Branched-Chain Amino Acids and Insulin Metabolism: The Insulin Resistance Atherosclerosis Study (IRAS)

OBJECTIVE

Recent studies using untargeted metabolomics approaches have suggested that plasma branched-chain amino acids (BCAAs) are associated with incident diabetes. However, little is known about the role of plasma BCAAs in metabolic abnormalities underlying diabetes and whether these relationships are consistent across ethnic populations at high risk for diabetes. We investigated the associations of BCAAs with insulin sensitivity (S_I), acute insulin response (AIR), and metabolic clearance of insulin (MCRI) in a multiethnic cohort.

RESEARCH DESIGN AND METHODS

In 685 participants without diabetes of the Insulin Resistance Atherosclerosis Study (IRAS) (290 Caucasians, 165 African Americans, and 230 Hispanics), we measured plasma BCAAs (sum of valine, leucine, and isoleucine) by mass spectrometry and S_I, AIR, and MCRI by frequently sampled intravenous glucose tolerance tests.

RESULTS

Elevated plasma BCAAs were inversely associated with S_I and MCRI and positively associated with fasting insulin in regression models adjusted for potential confounders (β = −0.0012 [95% CI −0.0018, −0.00059], P < 0.001 for S_I; β = −0.0013 [95% CI −0.0018, −0.00082], P < 0.001 for MCRI; and β = 0.0015 [95% CI 0.0008, 0.0023], P < 0.001 for fasting insulin). The association of BCAA with S_I was significantly modified by ethnicity, with the association only being significant in Caucasians and Hispanics. Elevated plasma BCAAs were associated with incident diabetes in Caucasians and Hispanics (multivariable-adjusted odds ratio per 1-SD increase in plasma BCAAs: 1.67 [95% CI 1.21, 2.29], P = 0.002) but not in African Americans. Plasma BCAAs were not associated with S_I-adjusted AIR.

CONCLUSIONS

Plasma BCAAs are associated with incident diabetes and underlying metabolic abnormalities, although the associations were generally stronger in Caucasians and Hispanics.     

Relationship of Insulin Sensitivity,Insulin Secretion,and Adiposity With Insulin Clearance in a Multiethnic Population: The Insulin Resistance Atherosclerosis Study

OBJECTIVE

We aimed to examine insulin clearance, a compensatory mechanism to changes in insulin sensitivity, across sex, race/ethnicity populations, and varying states of glucose tolerance.

RESEARCH DESIGN AND METHODS

We measured insulin sensitivity index (S_I), acute insulin response (AIR), and metabolic clearance rate of insulin (MCRI) by the frequently sampled intravenous glucose tolerance test in 1,295 participants in the Insulin Resistance Atherosclerosis Study.

RESULTS

MCRI was positively related to S_I and negatively to AIR and adiposity across sex, race/ethnicity populations, and varying states of glucose tolerance, adiposity, and family history of diabetes. Differences in MCRI by race/ethnicity (lower in African Americans and Hispanics compared with non-Hispanic whites) and glucose tolerance were largely explained by differences in adiposity, S_I, and AIR.

CONCLUSIONS

Insulin sensitivity, insulin secretion, and adiposity are correlates of insulin clearance and appear to explain differences in insulin clearance by race/ethnicity and glucose tolerance status.Reduced insulin clearance has been demonstrated in experimental models of insulin resistance (1) and conditions associated with insulin resistance (2–5). Insulin clearance partially explains the variability of fasting insulin independently of the effect of insulin resistance, insulin secretion, adiposity, and plasma glucose (6). In response to their higher insulin resistance, minority populations have lower insulin clearance than non-Hispanic whites (4,5,7). In these studies, however, results were not adjusted for insulin resistance. Therefore, we aimed to examine insulin clearance across sex, race/ethnicity populations, and varying states of glucose tolerance in the Insulin Resistance Atherosclerosis Study (IRAS) (8).     

Disposition Index, Glucose Effectiveness, and Conversion to Type 2 Diabetes: The Insulin Resistance Atherosclerosis Study (IRAS)

OBJECTIVE

Disposition index (DI) and glucose effectiveness (S_G) are risk factors for diabetes. However, the effect of DI and S_G on future diabetes has not been examined in large epidemiological studies using direct measures.

RESEARCH DESIGN AND METHODS

Insulin sensitivity index (S_I), acute insulin response (AIR), and S_G were measured in 826 participants (aged 40–69 years) in the Insulin Resistance Atherosclerosis Study (IRAS) by the frequently sampled intravenous glucose tolerance test. DI was expressed as S_I × AIR. At the 5-year follow-up examination, 128 individuals (15.5%) had developed diabetes.

RESULTS

The area under the receiver operating characteristic curve of a model with S_I and AIR was similar to that of DI (0.767 vs. 0.774, P = 0.543). In a multivariate logistic regression model that included both DI and S_G, conversion to diabetes was predicted by both S_G (odds ratio × 1 SD, 0.61 [0.47–0.80]) and DI (0.68 [0.54–0.85]) after adjusting for demographic variables, fasting and 2-h glucose concentrations, family history of diabetes, and measures of obesity. Age, sex, race/ethnicity, glucose tolerance status, obesity, and family history of diabetes did not have a significant modifying impact on the relation of S_G and DI to incident diabetes.

