammation and type 2 diabetes incidence. We assessed potential variability in this association in the major U.S. racial/ethnic groups.

RESEARCH DESIGN AND METHODS

Incident type 2 diabetes was assessed among men and women aged 45–84 years without prior clinical cardiovascular disease or diabetes in the prospective Multi-Ethnic Study of Atherosclerosis. Interleukin (IL)-6, fibrinogen, and C-reactive protein (CRP) were measured at baseline (2000–2002); fasting glucose and diabetes medication use was assessed at baseline and three subsequent in-person exams through 2007. Type 2 diabetes was defined as use of diabetes drugs or glucose ≥126 mg/dl. Covariates included baseline demographics, clinic, smoking, alcohol, exercise, hypertension medication, systolic blood pressure, insulin resistance, and BMI. Cox proportional hazards regression was used to calculate hazard ratios (HRs) by quartiles of CRP, IL-6, and fibrinogen.

RESULTS

Among 5,571 participants (mean age 61.6 years, 53% female, 42.1% white, 11.5% Chinese, 25.7% black, and 20.7% Hispanic), 410 developed incident diabetes during a median follow-up time of 4.7 years (incidence 16.8 per 1,000 person-years). CRP, IL-6, and fibrinogen levels were associated with incident diabetes in the entire sample. After adjustment, the associations were attenuated; however, quartile 4 (versus quartile 1) of IL-6 (HR 1.5 [95% CI 1.1–2.2]) and CRP (1.7 [1.3–2.4]) remained associated with incident diabetes. In stratified analyses, similar associations were observed among white, black, and Hispanic participants.

CONCLUSIONS

Higher levels of inflammation predict short-term incidence of type 2 diabetes in a multiethnic American sample.A number of prospective studies (1–8) have demonstrated an association between high levels of inflammation and the development of type 2 diabetes. In this report, we assess three inflammatory markers: C-reactive protein (CRP), interleukin (IL)-6, and fibrinogen. CRP is an acute-phase reactant mainly produced in the liver. Recent studies have shown that CRP can also be produced by fat cells (9), which raises the possibility that CRP may simply be a marker of obesity in people who go on to develop diabetes. Fibrinogen is involved in clotting but is also an acute-phase reactant and has been previously linked to incident diabetes (8). IL-6 is made by leukocytes and other tissues that play a role in glucose homeostasis, including pancreatic islet cells, hepatocytes, adipocytes, and skeletal muscle cells, and is associated with incident diabetes (10). The graded positive association between most inflammatory markers and diabetes incidence remains significant following adjustment for established diabetes risk factors. However, a study (11) in the Pima population showed no association between inflammatory markers and the risk of diabetes after adjusting for established risk factors for diabetes. Although a sizable number of studies have documented the inflammatory marker–diabetes association, studies on ethnic/racial variations in this association are limited, despite the well-documented increased prevalence of diabetes in nonwhite populations in the U.S. (12). The aims of this analysis are 1) to explore the ability of CRP, IL-6, and fibrinogen to predict the incidence of diabetes in a prospective, multiethnic cohort and 2) to determine the extent to which observed associations are similar across racial/ethnic groups. We also consider whether observed associations are independent of the major known risk factors for diabetes (obesity, family history, insulin resistance, hypertension, age, and physical inactivity) (13).     

Fasting and 2-hour plasma glucose and insulin: relationship with risk factors for cardiovascular disease in overweight nondiabetic children

OBJECTIVE

To determine whether elevated fasting or 2-h plasma glucose and/or insulin better reflects the presence of cardiovascular disease (CVD) risk markers in an overweight pediatric population with normal glucose tolerance.

RESEARCH DESIGN AND METHODS

A total of 151 overweight youths (8–17 years old) were evaluated with oral glucose tolerance tests and measurement of CVD risk factors. The study population was categorized according to quartiles of fasting and 2-h glucose and insulin levels. ANCOVA, adjusted for age, sex, race, Tanner stage, and percent body fat (measured by dual-energy X-ray absorptiometry), was used to compare metabolic variables between the quartiles of glucose and insulin groups.

RESULTS

Increasing quartiles of fasting and 2-h insulin were associated with increasing CVD risk factors. Glucose quartiles on the other hand, either fasting or at 2 h, were not.

