Fasting Glucose Level and the Risk of Incident Atherosclerotic Cardiovascular Diseases

OBJECTIVE

Although diabetes increases the risk of cardiovascular disease (CVD) and mortality, the dose-response relationship between fasting glucose levels below those diagnostic of diabetes with cardiovascular events has not been well characterized.

RESEARCH DESIGN AND METHODS

A prospective cohort study of more than one million Koreans was conducted with a mean follow-up of 16 years. A total of 1,197,384 Korean adults with no specific medical conditions diagnosed were classified by baseline fasting serum glucose level. Associations of fasting glucose level with CVD incidence and mortality, stroke incidence and mortality, and all-cause mortality were analyzed using multivariate proportional hazards regression.

RESULTS

The relationships between fasting glucose levels and CVD risks generally followed J-shape curves, with lowest risk in the glucose range of 85–99 mg/dL. As fasting glucose levels increased to >100 mg/dL, risks for CVD, ischemic heart disease, myocardial infarction, and thrombotic stroke progressively increased, but risk for hemorrhagic stroke did not. Fasting glucose levels <70 mg/dL were associated with increased risk of all stroke (hazard ratio 1.06, 95% CI 1.01–1.11) in men and (hazard ratio 1.11, 1.05–1.17) in women.

CONCLUSIONS

Both low glucose level and impaired fasting glucose should be considered as predictors of risk for stroke and coronary heart disease. The fasting glucose level associated with the lowest cardiovascular risk may be in a narrow range.Diabetes is a well-established risk factor for cardiovascular disease (CVD) and all-cause mortality (1–3). Impaired fasting glucose (IFG), defined by the American Diabetes Association as having a fasting plasma glucose level of 100–125 mg/dL (5.6–7.0 mmol/L) or a 2-h value on the oral glucose tolerance test of 140–199 mg/dL (7.8–11.1 mmol/L) (4) was associated with CVD risk in several studies (1,5–7). The evidence is inconsistent, however, and the clinical relevance of IFG as a predictor of CVD is still unclear (8–11). In addition, the shape of the dose-response relationship between CVD risk and fasting glucose level has not been well characterized across the full range of fasting blood glucose values.It is unclear whether there is an optimum fasting glucose level associated with the lowest level of CVD risk (12,13), or whether risk increases at very low fasting glucose levels (14). Several studies have shown J-shape or U-shape relationships between fasting glucose levels and mortality (3,5,14,15).The Korean Cancer Prevention Study (16,17) (KCPS) is a cohort study of >1.3 million Korean adults designed to evaluate major risk factors for chronic diseases and mortality. The large sample size of this cohort facilitated detailed characterization of the dose-response relationship of fasting glucose level with the incidence of clinical CVD end points.     

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.     

Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled by Established Basal Insulin: A 24-week,randomized, placebo-controlled comparison (GetGoal-L)

OBJECTIVE

To examine the efficacy and safety of adding the once-daily glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide to established basal insulin therapy alone or together with metformin, in people with type 2 diabetes and elevated glycated hemoglobin (HbA_1c).

RESEARCH DESIGN AND METHODS

We conducted a double-blind, parallel-group, placebo-controlled trial. Patients (n = 495) with established basal insulin therapy but inadequate glycemic control were randomized to add lixisenatide 20 μg or placebo for 24 weeks. Basal insulin dosage was unchanged except to limit hypoglycemia. HbA_1c reduction from baseline was the primary end point.

RESULTS

Mean duration of diabetes was 12.5 years, duration of insulin use was 3.1 years, insulin dosage was 55 units/day, and baseline HbA_1c was 8.4%. With lixisenatide, the placebo-corrected change of HbA_1c from baseline was –0.4% (95% CI –0.6 to –0.2; P = 0.0002), and mean HbA_1c at end point was 7.8%. HbA_1c <7.0% (53 mmol/mol) was attained by more lixisenatide (28%) than placebo (12%; P < 0.0001) participants. Lixisenatide reduced plasma glucose levels after a standardized breakfast (placebo-corrected reduction, –3.8 mmol/L; P < 0.0001); seven-point glucose profiles showed a reduction persisting through the day. Reductions in body weight (placebo corrected, –1.3 kg; P < 0.0001) and insulin dosage (–3.7 units/day; P = 0.012) were greater with lixisenatide. Main adverse events (AEs) with lixisenatide were gastrointestinal. Symptomatic hypoglycemia was 28% for lixisenatide and 22% for placebo; 4 of 328 subjects (1.2%) had severe hypoglycemia with lixisenatide vs. 0 of 167 with placebo.

