GHb Level and Subsequent Mortality Among Adults in the U.S.

OBJECTIVE

To examine the association of hyperglycemia, as measured by GHb, with subsequent mortality in a nationally representative sample of adults.

RESEARCH DESIGN AND METHODS

We included adults aged ≥20 years who participated in Third National Health and Nutrition Examination Survey (1988–1994) and had complete information, including baseline diabetes status by self-report and measured GHb (n = 19,025) and follow-up through the end of 2000 for mortality.

RESULTS

In the overall population, higher levels of GHb were associated with increased risk of mortality from all causes, heart disease, and cancer. After adjustment for potential risk factors, the relative hazard (RH) for adults with GHb ≥8% compared with adults with GHb <6% was 2.59 (95% CI 1.88–3.56) for all-cause mortality, 3.38 (1.98–5.77) for heart disease mortality, and 2.64 (1.17–5.97) for cancer mortality. Among adults with diagnosed diabetes, having GHb ≥8% compared with GHb <6% was associated with higher all-cause mortality (RH 1.68, 95% CI 1.03–2.74) and heart disease mortality (2.48, 1.09–5.64), but there was no increased risk of cancer mortality by GHb category. Among adults without diagnosed diabetes, there was no significant association of all-cause, heart disease, or cancer mortality and GHb category.

CONCLUSIONS

These results highlight the importance of GHb levels in mortality risk among a nationally representative sample of adults with and without diagnosed diabetes and indicate that higher levels are associated with increased mortality in adults with diabetes.Hperglycemia has been associated with a wide range of adverse outcomes for individuals with glucose values both above and below the threshold for diabetes, including increased cardiovascular disease (CVD) and mortality (1). Studies have consistently found undiagnosed diabetes to be associated with increased risk of mortality (2–4), and many studies have also shown levels of glucose that are elevated, but not enough for a diagnosis of diabetes, such as impaired fasting glucose, to be associated with increased mortality (2–4).However, most of these studies are based on fasting or postprandial glucose (1–4), and few are based on GHb levels (3,5–8). The GHb level may be a better indicator of hyperglycemia because it provides a measure of an individual''s average glucose levels for the previous 3 months. Thus, it may provide a more stable snapshot of glucose levels when used in prospective cohort studies to examine the association of subsequent risk. Currently, GHb is monitored in the treatment of diabetes, and GHb targets for prevention of complications among individuals with diabetes have been established (9). Interest in the use of GHb for the diagnosis of diabetes is increasing (10), and an international effort is underway to standardize the measurement of GHb (11). This focus of GHb in clinical care measures (12) raises important questions about the long-term predictability of GHb.Examination of the relationship of GHb with mortality reveals several areas of uncertainty, including whether the relationship of GHb with mortality is similar among individuals with and without diabetes from both prospective cohort studies and clinical trials. A few prospective cohort studies have examined the association of GHb with risk of mortality (5–8) and shown an increased risk of mortality with increasing GHb level. Only two studies included individuals with diabetes, but these studies did not examine GHb levels by diabetes status, and none were representative of the general U.S. population.Recently published findings from three clinical trials among adults with diabetes have added to this uncertainty. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that lower GHb levels increased risk of mortality and did not decrease CVD events (13). Whereas the Action in Diabetes and Vascular Disease—Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study showed that lowering of GHb levels was associated with a decrease in micro- and macrovascular events and deaths from CVD (14) and the Veterans Administration Diabetes Trial reported that lower GHb levels were not associated with a reduction in cardiovascular events (15). These findings have not led to any changes in glycemic control recommendations (16).The Third National Health and Nutrition Examination Survey (NHANES III) is the first nationally representative survey to include a measure of GHb and has mortality status available through linkage to the National Death Index. The objective of this study was to examine the association of GHb with subsequent mortality in a nationally representative sample of U.S. adults.     

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

Osteoprotegerin and mortality in type 2 diabetic patients

OBJECTIVE

Plasma osteoprotegerin (OPG) is an emerging strong and independent predictor of cardiovascular disease (CVD) in high-risk populations. OPG is a bone-related glycopeptide produced by vascular smooth muscle cells, and increased plasma OPG levels may reflect arterial vascular damage. We aimed to investigate the prognostic value of OPG in relation to all-cause and cardiovascular mortality in a cohort of type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

In a prospective observational follow-up study, 283 type 2 diabetic patients (172 men; aged 53.9 ± 8.8 years) were followed for a median of 16.8 years (range 0.2–23.0). Baseline plasma OPG concentrations were determined by immunoassay.

RESULTS

During follow-up, 193 (68%) patients died. High versus low levels of OPG predicted all-cause mortality (covariate-adjusted for urinary albumin excretion rate [UAER], estimated glomerular filtration rate, and conventional risk factors); hazard ratio (HR) 1.81 [95% CI 1.21–2.69]. The all-cause predictive effect of OPG was independent of NH₂-terminal pro-brain natriuretic peptide (NT-proBNP) and was also useful within groups divided according to level of UAER. In total, 103 (73%) patients died because of CVD. High and medium versus low levels of OPG predicted cardiovascular mortality (unadjusted HR 1.86 [95% CI 1.07–3.23] and 3.51 [2.10–5.85], respectively). However, after adjustment for the covariates, HRs were no longer significant.

CONCLUSIONS

Elevated plasma OPG is a strong predictor of all-cause mortality in type 2 diabetic patients. The effect of OPG on all-cause mortality was independent of conventional cardiovascular risk factors, UAER, and NT-proBNP levels.Plasma osteoprotegerin (OPG) is a promising strong and independent predictor of cardiovascular disease (CVD) in high-risk individuals, such as type 1 diabetic patients with nephropathy and nondiabetic patients after kidney transplantation or myocardial infarction (1–4). OPG is a member of the tumor necrosis factor receptor superfamily acting as a soluble decoy receptor for the receptor activator of nuclear factor-κβ ligand (RANKL) to prevent osteoclast activation and bone resorption (5). OPG mRNA has been detected in a variety of human tissues, including the lung, heart, and kidney (5). This bone-related glycoprotein is present in the arterial wall, and plasma OPG has been suggested to reflect the increased OPG content in arterial tissue observed in diabetic patients (6). OPG is upregulated in calcified coronary plaques (7) and associated with angiographic disease severity and cardiovascular events independent of conventional risk factors (8,9). Therefore, increased plasma OPG levels are suggested to be a marker of arterial vascular damage.CVD is the major determinant of morbidity and mortality in patients with type 2 diabetes and, in particular, patients with an elevated urinary albumin excretion rate (UAER) (10). Increased OPG levels are associated with diabetes (11). Recently, an elevated plasma OPG level was shown to predict increased mortality in patients with type 1 diabetes and diabetic nephropathy (4) and also to predict increased incidence of cardiovascular events among patients with uncomplicated type 2 diabetes who were followed for 18 months (12). However, the prognostic importance of OPG in type 2 diabetic patients with long follow-up and elevated UAER is unknown. Therefore, this study examines the predictive value of plasma OPG in relation to all-cause and cardiovascular mortality in a large cohort of type 2 diabetic patients followed prospectively for 17 years.     