CONCLUSIONS

These data suggest that hyperinsulinemia may be the earliest and/or primary metabolic alteration in childhood associated with risk markers for CVD. Prospective studies are needed.The prevalence of childhood overweight is increasing relentlessly (1–2). An increase in the rates of pre-diabetes and type 2 diabetes seems to follow the upward trend of obesity (3). Longitudinal studies in adults demonstrate that cardiovascular disease (CVD) changes are established before a diagnosis of diabetes is made and correlate better with 2-h glucose levels (4–5). Guidelines on diabetes and CVD from the European Society of Cardiology and the European Association for the Study of Diabetes have summarized that 2-h glucose provides better information about risk for CVD than fasting glucose and predicts increased cardiovascular risk in subjects with normal fasting glucose levels (6).Meta-analyses of prospective data from 11 populations have shown that hyperinsulinemia, defined by the highest quartile cutoff for fasting insulin, was associated with cardiovascular mortality independently of other risk factors (7). A review of 19 Western prospective studies showed that the odds ratio (OR) for coronary heart disease for raised fasting insulin as well as nonfasting insulin were more modest than previously suspected (OR 1.12 [95% CI 0.98–1.28] and 1.35 [1.14–1.60], respectively) (8).No studies have evaluated whether a fasting or 2-h glucose and/or insulin value reflects better the presence of CVD risk factors in overweight children with normal glucose tolerance. The purpose of this investigation was to assess the relationship between glucose and insulin quartiles and CVD risk factors in an overweight pediatric population.     

Pedometers and Text Messaging to Increase Physical Activity: Randomized controlled trial of adolescents with type 1 diabetes

OBJECTIVE

To assess whether pedometers and text messaging increase physical activity in adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

A 12-week randomized controlled trial was conducted. A total of 78 subjects participated in the trial (mean ± SD age 14.4 ± 2.37 years, 36 [47%] male). Intervention participants wore an open pedometer and received regular motivational text messages. Control participants received usual care. Primary outcomes were daily step count (4-day closed pedometer) and physical activity questionnaire.

RESULTS

Baseline median step count was 11,063 steps/day (range 1,541–20,158). At 12 weeks, mean daily step count reduced by 840 (95% CI −1,947 to 266) in the control group and by 22 (−1,407 to 1,364) in the intervention group (P = 0.4). Mean self-reported moderate or vigorous physical activity increased by 38.5 min/week in the control group and by 48.4 in the intervention group (P = 0.9).

CONCLUSIONS

A 12-week intervention using pedometers and text messaging as motivational tools in adolescents with type 1 diabetes did not increase physical activity.Adolescents with type 1 diabetes require ongoing care and support to manage diabetes (1,2). Physical activity is an important contributor to glycemic control (3), has multiple effects on blood glucose, insulin sensitivity, weight management, mental health, social development (4,5), and subsequent cardiovascular disease risk (6), but may not be seen as a priority by adolescents. Physical activity often declines during adolescence because physical education at school is no longer compulsory; adolescents may stop playing weekend sports, receive a driver''s license, participate in after-school programs, or receive weekend jobs (7,8).     

Importance of Time Spent Standing for Those at Risk of Diabetic Foot Ulceration

OBJECTIVE

Despite the high cumulative plantar stress associated with standing, previous physical activity reports of diabetic patients at risk of foot ulceration have not taken this activity into account. This study aimed to monitor spontaneous daily physical activity in diabetic peripheral neuropathy (DPN) patients and examine both walking and standing activities as important foot-loading conditions.

RESEARCH DESIGN AND METHODS

Thirteen DPN patients were asked to wear a body-worn sensor for 48 h. Body postures (sitting, standing, and lying) and locomotion (walking, number of steps, and postural transition) were extracted.

RESULTS

Patients daily spent twice as much time standing (13 ± 5%) as walking (6 ± 3%). They spent 37 ± 6% of time sitting and 44 ± 8% lying down. The average number of steps per day was 7,754 ± 4,087, and the number of walking episodes was 357 ± 167 with maximum duration of 3.9 ± 3.8 min.

CONCLUSIONS

The large portion of DPN patients'' time spent standing with the feet loaded requires further consideration when treating and preventing foot ulcers.Clinicians are cautious about advising extra activity in patients at risk of developing diabetic foot ulcers (DFUs). There is concern about excessive loading of the foot causing DFUs. However, the published data regarding this association are not clear.Contrary to expectations, previous studies looking at physical activity levels in individuals at high risk for DFUs have found these individuals to be less active than healthy counterparts (1–3). Maluf and Mueller (1) stratified steps per day in patients with diabetes and varying levels of foot complications. Patients with diabetic peripheral neuropathy (DPN) took ∼8,000 steps/day whereas patients with a history of DFUs took ∼5,500 steps/day (1). Armstrong et al. (4) corroborated diminished steps per day in high-risk patients, reporting ∼4,500 steps/day in this population.In trying to obtain a more complete picture of the trauma associated with physical activity of patients at high risk of DFUs, a means of calculating cumulative plantar stress from steps taken was suggested (1). Cumulative stress was described as the product of the forefoot pressure-time integral and the number of strides per day (1). Patients with a history of DFUs actually demonstrated 41% less cumulative plantar stress than control and DPN patients matched for age and BMI (1). With previous studies indicating a lower volume of total physical activity in DFU patients, variability in physical activity has been identified as a likely contributor to DFU formation (5).These previous studies assessing physical activity in patients at risk of DFUs used pedometers to measure steps per day. Until recently, it has not been possible to unobtrusively assess other types of foot loading activities, such as standing or bouts of activity using a single wearable sensor (6–8). A greater understanding of the complete physical activity of those at risk of DFUs may provide greater insight into DFU development and prevention. This study aimed to describe the quality and quantity of activities of daily living in DPN patients.     

