Hypertriglyceridemic Waist Phenotype Predicts Increased Visceral Fat in Subjects With Type 2 Diabetes

OBJECTIVE

Greater accumulation of visceral fat is strongly linked to risk of cardiovascular disease. However, elevated waist circumference by itself does not always identify individuals with increased visceral fat.

RESEARCH DESIGN AND METHODS

We examined 375 subjects with type 2 diabetes from the CHICAGO cohort for presence of hypertriglyceridemic waist phenotype (waist circumference >90 cm in men or >85 cm in women, in conjunction with a plasma triglyceride concentration of ≥177 mg/dl) to determine its usefulness for identifying subjects with increased amounts of visceral fat. We divided subjects into three groups: group 1 (low waist circumference and low triglycerides; waist circumference ≤90 cm in men or ≤85 cm in women and triglyceride <177 mg/dl, n = 18), group 2 (high waist circumference and low triglycerides; waist circumference >90 cm in men or >85 cm in women and triglycerides <177 mg/dl, n = 230), and group 3 (high waist circumference and high triglycerides; waist circumference >90 cm in men or >85 cm in women and triglycerides ≥177 mg/dl, n = 127).

RESULTS

Subjects in group 3 had significantly higher visceral fat (P < 0.0001), A1C (P < 0.01), and coronary artery calcium (P < 0.05) compared with group 2, despite similar age, BMI, and waist circumference. The relationship of the phenotype to atherosclerosis, however, was attenuated by adjustment for HDL cholesterol, triglyceride-rich lipoprotein cholesterol, apolipoprotein B, or LDL particle number.

CONCLUSIONS

The presence of hypertriglyceridemic waist phenotype in subjects with type 2 diabetes identifies a subset with greater degree of visceral adiposity. This subset also has greater degree of subclinical atherosclerosis that may be related to the proatherogenic lipoprotein changes.Despite the strong association of obesity, especially abdominal obesity, to metabolic and cardiovascular disease, not all obese individuals carry the same metabolic and cardiovascular risk (1,2). The metabolic syndrome (a cluster of metabolic abnormalities that include glucose intolerance, central obesity, dyslipidemia, and hypertension) has been used to identify individuals at high risk for type 2 diabetes and cardiovascular disease (3,4). A hypertriglyceridemic waist phenotype defined as an elevated waist circumference (>90 cm in men or >85 cm in women) along with an elevated plasma triglyceride concentration (defined as a level ≥177 mg/dl) has been proposed and shown to be a stronger marker of cardiovascular risk and a better predictor of cardiovascular disease than the metabolic syndrome in nondiabetic subjects (5,6). Deposition of visceral fat may be most closely linked to the metabolic and cardiovascular risk associated with both the metabolic syndrome and the hypertriglyceridemic waist phenotype (6).The CHICAGO cohort is a well-characterized group of men and women with type 2 diabetes who had measurements of abdominal fat depots by computed tomography (CT) and coronary artery calcium (CAC) by electron-beam tomography (7–9). We evaluated the prevalence of hypertriglyceridemic waist phenotype in this cohort and report its usefulness for identifying subjects with diabetes who have higher levels of visceral fat. We further examined the metabolic and cardiovascular impact of this phenotype in subjects with type 2 diabetes.     

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.     

Type 2 Diabetes and 10-Year Risk of Dementia and Cognitive Impairment Among Older Mexican Americans

OBJECTIVE

Type 2 diabetes has been linked with increased risk of dementia and cognitive impairment among older adults and with premature mortality in young and middle-aged adults. No studies have evaluated the association between diabetes and dementia among Mexican Americans, a population with a high burden of diabetes. We evaluated the association of diabetes with incidence of dementia and cognitive impairment without dementia (CIND) among older Mexican Americans while accounting for competing risk from death.

RESEARCH DESIGN AND METHODS

This study included 1,617 participants 60–98 years of age from the Sacramento Area Latino Study on Aging followed up to 10 years from 1998. We evaluated the association between diabetes and dementia/CIND with competing risk regression models.

RESULTS

Participants free of dementia/CIND at baseline (n = 1,617) were followed annually up to 10 years. There were 677 (41.9%) participants with diabetes, 159 (9.8%) incident dementia/CIND cases, and 361 (22.3%) deaths. Treated and untreated diabetes (hazard ratio 2.12 [95% CI 1.65–2.73] and 2.15 [1.58–2.95]) and dementia/CIND (2.48 [1.75–3.51]) were associated with an increased risk of death. In models adjusted for competing risk of death, those with treated and untreated diabetes had an increased risk of dementia/CIND (2.05 [1.41–2.97] and 1.55 [0.93–2.58]) compared with those without diabetes.

CONCLUSIONS

These findings provide evidence that the association between type 2 diabetes and dementia/CIND among Mexican Americans remains strong after accounting for competing risk of mortality. Treatments that modify risk of death among those with diabetes may change future dementia risk.Type 2 diabetes is a common and established risk factor for vascular disease and mortality (1). Prevalence of type 2 diabetes is higher among older adults, and several minority racial/ethnic groups in the U.S. are disproportionally affected. Several prospective epidemiologic studies have found that older adults with type 2 diabetes have an approximately twofold increased risk of dementia (2–9), but others have not (10–13), and the mechanism is controversial (14,15). Possible mechanisms linking type 2 diabetes to dementia and cognitive impairment include chronic hyperglycemia or hypoglycemia, hyperinsulinemia or insulin resistance, effects of inflammatory cytokines and oxidative stress, and β-amyloid deposition in the brain (14,15). The type 2 diabetes–dementia association has not been evaluated among Mexican Americans, a population with a high prevalence of type 2 diabetes (16), poor glycemic control among those with diabetes (17), and higher rates of complications compared with non-Hispanic whites (18).Mortality occurs at younger ages among people with type 2 diabetes (19). Mortality rates are nearly twice as high among people with type 2 diabetes compared with people without diabetes (19–21). Cognitive decline is also associated with higher mortality rates (22,23). Premature death in those with diabetes may influence the risk of dementia or cognitive impairment associated with type 2 diabetes. Previous studies of the association between type 2 diabetes and dementia have not accounted for competing risk of death. In this paper, we evaluate the association between type 2 diabetes and incidence of dementia and cognitive impairment without dementia (CIND) in a cohort of older Mexican Americans followed for 10 years, accounting for the competing risk of death.     