Long-Term Cardiovascular Risk in Type 2 Diabetic Compared With Nondiabetic First Acute Myocardial Infarction Patients: A population-based cohort study in southern Europe

OBJECTIVE

The aim of this study was to determine whether long-term cardiovascular risk differs in type 2 diabetic patients compared with first acute myocardial infarction patients in a Mediterranean region, considering therapy, diabetes duration, and glycemic control.

RESEARCH DESIGN AND METHODS

A prospective population-based cohort study with 10-year follow-up was performed in 4,410 patients aged 30–74 years: 2,260 with type 2 diabetes without coronary heart disease recruited in 53 primary health care centers and 2,150 with first acute myocardial infarction without diabetes recruited in 10 hospitals. We compared coronary heart disease incidence and cardiovascular mortality rates in myocardial infarction patients and diabetic patients, including subgroups by diabetes treatment, duration, and A1C.

RESULTS

The adjusted hazard ratios (HRs) for 10-year coronary heart disease incidence and for cardiovascular mortality were significantly lower in men and women with diabetes than in myocardial infarction patients: HR 0.54 (95% CI 0.45–0.66) and 0.28 (0.21–0.37) and 0.26 (0.19–0.36) and 0.16 (0.10–0.26), respectively. All diabetic patient subgroups had significantly fewer events than myocardial infarction patients: the HR of cardiovascular mortality ranged from 0.15 (0.09–0.26) to 0.36 (0.24–0.54) and that of coronary heart disease incidence ranged from 0.34 (0.26–0.46) to 0.56 (0.43–0.72).

CONCLUSIONS

Lower long-term cardiovascular risk was found in type 2 diabetic and all subgroups analyzed compared with myocardial infarction patients. These results do not support equivalence in coronary disease risk for diabetic and myocardial infarction patients.The prevalence of diabetes is reaching epidemic proportions in developed countries (1). For example, the U.S. has 18 million diabetic patients, Spain has >2 million diabetic patients, and management of the disease costs >$132 and >$3.3 billion per year, respectively (2).Some studies (3–5), several of them with great influence on important guidelines for cardiovascular prevention (3), suggest that the cardiovascular risk of diabetic patients is similar to that of coronary heart disease secondary prevention patients. Other reports, however, do not confirm these observations (6–10).Part of the discrepancy may stem from differences in the duration of diabetes, type of treatment, and baseline glucose control of diabetic patients included in the studies (3–5). These limit comparability, given the fact that time of evolution and treatment required to attain appropriate glycemic control are key determinants of prognosis (10–16).Among population-based cohort studies that compared the prognosis of diabetic patients with that of myocardial infarction patients without diabetes (3–10), only two analyzed the role of diabetes duration (11,12). Even these studies did not include unstable angina among the end points and risk was not stratified by type of treatment. To our knowledge, the effect of type 2 diabetes on coronary heart disease incidence has barely been studied in southern Europe, a region known for low cardiovascular mortality (17). The aim of this study was to determine whether long-term cardiovascular risk differed between type 2 diabetic patients and first acute myocardial infarction patients and to assess the influence of diabetes duration, type of treatment, and glycemic control at baseline.     

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

Educational Disparities in Mortality Among Adults With Diabetes in the U.S.

OBJECTIVE

To measure relative and absolute educational disparities in mortality among U.S. adults with diabetes and to compare their magnitude with disparities observed within the nondiabetic population.

RESEARCH DESIGN AND METHODS

A total of 85,867 individuals (5,007 with diabetes), aged 35–84 years, who participated in the National Health Interview Survey from 1986 to 1996 were followed for mortality through 31 December 2002. Relative and absolute educational disparities in all-cause, cardiovascular disease (CVD), and non-CVD mortality were measured.

RESULTS

In relative terms, the risk of all-cause mortality was 28% higher in diabetic adults with the lowest versus the highest position on the educational scale (relative index of inequality 1.28 [95% CI 1.08–1.53]). This inverse relationship reflected marked disparities in CVD mortality and was found in all age, sex, and race/ethnicity groups except Hispanics. Although substantial, this relative educational gradient in mortality among adults with diabetes was smaller than in the nondiabetic population. In absolute terms, diabetic adults with the lowest position on the educational scale suffered 503 excess deaths per 10,000 person-years of follow-up compared with those with the highest position. These absolute disparities were stronger than in the nondiabetic population. The results were even more striking for CVD mortality.

CONCLUSIONS

The risk of mortality differs substantially according to educational level among individuals with diabetes in the U.S. Although relative educational disparities in mortality are weaker in adults with versus without diabetes, their absolute impact is greater and translates into a major mortality burden.In the U.S., >20 million adults have diabetes, and the prevalence is expected to rise substantially in the coming decades (1,2). Diabetes complications impose an enormous burden on public health, and people with diabetes have an age-adjusted mortality rate approximately twice as high as those without (3).The public health burden of diabetes is unevenly distributed across socioeconomic strata. First, diabetes is more common in ethnic minorities and people of low education and income level (4,5). Second, in people with diabetes, socioeconomic position (SEP) may influence major determinants of health, such as access to care, quality of care, and health behaviors (6). Correspondingly, SEP may have a profound impact on the morbidity and mortality associated with diabetes. In Europe, socioeconomic health disparities have been reported among people with diabetes in various settings (5,6); though, two large record linkage studies (7,8) found that the magnitude of socioeconomic differentials in survival was weaker in people with diabetes than in the general population, a result that has remained largely unexplained. In the U.S., only few studies have focused on SEP-related disparities among people with diabetes and then only in selected subpopulations (9–12), making it difficult to determine the impact of such disparities at the population level and their public health importance.To fully monitor health disparities, the general consensus is that both relative and absolute measures are required (13,14). The objective of this study was to quantify relative and absolute educational disparities in mortality within the U.S. diabetic population according to cause of death and across age, sex, and race/ethnicity strata and to compare the magnitude of these disparities to those found in the nondiabetic population.     