Retinal vascular geometry predicts incident retinopathy in young people with type 1 diabetes: a prospective cohort study from adolescence

OBJECTIVE

To examine the association between retinal vascular geometry and subsequent development of incident retinopathy in young patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS

A prospective cohort study of 736 people with type 1 diabetes aged 12 to 20 years, retinopathy-free at baseline, attending an Australian tertiary care hospital. Retinopathy was determined from seven-field retinal photographs according to the modified Airlie House Classification. Retinal vascular geometry, including length/diameter ratio (LDR) and simple tortuosity (ST), was quantified in baseline retinal photographs. Generalized estimating equations were used to determine risk of retinopathy associated with baseline LDR and ST, adjusting for other factors.

RESULTS

After a median 3.8 (interquartile range 2.4–6.1) years of follow-up, incident retinopathy developed in 287 of 736 (39%). In multivariate analysis, lower arteriolar LDR (odds ratio 1.8 [95% CI 1.2–2.6]; 1st vs. 4th quartile) and greater arteriolar ST (1.5 [1.0–2.2]; 4th vs. 1st quartile) predicted incident retinopathy after adjusting for diabetes duration, sex, A1C, blood pressure, total cholesterol, and BMI. In subgroup analysis by sex, LDR predicted incident retinopathy in male and female participants (2.1 [1.1–4.0] and 1.7 [1.1–2.7]; 1st vs. 4th quartiles, respectively) and greater arteriolar ST predicted incident retinopathy in male participants (2.4 [1.1–4.4]; 4th vs. 1st quartile) only.

CONCLUSIONS

Lower arteriolar LDR and greater ST were independently associated with incident retinopathy in young people with type 1 diabetes. These vascular geometry measures may serve as risk markers for diabetic retinopathy and provide insights into the early structural changes in diabetic microvascular complications.The retina offers a unique opportunity to noninvasively and repeatedly examine the microvasculature in vivo. Improved imaging techniques and advances in computer-based retinal image analysis have allowed a better understanding of retinal vascular parameters and their relationship with pathophysiologic processes in and beyond the retina (1,2). Diabetic retinopathy (DR) is the most common microvascular complication in type 1 diabetes and is a risk indicator of other complications, with mild retinopathy being associated with several-fold increases in the risk of stroke, coronary heart disease, and heart failure independent of other risk factors (3). A better understanding of DR may allow prevention and early treatment of those at risk for vision loss and life-threatening cardiovascular disease.Hypothetically, optimal retinal microvascular architecture will deliver the most efficient blood flow (4). Alterations in retinal architecture may reflect early vascular dysfunction, concurrent compensatory mechanisms, and predict later disease (5). Indeed, subtle variations in retinal vessel caliber have been associated with cardiovascular risk factors (6) and, more recently, diabetic retinopathy and nephropathy (7,8). Some diabetes studies, however, have highlighted the variable nature of retinal caliber with ambient glycemia (9). Thus, geometric parameters, such as vessel simple tortuosity (ST), which reflects the undulation of a vessel along its course, and length/diameter ratio (LDR), which uses the axial length between two defined branching points divided by the vessel’s diameter, may be more robust predictors of diabetic microvascular and macrovascular complications.We previously demonstrated in a cross-sectional analysis that an adverse diabetes risk profile (higher A1C and systolic blood pressure) is associated with lower retinal arteriolar LDR and greater tortuosity in young people with type 1 diabetes (10). We therefore hypothesized that changes in LDR and ST might predict incident retinopathy and conducted this study to prospectively assess the association between retinal vascular geometric parameters (LDR and ST) and incident retinopathy in young patients with type 1 diabetes.     

Long-Term Trends in Cardiorespiratory Fitness and the Incidence of Type 2 Diabetes

OBJECTIVE

Whereas single assessments of cardiorespiratory fitness have been shown to predict lower incidence of type 2 diabetes, there are no data on long-term trends in fitness and risk. We investigated the relationship between long-term trends in fitness and the incidence of type 2 diabetes.

RESEARCH DESIGN AND METHODS

A cohort of 4,187 Japanese men free of diabetes completed annual health checkups and fitness tests for estimated maximal oxygen uptake at least four times over 7 years (1979–1985). We modeled the trend in fitness over 7 years for each man using simple linear regression. Men were then divided into quartiles based on the regression coefficient (slope) from the model. During the follow-up period (1985–1999), 274 men developed diabetes. Hazard ratios (HRs) and 95% CIs for the incidence of diabetes were obtained using the Cox proportional hazards model.

RESULTS

Men in the lowest quartile of the distribution decreased in fitness over the 7 years (median slope −1.25 ml/kg/min), whereas men in the highest quartile increased in fitness (median slope 1.33 ml/kg/min). With adjustment for age, initial fitness level, BMI, systolic blood pressure, cigarette smoking, alcohol intake, and a family history of diabetes and use of the lowest quartile, the HRs (95% CI) for the second through fourth quartiles were 0.64 (0.46–0.89), 0.40 (0.27–0.58), and 0.33 (0.21–0.50), respectively (P_trend < 0.001).