CONCLUSIONS

The predictive power of DI is comparable to that of its components, S_I and AIR. S_G and DI independently predict conversion to diabetes similarly across race/ethnic groups, varying states of glucose tolerance, family history of diabetes, and obesity.Both insulin sensitivity and first-phase insulin secretion are independent determinants of conversion to diabetes in different ethnic groups and varying states of glucose tolerance, family history of diabetes, and obesity (1). First-phase insulin secretion compensates for the worsening of insulin sensitivity (2). In studies using direct methods, such as the frequently sampled intravenous glucose tolerance test (FSIGTT) with minimal model analysis, this relationship is hyperbolic (2) and similar across glucose tolerance categories (3). Known as the disposition index (DI), the product of measures of insulin sensitivity and first-phase insulin secretion, it has been shown to predict conversion to diabetes (4–6). The evidence, however, comes from studies that have enrolled relatively few participants or targeted persons from a single ethnic group. Since direct methods have demanding technical requirements, the product of measures of insulin sensitivity and insulin secretion derived from the oral glucose tolerance test has attracted interest. This product has been shown to have a modest correlation with minimal model–derived DI, to decrease as glucose tolerance status deteriorates, and to predict the development of diabetes independent of other risk factors including fasting and 2-h glucose concentrations (7,8). It includes the incretin effect and therefore may not always follow the hyperbolic law (7–9). The hyperbolic paradigm of the minimal model–derived DI has also been criticized (10). Furthermore, its predictive power has not been tested for large epidemiological studies.In addition to the insulin-dependent component of glucose tolerance (or DI), the insulin-independent component (glucose effectiveness [S_G]) has already been explored in mice (11) and humans (12). S_G is the capacity of glucose to enhance its own cellular uptake and to suppress endogenous glucose production. Although reduced in individuals with impaired glucose tolerance (IGT) and diabetes (4,13), S_G contributes to glucose tolerance even in conditions of significant insulin resistance, including diabetes (13). Reduced S_G has also been described in healthy individuals following the infusion of cortisol or glucagon, individuals in states of very low caloric intake, women with polycystic ovary syndrome, and the elderly (13–15). Contrary to the insulin sensitivity index (S_I), S_G may not be influenced by exercise (16) or weight loss interventions (17). In relatively small studies, S_G has been shown to predict future diabetes (4,5,18), but its contribution to the development of diabetes remains largely unknown.Since the hyperbolic paradigm has not been tested in large epidemiological studies, our first objective was to analyze the risk of future diabetes associated with minimal model-derived DI relative to its components, S_I, and acute insulin response (AIR). The second objective was to assess the relative contribution of the insulin-independent component of glucose tolerance, S_G, to the development of diabetes. To meet these aims, we used data from the Insulin Resistance Atherosclerosis Study (IRAS), a multicenter observational epidemiological study of different ethnic groups and varying states of glucose tolerance (19).     

Limited overlap between intermediate hyperglycemia as defined by A1C 5.7-6.4%, impaired fasting glucose, and impaired glucose tolerance

OBJECTIVE

We compared the prevalences and overlap between intermediate hyperglycemia (IH), defined by a hemoglobin A_1c (A1C) 5.7–6.4%, impaired fasting glucose (IFG), and impaired glucose tolerance (IGT).

RESEARCH DESIGN AND METHODS

Oral glucose tolerance test results and A1C measurements were evaluated as markers of IH in an unselected cohort of 486 nondiabetic adults from Finland.

RESULTS

The overall prevalence of IH was 34%. Prevalences of isolated A1C 5.7–6.4%, IGT, and IFG were 8.0, 13.2, and 4.5%, respectively. Overlap between these three markers was uncommon. Isolated A1C 5.7–6.4% was associated with a higher BMI compared with isolated IFG and IGT and with a more adverse lipid profile compared with isolated IFG.

CONCLUSIONS

Prevalence of isolated IH was high, with limited overlap between the definitions. Differences in cardiovascular disease risk factors were observed among the groups. This study demonstrates that an A1C of 5.7–6.4% detects, in part, different individuals with IH compared with IFG and IGT.Hemoglobin A_1c (A1C) at a range of 5.7–6.4% was proposed as an indicator of increased risk for type 2 diabetes (1) in addition to the currently used criteria of intermediate hyperglycemia (IH) as follows: impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).The use of A1C in a nondiabetic range may detect a different prevalence of IH compared with IFG or IGT (2). However, the degree of overlap between these markers is not well reported. Recent studies from diabetic populations have yielded conflicting data regarding differences in cardiovascular disease (CVD) risk factor profiles among those diagnosed by A1C ≥6.5% and oral glucose tolerance test (OGTT) (3,4). Studies comparing CVD risk factor profiles among individuals with IH diagnosed by A1C 5.7–6.4% and OGTT are lacking.We hypothesized that these three different markers of IH, in part, detect different individuals and that individuals with A1C 5.7–6.4% would be characterized by a more unfavorable CVD risk profile than individuals diagnosed by OGTT. To this aim, we conducted a population-based observational study to compare 1) diagnosis of IH based on A1C 5.7–6.4% with OGTT and 2) differences in CVD risk factors among the three groups.     

Five-Year Change in Visceral Adipose Tissue Quantity in a Minority Cohort: The Insulin Resistance Atherosclerosis Study (IRAS) Family Study

OBJECTIVE

To describe the 5-year change in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas.