Demands of Multiple Behavior Change in Type 2 Diabetes Risk Reduction

The purpose of this study was to explore individual experiences of participation in multiple activities recommended for type 2 diabetes risk reduction. Twelve individuals at risk for type 2 diabetes described their experiences regarding risk-reduction activities. A grounded theory method guided data collection and analysis. Data analysis revealed facilitators and inhibitors associated with participation in recommended multiple behavior change for type 2 diabetes risk reduction. Our findings emphasize social and personal factors that increase or decrease the likelihood of adherence to prevention recommendations. Findings suggest that health care providers provide structured yet individualized recommendations to support multiple behavior change efforts.     

Lipid and Inflammatory Cardiovascular Risk Worsens Over 3 Years in Youth With Type 2 Diabetes: The TODAY clinical trial

OBJECTIVE

Type 2 diabetes increases cardiovascular risk. We examined lipid profiles and inflammatory markers in 699 youth with recent-onset type 2 diabetes in the TODAY clinical trial and compared changes across treatment groups: metformin alone (M), metformin plus rosiglitazone (M+R), and metformin plus intensive lifestyle program (M+L).

RESEARCH DESIGN AND METHODS

Multiethnic youth with type 2 diabetes received M, M+R, or M+L. Statin drugs were begun for LDL cholesterol (LDL) ≥130 mg/dL or triglycerides ≥300 mg/dL. Lipids, apolipoprotein B (apoB), LDL particle size, high-sensitivity c-reactive protein (hsCRP), homocysteine, plasminogen activator inhibitor-1 (PAI-1), and HbA_1c were measured over 36 months or until loss of glycemic control.

RESULTS

LDL, apoB, triglycerides, and non-HDL cholesterol (HDL) rose over 12 months and then stabilized over the next 24 months. Participants with LDL ≥130 mg/dL or using LDL-lowering therapy increased from 4.5 to 10.7% over 36 months, while 55.9% remained at LDL goal (<100 mg/dL) over that time. Treatment group did not impact LDL, apoB, or non-HDL. Small dense LDL (particle size, ≤0.263 relative flotation rate) was most common in M. Triglycerides were lower in M+L than M, and M+L attenuated the negative effect of hyperglycemia on triglycerides and HDL in females. hsCRP, PAI-1, and homocysteine increased over time. However, hsCRP was lower in M+R compared with M or M+L.

CONCLUSIONS

Dyslipidemia and chronic inflammation were common in youth with type 2 diabetes and worsened over time. Diabetes treatment, despite some treatment group differences in lipid and inflammatory marker change over time, is generally inadequate to control this worsening risk.The marked increase in type 2 diabetes in adolescents and youth has raised the specter of early cardiovascular disease (CVD) in affected individuals. In adults with type 2 diabetes, the risks of diabetes-specific microvascular complications are largely related to the level of glycemia and duration of disease (1–3). Indicators of atherosclerosis, or macrovascular disease, are already present in youth with type 2 diabetes and dyslipidemia (4,5). Youth with type 2 diabetes are known to have higher levels of LDL cholesterol (LDL), triglycerides, and non-HDL cholesterol (HDL) and lower levels of HDL than youth without diabetes or youth with type 1 diabetes (6). Elevated inflammatory markers have also been reported in adolescents with type 2 diabetes (7). However, the true prevalence of dyslipidemia and the proinflammatory state in youth and adolescents with type 2 diabetes, the evolution of risk over time, and whether glucose-lowering interventions ameliorate the atherogenic profile are unknown. The TODAY study provides the opportunity to address these critical questions and determine whether three diabetes treatments differentially affected cardiovascular risk factors.TODAY was a multiethnic, multicenter clinical trial of newly diagnosed children and adolescents with type 2 diabetes randomized to one of three interventions: metformin alone (M; n = 232), metformin plus rosiglitazone (M+R; n = 233), or metformin plus an intensive lifestyle program (M+L; n = 234) (8–10). The primary results have recently been published in detail (10). Briefly, of the 699 TODAY participants, 319 (45.6%) reached the primary outcome (loss of glycemic control defined as HbA_1c ≥8% [64 mmol/mol] for 6 months or inability to wean from temporary insulin therapy within 3 months after metabolic decompensation) over an average follow-up of 3.86 years (10). Regarding glycemic control, M+R was superior to M (P = 0.006); M+L was intermediate but not different from M (10).We hypothesized that 1) lipid profiles (LDL, non-HDL, apolipoprotein B [apoB], LDL particle density, triglycerides, and HDL) and inflammatory markers (high-sensitivity c-reactive protein [hsCRP], homocysteine, plasminogen activator inhibitor-1 [PAI-1], and nonesterified fatty acids [NEFA]) would indicate increased CVD risk in youth with recent-onset type 2 diabetes; 2) in the setting of standardized protocol-driven clinical management of hyperlipidemia in a randomized clinical trial for 36 months (or until attainment of primary outcome, loss of glycemic control), cardiovascular risk change would improve more with M+R and M+L than with M. Associations of race-ethnicity and sex with differences in dyslipidemia and inflammatory markers were also assessed.     