CONCLUSIONS

These results indicate that the long-term trend in fitness is a strong predictor of the incidence of type 2 diabetes in Japanese men.Type 2 diabetes is a global problem with devastating human, social, and economic impact. Today >240 million people worldwide are living with diabetes. Each year another 7 million people develop diabetes. Thus, the prevention of type 2 diabetes is an important public health priority (1).It is well known that physical inactivity is one of the primary causes of type 2 diabetes (2,3). Previous cohort studies also have shown a strong inverse relationship between cardiorespiratory fitness and the incidence of type 2 diabetes (4–7). However, these studies considered only once or twice measures of fitness level at baseline as the exposure. There are no data on long-term trends in activity or fitness as they relate to the risk of developing type 2 diabetes. Several randomized controlled trials of lifestyle, including physical activity, healthful diet, and weight reduction, in relation to type 2 diabetes over a period of years, have shown that such lifestyle changes decrease the incidence of developing type 2 diabetes among individuals with impaired glucose tolerance (8–10). No data are available from individuals at usual risk. This study was thus designed to investigate the relationship between long-term trends in fitness and the incidence of type 2 diabetes using a cohort study design among nondiabetic Japanese men.     

Serum Cathepsin S Is Associated With Decreased Insulin Sensitivity and the Development of Type 2 Diabetes in a Community-Based Cohort of Elderly Men

OBJECTIVE

To investigate associations between serum cathepsin S, impaired insulin sensitivity, defective insulin secretion, and diabetes risk in a community-based sample of elderly men without diabetes.

RESEARCH DESIGN AND METHODS

Serum cathepsin S, insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin secretion (early insulin response during an oral glucose tolerance test) were measured in 905 participants of the Uppsala Longitudinal Study of Adult Men (mean age, 71 years). Thirty participants developed diabetes during 6 years of follow-up.

RESULTS

After adjustment for age, anthropometric variables, and inflammatory markers, higher cathepsin S was associated with decreased insulin sensitivity (regression coefficient per SD increase −0.09 [95% CI −0.14 to −0.04], P = 0.001), but no association with early insulin response was found. Moreover, higher cathepsin S was associated with a higher risk for developing diabetes (odds ratio per SD increase 1.48 [1.08–2.01], P = 0.01).

CONCLUSIONS

Cathepsin S activity appears to be involved in the early dysregulation of glucose and insulin metabolism.Adipokines, inflammatory cytokines secreted from adiopose tissue, have been suggested to play a key role in the development of insulin resistance and diabetes (1). Cathepsin S is a potent cysteine protease that is highly expressed and secreted in adipose tissue of obese individuals (2) and has been suggested to be an important regulator of inflammatory activity (3). We thus hypothesized that cathepsin S levels would be involved in the early dysregulation of glucose and insulin metabolism before development of diabetes. Accordingly, we investigated the association between serum cathepsin S and the two major underlying causes of diabetes—impaired insulin sensitivity and impaired insulin secretion—in a community-based sample of elderly men without diabetes. In secondary analyses, we also investigated the longitudinal association between serum cathepsin S and the incidence of diabetes.     

Evidence of a Strong Association Between Frequency of Self-Monitoring of Blood Glucose and Hemoglobin A1c Levels in T1D Exchange Clinic Registry Participants

OBJECTIVE

Despite substantial evidence of the benefit of frequent self-monitoring of blood glucose (SMBG) in type 1 diabetes, certain insurers limit the number of test strips that they will provide. The large database of the T1D Exchange clinic registry provided an opportunity to evaluate the relationship between the number of SMBG measurements per day and HbA_1c levels across a wide age range of children and adults.

RESEARCH DESIGN AND METHODS

The analysis included 20,555 participants in the T1D Exchange clinic registry with type 1 diabetes ≥1 year and not using a continuous glucose monitor (11,641 younger than age 18 years and 8,914 18 years old or older). General linear models were used to assess the association between the number of SMBG measurements and HbA_1c levels after adjusting for potential confounding variables.

RESULTS

A higher number of SMBG measurements per day were associated with non-Hispanic white race, insurance coverage, higher household income, and use of an insulin pump for insulin delivery (P < 0.001 for each factor). After adjusting for these factors, a higher number of SMBG measurements per day was strongly associated with a lower HbA_1c level (adjusted P < 0.001), with the association being present in all age-groups and in both insulin pump and injection users.