RESEARCH DESIGN AND METHODS

Absolute change in VAT and SAT measured by abdominal computed tomography scans has been obtained at a 5-year interval from African Americans (n = 389) and Hispanic Americans (n = 844), aged 20–69 years, in 10-year age-groups.

RESULTS

Mean 5-year increases in VAT areas in women were 18, 7, 4, 0.4, and −3 cm² for African Americans and 13, 7, 3, 1, and −15 cm² for Hispanics, across the 5 age decades (trend not significant). Mean 5-year increases in SAT areas in women were 88, 46, 19, 17, and 14 cm² for African Americans and 53, 20, 17, 12, and 1 cm² for Hispanics, across the 5 age decades (P < 0.05 for both). Similar trends have been observed in men.

CONCLUSIONS

Accumulation of abdominal fat is greatest in young adulthood. These data may be useful in identifying subgroups at risk of type 2 diabetes.Longitudinal studies have shown a direct relationship between levels of visceral adipose tissue (VAT) and future risk of impaired glucose tolerance and type 2 diabetes, independent of total adiposity (1–4). The Diabetes Prevention Program showed that reductions in VAT and subcutaneous adipose tissue (SAT) led to decreased risk of type 2 diabetes (5). These studies suggest that central adiposity is an independent risk factor for type 2 diabetes. With IRAS (Insulin Resistance Atherosclerosis Study) Family Study data, we describe the natural progression of abdominal adiposity assessed by computed tomography over 5 years in African Americans and Hispanics.     

The Association Between A1C and Subclinical Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis

OBJECTIVE

To test the hypothesis that A1C is associated with subclinical cardiovascular disease (CVD) in a population without evident diabetes, after adjusting for traditional CVD risk factors and BMI.

RESEARCH DESIGN AND METHODS

This was a cross-sectional study of 5,121 participants without clinically evident CVD or diabetes (fasting glucose ≥7.0 mmol/l or use of diabetes medication), aged 47–86 years, enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). Measurements included carotid intimal-medial wall thickness (CIMT) and coronary artery calcification (CAC). Results were adjusted for age, sex, ethnicity, smoking, systolic blood pressure, LDL cholesterol, HDL cholesterol, antihypertensive medication use, lipid-lowering medication use, and BMI.

RESULTS

Compared with those in the lowest quartile for A1C ([mean ± SD] 5.0 ± 0.2%), participants in the highest quartile (6.0 ± 0.3%) had higher adjusted mean values for common CIMT (0.85 vs. 0.87 mm, P = 0.003) and internal CIMT (1.01 vs. 1.08 mm, P = 0.003). A1C quartile was not associated with prevalence of CAC in the entire cohort (P = 0.27); however, the association was statistically significant in women (adjusted prevalence of CAC in lowest and highest A1C quartiles 37.5 vs. 43.0%, P = 0.01). Among those with some CAC, higher A1C quartile tended to be associated with higher CAC score, but the results were not statistically significant (adjusted P = 0.11).

CONCLUSIONS

In this multiethnic cohort, there were small, positive associations between A1C, common CIMT, and internal CIMT in the absence of clinically evident diabetes. An association between higher A1C and CAC prevalence was evident only in women.Higher level of A1C, a measurement of recent glycemia status, has been associated with clinical cardiovascular disease (CVD) in both the diabetic and nondiabetic population (1–3), but little information is available on the association between A1C and subclinical CVD in nondiabetic populations. Studies of subclinical CVD, including coronary artery calcification (CAC) and carotid intimal-medial wall thickness (CIMT), can provide complementary information to studies of clinical CVD outcomes by providing a more focused understanding of the factors that contribute to atherosclerosis, whereas studies of clinical CVD events are also influenced by factors related to plaque rupture and thrombosis. CAC and CIMT are associated with future risk of CVD events (4,5) and offer an opportunity to better understand the factors that contribute to the development and natural progression of early stage CVD.To date, the few studies that have examined the association between A1C and subclinical CVD in individuals without diabetes have shown mixed results. Sander et al. (6) found that A1C was associated with progression of common CIMT over 2 years, particularly when C-reactive protein (CRP) was also elevated. Doruk et al. (7) found no significant association between A1C and CIMT (mean of 12 common and internal CIMT measurements) in 78 elderly nondiabetic participants. Aihara et al. (8) showed that A1C was significantly associated with maximum plaque thickness (or CIMT if plaque was absent) in the internal or common carotid arteries in 306 Japanese participants; however, the association was not independent of diabetes status and was not described among nondiabetic participants. Temelkova-Kurktschiev et al. (9) showed that fasting glucose, glucose measured 2 h after an oral glucose load (2-h glucose), and A1C were each associated with common CIMT in 582 German participants without clinically diagnosed diabetes after adjusting for age and sex, but 30% of these participants had undiagnosed diabetes.To our knowledge, there are no published studies examining the association between A1C and CAC in participants without clinically evident diabetes and no large studies of A1C and CIMT in minority ethnic populations. The purpose of this study was to test the hypothesis that A1C within the range observed in subjects without clinically evident diabetes is associated with subclinical CVD after accounting for traditional CVD risk factors and that this association persists after further adjustment for BMI. Secondary aims of this study were to determine whether the association between A1C and subclinical CVD varied by sex or race/ethnicity and whether results were explained by differences in other nontraditional CVD risk factors (triglycerides, CRP, intentional exercise, and albuminuria).     