Differential Association Between HDL Subclasses and the Development of Type 2 Diabetes in a Prospective Study of Japanese Americans

OBJECTIVERecent studies have suggested that HDL cholesterol is inversely associated with the development of type 2 diabetes. However, little is known about the association between different HDL subclasses and the risk for future type 2 diabetes.RESULTSIn univariate analysis, total HDL and HDL2 cholesterol were inversely associated with the incidence of type 2 diabetes, but HDL3 cholesterol was not. In multivariate analysis, total HDL cholesterol (odds ratio per 1-SD increment, 0.72 [95% CI 0.52–0.995], P = 0.047) and HDL2 cholesterol (odds ratio per 1-SD increment, 0.64 [95% CI 0.44–0.93], P = 0.018) were inversely associated with the risk for type 2 diabetes independent of age, sex, BMI, waist circumference, family history of diabetes, lifestyle factors, systolic blood pressure, lipid-lowering medication use, triglyceride level, HOMA-insulin resistance, and 2-h glucose; however, HDL3 cholesterol was not associated with diabetes risk. The association between diabetes risk and total HDL and HDL2 cholesterol became insignificant after adjustment for VAT area.CONCLUSIONSSubjects with higher HDL2 cholesterol were at lower risk for incident type 2 diabetes, but this association was confounded by and not independent of VAT. Higher HDL3 cholesterol was not associated with diabetes risk.     

Statin Therapy and Risk of Developing Type 2 Diabetes: A Meta-Analysis

OBJECTIVE

Although statin therapy reduces cardiovascular risk, its relationship with the development of diabetes is controversial. The first study (West of Scotland Coronary Prevention Study [WOSCOPS]) that evaluated this association reported a small protective effect but used nonstandardized criteria for diabetes diagnosis. However, results from subsequent hypothesis-testing trials have been inconsistent. The aim of this meta-analysis is to evaluate the possible effect of statin therapy on incident diabetes.

RESEARCH DESIGN AND METHODS

A systematic literature search for randomized statin trials that reported data on diabetes through February 2009 was conducted using specific search terms. In addition to the hypothesis-generating data from WOSCOPS, hypothesis-testing data were available from the Heart Protection Study (HPS), the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), and the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA), together including 57,593 patients with mean follow-up of 3.9 years during which 2,082 incident diabetes cases accrued. Weighted averages were reported as risk ratios (RRs) with 95% CIs using a random-effects model. Statistical heterogeneity scores were assessed with the Q and I² statistic.

RESULTS

In the meta-analysis of the hypothesis-testing trials, we observed a small increase in diabetes risk (RR 1.13 [95% CI 1.03–1.23]) with no evidence of heterogeneity across trials. However, this estimate was attenuated and no longer significant when the hypothesis-generating trial WOSCOPS was included (1.06 [0.93–1.25]) and also resulted in significant heterogeneity (Q 11.8 [5 d.f.], P = 0.03, I² = 57.7%).

CONCLUSIONS

Although statin therapy greatly lowers vascular risk, including among those with and at risk for diabetes, the relationship of statin therapy to incident diabetes remains uncertain. Future statin trials should be designed to formally address this issue.The role of statins in primary and secondary prevention of cardiovascular disease (CVD), including among patients with type 2 diabetes, is well established. However, the relationship of statin therapy to incident type 2 diabetes is controversial. In the first study that evaluated this association using the West of Scotland Coronary Prevention Study (WOSCOPS) published in 2001, pravastatin at 40 mg/day was reported to be associated with a 30% risk reduction for incident diabetes, although the upper bound of the 95% CI for that observation was 0.99 (1). The WOSCOPS, however, required an increase in fasting glucose ≥36 mg/dl above baseline for diagnosis of incident diabetes in addition to the standard diagnostic criteria of fasting glucose ≥126 mg/dl. Subsequent hypothesis-testing analyses from randomized trials of pravastatin, simvastatin, atorvastatin, and rosuvastatin have suggested either no risk or a slight hazard; in one head-to-head comparison, use of atorvastatin 80 mg was slightly more likely than 40 mg pravastatin to result in incident diabetes, data which have suggested to some that this effect may relate to dose or potency (2–6). Further, in the recent Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), statin treatment was associated with a small increase in physician-diagnosed diabetes, although without an increase in glucose levels (relative risk [RR] 1.25 [95% CI 1.05–1.49]). Given these uncertainties, we conducted a meta-analysis of available trials to identify what role, if any, statin therapy might have in the development of type 2 diabetes.     

Visceral adiposity and risk of type 2 diabetes: a prospective study among Japanese Americans

OBJECTIVE: We conducted a prospective study among Japanese Americans of diabetes incidence in relation to visceral and regional adiposity, fasting insulin and C-peptide, and a measure of insulin secretion, because little prospective data exist on these associations. RESEARCH DESIGN AND METHODS: Baseline variables included plasma glucose, C-peptide, and insulin measured after an overnight fast and 30 and 120 min after a 75-g oral glucose tolerance test; abdominal, thoracic, and thigh fat areas by computed tomography (CT); BMI (kg/m2); and insulin secretion (incremental insulin response [IIR]). RESULTS: Study subjects included 290 second-generation (nisei) and 230 third-generation (sansei) Japanese Americans without diabetes, of whom 65 and 13, respectively, developed diabetes. Among nisei, significant predictors of diabetes risk for a 1 SD increase in continuous variables included intra-abdominal fat area (IAFA) (odds ratio, 95% CI) (1.6, 1.1-2.3), fasting plasma C-peptide (1.4, 1.1-1.8), and the IIR (0.5, 0.3-0.9) after adjusting for age, sex, impaired glucose tolerance, family diabetes history, and CT-measured fat areas other than intra-abdominal. Intra-abdominal fat area remained a significant predictor of diabetes incidence even after adjustment for BMI, total body fat area, and subcutaneous fat area, although no measure of regional or total adiposity was related to development of diabetes. Among sansei, all adiposity measures were related to diabetes incidence, but, in adjusted models, only IAFA remained significantly associated with higher risk (2.7, 1.4-5.4, BMI-adjusted). CONCLUSIONS: Greater visceral adiposity precedes the development of type 2 diabetes in Japanese Americans and demonstrates an effect independent of fasting insulin, insulin secretion, glycemia, total and regional adiposity, and family history of diabetes.     