CONCLUSIONS

There is a strong association between higher SMBG frequency and lower HbA_1c levels. It is important for insurers to consider that reducing restrictions on the number of test strips provided per month may lead to improved glycemic control for some patients with type 1 diabetes.The advent in the 1980s of meters for self-monitoring of blood glucose (SMBG) has had a substantial impact on the management of type 1 diabetes (1). Several studies have demonstrated a strong correlation between frequency of SMBG and glycemic control (2–5). However, acceptance of the value of frequent SMBG has not been universal and many insurers limit the number of test strips that they will provide to four to six strips per day. In the past year, the Washington State Healthcare Authority questioned whether sufficient evidence is available to justify unlimited coverage of SMBG test strips for patients with type 1 diabetes (6).The large database of the T1D Exchange clinic registry provided an opportunity to evaluate the relationship between the number of SMBG measurements per day and HbA_1c across a wide age range of children and adults, and to evaluate factors associated with the number of SMBG measurements per day.     

Circulating Estrone Levels Are Associated Prospectively With Diabetes Risk in Men of the Framingham Heart Study

OBJECTIVE

In postmenopausal women and preclinical murine models, estrogen administration reduces diabetes risk; however, the relationship of estradiol and estrone to diabetes in men is poorly understood. We determined the relationship between circulating estradiol and estrone levels and diabetes risk in community-dwelling men of the Framingham Heart Study (FHS).

RESEARCH DESIGN AND METHODS

Cross-sectional relationships of estradiol and estrone levels with diabetes were assessed at examination 7 (1998–2001) in FHS generation 2 men (n = 1,458); prospective associations between hormone levels at examination 7 and incident diabetes were assessed 6.8 years later at examination 8. Type 2 diabetes mellitus was defined as fasting glucose >125 mg/dL, medication use, or both. Estradiol, estrone, and testosterone levels were measured with liquid chromatography–tandem mass spectrometry, and free estradiol and estrone were calculated.

RESULTS

In cross-sectional models, men with elevated estrone and estradiol had 40% and 62% increased likelihoods of existing diabetes per cross-sectional doubling of estrone and estradiol levels, respectively. Free estrone (cross-sectional odds ratio 1.28 [95% CI 1.02–1.62], P = 0.04) was associated with impaired fasting glucose at examination 7. There was an increase in risk of existing diabetes with increasing quartiles of total and free estrone and estradiol and an increase in risk of incident diabetes with increasing quartiles of estrone levels. In multivariate longitudinal analyses, a twofold increase in total or free estrone levels at examination 7 was associated with 77 and 93% increases, respectively, in odds of incident diabetes at examination 8.

CONCLUSIONS

Although both estradiol and estrone exhibit cross-sectional associations with diabetes in men, in longitudinal analyses estrone is a more sensitive marker of diabetes risk than is estradiol.Aging is associated with a decline in glucose tolerance, resulting in higher prevalence of type 2 diabetes mellitus (T2DM) and impaired fasting glucose (IFG) in older adults (1). Previous studies have suggested a role of endogenous sex hormones in the development of T2DM. Age-related decline in testosterone levels has been associated with an increased risk of T2DM in older men (2–5); however, the effects of low or high estrone and estradiol levels on T2DM risk in men are not clear.Epidemiologic studies (6,7) and randomized trials (8–10) in women have suggested that hormone therapy reduces the risk of T2DM in postmenopausal women. Furthermore, genetic disruption of estrogen receptor α (ERα) in mice is associated with adiposity and insulin resistance (11). Only a few cross-sectional studies in older men have addressed the relationships between estradiol and T2DM, and the data are conflicting; some studies have shown a positive correlation of estradiol levels with T2DM (12,13), whereas others have found no significant association (5,14). The relationship between estrone and T2DM has not been studied in men. Most studies used immunoassays for the measurement of estradiol levels, for which accuracy in the low range has been questioned (15–17).By using data from the Framingham Offspring Study, we determined whether circulating estrone and estradiol levels are associated with T2DM or IFG in community-dwelling older men. In longitudinal analyses restricted to nondiabetic men, we evaluated whether these hormones were predictive of incident T2DM during a follow-up period of approximately 7 years. This analysis is among the first population-based assessments of the association between estradiol and estrone—here measured with liquid chromatography–tandem mass spectrometry (LC-MS/MS), widely considered the reference method with the highest specificity and sensitivity—with T2DM risk in men (18).     

Association Between Serum IGF-1 and Diabetes Among U.S. Adults

OBJECTIVE

Serum insulin-like growth factor (IGF)-1 may have a role in the maintenance of glucose homeostasis. We examined the association between serum IGF-1 and diabetes in a representative sample of U.S. adults.

RESEARCH DESIGN AND METHODS

Third National Health and Nutrition Examination Survey (NHANES III) participants aged ≥18 years (n = 5,511) were the subjects of the study. The main outcome was the presence of diabetes (n = 387).

RESULTS

Lower serum IGF-1 levels were positively associated with diabetes after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, BMI, hypertension, glomerular filtration rate, and serum cholesterol. Compared with quartile 4 of IGF-1 (referent), the odds ratio (OR) of diabetes associated with quartile 1 was OR 2.16 (95% CI 1.24–3.76); P-trend = 0.002. However, the observed association between IGF-1 and diabetes was present only in those <65 years of age (OR = 3.05; P-trend = 0.006) and disappeared in those ≥65 years of age (OR = 0.51; P-trend = 0.18); P-interaction = 0.0056.