CONCLUSIONS

By improving HbA_1c and postprandial hyperglycemia without weight gain in type 2 diabetes with inadequate glycemic control despite stable basal insulin, lixisenatide may provide an alternative to rapid-acting insulin or other treatment options.In type 2 diabetes, additional therapies are needed over time to maintain acceptable glycemic control (1–3). When lifestyle measures and oral antihyperglycemic agents are no longer sufficient, the addition of basal insulin optimized by systematic titration of dosage can restore glycated hemoglobin (HbA_1c) to 7.0% for 50–60% of people with type 2 diabetes (2,4,5). However, some people do not initially achieve this glycemic target with basal insulin plus oral therapy, and others experience later deterioration of control (6–9). Further therapy, especially for postprandial hyperglycemia, is then needed. A traditional option has been to add one or more injections of prandial insulin (10), but adding a glucagon-like peptide-1 receptor agonist (GLP-1RA) is a recently proposed alternative that may improve glycemic control without additional weight gain and, perhaps, with less hypoglycemia. Drugs of this class have effects that complement those of basal insulin; they potentiate endogenous insulin responses to hyperglycemia, suppress inappropriately elevated glucagon secretion, and favor weight loss by promoting satiety (11,12). In addition, GLP-1RAs can slow gastric emptying, further blunting postprandial hyperglycemia. However, slowing of gastric emptying appears to be greater with short-acting than with long-acting GLP-1RAs (13), possibly related to the observation that, with time, continuous exposure of GLP-1 leads to a reduction in its effect on gastric emptying (14).Lixisenatide is a novel GLP-1RA that, like other drugs of its class, has demonstrated significant improvements in glycemic control, low rates of hypoglycemia, and a beneficial effect on weight (15–17). Lixisenatide taken once daily (15) improves HbA_1c levels by reducing fasting plasma glucose (FPG) and has robust postprandial glucose (PPG) effects (18,19). Lixisenatide was granted marketing authorization by the European Medicines Agency in February 2013 (20). The objective of this study was to examine the efficacy and safety of adding once-daily lixisenatide to established basal insulin therapy (dosage maintained except for the avoidance of hypoglycemia), alone or together with metformin, in people with long-duration type 2 diabetes and inadequate glycemic control.     

Benefits of Liraglutide Treatment in Overweight and Obese Older Individuals With Prediabetes

OBJECTIVE

The aim was to evaluate the ability of liraglutide to augment weight loss and improve insulin resistance, cardiovascular disease (CVD) risk factors, and inflammation in a high-risk population for type 2 diabetes (T2DM) and CVD.

RESEARCH DESIGN AND METHODS

We randomized 68 older individuals (mean age, 58 ± 8 years) with overweight/obesity and prediabetes to this double-blind study of liraglutide 1.8 mg versus placebo for 14 weeks. All subjects were advised to decrease calorie intake by 500 kcal/day. Peripheral insulin resistance was quantified by measuring the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Traditional CVD risk factors and inflammatory markers also were assessed.

RESULTS

Eleven out of 35 individuals (31%) assigned to liraglutide discontinued the study compared with 6 out of 33 (18%) assigned to placebo (P = 0.26). Subjects who continued to use liraglutide (n = 24) lost twice as much weight as those using placebo (n = 27; 6.8 vs. 3.3 kg; P < 0.001). Liraglutide-treated subjects also had a significant improvement in SSPG concentration (−3.2 vs. 0.2 mmol/L; P < 0.001) and significantly (P ≤ 0.04) greater lowering of systolic blood pressure (−8.1 vs. −2.6 mmHg), fasting glucose (−0.5 vs. 0 mmol/L), and triglyceride (−0.4 vs. −0.1 mmol/L) concentration. Inflammatory markers did not differ between the two groups, but pulse increased after liraglutide treatment (6.4 vs. −0.9 bpm; P = 0.001).