��-Cell�CMediated Signaling Predominates Over Direct ��-Cell Signaling in the Regulation of Glucagon Secretion in Humans

OBJECTIVE

Given evidence of both indirect and direct signaling, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans.

RESEARCH DESIGN AND METHODS

We measured plasma glucagon concentrations before and after ingestion of a formula mixed meal and, on a separate occasion, ingestion of the sulfonylurea glimepiride in 24 basal insulin-infused, demonstrably β-cell–deficient patients with type 1 diabetes and 20 nondiabetic, demonstrably β-cell–sufficient individuals; the latter were infused with glucose to prevent hypoglycemia after glimepiride.

RESULTS

After the mixed meal, plasma glucagon concentrations increased from 22 ± 1 pmol/l (78 ± 4 pg/ml) to 30 ± 2 pmol/l (103 ± 7 pg/ml) in the patients with type 1 diabetes but were unchanged from 27 ± 1 pmol/l (93 ± 3 pg/ml) to 26 ± 1 pmol/l (89 ± 3 pg/ml) in the nondiabetic individuals (P < 0.0001). After glimepiride, plasma glucagon concentrations increased from 24 ± 1 pmol/l (83 ± 4 pg/ml) to 26 ± 1 pmol/l (91 ± 4 pg/ml) in the patients with type 1 diabetes and decreased from 28 ± 1 pmol/l (97 ± 5 pg/ml) to 24 ± 1 pmol/l (82 ± 4 pg/ml) in the nondiabetic individuals (P < 0.0001). Thus, in the presence of both β-cell and α-cell secretory stimuli (increased amino acid and glucose levels, a sulfonylurea) glucagon secretion was prevented when β-cell secretion was sufficient but not when β-cell secretion was deficient.

CONCLUSIONS

These data indicate that, among the array of signals, indirect reciprocal β-cell–mediated signaling predominates over direct α-cell signaling in the regulation of glucagon secretion in humans.The regulation of pancreatic islet α-cell glucagon secretion is complex (1–10). It involves direct signaling of α-cells (1) and indirect signaling of α-cells by β-cell (2–6) and δ-cell (7) secretory products, the autonomic nervous system (8,9), and gut incretins (10).Appropriate glucagon secretory responses occur from the perfused pancreas (3,5) and perifused islets (2). Low plasma glucose concentrations stimulate glucagon secretion from the transplanted (i.e., denervated) human pancreas (11) and the denervated dog pancreas (12). Therefore, we have focused on the intraislet regulation of glucagon secretion. Furthermore, because selective destruction of β-cells results in loss of the glucagon response to hypoglycemia in type 1 diabetes (13), and partial reduction of the β-cell mass in minipigs results in impaired postprandial suppression of glucagon secretion (14), we have focused on the role of β-cell–mediated signaling in the regulation of glucagon secretion.Findings from studies of the perfused rat (3,4) and human (5) pancreas, rats in vivo (6), rat islets (2), isolated rat α-cells (2), and humans (15–18) have been interpreted to indicate that a β-cell secretory product or products tonically restrains basal α-cell glucagon secretion during euglycemia and that a decrease in β-cell secretion, coupled with low glucose concentrations at the α-cells, signals an increase in glucagon secretion in response to hypoglycemia. Parenthetically, the relative roles of the candidate β-cell secretory products (insulin, zinc, γ-aminobutyric acid, and amylin, among others) (2) that normally restrain α-cell glucagon secretion remain to be determined. However, that interpretation rests, in part, on results of studies in isolated rat α-cells (2), which are debated (1), and on the evidence that the islet microcirculation flows from β-cells to α-cells to δ-cells (4), which is also debated (19). Furthermore, it does not address the plausible possibility that a decrease in intraislet δ-cell somatostatin secretion might also signal an increase in α-cell glucagon secretion during hypoglycemia (7).Given that interpretation, it follows that an increase in β-cell secretion would signal a decrease in glucagon secretion in the postprandial state (14). The concept is an interplay of indirect reciprocal β-cell–mediated signaling of α-cells and of direct α-cell signaling in the regulation of glucagon secretion.There is, in our view, compelling evidence that, among other mechanisms, both indirect reciprocal β-cell–mediated signaling of α-cells (2–6) and direct α-cell signaling (1) are involved in the regulation of glucagon secretion by nutrients, hormones, neurotransmitters, and drugs. Given that premise, we posed the question: Which of these predominates in humans? Accordingly, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans. To do so, we measured plasma glucagon responses to ingestion of a mixed meal and, on a separate occasion, to ingestion of the sulfonylurea glimepiride in patients with type 1 diabetes and in nondiabetic individuals. We conceptualized patients with type 1 diabetes as a model of α-cells isolated from β-cells because their β-cells had been destroyed but they have functioning α-cells. (Their α-cells are not, of course, isolated from other islet cells, including δ-cells.) Increased plasma amino acid and glucose levels after a mixed meal and sulfonylureas normally stimulate β-cell secretion; increased plasma amino acid and perhaps glucose (2) levels after a mixed meal and sulfonylureas (1) stimulate α-cell secretion. Our hypothesis predicts that such factors that normally stimulate both β-cells and α-cells would stimulate glucagon secretion in patients with type 1 diabetes but not in nondiabetic individuals, i.e., in the virtual absence and the presence of β-cell function, respectively. Indeed, a mixed meal (20,21) and the secretagogues tolbutamide (22), glyburide (23), and repaglinide (23) have been reported to raise plasma glucagon concentrations in patients with type 1 diabetes, but all of those studies lacked nondiabetic control subjects.     

BMI-mortality paradox and fitness in African American and Caucasian men with type 2 diabetes

OBJECTIVE

To assess the association between BMI, fitness, and mortality in African American and Caucasian men with type 2 diabetes and to explore racial differences in this association.