Chronotype Is Independently Associated With Glycemic Control in Type 2 Diabetes

OBJECTIVE

To examine whether chronotype and daily caloric distribution are associated with glycemic control in patients with type 2 diabetes independently of sleep disturbances.

RESEARCH DESIGN AND METHODS

Patients with type 2 diabetes had a structured interview and completed questionnaires to collect information on diabetes history and habitual sleep duration, quality, and timing. Shift workers were excluded. A recently validated construct derived from mid-sleep time on weekends was used as an indicator of chronotype. One-day food recall was used to compute the temporal distribution of caloric intake. Hierarchical linear regression analyses controlling for demographic and sleep variables were computed to determine whether chronotype was associated with HbA_1c values and whether this association was mediated by a higher proportion of caloric intake at dinner.

RESULTS

We analyzed 194 completed questionnaires. Multiple regression analyses adjusting for age, sex, race, BMI, insulin use, depressed mood, diabetes complications, and perceived sleep debt found that chronotype was significantly associated with glycemic control (P = 0.001). This association was partially mediated by a greater percentage of total daily calories consumed at dinner.

CONCLUSIONS

Later chronotype and larger dinner were associated with poorer glycemic control in patients with type 2 diabetes independently of sleep disturbances. These results suggest that chronotype may be predictive of disease outcomes and lend further support to the role of the circadian system in metabolic regulation.The circadian system, controlled by the master circadian clock located in the suprachiasmatic nuclei of the hypothalamus, plays a major role in regulating daily rhythms of sleep/wake and various metabolic outputs, such as feeding behavior, peripheral tissue metabolism, and hormone secretions (1–3). Despite having this genetically regulated master circadian clock, humans living in modern industrialized societies with 24-h access to light often engage in behaviors that are inappropriately timed relative to their endogenous circadian rhythms. This mismatch in timing is termed “circadian misalignment” and has been associated with a number of negative health outcomes. Night shift work is an example of severe circadian misalignment, as workers are awake, active, and eating during their circadian night and trying to sleep and fast during their circadian day. Epidemiologic studies reveal that shift work is associated with health problems including peptic ulcer disease, coronary heart disease, and metabolic syndrome, as well as certain types of cancers (4). In controlled laboratory studies, experimentally induced circadian misalignment in healthy human volunteers resulted in impaired glucose tolerance (5,6). In animal experiments, mice fed a high-fat diet during their inactive period gained significantly more weight than mice fed during their active phase, despite consuming the equivalent amount of calories (7). Taken together, these data suggest that severe circadian misalignment involving eating and sleeping at an abnormal circadian time leads to impaired energy metabolism.Many individuals in modern society experience a form of mild circadian misalignment, especially during the work or school week as they follow social rhythms imposed by professional obligation, school schedules, family, and other commitments (8). The degree of misalignment is dependent on the individual’s “chronotype” (8). Chronotype is a construct that captures an individual’s preference for being a “morning” or “evening” person. Late chronotype is typically associated with a greater degree of misalignment between social rhythms and the circadian clock (8). This misalignment phenomenon has been termed “social jetlag,” as it resembles the condition experienced after traveling across time zones (8) and can be observed by comparing the difference in sleep timing between work/school days and free days. In a large population study, larger amounts of social jetlag were recently reported to be associated with higher BMI in overweight individuals (9). In addition, a recent study found that patients with type 2 diabetes had significantly later bedtimes and wake times than participants without diabetes, suggesting that chronotype may play a role in glucose metabolism (10).In addition to chronic circadian misalignment, late chronotypes or “evening types” tend to minimize or skip breakfast (11,12). Therefore, the daily distribution of food intake may be mismatched with circadian-controlled metabolic rhythms. It is well recognized that glucose tolerance is worse in the evening (13), suggesting that eating late may result in adverse metabolic consequences. Indeed, a study of healthy volunteers reported that the amount of calories consumed after 8:00 p.m. predicted a higher BMI after controlling for sleep timing and duration (14), suggesting that the timing of food intake across the waking day is of metabolic relevance.To date, little is known about chronotypic variations in patients with type 2 diabetes and the potential associations with glycemic control. There is abundant evidence that sleep disturbances such as short sleep duration and poor sleep quality are linked to the risk of diabetes and obesity, as well as glycemic control in subjects with type 2 diabetes (15,16), but little is known about the association between chronotype and metabolism independently of these sleep characteristics. The aim of this study was to examine whether chronotype was independently associated with glycemic control in patients with type 2 diabetes. We hypothesized that late chronotype would be associated with worse glycemic control independently of sleep disturbances. Because the distribution of food intake across the day is associated with chronotype, we also examined whether daily caloric distribution contributed to glycemic control. We hypothesized that a greater percentage of daily calories consumed at dinner would be associated with worse glycemic control.     

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.     