CONCLUSIONS

The addition of liraglutide to calorie restriction significantly augmented weight loss and improved insulin resistance, systolic blood pressure, glucose, and triglyceride concentration in this population at high risk for development of T2DM and CVD.Approximately one-third of adults in the United States have prediabetes (1,2) and are at risk for type 2 diabetes (T2DM) and cardiovascular disease (CVD) (3). Weight loss has been demonstrated to prevent T2DM (4–7) and to improve CVD risk factors (5) in the prediabetes population. In the Diabetes Prevention Program study, a weight loss goal of 7% was associated with a significant reduction in T2DM incidence (4). However, with intensive guidance, only half of the individuals were able to attain this weight loss goal at 24 weeks, and 38% attained this goal at 3 years. With self-guided weight loss programs, the percentage who can achieve a 7% weight reduction may be <20% (8).Liraglutide, a glucagon-like peptide 1 (GLP-1) analog, is approved for the treatment of T2DM. In addition to improving glucose tolerance, GLP-1 action has been associated with weight loss in individuals with T2DM (9). Only a few studies have evaluated the effect of GLP-1 action in individuals without diabetes (10–12), and none has focused on individuals with prediabetes.The purpose of this study was to evaluate the effect of liraglutide treatment compared with matching placebo injections in older (mean age, 58 ± 8 years) overweight/obese individuals with prediabetes—those at highest risk for development of T2DM and CVD. Specifically, we assessed the ability of liraglutide treatment to augment weight loss and to improve insulin resistance, CVD risk factors, and inflammatory markers.     

Efficacy and Safety of Lixisenatide Once Daily Versus Exenatide Twice Daily in Type 2 Diabetes Inadequately Controlled on Metformin: A 24-week,randomized, open-label,active-controlled study (GetGoal-X)

OBJECTIVE

To compare efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled with metformin.

RESEARCH DESIGN AND METHODS

Adults with diabetes inadequately controlled (HbA_1c 7–10%) with metformin were randomized to lixisenatide 20 μg once daily (n = 318) or exenatide 10 μg twice daily (n = 316) in a 24-week (main period), open-label, parallel-group, multicenter study. The primary objective was a noninferiority assessment of lixisenatide versus exenatide in HbA_1c change from baseline to week 24.

RESULTS

Lixisenatide once daily demonstrated noninferiority in HbA_1c reduction versus exenatide twice daily. The least squares mean change was −0.79% (mean decrease 7.97 to 7.17%) for lixisenatide versus −0.96% (mean decrease 7.96 to 7.01%) for exenatide, and treatment difference was 0.17% (95% CI, 0.033–0.297), meeting a predefined noninferiority upper CI margin of 0.4%. Responder rate (HbA_1c <7.0%) and improvements in fasting plasma glucose were comparable. Both agents induced weight loss (from 94.5 to 91.7 kg and from 96.7 to 92.9 kg with lixisenatide and exenatide, respectively). Incidence of adverse events (AEs) was similar for lixisenatide and exenatide, as was incidence of serious AEs (2.8 and 2.2%, respectively). Discontinuations attributable to AEs occurred in 33 lixisenatide (10.4%) and 41 exenatide (13.0%) patients. In the lixisenatide group, fewer participants experienced symptomatic hypoglycemia (2.5 vs. 7.9%; P < 0.05), with fewer gastrointestinal events (especially nausea; 24.5 vs. 35.1%; P < 0.05).