RESEARCH DESIGN AND METHODS

We used prospective observational data from Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, California. Our cohort (N = 4,156; mean age 60 ± 10.3 years) consisted of 2,013 African Americans (mean age, 59.5 ± 9.9 years), 2,000 Caucasians (mean age, 60.8 ± 10.5 years), and 143 of unknown race/ethnicity. BMI, cardiac risk factors, medications, and peak exercise capacity in metabolic equivalents (METs) were assessed during 1986 and 2010. All-cause mortality was assessed across BMI and fitness categories.

RESULTS

There were 1,074 deaths during a median follow-up period of 7.5 years. A paradoxic BMI–mortality association was observed, with significantly higher risk among those with a BMI between 18.5 and 24.9 kg/m² (hazard ratio [HR] 1.70 [95% CI 1.36–2.1]) compared with the obese category (BMI ≥35 kg/m²). This association was accentuated in African Americans (HR 1.95 [95% CI 1.44–2.63]) versus Caucasians (HR 1.53 [1.0–2.1]). The fitness–mortality risk association for the entire cohort and within BMI categories was inverse, independent, and graded. Mortality risks were 12% lower for each 1-MET increase in exercise capacity, and ∼35–55% lower for those with an exercise capacity >5 METs compared with the least fit (≤5 METs).

CONCLUSIONS

A paradoxic BMI–mortality risk association was observed in African American and Caucasian patients with diabetes. The exercise capacity–mortality risk association was inverse, independent, and graded in all BMI categories but was more potent in those with a BMI ≥25 kg/m².Obesity is now a major health issue in the U.S., adversely affecting nearly all the major coronary heart disease risk factors, including type 2 diabetes mellitus (DM) (1,2). Recent evidence from large epidemiologic studies support a significantly higher mortality risk only in individuals with a relatively low BMI, with no excess risk associated with obesity observed in some populations (3). Others have reported reductions in mortality risk among overweight or obese subjects, a puzzling observation that has been termed the obesity paradox (4–6). This paradoxic relationship appears to occur in only particular clinical populations, such as heart failure, the elderly, or patients referred for exercise testing for clinical reasons (1,2,4–6). Recent evidence from a large cohort of Asian subjects also suggests that the obesity paradox may be related to socioeconomics, ethnicity, or both. Higher BMI was associated with greater risk among East Asian subjects, but not among South Asian subjects (3).Obesity often coexists in individuals with type 2 DM; however, the association between BMI and mortality risk is less clear in this population. For example, no such association was found in the large United Kingdom Prospective Diabetes Study (UKPDS) (7). In contrast, in the Translating Research Into Action for Diabetes (TRIAD) study (8), higher mortality rates were only reported in those with a BMI <26 kg/m² compared with overweight individuals (BMI 26–29.9 kg/m²). A V-shaped association was observed in a Chinese cohort (9) and a U-shaped association in a large Ukrainian cohort (10).Increased physical activity patterns and higher exercise capacity are associated with lower mortality in nondiabetic (11–14) and diabetic individuals (15–18). This reduction in mortality occurs in proportion to the level of fitness and is independent of BMI (15–18). We recently reported an inverse and graded association between exercise capacity and mortality risk in men with type 2 DM. The association was stronger and more graded in Caucasians compared with African Americans (18).Collectively, the aforementioned studies suggest that the BMI–mortality association in individuals with type 2 DM is not well defined. Moreover, the role of fitness in this association and possible racial differences has not been adequately addressed. Therefore, in the current study, we sought to assess the relationship between adiposity, exercise capacity, and all-cause mortality in African American and Caucasian male veterans with type 2 DM.     

Cardiovascular Disease Mortality in Europeans in Relation to Fasting and 2-h Plasma Glucose Levels Within a Normoglycemic Range

OBJECTIVE

To study mortality in relation to fasting plasma glucose (FPG) and 2-h plasma glucose levels within the normoglycemic range.

RESEARCH DESIGN AND METHODS

Data from 19 European cohorts comprising 12,566 men and 10,874 women who had FPG <6.1 mmol/l and 2-h plasma glucose <7.8 mmol/l at baseline examination were analyzed. Multivariate-adjusted hazard ratios (HRs) and 95% CIs for deaths from cardiovascular disease (CVD), non-CVD, and all causes were estimated for individuals whose 2-h plasma glucose > FPG (group II) compared with those whose 2-h plasma glucose ≤ FPG (group I).

RESULTS

A total of 827 (246) CVD and 611 (351) non-CVD and 1,438 (597) all-cause deaths occurred in men (women). Group II was older and had higher BMI, blood pressure, and fasting insulin than group I. The multivariate-adjusted HRs (95% CIs) for CVD, non-CVD, and all-cause mortality were 1.22 (1.05–1.41), 1.09 (0.92–1.29), and 1.16 (1.04–1.30) in men and 1.40 (1.03–1.89), 0.99 (0.79–1.25), and 1.13 (0.94–1.35) in women, respectively, for group II as compared with group I. HRs were 1.25 (1.05–1.50), 1.09 (0.89–1.34), and 1.18 (1.03–1.35) in men and 1.60 (1.03–2.48), 1.05 (0.78–1.42), and 1.18 (0.93–1.51) in women, respectively, after additional adjustment for fasting insulin in a subgroup of individuals.

CONCLUSIONS

In individuals with both FPG and 2-h plasma glucose within the normoglycemic range, high 2-h plasma glucose was associated with insulin resistance and increased CVD mortality.It is well known that type 2 diabetes (1,2) and nondiabetic hyperglycemia such as impaired glucose tolerance are risk factors for cardiovascular disease (CVD) mortality (3–5). The relations of fasting plasma glucose (FPG) and 2-h plasma glucose with CVD mortality and morbidity have been extensively investigated during the last few decades (6–9). Evidence has shown that 2-h plasma glucose is a stronger risk predictor than FPG for incident coronary heart disease (6) and CVD mortality (7), but little is known about the impact of FPG versus 2-h plasma glucose in the normoglycemic range. It has been suggested that individuals with normoglycemia, whose 2-h plasma glucose did not return to the FPG levels during an oral glucose tolerance test (OGTT) had a significantly higher risk of developing type 2 diabetes (10) and a worse cardiovascular risk factor profile (11) than individuals whose 2-h plasma glucose returned to the FPG levels. In the current study, based on the data of the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study, we compared CVD mortality in individuals whose 2-h plasma glucose was higher than FPG with those whose 2-h plasma glucose was equal to or lower than FPG.     