Transthyretin Predicts Cardiovascular Outcome in Hemodialysis Patients With Type 2 Diabetes

OBJECTIVE

BMI and albumin are commonly accepted parameters to recognize wasting in dialysis patients and are powerful predictors of morbidity and mortality. However, both parameters reveal limitations and may not cover the entire range of patients with wasting. The visceral protein transthyretin (TTR) may be helpful in overcoming the diagnostic and prognostic gap. Therefore, the aim of this study was to assess the association of TTR with morbidity and mortality in hemodialysis patients.

RESEARCH DESIGN AND METHODS

The TTR concentration was determined in plasma samples of 1,177 hemodialysis patients with type 2 diabetes. Cox regression analyses were used to determine hazard ratios (HRs) for the risk of cardiovascular end points (CVEs) and mortality according to quartiles of TTR concentration for the total study cohort and the subgroups BMI ≥23 kg/m², albumin concentration ≥3.8 g/dL, and a combination of both.

RESULTS

A low TTR concentration was associated with an increased risk for CVE for the total study cohort (HR 1.65 [95% CI 1.27–2.14]), patients with BMI ≥23 kg/m² (1.70 [1.22–2.37]), albumin ≥3.8 g/dL (1.68 [1.17–2.42]), and the combination of both (1.69 [1.13–2.53]). Additionally, a low TTR concentration predicted mortality for the total study cohort (1.79 [1.43–2.24]) and patients with BMI ≥23 kg/m² (1.46 [1.09–1.95]).

CONCLUSIONS

The current study demonstrated that TTR is a useful predictor for cardiovascular outcome and mortality in diabetic hemodialysis patients. TTR was particularly useful in patients who were not identified to be at risk by BMI or albumin status.Transthyretin (TTR), formerly referred to as prealbumin, is known as a sensitive indicator of inflammation and malnutrition (1,2) and has also been described as a marker of body composition (3,4). With regard to hemodialysis patients, TTR is a well-accepted marker of protein-energy wasting (PEW), which is highly prevalent in patients with end-stage renal disease (5,6). PEW represents a syndrome characterized by depletion of body energy and protein stores, inflammation, and development of comorbidities (7) and is highly associated with the risk of death as well as fatal and nonfatal cardiovascular disease (CVD) in hemodialysis patients (8,9). An expert panel suggested a combination of several parameters for the diagnosis of PEW (7); among these, the most frequently and routinely applied are BMI and serum albumin concentration. Both parameters are known to be inversely associated with mortality and morbidity in hemodialysis patients (10–12).However, BMI and serum albumin concentration have several limitations in diagnosing PEW and subsequently the risk for all-cause mortality and CVD. Among other things, it has been criticized that BMI is not able to discriminate between fat and lean body mass, and a high body mass might be misinterpreted as an appropriate nutritional status. Consequently, patients may be misclassified and wasting may not be recognized. On the other hand, the detrimental effects of being overweight and obesity may also not be recognized or underestimated (13–15). Furthermore, the importance of serum albumin concentration is probably limited since it is more sensitive to inflammation than to nutrition (16), and thus nutrition-related complications are insufficiently considered (13). Additionally, serum albumin is sensitive to hydration status (17,18), and in diabetic patients, the capillary permeability of serum albumin is increased, which might adulterate the serum levels (19).In this context, the analysis of TTR might be useful in overcoming the resulting diagnostic and prognostic gap since TTR is known to be very sensitive to changes in visceral protein stores, correlated with muscle mass, and not affected by hydration status (3,20). Therefore, we hypothesized that TTR may likewise be a potent predictor of mortality and morbidity in hemodialysis patients beyond BMI and serum albumin concentration. Furthermore, since diabetes is a major risk factor for chronic kidney disease, aggravates PEW, and unequivocally increases the risk for cardiovascular events and mortality (6,21,22), the current study was particularly focused on hemodialysis patients with type 2 diabetes using data from the German Diabetes and Dialysis (4D) study.     

Growth-Differentiation Factor 15 Predicts Worsening of Albuminuria in Patients With Type 2 Diabetes

OBJECTIVE

Development of micro- or macroalbuminuria is associated with increased risk of cardiorenal complications, particularly in diabetes. For prevention of transition to micro- or macroalbuminuria, more accurate prediction markers on top of classical risk markers are needed. We studied a promising new marker, growth-differentiation factor (GDF)-15, to predict transition to increasing stage of albuminuria in type 2 diabetes mellitus (T2DM). In addition, we looked at the GDF-15 potential in nondiabetic subjects with hypertension (HT).

RESEARCH DESIGN AND METHODS

Case and control subjects were selected from the PREVEND cohort, a large (n = 8,592), prospective general population study on the natural course of albuminuria, with >10 years of follow-up and repeated albuminuria measurements. We found 24 T2DM and 50 HT case subjects transitioning from normo- to macroalbuminuria and 9 T2DM and 25 HT case subjects transitioning from micro- to macroalbuminuria (average follow-up 2.8 years). Control subjects with stable albuminuria were pair matched for age, sex, albuminuria status, and diabetes duration. GDF-15 was measured in samples prior to albuminuria transition.

RESULTS

Prior to transition, GDF-15 was significantly higher in case subjects with T2DM than in control subjects (median [IQR] 1,288 pg/mL [885–1,546] vs. 948 pg/mL [660–1,016], P < 0.001). The odds ratio for transition in albuminuria increased significantly per SD of GDF-15 (2.9 [95% CI 1.1–7.5], P = 0.03). GDF-15 also improved prediction of albuminuria transition, with significant increases in C statistic (from 0.87 to 0.92, P = 0.03) and integrated discrimination improvement (0.148, P = 0.001). In HT, GDF-15 was also independently associated with transition in albuminuria stage (2.0 [1.1–3.5], P = 0.02) and improved prediction significantly.