Plasma and dietary vitamin E in relation to incidence of type 2 diabetes: The Insulin Resistance and Atherosclerosis Study (IRAS)

OBJECTIVE: To evaluate the association of vitamin E with incidence of type 2 diabetes and to do so separately among individuals who did and those who did not report regular use of vitamin supplementation. RESEARCH DESIGN AND METHODS: The Insulin Resistance Atherosclerosis Study (IRAS) included 895 nondiabetic adults at baseline (including 303 with impaired glucose tolerance [IGT]), 148 of whom developed type 2 diabetes according to World Health Organization (WHO) criteria during the 5-year follow-up. At baseline, dietary vitamin E was estimated by a validated food frequency interview, usual supplement use was confirmed by supplement label, and plasma alpha-tocopherol was measured. Analyses were conducted separately for individuals who did (n = 318) and did not (n = 577) use vitamin E supplements. RESULTS: Among supplement nonusers, reported mean intake of vitamin E (mg alpha-tocopherol equivalents [alpha-TE]) did not differ between those who remained nondiabetic (n = 490) and those who developed diabetes (n = 87) (10.5 +/- 5.5 vs. 9.5 +/- 4.8 [means +/- SD], respectively, NS). After adjustment for demographic variables, obesity, physical activity, and other nutrients, the association remained nonsignificant (odds ratio [OR] 0.80, 95% CI 0.13-5.06) for the highest level of intake (> or =20 mg alpha-TE) compared with the lowest level (1-4 alpha-TE). However, results for plasma concentration of alpha-tocopherol showed a significant protective effect both before and after adjustment for potential confounders (adjusted OR 0.12, 95% CI 0.02-0.68, for the highest quintile vs. the lowest quintile; overall test for trend, P < 0.01). Among individuals who reported habitual use of vitamin E supplements (at least once per month in the year before baseline; 259 remained nondiabetic and 59 developed diabetes), no protective effect was observed for either reported intake of vitamin E or plasma concentration of alpha-tocopherol CONCLUSIONS: A protective effect of vitamin E may exist within the range of intake available from food. This effect may go undetected within studies of high-dose supplement use, which appears to hold no additional protective benefit.     

Association Between Insulin Resistance and Cardiovascular Disease Risk Varies According to Glucose Tolerance Status: A Nationwide Prospective Cohort Study

OBJECTIVETo investigate whether the association between insulin resistance and cardiovascular disease (CVD) differs by glucose tolerance status.RESEARCH DESIGN AND METHODSWe analyzed a nationwide sample of 111,576 adults without CVD at baseline, using data from the China Cardiometabolic Disease and Cancer Cohort Study. Insulin resistance was estimated by sex-specific HOMA of insulin resistance (HOMA-IR) quartiles for participants with normal glucose tolerance, prediabetes, or diabetes, separately, and by 1 SD of HOMA-IR for the overall study participants. We used Cox proportional hazards models to examine the association between insulin resistance and incident CVD according to glucose tolerance status and evaluate the CVD risk associated with the combined categories of insulin resistance and obesity in prediabetes and diabetes, as compared with normal glucose tolerance. Models were adjusted for age, sex, education attainment, alcohol drinking, smoking, physical activity, and diet quality.RESULTSIn participants with normal glucose tolerance, prediabetes, and diabetes defined by three glucose parameters, multivariable-adjusted hazard ratios (95% CIs) for incident CVD associated with the highest versus the lowest quartile of HOMA-IR were 1.03 (0.82–1.30), 1.23 (1.07–1.42), and 1.61 (1.30–2.00), respectively; the corresponding values for CVD per 1-SD increase in HOMA-IR were 1.04 (0.92–1.18), 1.12 (1.06–1.18), and 1.15 (1.09–1.21), respectively (P for interaction = 0.011). Compared with participants with normal glucose tolerance, in participants with prediabetes, the combination of the highest HOMA-IR quartile and obesity showed 17% (95% CI 2–34%) higher risk of CVD, while the combination of the lowest two HOMA-IR quartiles and nonobesity showed 15–17% lower risk of CVD. In participants with diabetes, the upper two HOMA-IR quartiles exhibited 44–77% higher risk of CVD, regardless of obesity status. Consistent findings were observed for glucose tolerance status defined by different combinations of glycemic parameters.CONCLUSIONSGlucose intolerance status exacerbated the association between insulin resistance and CVD risk. Compared with adults with normal glucose tolerance, adults with prediabetes who were both insulin resistant and obese exhibited higher risks of CVD, while in adults with diabetes, the CVD risk related to insulin resistance remained, regardless of obesity.     

Pericardial Adipose Tissue, Atherosclerosis, and Cardiovascular Disease Risk Factors: The Jackson Heart Study

OBJECTIVE

Pericardial adipose tissue (PAT), a regional fat depot that surrounds the heart, is associated with an unfavorable cardiometabolic risk factor profile. The associations among PAT, cardiometabolic risk factors, and coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) in African American populations have not been explored.

RESEARCH DESIGN AND METHODS

A total of 1,414 African Americans (35% men; mean ± SD age 58 ± 11 years) drawn from the Jackson Heart Study (JHS) underwent multidetector computed tomography assessment of abdominal visceral adipose tissue (VAT) and PAT between 2007 and 2009. Cardiometabolic risk factors, CAC, and AAC were examined in relation to increments of PAT and VAT.