Effect of diabetes on severity and hospital mortality in patients with acute pancreatitis: a national population-based study

OBJECTIVE

Diabetes may increase the risk of acute pancreatitis (AP). We aimed to further investigate whether diabetes may also adversely affect outcomes of patients with AP.

RESEARCH DESIGN AND METHODS

In this retrospective cohort study, we compared 18,990 first-attack AP with diabetes to 37,980 matched control subjects from Taiwan’s National Health Insurance Research Database between 2000 and 2009. Primary outcomes were development of severe AP, defined by a modified Atlanta classification scheme, and hospital mortality. Analyses were performed using univariable and multivariable logistic regression model with generalized estimating equations accounting for hospital clustering effect.

RESULTS

After baseline characteristics were adjusted, AP patients with diabetes had a higher risk of a severe attack than their nondiabetic counterparts (adjusted odds ratio [OR] 1.21, 95% CI 1.16–1.26). When severity criteria were analyzed individually, diabetic AP patients had a 58% higher risk of intensive care unit admission and a 30% higher risk of local complications, but a 16% lower risk of gastrointestinal bleeding, than AP patients without diabetes. The risk of organ failure at least one system) was similar between the two groups. Conversely, AP patients with diabetes were associated with a lower risk of hospital mortality (adjusted OR 0.77, 95% CI 0.65–0.91).

CONCLUSIONS

Although diabetes may adversely affect the disease process of AP, it seems to protect patients from AP-related mortality.Acute pancreatitis (AP) is an acute inflammatory disease of the pancreas. The local inflammation is usually self-limited within a few days, but it can be destructive and cause a severe local complication and/or systemic reaction leading to organ failures and death. Although the case-fatality rate has been decreasing over the decades (1,2), severe cases still carry a high mortality (20–50%) and consume nearly half of the resources and costs incurred by all patients with AP (3). Accordingly, many efforts have been made to identify correlates of severity and predictors for mortality in patients with AP (4–6).In addition to older people (7), patients with certain comorbidities, such as obesity (8), hypertriglyceridemia (9), chronic renal failure (10), and systemic lupus erythematosus (11), are shown to be associated with greater risk of not only the incidence but also the severity and mortality of AP. Among various comorbidities, diabetes mellitus is relatively common in patients with AP; the prevalence was 11% in Japan (12), 17.7% in California (U.S.), (13) and 19.3% in Taiwan (3). These figures are expected to continuously increase in the future because diabetic patients not only are at risk for developing AP (14–16) but also are growing in prevalence worldwide (17). Nonetheless, the effect of diabetes on outcomes of patients with AP has not been adequately studied, and the results of available reports are inconsistent (13,18). For example, Frey and colleagues examined the effect of comorbidities on patients with AP and found that diabetes was not associated with early mortality (13), whereas Graham and coworkers assessed the effect of diabetes on critically ill patients and showed a reduced risk of hospital mortality in a subgroup patients with AP (18). In both studies, however, the effect of diabetes was not specifically examined and detailed analyses were not performed (13,18).In a recent national population-based study on Taiwanese patients with first-attack AP, we found that the prevalence of diabetes increased from 15.6% in 2000 to 2001 to 19.7% in 2008 to 2009 (1). In this study, we used the same cohort (1) to further investigate the effect of diabetes on outcomes of these patients. Because diabetic patients are likely to have a higher comorbid burden and hence a poorer reserve for acute illnesses, we hypothesized that diabetes is associated with a higher risk of severe attacks and hospital mortality in adult patients with first-attack AP.     

Trends in death rates among U.S. adults with and without diabetes between 1997 and 2006: findings from the National Health Interview Survey

OBJECTIVE

To determine whether all-cause and cardiovascular disease (CVD) death rates declined between 1997 and 2006, a period of continued advances in treatment approaches and risk factor control, among U.S. adults with and without diabetes.

RESEARCH DESIGN AND METHODS

We compared 3-year death rates of four consecutive nationally representative samples (1997–1998, 1999–2000, 2001–2002, and 2003–2004) of U.S. adults aged 18 years and older using data from the National Health Interview Surveys linked to National Death Index.

RESULTS

Among diabetic adults, the CVD death rate declined by 40% (95% CI 23–54) and all-cause mortality declined by 23% (10–35) between the earliest and latest samples. There was no difference in the rates of decline in mortality between diabetic men and women. The excess CVD mortality rate associated with diabetes (i.e., compared with nondiabetic adults) decreased by 60% (from 5.8 to 2.3 CVD deaths per 1,000) while the excess all-cause mortality rate declined by 44% (from 10.8 to 6.1 deaths per 1,000).

CONCLUSIONS

Death rates among both U.S. men and women with diabetes declined substantially between 1997 and 2006, reducing the absolute difference between adults with and without diabetes. These encouraging findings, however, suggest that diabetes prevalence is likely to rise in the future if diabetes incidence is not curtailed.Diabetes has been associated with an average 10 years of life lost for individuals diagnosed during middle age (1). Fortunately, numerous evidence-based interventions exist, ranging from glycemic and cardiovascular disease (CVD) risk factor control to early screening for diabetes complications (2). These have been paralleled by population-wide improvements in glycemic control, CVD risk factors, and rates of several diabetes complications (3–5). Despite these improvements, it remains unclear whether longevity has increased uniformly among diabetic populations. Studies in specific diabetic cohorts in Framingham, Minnesota, and North Dakota suggest mortality declined during the 1990s (6–8). Analyses of consecutive cohorts of the U.S. population from the 1970s through the 1990s, however, found that all-cause and CVD death rates declined among diabetic men but not diabetic women (9,10). However, no national studies have examined mortality trends among the U.S. diabetic population since the 1990s, and the intervening years have been a period of continued advances in treatment approaches and risk factor levels. Newly available mortality follow-up data linked to the National Health Interview Survey (NHIS) provide a unique opportunity to determine whether CVD and all-cause mortality has improved among the U.S. population during recent decades as well as whether the excess mortality associated with diabetes has declined (11,12).     