CONCLUSIONS

We identified GDF-15 as a clinically valuable marker for predicting transition in albuminuria stage in T2DM beyond conventional risk markers. These findings were confirmed in nondiabetic HT subjects.The prevalence of chronic kidney disease is increasing and has become a major public health challenge (1). This increase in chronic kidney disease is largely due to the rapidly expanding epidemic of type 2 diabetes mellitus (T2DM) leading to diabetic nephropathy and ultimately end-stage renal disease (2). Transition to increasing stages of albuminuria (i.e., normo- to microalbuminuria and micro- to macroalbuminuria) is considered a hallmark of progression of renal disease in diabetes (3). However, once disease has transitioned from normo- to microalbuminuria or to macroalbuminuria, regression of disease is very difficult to achieve. Indeed, recent trials in normo-, micro-, and macroalbuminuric diabetic subjects showed that early intervention (in normoalbuminuric stage) is more effective than late intervention (4). Early markers that detect those who have an increased risk for developing micro- or macroalbuminuria could thus help to reduce the number of patients at renal risk through selective and appropriate treatment of such patients (5,6).Many risk factors have been linked to transition from normo- to micro- and from micro- to macroalbuminuria, such as hyperglycemia, hypercholesterolemia, and hypertension (7). However, accurate risk stratification remains challenging. Novel biomarkers may help to improve the identification of subjects at risk, as well as improve insight into the underlying pathophysiology of the development of micro- or macroalbuminuria. Whereas several promising novel biomarkers have been described in the literature, this had not led to improved risk stratification in T2DM (8).The lack of well-designed prospective studies that first stored samples of individuals for novel risk marker analyses and then followed the course of albuminuria over time may explain the paucity of knowledge on the prognostic value of novel biomarkers to improve risk stratification. We performed a nested case-control study in the large general population cohort Prevention of REnal and Vascular End-stage Disease (PREVEND) to investigate novel biomarkers that may precede and predict the transition in albuminuria (9).Growth differentiation factor (GDF)-15, a member of the transforming growth factor-β family, is a promising novel biomarker that has been implicated as a predictor for cardiovascular and all-cause mortality (10–12). Interestingly, it was also associated with renal outcome and a faster decline of estimated glomerular filtration rate (eGFR) as well as mortality in type 1 diabetic patients with macroalbuminuria (13). It is unclear whether these findings regarding renal outcome are also applicable to patients with type 2 diabetes. In the current study, we investigated whether circulating GDF-15 levels precede and predict the development of micro- or macroalbuminuria in type 2 diabetic patients. To test whether this is specific to diabetes, we performed a replication study to assess the predictive value of GDF-15 in nondiabetic hypertensive patients.     

Persistence of Risk for Type 2 Diabetes After Gestational Diabetes Mellitus

OBJECTIVEGestational diabetes mellitus complicates ∼6% of pregnancies and strongly predicts subsequent type 2 diabetes. It has not been fully elucidated how risk depends on the number of affected pregnancies or how long the excess risk persists.RESEARCH DESIGN AND METHODSWe assessed reproductive histories in relation to risk of type 2 diabetes using a nationwide cohort of 50,884 women. Among participants who initially did not have diabetes, 3,370 were diagnosed with diabetes during 10 years of follow-up. We used Cox proportional hazards models that allowed risk to depend on age, cumulative number of pregnancies with gestational diabetes mellitus, and time since the most recent affected pregnancy, adjusting for BMI, educational level, and race/ethnicity.RESULTSHistory of one or more pregnancies with gestational diabetes mellitus predicted elevated age-specific risk of type 2 diabetes, with a hazard ratio of 3.87 (95% CI 2.60–5.75) 6–15 years after an affected pregnancy. Risk increased steeply with multiple affected pregnancies. The age-specific associations attenuated over time after an affected pregnancy, with an estimated 24% reduction of the hazard ratio per decade. Risk remained elevated, however, for >35 years.CONCLUSIONSGestational diabetes mellitus predicted markedly increased rates of type 2 diabetes. Relative risk increased substantially with each additional affected pregnancy. The estimated hazard ratio declined with time after a pregnancy with gestational diabetes mellitus but remained elevated for >35 years. Women recalling a history of gestational diabetes mellitus should be screened regularly for type 2 diabetes, even late in life.     

Fibroblast Growth Factor 21 Predicts the Metabolic Syndrome and Type 2 Diabetes in Caucasians

OBJECTIVE

The incidence of the metabolic syndrome and type 2 diabetes mellitus (T2DM) is rising worldwide. Liver-derived fibroblast growth factor (FGF)-21 affects glucose and lipid metabolism. The aim of this study was to analyze the predictive value of FGF-21 on the incidence of T2DM and the metabolic syndrome.

RESEARCH DESIGN AND METHODS

The Metabolic Syndrome Berlin Potsdam (MeSyBePo) recall study includes 440 individuals. Glucose metabolism was analyzed using an oral glucose tolerance test, including insulin measurements. FGF-21 was measured using enzyme-linked immunosorbent assay. Primary study outcome was diabetes and the metabolic syndrome incidence and change of glucose subtraits.

RESULTS

During a mean follow-up of 5.30 ± 0.1 years, 54 individuals developed the metabolic syndrome, 35 developed T2DM, and 69 with normal glucose tolerance at baseline progressed to impaired glucose metabolism, defined as impaired fasting glucose, impaired glucose tolerance, or T2DM. FGF-21 predicted incident metabolic syndrome (lnFGF-21 odds ratio [OR] 2.6 [95% CI 1.5 – 4.5]; P = 0.001), T2DM (2.4 [1.2–4.7]; P = 0.01), and progression to impaired glucose metabolism (2.2 [1.3 – 3.6]; P = 0.002) after adjustment for age, sex, BMI, and follow-up time. Additional adjustment for waist-to-hip ratio, systolic blood pressure, HDL cholesterol, triglycerides, and fasting glucose did not substantially modify the predictive value of FGF-21.