CONCLUSIONS

Low IGF-1 levels are associated with diabetes among young subjects.Insulin-like growth factor (IGF)-1 is involved in the regulation of growth and cellular proliferation in the human body (1,2). IGF-1 is similar in structure to insulin. Reduced IGF-1 levels have been proposed to have a role in diabetes (3–5). The two previous studies on IGF-1 and diabetes were restricted to elderly populations (6) or had limited sample size (7). There also is some inconsistency in the findings of the two studies: one study (7) found a positive association with decreasing IGF-1, while the other study (6) did not find an association. Therefore, this study examined the independent association between IGF-1 and diabetes in a representative sample of U.S. adults.     

Alternative Markers of Hyperglycemia and Risk of Diabetes

OBJECTIVE

Fructosamine, glycated albumin, and 1,5-anhydroglucitol (1,5-AG) are of interest for monitoring short-term glycemic control in patients with diabetes; however, their associations with diabetes risk are uncharacterized.

RESEARCH DESIGN AND METHODS

We used Cox proportional hazards models to examine the associations of fructosamine, glycated albumin, and 1,5-AG with incident diabetes in 1,299 participants, from the Atherosclerosis Risk in Communities (ARIC) Study (2005–2006), who had no history of diagnosed diabetes at baseline. Incident diabetes was self-reported during annual telephone calls.

RESULTS

There were 119 new cases of diabetes during a median follow-up of 3.3 years. When compared with the lowest quartile, the fourth quartiles of fructosamine and glycated albumin were significantly associated with diabetes risk (hazard ratio [HR] 3.99 [95% CI 1.93–8.28] and 5.22 [2.49–10.94], respectively). The fourth quartile of 1,5-AG was associated with a significantly lower diabetes risk (0.27 [0.14–0.55]). Associations were attenuated but still significant after adjustment for hemoglobin A_1c (A1C) or fasting glucose.

CONCLUSIONS

Fructosamine, glycated albumin, and 1,5-AG were associated with the subsequent development of diabetes independently of baseline A1C and fasting glucose. Our results suggest these alternative biomarkers may be useful in identifying persons at risk for diabetes.Nontraditional serum markers of short-term glucose control may enhance our ability to monitor hyperglycemia in persons with diabetes. Fructosamine, glycated albumin, and 1,5-anhydroglucitol (1,5-AG) have been of recent interest, particularly for use in populations in which interpretation of glycated hemoglobin (A1C) may be problematic (1–3), such as in the setting of anemia, hemolysis, or renal disease (4–6). Fructosamine is produced when blood glucose forms ketoamines by covalently binding to serum proteins (7). Similarly, glycated albumin is formed via glycation of serum albumin (1). 1,5-AG is a serum monosaccharide that is excreted in the urine at an accelerated rate in the presence of glycosuria (2). Whereas fructosamine and glycated albumin increase in the presence of hyperglycemia, 1,5-AG decreases in the setting of elevated circulating glucose concentrations (1,7). The 1,5-AG is approved by the Food and Drug Administration for short-term monitoring of glycemic control in persons with diabetes and has been suggested for use in monitoring postprandial hyperglycemia (8,9).Despite growing interest in fructosamine, glycated albumin, and 1,5-AG for monitoring short-term glycemic control (3,10,11), few studies have measured these novel serum measures in initially nondiabetic populations. It is unknown if they are associated with the future diagnosis of diabetes. It is also unknown if these markers provide distinct information apart from A1C or fasting glucose concentrations. The purpose of this study was to examine the relationships of fructosamine, glycated albumin, and 1,5-AG with the risk of diagnosed diabetes and to determine if the associations were independent of baseline A1C or fasting glucose.     

Racial differences in association of elevated interleukin-18 levels with type 2 diabetes: the atherosclerosis risk in communities study

OBJECTIVE

Elevated plasma interleukin-18 (IL-18) has been linked to onset of diabetes mellitus (DM) and its complications. However, so far this association has been shown only in predominantly white populations. We examined IL-18 levels and their association with incident DM in a racially heterogeneous population.

RESEARCH DESIGN AND METHODS

In a nested case-cohort design representing a 9-year follow-up of 9,740 middle-aged, initially healthy, nondiabetic white and African American participants of the Atherosclerosis Risk in Communities Study, we selected and measured analytes on race-stratified (50% white, 50% African American) random samples of both cases of incident diabetes (n = 548) and eligible members of the full cohort (n = 536).

RESULTS

Baseline IL-18 levels were significantly higher in white participants compared with African American participants (P < 0.001). Although white participants in the fourth (versus first) quartile of IL-18 levels had a significant hazard ratio (HR) for developing DM (HR: 2.1, 95% CI: 1.3–3.4), after adjustment for age, sex, and study center, no difference was seen among African Americans (HR: 1.0, 95% CI: 0.6–1.7). Unlike those in African Americans, IL-18 levels in whites had a significant correlation with age (P < 0.01); anthropometric characteristics such as waist circumference (P < 0.001), height (P = 0.04), waist-to-hip ratio (P < 0.001), and BMI (P < 0.01); and total (P < 0.001) and high-molecular-weight (P < 0.001) adiponectin.