RESULTS

PAT was significantly correlated with BMI, waist circumference, and VAT (r = 0.35, 0.46, and 0.69; all P < 0.0001). PAT (per 1-SD increase) was associated with elevated levels of systolic blood pressure (P < 0.04), fasting glucose, triglycerides, and C-reactive protein and lower levels of HDL (all P values<0.0001). PAT was also associated with metabolic syndrome (odds ratio [OR] 1.89; P < 0.0001), hypertension (1.48; P < 0.0006), and diabetes (1.40; P < 0.04); all associations were diminished after further adjustment for VAT (most P > 0.05). However, the association of PAT with CAC but not with AAC remained significant (OR 1.34 [95% CI 1.10–1.64]; P < 0.004) after multivariable and VAT adjustment.

CONCLUSIONS

PAT is significantly correlated with most cardiometabolic risk factors and CAC in the JHS cohort. The results suggest that PAT is an important VAT depot that may exert a local effect on the coronary vasculature.Pericardial adipose tissue (PAT) is an ectopic fat depot associated with measures of adiposity and metabolic risk factors and a predictor of coronary heart disease events (1–5). As a newly proposed marker of the visceral fat depot, PAT may exert a paracrine effect on nearby anatomic structures by actively secreting a number of proatherogenic and proinflammatory hormones, cytokines, and chemokines (1,6,7). However, the understanding of the relationship between the extra-abdominal visceral fat depot including PAT and cardiovascular disease (CVD) risk factors in nonwhite populations is lacking. In particular, African Americans have much higher rates of obesity and have experienced different levels of CVD risk in relation to obesity (8,9). Therefore, additional data are needed to clarify the role of PAT in relation to CVD in this population. Thus, to better understand the impact of obesity on metabolic risk factors in African Americans, the purpose of this study was to examine the associations of computed tomography (CT) measures of PAT with other measures of adiposity, such as BMI and abdominal visceral adipose tissue (VAT) as well as cardiometabolic risk factors.     

Novel Risk Factors and the Prediction of Type 2 Diabetes in the Atherosclerosis Risk in Communities (ARIC) Study

OBJECTIVE

The objective of this study was to determine potential added value of novel risk factors in predicting the development of type 2 diabetes beyond that provided by standard clinical risk factors.

RESEARCH DESIGN AND METHODS

The Atherosclerosis Risk in Communities (ARIC) Study is a population-based prospective cohort study in four U.S. communities. Novel risk factors were either measured in the full cohort or in a case-control sample nested within the cohort. We started with a basic prediction model, previously validated in ARIC, and evaluated 35 novel risk factors by adding them independently to the basic model. The area under the curve (AUC), net reclassification index (NRI), and integrated discrimination index (IDI) were calculated to determine if each of the novel risk factors improved risk prediction.

RESULTS

There were 1,457 incident cases of diabetes with a mean of >7.6 years of follow-up among 12,277 participants at risk. None of the novel risk factors significantly improved the AUC. Forced expiratory volume in 1 s was the only novel risk factor that resulted in a significant NRI (0.54%; 95% CI: 0.33–0.86%). Adiponectin, leptin, γ-glutamyl transferase, ferritin, intercellular adhesion molecule 1, complement C3, white blood cell count, albumin, activated partial thromboplastin time, factor VIII, magnesium, hip circumference, heart rate, and a genetic risk score each significantly improved the IDI, but net changes were small.

CONCLUSIONS

Evaluation of a large panel of novel risk factors for type 2 diabetes indicated only small improvements in risk prediction, which are unlikely to meaningfully alter clinical risk reclassification or discrimination strategies.A number of risk prediction tools for type 2 diabetes have been developed that could be used for opportunistic screening in clinical practice; however, at this time, there is no widely accepted risk prediction score that has been developed and validated in routine clinical practice (1,2). Developing a tool that successfully identifies those at high risk of type 2 diabetes is important because the disease is largely preventable through lifestyle and/or pharmacologic interventions (3). Therefore, the successful identification of at-risk individuals, via risk prediction models, would create greater opportunities for clinicians to intervene to prevent or delay the onset of type 2 diabetes and the complications associated with this disease (4).Within the last decade, a number of potential new risk factors for type 2 diabetes have been identified that are related to chronic inflammation, metabolic abnormalities, endothelial dysfunction, oxidative stress, and a prothrombotic state. Many of these factors have been found to be independently associated with type 2 diabetes in prospective cohort studies, including the Atherosclerosis Risk in Communities (ARIC) Study (5–21). Likewise, a number of common gene variants have been identified that are associated with type 2 diabetes in both candidate gene and genome-wide association studies. Because there is a possibility that one or more of these novel risk factors could serve in a tool for predicting type 2 diabetes, allowing clinicians to intervene and prevent the onset of disease, it is important to identify those risk factors that may refine and improve tools for risk prediction. Therefore, the purpose of this analysis is to identify novel risk factors that could improve type 2 diabetes risk prediction.     