CONCLUSIONS

FGF-21 is an independent predictor of the metabolic syndrome and T2DM in apparently healthy Caucasians. These results may indicate FGF-21 resistance precedes the onset of the metabolic syndrome and T2DM.Numerous adipose tissue–derived hormones, the so-called adipokines, have been shown to predict and to be involved in the pathogenesis of type 2 diabetes mellitus (T2DM) (1,2). Recent data revealed increasing evidence that liver-derived hormones might affect glucose and lipid metabolism. Among these “hepatokines,” fibroblast growth factor (FGF)-21 has recently received increasing attention. FGF-21 expression and secretion is induced in the liver during periods of fasting (3,4). Recent studies suggested that fatty acids induce the expression and secretion of FGF-21 in a peroxisome proliferator–activated receptor-α (PPAR-α)–dependent fashion (5,6). FGF-21 signaling requires FGF receptor and the adapter molecule, β-Klotho (7,8), which targets FGF-21 primarily to the liver itself, but also to pancreas and adipose tissue. FGF-21 signaling has been suggested to affect glucose, lipid, cholesterol, and bile acid metabolism (3,9), which has turned FGF-21 into a reasonable candidate directly affecting the pathophysiology of the metabolic syndrome and T2DM. Notably, studies in animal models have found FGF-21 has antidiabetic properties (10), whereas a number of human studies observed increased circulating FGF-21 levels in subjects with existing insulin resistance, impaired glucose tolerance (IGT), and hypertriglyceridemia (11–13). Zhang and coworkers (13) demonstrated that FGF-21 is independently associated with the metabolic syndrome in Asian individuals, and another study in an Asian cohort recently demonstrated that genetic polymorphisms within a 3′-untranslated region of FGF-21 are also associated with the metabolic syndrome (14). Most interestingly an association between FGF-21 and incident diabetes was observed in an Asian cohort (15). However, whether FGF-21 predicts metabolic syndrome and whether the findings in Asian individuals are comparably found in Caucasian individuals is unclear. We therefore investigated whether FGF-21 predicts incident metabolic syndrome and T2DM, both defined by World Health Organization (WHO) criteria, and the progression of healthy controls to impaired glucose metabolism (IGM), defined as incident impaired fasting glucose (IFG), IGT, or incident diabetes, in a cohort of apparently healthy individuals.     

Visceral adiposity and the risk of impaired glucose tolerance: a prospective study among Japanese Americans

OBJECTIVE: Greater visceral adiposity, higher insulin resistance, and impaired insulin secretion increase the risk of type 2 diabetes. Whether visceral adiposity increases risk of impaired glucose tolerance (IGT) independent of other adipose depots, insulin resistance, and insulin secretion is not known. RESEARCH DESIGN AND METHODS: Study subjects included 128 Japanese Americans with normal glucose tolerance at entry. Baseline variables included plasma glucose and insulin measured after an overnight fast and during a 75-g oral glucose tolerance test, fat areas by computed tomography, insulin secretion (incremental insulin response [IIR] [30 min insulin - fasting insulin]/30 min glucose), and insulin resistance index (homeostasis model assessment for insulin resistance [HOMA-IR]). RESULTS: During the 10- to 11-year follow-up period, we confirmed 57 cases of IGT. Significant predictors of IGT included intra-abdominal fat area (IAFA) (odds ratio [OR] for a 1 SD increase 3.82, 95% CI 1.63-8.94 at a fasting plasma glucose [FPG] level of 4.5 mmol/l), HOMA-IR (2.41, 1.15-5.04), IIR (0.30, 0.13-0.69 at an FPG level of 4.5 mmol/l), the interactions of IAFA by FPG (P = 0.003), and IIR by FPG (P = 0.030) after adjusting for age, sex, FPG, and BMI. The multiple-adjusted OR of IAFA increased and that of IIR decreased as FPG level decreased because of these interactions. Even after adjustment for total fat area, total subcutaneous fat area, or abdominal subcutaneous fat area, all of these associations remained a significant predictor of IGT incidence. CONCLUSIONS: Greater visceral adiposity increases the risk of IGT independent of insulin resistance, insulin secretion, and other adipose depots in Japanese Americans.     

Nonlaboratory-Based Risk Assessment Algorithm for Undiagnosed Type 2 Diabetes Developed on a Nation-Wide Diabetes Survey

OBJECTIVE

To develop a New Chinese Diabetes Risk Score for screening undiagnosed type 2 diabetes in China.

RESEARCH DESIGN AND METHODS

Data from the China National Diabetes and Metabolic Disorders Study conducted from June 2007 to May 2008 comprising 16,525 men and 25,284 women aged 20–74 years were analyzed. Undiagnosed type 2 diabetes was detected based on fasting plasma glucose ≥7.0 mmol/L or 2-h plasma glucose ≥11.1 mmol/L in people without a prior history of diabetes. β-Coefficients derived from a multiple logistic regression model predicting the presence of undiagnosed type 2 diabetes were used to calculate the New Chinese Diabetes Risk Score. The performance of the New Chinese Diabetes Risk Score was externally validated in two studies in Qingdao: one is prospective with follow-up from 2006 to 2009 (validation 1) and another cross-sectional conducted in 2009 (validation 2).