CONCLUSIONS

There are racial differences in levels of IL-18 and the association of IL-18 with risk factors and incident type 2 DM. In addition, there seems to be a complex interplay of inflammation and adiposity in the development of DM.Diabetes and its complications lead to an enormous disease burden. It has been estimated that 366 million people worldwide will develop diabetes by the year 2030 (1). Studies have shown that parental history of diabetes, anthropometric measures, and systolic blood pressure (SBP), alone or combined with simple laboratory measures including fasting glucose and lipid parameters, can characterize the risk for diabetes in middle-aged adults (2). In addition, there is growing evidence to suggest that insulin resistance and diabetes are associated with chronic inflammation (3,4). Several proinflammatory cytokines are found to be elevated in diabetes and its complications (5). In contrast, anti-inflammatory molecules like adipocytokines have been consistently lower in individuals with diabetes and metabolic syndrome (6,7), a finding that indicates their protective role in the pathogenesis of diabetes. However, the exact pathological mechanisms underlying these inflammatory and anti-inflammatory pathways are largely unknown.Interleukin-18 (IL-18) is a cytokine that is produced constitutively in several different cells in the body including macrophages, endothelial cells, vascular smooth muscle cells, dendritic cells, and Kupffer cells, as well as adipocytes (8). It is expressed as an inactive precursor molecule that is cleaved by the enzyme caspase-1 (9). IL-18 is proinflammatory and enhances maturation of T cells and natural killer cells and promotes production and release of other cytokines, chemokines, and adhesion molecules (9). IL-18 induces the production of tumor necrosis factor (TNF)-α, which in turn promotes the synthesis and release of IL-6 and C-reactive protein (CRP) (10).Elevated levels of IL-18 have been associated with obesity, metabolic syndrome, insulin resistance, dyslipidemia, and atherosclerosis (11,12). Recently, two studies have shown that elevated levels of IL-18 are associated with higher risk of diabetes (13,14). Both of these studies looked at populations of European descent. It is unknown if a similar association exists for other ethnicities. In a study involving the Atherosclerosis Risk in Communities Study (ARIC) cohort, Duncan et al. (4) showed that low-grade inflammation was associated with onset of diabetes. However, the authors noted that although an inflammation score was robustly associated with onset of diabetes in whites, no association was found in the African American population. They postulated that not all sources of low-grade systemic inflammatory states increase the risk of developing diabetes.With this background, we aimed to determine whether elevated levels of IL-18 were associated with incident diabetes, independent of traditional risk factors, in a heterogeneous population such as the ARIC cohort and whether racial differences exist with this association.     

Increased Pulse Pressure Independently Predicts Incident Atrial Fibrillation in Patients With Type 2 Diabetes

OBJECTIVE

To examine whether baseline pulse pressure (PP), a marker of arterial stiffness, is associated with subsequent development of atrial fibrillation (AF) in type 2 diabetes.

RESEARCH DESIGN AND METHODS

A total of 350 type 2 diabetic patients, who were free from AF at baseline, were followed for 10 years. A standard electrocardiogram was performed annually and a diagnosis of incident AF was confirmed in affected participants by a single cardiologist.

RESULTS

During the follow-up, 32 patients (9.1% of total) developed incident AF. After adjustments for age, sex, BMI, diabetes duration, presence of left ventricular hypertrophy, hypertension treatment, kidney dysfunction, and pre-existing history of coronary heart disease, heart failure, and mild valvular disease, baseline PP was associated with an increased incidence of AF (adjusted odds ratio 1.76 for each SD increment [95% CI 1.1–2.8]; P < 0.01).

CONCLUSIONS

Our findings suggest that increased PP independently predicts incident AF in patients with type 2 diabetes.Atrial fibrillation (AF) is the most common sustained arrhythmia and contributes to substantial increases in morbidity and mortality (1–3). Increased pulse pressure (PP), a marker of arterial stiffness, has been reported to be an important predictor of new-onset AF in U.S. adults, independently of several clinical AF risk factors (4). In this prospective, observational study, we tested the hypothesis that baseline PP predicts subsequent development of incident AF in patients with type 2 diabetes.     

Association Between Circulating Soluble Receptor for Advanced Glycation End Products and Atherosclerosis: Observations from the Dallas Heart Study

OBJECTIVE

To determine the association between circulating soluble receptor for advanced glycation end products (sRAGE) and coronary atherosclerosis.

RESEARCH DESIGN AND METHODS

Using data from the Dallas Heart Study, a probability-based population sample, the association between plasma levels of sRAGE and coronary artery calcium (CAC) was assessed among 2,571 subjects with complete imaging and sRAGE data.