Nonlinear Associations Between Cumulative Dietary Risk Factors and Cardiovascular Diseases,Cancer, and All-Cause Mortality: A Prospective Cohort Study From UK Biobank

ObjectiveTo develop a score from cumulative dietary risk factors and examine its nonlinear associations with cardiovascular disease (CVD) and cancer incidence and mortality, as well as all-cause mortality.Patients and MethodsThere were 422,702 participants from UK Biobank included in this prospective study. Cumulative dietary risk factors were represented using a score ranging from 0 (healthiest) to 9 (least healthy). This was derived from 9 food items based on current UK guidelines using baseline data. Associations between the cumulative score and health outcomes were investigated using nonlinear penalized cubic splines fitted in Cox proportional hazard models. Follow-up was conducted until June 2020 for mortality, and for incidence, up to June 2020 in England and March 2017 in Wales and Scotland.ResultsThe median follow-up period was 9.0 years for incidence outcomes and 9.3 years for mortality outcomes. Each 1-point increment in the cumulative dietary risk factors score was associated with higher risk for incidence and mortality of the outcomes studied. The highest risks were identified for mortality due to heart failure (8.0% higher), CVD, and ischemic heart disease (both 7.0% higher). In addition, a higher diet score accounted for 18.8% of all deaths, 4.47% of incident cases of CVD, 25.5% of CVD deaths, 7.7% of incident cancers, and 18.2% of all cancer deaths.ConclusionOur findings show that dietary risk factors contributed to a large proportion of CVD and cancer events, as well as deaths, among those who did not meet most dietary recommendations.     

Changes in Insulin Secretion and Insulin Sensitivity in Relation to the Glycemic Outcomes in Subjects With Impaired Glucose Tolerance in the Indian Diabetes Prevention Programme-1 (IDPP-1)

OBJECTIVE

The Indian Diabetes Prevention Programme-1 (IDPP-1) showed that lifestyle modification (LSM) and metformin were effective for primary prevention of diabetes in subjects with impaired glucose tolerance (IGT). Among subjects followed up for 3 years (n = 502), risk reductions versus those for the control group were 28.5, 26.4, and 28.2% in LSM, metformin (MET), and LSM plus MET groups, respectively. In this analysis, the roles of changes in secretion and action of insulin in improving the outcome were studied.

RESEARCH DESIGN AND METHODS

For this analysis, 437 subjects (93 subjects with normoglycemia [NGT], 150 subjects with IGT, and 194 subjects with diabetes) were included. Measurements of anthropometry, plasma glucose, and plasma insulin at baseline and at follow-up were available for all of them. Indexes of insulin resistance (homeostasis model assessment of insulin resistance) and β-cell function (insulinogenic index [ΔI/G]: 30-min fasting insulin divided by 30-min glucose) were also analyzed in relation to the outcome.

RESULTS

Subjects with IGT showed a deterioration in β-cell function with time. Individuals with higher insulin resistance and/or low β-cell function at baseline had poor outcome on follow-up. In relation to no abnormalities, the highest incidence of diabetes occurred when both abnormalities coexisted (54.9 vs. 33.7%, χ² = 7.53, P = 0.006). Individuals having abnormal insulin resistance (41.1%) or abnormal ΔI/G (51.2%, χ² = 4.87, P = 0.027 vs. no abnormalities) had lower incidence. Normal β-cell function with improved insulin sensitivity facilitated reversal to NGT, whereas deterioration in both resulted in diabetes. The beneficial changes were better with intervention than in the control group. Intervention groups had higher rates of NGT and lower rates of diabetes.

CONCLUSIONS

In the IDPP-1 subjects, beneficial outcomes occurred because of improved insulin action and sensitivity caused by the intervention strategies.Primary prevention studies in diabetes have been done in subjects with a high risk for diabetes, such as those with impaired glucose tolerance (IGT) (1–6) or with a history of gestational diabetes mellitus (7). Lifestyle modification (LSM) (1–5) and/or pharmacological agents such as metformin (MET) (1,5) and glitazones (6) have been shown to be effective in reducing the rate of conversion of IGT to diabetes in different ethnic groups. The benefits are seen in association with weight reduction in the obese population (1,2) or without significant weight changes in relatively nonobese population (3,5). The mechanisms that result in the beneficial changes are associated with two important pathophysiological components, namely impaired secretion and impaired action of insulin.The Indian Diabetes Prevention Programme-1 (IDPP-1) had shown that moderate, but consistent, LSM or use of MET reduced the risk of deterioration of IGT to diabetes by 28% in relation to that in a control group who had no intervention in a 3-year follow-up period (5). Combining LSM with MET showed no added benefit.IGT, an intermediate state in the natural history of type 2 diabetes, is characterized by a worsening in insulin resistance and insulin secretion (8). Asian Indians have higher rates of insulin resistance than Europeans and other white populations despite being relatively nonobese (9,10).The chief pathophysiological components of type 2 diabetes, namely impaired secretion and action of insulin are detectable many years before the diagnosis of clinical diabetes (11). A combined occurrence of both defects due to gradual deterioration, eventually results in diabetes. This analysis was done to identify the changes in insulin secretion and insulin action that produced the improved outcome with the primary prevention strategies in the IDPP-1 cohort.     