Peri-Conceptional A1C and Risk of Serious Adverse Pregnancy Outcome in 933 Women With Type 1 Diabetes

OBJECTIVE

To study the association between peri-conceptional A1C and serious adverse pregnancy outcome (congenital malformations and perinatal mortality).

RESEARCH DESIGN AND METHODS

Prospective data were collected in 933 singleton pregnancies complicated by type 1 diabetes.

RESULTS

The risk of serious adverse outcome at different A1C levels was compared with the background population. The risk was significantly higher when peri-conceptional A1C exceeded 6.9%, and the risk tended to increase gradually with increasing A1C. Women with A1C exceeding 10.4% had a very high risk of 16%. Congenital malformation rate increased significantly at A1C above 10.4%, whereas perinatal mortality was increased even at A1C below 6.9%.

CONCLUSIONS

These results support recent guidelines of preconceptional A1C levels <7% in women with type 1 diabetes.Recently, guidelines for management of pregnancy in women with pregestational diabetes have recommended pregestational A1C values <7.0% (1,2) and <6.1% (3). Previous studies have reported information of early A1C including 116–691 pregnancies (4–10). We aimed to study whether there is a threshold value for peri-conceptional A1C in women with type 1 diabetes below which the risk of serious adverse pregnancy outcome (congenital malformation and perinatal mortality) is not increased.     

Dietary Patterns and Risk for Diabetes: The Multiethnic Cohort

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

Impact of lifestyle-related factors on all-cause and cause-specific mortality in patients with type 2 diabetes: the Taichung Diabetes Study

OBJECTIVE

To examine whether combined lifestyle behaviors have an impact on all-cause and cause-specific mortality in patients aged 30–94 years with type 2 diabetes (T2DM).

RESEARCH DESIGN AND METHODS

Participants included 5,686 patients >30 years old with T2DM who were enrolled in a Diabetes Care Management Program at a medical center in central Taiwan before 2007. Lifestyle behaviors consisted of smoking, alcohol drinking, physical inactivity, and carbohydrate intake. The main outcomes were all-cause and cause-specific mortality. Cox proportional hazards models were used to examine the association between combined lifestyle behaviors and mortality.

RESULTS

The mortality rate among men was 24.10 per 1,000 person-years, and that among women was 17.25 per 1,000 person-years. After adjusting for the traditional risk factors, we found that combined lifestyle behavior was independently associated with all-cause mortality and mortality due to diabetes, cardiovascular disease, and cancer. Patients with three or more points were at a 3.50-fold greater risk of all-cause mortality (95% CI 2.06–5.96) and a 4.94-fold (1.62–15.06), 4.24-fold (1.20–14.95), and 1.31-fold (0.39–4.41) greater risk of diabetes-specific, CVD-specific, and cancer-specific mortality, respectively, compared with patients with zero points. Among these associations, the combined lifestyle behavior was not significantly associated with cancer mortality.

CONCLUSIONS

Combined lifestyle behavior is a strong predictor of all-cause and cause-specific mortality in patients with T2DM.Type 2 diabetes (T2DM) and its complications are leading causes of premature mortality, imposing a heavy burden at the individual and societal level (1,2). With the Westernization of diet behaviors, the prevalence of T2DM has increased dramatically in Taiwan. The National Nutrition Survey in Taiwan revealed that the prevalence of T2DM among men aged ≥65 years had increased dramatically: from 13.1 to 17.6 to 28.5% in 1993–1996, 2002, and 2005–2008, respectively (3). The International Diabetes Federation (2) proposed that the causes of the increase in diabetes prevalence were population aging and unhealthy lifestyle behaviors. The components of these unhealthy lifestyle behaviors included being physically inactive, smoking, alcohol drinking, and having an unhealthy diet (4–6).T2DM is also an important cause of microvascular and macrovascular diseases. Lifestyle modifications in conjunction with antidiabetes medications can prevent premature morbidity and mortality (5,7). However, for individuals with diabetes, the most difficult task is to strike a balance between the individual’s desires and compliance with behavior modification for disease management. It has been reported that individuals with diabetes who practice healthy lifestyle behaviors have better glycemic control (8) and that better glycemic control is associated with lower mortality (9). Although the effects of these individual or combined lifestyle behaviors on mortality have been well studied in general populations (10–18), little is known about the association between these lifestyle behaviors and mortality in patients with T2DM (5,19). Understanding the relationships of these modifiable predictors on mortality in patients with T2DM will have great clinical significance for diabetes care.The Taichung Diabetes Study is a population-based cohort study of ~6,000 middle-aged and older ethnic Chinese patients with T2DM who enrolled in the Diabetes Care Management Program (DCMP) of a medical center in Taiwan. The DCMP provides financial incentives for physicians to increase exhaustive follow-up visits, including annual self-care education and assessment by care managers and a clinical nutrition practitioner, annual eye examinations, and four annual laboratory tests. The DCMP provided a unique opportunity to quantify the overall impact of lifestyle factors, including smoking, alcohol drinking, regular exercise, and carbohydrate intake, on mortality. The purpose of this study was to fill this gap in knowledge by investigating the prospective associations among lifestyle factors and all-cause, diabetes-, cardiovascular disease (CVD)-, and cancer-specific mortality, independently of HbA_1c, and several baseline traditional factors, in a large cohort of ethnic Chinese patients with T2DM who were followed up for more than 4 years.     

Plasma Growth Differentiation Factor-15 Independently Predicts All-Cause and Cardiovascular Mortality As Well As Deterioration of Kidney Function in Type 1 Diabetic Patients With Nephropathy

OBJECTIVE

Growth deferentiation factor-15 (GDF-15) is involved in inflammation and apoptosis. Expression is induced in the heart in response to ischemia and in atherosclerotic plaques. The aim of this study was to investigate GDF-15 levels in relation to all-cause mortality, cardiovascular mortality and morbidity, decline in glomerular filtration rate (GFR), and progression toward end-stage renal disease (ESRD).