RESULTS

The New Chinese Diabetes Risk Score includes age, sex, waist circumference, BMI, systolic blood pressure, and family history of diabetes. The score ranges from 0 to 51. The area under the receiver operating curve of the score for undiagnosed type 2 diabetes was 0.748 (0.739–0.756) in the exploratory population, 0.725 (0.683–0.767) in validation 1, and 0.702 (0.680–0.724) in validation 2. At the optimal cutoff value of 25, the sensitivity and specificity of the score for predicting undiagnosed type 2 diabetes were 92.3 and 35.5%, respectively, in validation 1 and 86.8 and 38.8% in validation 2.

CONCLUSIONS

The New Chinese Diabetes Risk Score based on nonlaboratory data appears to be a reliable screening tool to detect undiagnosed type 2 diabetes in Chinese population.Prevalence of type 2 diabetes is increasing dramatically worldwide. In China, the prevalence of type 2 diabetes increased from 5.5% in 2000–2001 (1) to 9.7% in 2007–2008 (2). Nearly 60% of individuals with type 2 diabetes had not been diagnosed previously (2). Mortality in individuals with previously undiagnosed type 2 diabetes was, however, as high as in those with known type 2 diabetes; both were higher than in people without type 2 diabetes (3). Obesity, hypertension, and dyslipidemia are also frequently clustered in an individual with undiagnosed type 2 diabetes (2,4,5). Early detection of type 2 diabetes and intervention may reduce exposure to long-term hyperglycemia and prevent or delay chronic diabetes complications. The currently used diagnostic tool for type 2 diabetes is 75-g oral glucose tolerance test (OGTT) and A1C (6). The OGTT is, however, time consuming, and the fasting status cannot be assured. The A1C test is less standard and relatively expensive. Consequently, their use in mass screening has been limited. Risk score developed based on demographic, anthropometric, and clinical information without a laboratory test has been proved to be a useful and cheap tool for a stepwise screening strategy for undiagnosed type 2 diabetes (7–17). This approach is particularly useful in China, considering a large population and an already high and still increasing prevalence of undiagnosed type 2 diabetes.A simple Chinese diabetes risk score has been reported based on data collected in Qingdao (7). Considering the diversity in economic development, culture, living environment, and dietary factors in different areas of China, we tried to develop a New Chinese Diabetes Risk Score for undiagnosed type 2 diabetes using the data of the China National Diabetes and Metabolic Disorders Study (exploratory population) that was conducted in 12 provinces and autonomous regions in addition to the municipalities of Beijing and Shanghai from June 2007 to May 2008. The performance of the New Chinese Diabetes Risk Score developed in this study is validated in two external studies in Qingdao. One of the two studies is prospective (validation 1) and the other cross-sectional (validation 2). The results of the validation of the indexed score are also compared with previously published diabetes risk scores that derived from Chinese (7), Caucasian (9,11,13,14,18), and other Asian populations (15,16,19,20).     

Sedentary Behavior and Diabetes Risk Among Women Over the Age of 65 Years: The OPACH Study

OBJECTIVETo evaluate whether sedentary time (ST) and/or sedentary behavior patterns are related to incident diabetes in the U.S.’s oldest age-groups.RESEARCH DESIGN AND METHODSWomen without physician-diagnosed diabetes (n = 4,839, mean ± SD age = 79 ± 7 years) wore accelerometers for ≥4 days and were followed up to 6 years for self-reported newly diagnosed diabetes requiring treatment with medications. Hazard ratios (HRs) for incident diabetes were estimated across quartiles of accelerometer-measured ST and mean bout duration with use of Cox proportional hazards models. We conducted isotemporal substitution analyses using Cox regression and tested associations with risk for diabetes after statistically replacing ST with light physical activity (PA) or moderate-to-vigorous PA (MVPA) and after replacing light PA with MVPA.RESULTSDuring 20,949 person-years, 342 diabetes cases were identified. Women in ST quartile (Q)2, Q3, and Q4 (vs. Q1) had incident diabetes HR 1.20 (95% CI 0.87–1.65), 1.33 (0.97–1.82), and 1.21 (0.86–1.70); P_trend = 0.04. Respective HRs following additional adjustment for BMI and MVPA were 1.04 (95% CI 0.74–1.47), 1.04 (0.72–1.50), and 0.85 (0.56–1.29); P_trend = 0.90. Fully adjusted isotemporal substitution results indicated that each 30 min of ST replaced with MVPA (but not light PA) was associated with 15% lower risk for diabetes (HR 0.85 [95% CI 0.75–0.96]; P = 0.01); the HR for replacing 30 min of light PA with MVPA was 0.85 (95% CI 0.73–0.98); P = 0.03. Mean bout duration was not associated with incident diabetes.CONCLUSIONSStatistically replacing ST or light PA with MVPA was associated with lower diabetes risk in older women. While reducing ST is important for several health outcomes, results indicate that to reduce diabetes risk among older adults, the primary public health focus should be on increasing MVPA.     

2型糖尿病合并脂肪肝的相关因素分析

目的:探讨2型糖尿病合并脂肪肝的相关因素。方法:2型糖尿病患者经B超证实有脂肪肝但无症状者35例,男性21例,女性14例,年龄57·06±13·32岁。选择同期住院的经B超证实无脂肪肝的2型糖尿病患者按性别、年龄进行配对共35例作为对照组。结果:2型糖尿病合并脂肪肝患者的BMI、TG、空腹C-P、餐后2hC-P、2hINS、AST、ALT明显高于无脂肪肝组,(BMI和TG,P<0·01,其余P<0·05)。TC、LDL-C及空腹INS也升高但无统计学差异。IAI(P<0·01)和HDL-C(P<0·05)则明显降低。结论:2型糖尿病合并脂肪肝与肥胖、血脂代谢紊乱、胰岛素抵抗密切相关,并导致肝转氨酶升高。提示:积极减肥,调脂治疗和改善胰岛素抵抗是治疗的关键。