High Burden of Subclinical and Cardiovascular Disease Risk in Adults With Metabolically Healthy Obesity: The Atherosclerosis Risk in Communities (ARIC) Study

OBJECTIVEIt is controversial whether adults who are obese but “metabolically healthy” have cardiovascular disease (CVD) risk comparable with that of normal-weight adults. High-sensitivity cardiac troponin T (hs-cTnT), a biomarker of myocardial damage, is useful in characterizing subclinical CVD. We categorized obesity phenotypes and studied their associations with subclinical and clinical CVD and CVD subtypes, including heart failure (HF).RESEARCH DESIGN AND METHODSWe conducted cross-sectional and prospective analyses of 9,477 adults in the Atherosclerosis Risk in Communities (ARIC) study. We used the Adult Treatment Panel III criteria and BMI to define obesity phenotypes as follows: metabolically healthy normal weight, metabolically healthy overweight, metabolically healthy obese, metabolically unhealthy normal weight, metabolically unhealthy overweight, and metabolically unhealthy obese.RESULTSAt baseline (1990–1992), mean age was 56 years, 56% were female, 23% were Black, and 25% had detectable hs-cTnT (≥6 ng/L). Over a median of 17 years of follow-up, there were 2,603 clinical CVD events. Those with the metabolically healthy obese (hazard ratio [HR] 1.38, 95% CI 1.15–1.67), metabolically unhealthy normal weight (HR 1.51, 95% CI 1.30–1.76), metabolically unhealthy overweight (HR 1.60, 95% CI 1.41–1.82), and metabolically unhealthy obese (HR 2.14, 95% CI 1.88–2.44) phenotypes had higher CVD risks in comparison with metabolically healthy normal weight. Detectable hs-cTnT (≥6 ng/L) was associated with higher CVD risk, even among metabolically healthy normal-weight adults. Metabolically healthy obese adults had higher HF risk (HR 1.65, 95% CI 1.30–2.09) in comparison with metabolically healthy normal weight.CONCLUSIONSThe metabolically healthy obese phenotype was associated with excess burden of clinical CVD, primarily driven by an excess risk of HF. hs-cTnT was useful in stratifying CVD risk across all obesity phenotypes, even among obese individuals who appear otherwise metabolically healthy.     

高血压病心肌重构与胰岛素样生长因子-1和胰岛素抵抗的相关性研究

目的探讨原发性高血压病心肌重构与胰岛素样生长因子-1(IGF-1 )和胰岛素抵抗(IR)之间的关系.方法对35例原发性高血压(EH)患者与26例正常者分别测定室间隔心肌背向散射积分(IBS)、IBS周期变异幅度(CVIB)及左心室质量指数(LVMI).用放射免疫法测定血清IGF-1、胰岛素水平及计算胰岛素敏感指数(ISI).结果 (1) EH组室间隔IBS、LVMI、IGF-1均高于正常组(P＜0 .01～0.05),ISI低于正常对照组(P＜0.05);(2) EH组 LVMI与IGF-1、IBS呈正相关(相关系数分别为0.424和0.478,P＜0.01和<0.05). 结论 LVMI与IGF-1密切相关, IGF-1和IR可能是参与高血压左室心肌重构的重要因素.     

Effect of Insulin Glargine and n-3FA on Carotid Intima-Media Thickness in People With Dysglycemia at High Risk for Cardiovascular Events: The Glucose Reduction and Atherosclerosis Continuing Evaluation Study (ORIGIN-GRACE)

OBJECTIVE

To evaluate the effects of insulin glargine and n-3 polyunsaturated fatty acid (n-3FA) supplements on carotid intima-media thickness (CIMT).

RESEARCH DESIGN AND METHODS

We enrolled 1,184 people with cardiovascular (CV) disease and/or CV risk factors plus impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes in a randomized multicenter 2 × 2 factorial design trial. Participants received open-label insulin glargine (targeting fasting glucose levels ≤5.3 mmol/L [95 mg/dL]) or standard glycemic care and double-blind therapy with a 1-g capsule of n-3FA or placebo. The primary trial outcome was the annualized rate of change in maximum CIMT for the common carotid, bifurcation, and internal carotid artery segments. Secondary outcomes were the annualized rates of change in maximum CIMT for the common carotid and the common carotid plus bifurcation, respectively. Baseline followed by annual ultrasounds were obtained during a median follow-up of 4.9 years.

RESULTS

Compared with standard care, insulin glargine reduced the primary CIMT outcome, but the difference was not statistically significant (difference = 0.0030 ± 0.0021 mm/year; P = 0.145) and significantly reduced the secondary CIMT outcomes (differences of 0.0033 ± 0.0017 mm/year [P = 0.049] and 0.0045 ± 0.0021 mm/year [P = 0.032], respectively). There were no differences in the primary and secondary outcomes between the n-3FA supplement and placebo groups.

CONCLUSIONS

In people with CV disease and/or CV risk factors and dysglycemia, insulin glargine used to target normoglycemia modestly reduced CIMT progression, whereas daily supplementation with n-3FA had no effect on CIMT progression.Atherosclerosis is the major cause of death and disability in people with type 2 diabetes and lesser degrees of dysglycemia (1,2). Large epidemiological studies show consistent independent associations between glycemia and cardiovascular (CV) risk (1–4), and the metabolic abnormalities associated with dysglycemia promote atherosclerosis (5). Exogenous insulin can provide effective glycemic control, but its effects on atherosclerosis are unknown. Moreover, some studies suggest possible proatherogenic effects (6,7).Essential long-chain n-3 polyunsaturated fatty acids (n-3FA) may have beneficial effects on atherosclerosis (8). Higher intake of fish or n-3FA supplements is associated with lower rates of coronary heart disease and death (9,10) and lower atherosclerotic burden (11,12), and some, but not all, previous trials reported reduced CV events in patients receiving n-3FA supplements (13–16). The effects of these supplements on human atherosclerosis progression were evaluated in a few small studies, which were inconclusive (17–21).Therefore, we evaluated the effects of insulin glargine and n-3FA supplements on carotid intima-media thickness (CIMT) in people with dysglycemia and additional risk factors for atherosclerosis progression in a substudy of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial (22–24).     