RESEARCH DESIGN AND METHODS

The study was a prospective observational follow-up study including 451 type 1 diabetic patients with diabetic nephropathy (274 men, aged 42.1 ± 0.5 years [means ± SD], diabetes duration 28.3 ± 8.9 years, GFR 76 ± 33 ml/min/1.73 m²) and a control group of 440 patients with longstanding type 1 diabetes and persistent normoalbuminuria (232 men, aged 45.4 ± 11.5 years, duration of diabetes 27.7 ± 10.1 years). The patients were followed for 8.1 (0.0–12.9) years (median [range]).

RESULTS

Among normoalbuminuric patients, GDF-15 above the median predicted an adjusted (age, systolic blood pressure [sBP], and estimated GFR) increased risk of all-cause mortality (hazard ratio [HR] 3.6 [95% CI 1.3–10.3]; P = 0.014). Among patients with diabetic nephropathy, higher (fourth quartile) versus lower (first quartile) GDF-15 levels predict all-cause mortality (covariate-adjusted [sex, age, smoking, blood pressure, A1C, cholesterol, GFR, N-terminal prohormone B-type natriuretic peptide, antihypertensive treatment, and previous cardiovascular events]; HR 4.86 [95% CI 1.37–17.30]) as well as fatal and nonfatal cardiovascular events (adjusted HR 5.59 [1.23–25.43] and 3.55 [1.08–11.64], respectively). In addition, higher GDF-15 levels predict faster decline in GFR (P < 0.001) but not development of ESRD.

CONCLUSIONS

Higher levels of GDF-15 are a predictor of all-cause and cardiovascular mortality and morbidity in patients with diabetic nephropathy. Furthermore, higher levels of GDF-15 are associated with faster deterioration of kidney function.Diabetes is associated with accelerated atherosclerosis and an increased risk of cardiovascular disease (CVD), which has become the major cause of morbidity and mortality among patients with diabetic nephropathy (1). Left ventricular hypertrophy, hypertension, and diabetes are leading predictors for the development of heart failure and sudden death (2,3). In general, the hypertrophic growth of the myocardium is regulated by a number of pro- and antigrowth factors, e.g., angiotensin-II and B-type natriuretic peptide (BNP) related to the transforming growth factor-β superfamily (4–6).Recently, growth differentiation factor-15 (GDF-15) has been identified as a novel anti-hypertrophic regulatory factor (7). GDF-15 is generated as a 40-kDa propeptide from which the NH₂-terminus is cleaved and a 30-kDa protein secreted as the active form (8).GDF-15 is induced in the hypertrophic and dilated cardiomyopathy following hypertension/volume overload, ischemia, and heart failure, possibly via proinflammatory cytokine and oxidative stress-dependent signaling pathways (9,10). GDF-15 is highly expressed in the infarcted myocardium in predominantly nondiabetic patients suffering an acute myocardial infarction (MI) (9) and in atherosclerotic plaques obtained from carotid artery surgery (11). In a nested case-control study, GDF-15 was shown to be associated with adverse cardiovascular outcomes in women (12). Furthermore, GDF-15 has been shown to predict mortality in patients with both ST-elevation MI (STEMI) and non–STEMI, independent of known biomarkers such as N-terminal prohormone B-type natriuretic peptide (NT-proBNP) (13,14).Therefore, we investigated the predictive value of circulating GDF-15 levels on all-cause mortality, fatal and nonfatal CVD, decline in GFR, as well as progression to end-stage renal disease (ESRD) in a well-characterized population of type 1 diabetic patients with or without diabetic nephropathy.     

Health-Related Quality of Life and Mortality in a General and Elderly Population of Patients With Type 2 Diabetes (ZODIAC-18)

OBJECTIVE

Diabetes negatively impacts the health-related quality of life (HRQOL) of patients with type 2 diabetes. An earlier analysis showed HRQOL to be associated with mortality, which suggests that measuring HRQOL could have clinical implications. We studied the association between HRQOL and total and cardiovascular mortality in patients with type 2 diabetes during long-term follow-up and specifically focused on old age and sex differences.

RESEARCH DESIGN AND METHODS

HRQOL was measured in a prospectively followed cohort of 1,353 patients with type 2 diabetes using the RAND-36. Cox proportional hazard models were used to measure the independent effect of baseline HRQOL on mortality.

RESULTS

During a mean follow-up of 9.6 years, 570 (42%) patients died, 280 of whom died of cardiovascular disease (49%). The Physical Component Score (PCS) and the Mental Component Score (MCS) were inversely associated with total mortality, with hazard ratios of 0.988 (95% CI 0.983–0.993) and 0.990 (95% CI 0.985–0.995), respectively. A 10-point-higher score on the PCS and MCS decreased the risk for total mortality by 11 and 10%, respectively. An inverse relationship with mortality was also seen for men, women, and for patients aged >75 years. Mental health was significantly related to mortality in men but not in women.

CONCLUSIONS

Lower physical and mental HRQOL was associated with a higher total mortality and cardiovascular mortality in patients with type 2 diabetes; this is also the case when studying men and women and the elderly separately. The dimension mental health, related to depression and anxiety, was only associated with mortality in men, not in women.Diabetes often leads to the development of physical disabilities that, in turn, can have a detrimental effect on a patient''s quality of life (QOL) (1). The importance of optimizing health-related QOL (HRQOL) has increasingly been recognized, not only because it represents an important goal for health care on its own but also because of the associations between poor HRQOL and adverse outcomes in people with type 2 diabetes, including poor response to therapy, disease progression, and even mortality (2–6).The relationship between HRQOL and mortality in patients with diabetes has been investigated previously in three studies (4–6). López Revuelta et al. (4) showed perceived mental health to be an independent predictor of morbidity and mortality in patients with end-stage renal disease. Most of the patients in this study had diabetes (65%). In a recently published study, the EQ-5D questionnaire was used to study the relationship between HRQOL and mortality, and lower HRQOL was associated with a higher mortality rate (5). Our study group previously showed the physical component summary of the RAND-36 to be an independent marker for total mortality in patients with type 2 diabetes (6). The investigators in two of three aforementioned studies reported results for individual health dimensions (4,6). Physical functioning and general health in Kleefstra et al.''s study (6) and general health, mental health, and role limitations due to emotional problems in López Revuelta et al.''s study (4) were associated with total mortality. Although previous studies (7–9) have shown an inverse relationship between HRQOL and mortality in the elderly population, no study has specifically focused on elderly patients with type 2 diabetes. Traditional risk factors become less predictive of mortality at increasing age (10). HRQOL is therefore of interest for elderly patients and may become increasingly important to clinicians for its predictive value.After these three studies, questions still remain regarding the relationship between the different health dimensions and mortality, the relationship between HRQOL and mortality in elderly patients with type 2 diabetes, and whether the relationship between HRQOL and mortality is different between men and women. The purpose of this study was to revisit the association between HRQOL and mortality after a longer follow-up period (10 years), with a special focus on the elderly (aged >75 years) and on possible sex differences.     