RESULTS

An inverse graded association was observed between sRAGE quartiles and CAC, with CAC prevalence of 28.5% in quartile 1 compared with 15.7% in quartile 4 (P < 0.0001). After multivariable adjustment, the associations between sRAGE levels in the first and second quartiles (versus fourth quartile) and CAC remained statistically significant (adjusted odds ratio 1.71 [95% CI 1.2–2.4] and 1.5 [1.0–2.1], respectively).

CONCLUSIONS

sRAGE is a novel biomarker that is inversely associated with coronary atherosclerosis. The role of sRAGE in the pathobiology of atherosclerosis and its potential prognostic and therapeutic implications warrant further investigation.The transmembrane receptor for advanced glycation end products (RAGE), expressed on a variety of cells including endothelial, smooth muscle, and mononuclear cells, binds advanced glycation end products and other proinflammatory ligands and modulates activity of several prothrombotic and proinflammatory mediators (1,2). Results from animal models provide evidence supporting a role for ligand-RAGE binding in the development and progression of atherosclerosis (3–5).A circulating isoform of RAGE, soluble RAGE (sRAGE), has been identified (6,7) and theorized to competitively inhibit transmembrane RAGE-ligand binding, thereby attenuating atherosclerosis (3–5). This hypothesis has been supported by animal experiments, where administration of sRAGE to mouse models retarded the progression of atherosclerosis (3–5).Few human studies have been performed evaluating the association between circulating sRAGE and human atherosclerosis (8,9). The objective of the present study was to determine the association between sRAGE and atherosclerosis.     

Implementing a State-Based Cardiovascular Disease and Diabetes Prevention Program

OBJECTIVE

To evaluate weight loss and cardiometabolic risk reduction achieved through an adapted Diabetes Prevention Program intervention among adults at high risk for cardiovascular disease (CVD) and diabetes.

RESEARCH DESIGN AND METHODS

Eight health care facilities implemented a group-based lifestyle intervention beginning in 2008. Participants attended 16 weekly core sessions followed by 6 monthly after core sessions.

RESULTS

A total of 1,003 participants were enrolled, 816 (81%) completed the core and 578 (58%) completed the after core. Of participants completing the core and after core, 45 and 49% achieved the 7% weight loss goal, respectively. There were significant improvements in blood pressure, fasting glucose, and LDL cholesterol among participants completing the intervention.

CONCLUSIONS

Our findings indicate it is feasible for state-coordinated CVD and diabetes prevention programs to achieve significant weight loss and improve cardiometabolic risk.The Diabetes Prevention Program (DPP) and other studies demonstrated that lifestyle intervention can prevent the development of type 2 diabetes and reduce cardiometabolic risk among participants, prompting many countries to begin implementing efforts to translate these studies into practice (1–5). In 2008, the Montana Department of Public Health and Human Services (DPHHS) implemented an adapted DPP, and preliminary results demonstrated feasibility and effectiveness (6). This report describes weight loss and cardiometabolic risk improvement among participants completing the intervention.     

Associations Between Dietary Fiber and Inflammation, Hepatic Function, and Risk of Type 2 Diabetes in Older Men: Potential mechanisms for the benefits of fiber on diabetes risk

OBJECTIVE

To examine the relationship between dietary fiber and the risk of type 2 diabetes in older men and the role of hepatic and inflammatory markers.

RESEARCH DESIGN AND METHODS

The study was performed prospectively and included 3,428 nondiabetic men (age 60–79 years) followed up for 7 years, during which there were 162 incident cases of type 2 diabetes.

RESULTS

Low total dietary fiber (lowest quartile ≤20 g/day) was associated with increased risk of diabetes after adjustment for total calorie intake and potential confounders (relative risk −1.47 [95% CI 1.03–2.11]). This increased risk was seen separately for both low cereal and low vegetable fiber intake. Dietary fiber was inversely associated with inflammatory markers (C-reactive protein, interleukin-6) and with tissue plasminogen activator and γ-glutamyl transferase. Adjustment for these markers attenuated the increased risk (1.28 [0.88–1.86]).

CONCLUSIONS

Dietary fiber is associated with reduced diabetes risk, which may be partly explained by inflammatory markers and hepatic fat deposition.Several prospective cohort studies have observed a protective effect of dietary fiber on the risk of type 2 diabetes (1–4). However, this has not been observed in all studies (4), and the biological mechanisms by which dietary fiber may be beneficial for diabetes are unclear. Several studies have shown inverse associations between dietary fiber and markers of inflammation, insulin sensitivity, and hepatic function (5–8), factors that have been linked to the development of diabetes in other studies (9). It has been suggested that dietary fiber may reduce diabetes risk through its effect on hepatic function and insulin sensitivity or by mediating the proinflammatory process (5,6). However, these possibilities have not been examined in detail. We assessed the prospective relationship between dietary fiber and the risk of type 2 diabetes in older men and evaluated whether this relationship is associated with serum inflammatory marker (interleukin-6 [IL-6] and C-reactive protein [CRP]) levels and hepatic function (γ-glutamyl transferase [GGT]).