Relationship Between Baseline Glycemic Control and Cognitive Function in Individuals With Type 2 Diabetes and Other Cardiovascular Risk Factors: The Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial

OBJECTIVE—Diabetes is associated with cognitive decline and dementia. However, the relationship between the degree of hyperglycemia and cognitive status remains unclear. This was explored using baseline cognitive measures collected in the ongoing Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.RESEARCH DESIGN AND METHODS—The relationship of A1C and fasting plasma glucose (FPG) levels to performance on four cognitive tests was assessed, adjusting for age and other determinants of cognitive status. The tests were the Digit Symbol Substitution Test (DSST), Mini Mental Status Examination (MMSE), Rey Auditory Verbal Learning Test, and Stroop Test.RESULTS—A statistically significant age-adjusted association was observed between the A1C level and the score on all four cognitive tests. Specifically, a 1% higher A1C value was associated with a significant 1.75-point lower DSST score (95% CI −1.22 to −2.28; P < 0.0001), a 0.20-point lower MMSE score (−0.11 to −0.28; P < 0.0001), a 0.11-point lower memory score (−0.02 to −0.19, P = 0.0142), and a worse score (i.e., 0.75 s more) on the Stroop Test (1.31–0.19, P = 0.0094). The association between the DSST score and A1C persisted in all multiple linear regression models. FPG was not associated with test performance.CONCLUSIONS—Higher A1C levels are associated with lower cognitive function in individuals with diabetes. The effect of glucose lowering on cognitive function will be determined by the ongoing ACCORD-MIND trial.Mild cognitive impairment represents an important phase on the path from normal cognitive function to dementia. Affected individuals have measurable deficits in cognitive function that may affect their ability to master complex behaviors such as those required for diabetes self-care (1). Moreover, because mild cognitive impairment is more common than frank dementia, its potential population health impact is high. For example, the prevalence of mild cognitive impairment (i.e., predementia) in the Cardiovascular Health Study was 19% in individuals aged >65 years and 29% in those aged >85 years.Diabetes is associated with premature mortality and is a risk factor for mild cognitive impairment and both vascular dementia (2–5) and Alzheimer''s disease (2,6–8). Indeed, individuals with diabetes are ∼1.5 times more likely to experience cognitive decline and frank dementia than individuals without diabetes (9). Precise reasons for the high morbidity and mortality of diabetes remain unknown; however, many studies have demonstrated a link between many of the consequences of diabetes and the degree of hyperglycemia as measured by the A1C or glucose level. Emerging evidence suggests that a relationship between measures of short-term glucose control and cognitive function also exists. For example, in a cross-sectional analysis of 378 high-functioning individuals with diabetes, higher A1C but not fasting plasma glucose (FPG) levels were consistently associated with lower scores on two cognitive tests (10). Smaller studies reported a similar relationship with indexes of dysglycemia (11,12); nevertheless, details regarding such a relationship remain unclear.The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is a randomized controlled trial of 10,251 individuals with established type 2 diabetes who have a high risk for cardiovascular disease (CVD) and whose screening A1C was ≥7.5%. It will determine whether therapeutic strategies targeting normoglycemia, normotension, and/or a normal lipid profile can reduce the rate of cardiovascular events more than standard therapeutic approaches in individuals with type 2 diabetes and either previous cardiovascular events or additional cardiovascular risk factors. The Memory in Diabetes (MIND) substudy of the ACCORD trial will determine whether these interventions reduce cognitive decline and structural brain changes in a subset of 2,977 randomized individuals from sites that participated in the MIND substudy. Baseline data from the MIND substudy provide a unique opportunity to assess the cross-sectional relationship between cognitive function and two different measures of glycemia: A1C and FPG.     

Low protein C and incidence of ischemic stroke and coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study

Summary.  Background:  Protein C is an important plasma natural anticoagulant. Although protein C deficiency increases risk of venous thrombosis, it remains uncertain whether low protein C increases risk of atherothrombosis. Objective:  To examine whether low protein C may be a risk factor for ischemic stroke or coronary events in a prospective population-based study. Patients/Methods:  The Atherosclerosis Risk in Communities Study assessed protein C antigen by ELISA at baseline in 1987–89 and followed participants ( n  =   13 879) for incident ischemic stroke or coronary events through 2005. Results:  Over a median of 16.9 years of follow-up, 613 ischemic strokes and 1257 coronary heart disease events occurred. Protein C was inversely associated with incidence of ischemic stroke. Adjusted for multiple risk factors, the rate ratios (95% CIs) from highest to lowest quintiles were 1.0, 1.16 (0.90–1.50), 1.22 (0.94–1.58), 1.18 (0.90–1.55) and 1.52 (1.17–1.98). This inverse association was stronger for non-lacunar and cardioembolic stroke than for lacunar stroke. In contrast, there was a positive association between protein C and coronary heart disease in incompletely adjusted models, but no association after adjustment for plasma lipids. Conclusions:  In this cohort study, low protein C was a risk factor for incident ischemic stroke but not coronary heart disease. Levels of protein C associated with stroke risk were not restricted to the traditional 'deficient' range for protein C (< 0.5 percentile), suggesting that other etiologies for a lower protein C, or genetic variants associated with more subtle changes in protein C, are playing a role in disease pathogenesis.