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

Maternal Family History of Diabetes Is Associated With a Reduced Risk of Cardiovascular Disease in Women With Type 2 Diabetes: The Fremantle Diabetes Study

OBJECTIVE

To investigate whether parental family history of diabetes influences cardiovascular outcomes in type 2 diabetes.

RESEARCH DESIGN AND METHODS

We studied 1,294 type 2 diabetic patients (mean age 64.1 years, 51.2% female) recruited to a community-based cohort study from 1993 to 1996 and followed until mid-2006. A data linkage system assessed all-cause and cardiac mortality, incident myocardial infarction, and stroke. Cox proportional hazards modeling was used to determine the influence of maternal or paternal family history on these outcomes.

RESULTS

A maternal family history of diabetes was reported by 20.4% of the cohort, 8.3% reported paternal family history, and 2.0% reported both parents affected. Maternal and paternal family history was associated with earlier age of diabetes onset, and maternal family history was associated with worse glycemic control. For all patients, maternal family history was significantly associated with reduced risk of all-cause mortality and cardiac mortality. When analyzed by sex, maternal family history had no effect on male patients, whereas female patients with diabetic mothers had significantly reduced hazard ratios for death from all causes (0.63 [95% CI 0.41–0.96]; P = 0.033), for death from cardiac causes (0.32 [0.14–0.72]; P = 0.006), and for first myocardial infarction (0.45 [0.26–0.76]; P = 0.003). Paternal family history status was not associated with these outcomes.

CONCLUSIONS

A maternal family history of diabetes confers relative protection against cardiovascular disease in female patients but not in male patients with type 2 diabetes. Paternal family history is associated with risks equivalent to those without a family history of diabetes. Some of the clinical heterogeneity of type 2 diabetes is related to maternal transmission effects with differential impact on male and female patients.The complex etiology of type 2 diabetes involves both genetic components and environmental exposures. In type 2 diabetes, there is a well documented association between a family history of the disease and its development (1,2). Maternal and paternal family histories of diabetes are both associated with an earlier age of onset (2–4), and this effect is more marked when multiple family members are affected (5). In addition, intrauterine exposure to diabetes increases the risk of diabetes in offspring (6), which may help explain the reported excess maternal transmission (7,8).Patients with familial diabetes have relatively poor glycemic control, but few other clinical differences have been reported (4,5,9,10). An early age of onset and poor glycemic control would both be expected to have a negative impact on the development of chronic complications, but no such longitudinal data have been published. In the present study, we examined relationships among parental diabetes and important clinical outcomes in type 2 diabetes, including incident coronary heart disease (CHD) and all-cause and cardiac mortality in a large community-based sample of patients with type 2 diabetes. We hypothesized that familial diabetes would indicate worse clinical outcomes. We investigated potential relationships in male and female patients separately, given the known differences in CHD incidence between men and women with diabetes (11).     

Prevalence, metabolic features, and prognosis of metabolically healthy obese Italian individuals: the Cremona Study

OBJECTIVE

Some obese individuals have normal insulin sensitivity. It is controversial whether this phenotype is associated with increased all-cause mortality risk.

RESEARCH DESIGN AND METHODS

Fifteen-year all-cause mortality data were obtained through the Regional Health Registry for 2,011 of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes in Italy. Individuals were divided in four categories according to BMI (nonobese: <30 kg/m²; obese: ≥30 kg/m²) and estimated insulin resistance (insulin sensitive: homeostasis model assessment of insulin resistance <2.5; insulin resistant ≥2.5).

RESULTS

Obese insulin-sensitive subjects represented 11% (95% CI 8.1–14.5) of the obese population. This phenotype had similar BMI but lower waist circumference, blood pressure, fasting glucose, triglycerides, and fibrinogen and higher HDL cholesterol than obese insulin-resistant subjects. In the 15-year follow-up, 495 deaths (cardiovascular disease [CVD]: n = 221; cancer: n = 180) occurred. All-cause mortality adjusted for age and sex was higher in the obese insulin-resistant subjects (hazard ratio 1.40 [95% CI 1.08–1.81], P = 0.01) but not in the obese insulin-sensitive subjects (0.99 [0.46–2.11], P = 0.97) when compared with nonobese insulin-sensitive subjects. Also, mortality for CVD and cancer was higher in the obese insulin-resistant subjects but not in the obese insulin-sensitive subjects when compared with nonobese insulin-sensitive subjects.

CONCLUSIONS

In contrast to obese insulin-resistant subjects, metabolically healthy obese individuals are less common than previously thought and do not show increased all-cause, cancer, and CVD mortality risks in a 15-year follow-up study.Metabolically healthy obese (MHO) individuals are considered as a subset of obese subjects without metabolic abnormalities (such as insulin resistance, proatherogenic lipoprotein profile, proinflammatory state, or hypertension) and a model for better understanding the pathogenesis of insulin resistance (1–3). The prevalence of the MHO phenotype in the general population, the reasons for not developing metabolic alterations, and the less aggressive therapeutic approach with respect to obese individuals with metabolic abnormalities are currently debated (4,5). In the Framingham Offspring Study, Meigs et al. (6) found that MHO individuals do not have increased risk of incident diabetes and cardiovascular disease (CVD). Conversely, in the Third National Health and Nutrition Examination Survey (NHANES III), Kuk et al. (7) reported increased all-cause mortality associated with the MHO phenotype. Finally, in a Scandinavian study (8), middle-aged overweight/obese subjects without metabolic syndrome also had an increased risk of CVD when compared with normal-weight individuals without metabolic syndrome. The present study shows the prevalence of the MHO phenotype, its metabolic features, and 15-year all-cause, CVD, and cancer mortality rates in the Caucasian population of the Cremona Study (9,10).