CONCLUSIONS

Add-on lixisenatide once daily in type 2 diabetes inadequately controlled with metformin demonstrated noninferior improvements in HbA_1c, with slightly lower mean weight loss, lower incidence of hypoglycemia, and better gastrointestinal tolerability compared with exenatide twice daily.The glucagon-like peptide-1 (GLP-1) receptor system has become an attractive target for type 2 diabetes therapies (1–5). GLP-1 receptor agonists increasingly have become established as effective therapeutic options in type 2 diabetes management (6,7).Glucose-lowering effects of GLP-1 receptor agonists are mediated by glucose-dependent stimulation of insulin release and inhibition of glucagon secretion, which decreases prandial blood glucose excursion and hepatic glucose production (1–5). Notably, GLP-1 receptor agonists achieve physiological blood glucose–insulin response with a low risk of hypoglycemia (as a result of their glucose-dependent action) (8), delay gastric emptying, and are associated with beneficial effects on weight and appetite reduction (9).Currently available GLP-1 receptor agonists include twice-daily and once-weekly formulations of exenatide, a once-daily formulation of liraglutide, and a once-daily formulation of lixisenatide. Both exenatide and liraglutide have been shown to improve glycemic control associated with beneficial effects on weight and a low risk of hypoglycemia (10,11). However, although exenatide and liraglutide share the same basic mechanisms, each has a distinct pharmacokinetic profile and molecular structure, with potential clinical implications in terms of efficacy against fasting plasma glucose (FPG) and postprandial plasma glucose, and in terms of regimen burden and safety. This has been demonstrated in a 26-week, randomized, parallel-group, open-label trial in adults with inadequately controlled type 2 diabetes who were assigned to receive additional liraglutide 1.8 mg once daily or additional exenatide 10 µg twice daily (11). Liraglutide reduced mean FPG more than did exenatide (−29.0 mg/dL vs. −10.8 mg/dL; P < 0.0001), whereas exenatide reduced postprandial plasma glucose increment after breakfast and dinner more than did liraglutide (breakfast: estimated treatment difference, 23.9 mg/dL; P < 0.0001; dinner: estimated treatment difference, 18.2 mg/dL; P = 0.0005) (11). These findings suggest that liraglutide and exenatide should not be used interchangeably, but instead should be prescribed on an individual basis according to the glycemic requirements of each patient.Lixisenatide is a once-daily prandial GLP-1 receptor agonist for the treatment of type 2 diabetes that was approved by the European Medicines Agency in February 2013 (12,13). It is a 44–amino-acid peptide that is amidated at the COOH terminal amino acid and shares some structural elements with the GLP-1 receptor agonist exenatide; the primary difference is the addition of six lysine residues at the C terminus (13). A 13-week, randomized, double-blind, placebo-controlled, dose-ranging study that evaluated the dose-dependent effects of lixisenatide (5, 10, 20, or 30 µg once daily or twice daily) found that lixisenatide 20 µg administered once daily provided the best efficacy-to-tolerability ratio, with no additional benefits with any of the twice-daily doses (14). Lixisenatide 20 μg once daily subsequently has been shown to significantly improve glycemic control, with low rates of hypoglycemia and beneficial weight effects, when administered as monotherapy (15), as add-on therapy to oral agents (14,16–18), and in combination with basal insulin with or without oral antidiabetic therapy (19–21).In the current study, we report the results from a head-to-head study (GetGoal-X) that compared the benefit/risk profile of lixisenatide once daily versus exenatide twice daily in patients with type 2 diabetes inadequately controlled with metformin monotherapy.     

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

Comparison of Cystic Fibrosis–Related Diabetes With Type 1 Diabetes Based on a German/Austrian Pediatric Diabetes Registry

OBJECTIVE

The prevalence of cystic fibrosis–related diabetes (CFRD) has increased with improved life expectancy of patients. Clinical and care characteristics were compared with type 1 diabetes mellitus (T1DM) in a multicenter analysis of pediatric data.

RESEARCH DESIGN AND METHODS

Auxological and treatment data from 47,227 patients aged younger than 21 years with CFRD or T1DM in the German/Austrian Diabetes Prospective Documentation Initiative registry were analyzed by multivariable mixed regression modeling.

RESULTS

Diabetes onset (mean [interquartile range]) occurred later in individuals with CFRD (14.5 [11.8–16.3] years) than in individuals with T1DM (8.5 [4.9–11.8] years), with female preponderance in CFRD (59.1% vs. 47.5%; P < 0.01). CFRD patients had lower BMI standard deviation scores (−0.85 [−1.59 to −0.12] vs. +0.52 [−0.10 to +1.16]; P < 0.01) and lower HbA_1c (6.87% vs. 7.97%; P < 0.01). Self-monitoring of blood glucose was more frequent in patients with T1DM (4.5 vs. 3.5; P < 0.01); 72% of CFRD patients received insulin. In insulin-treated patients, insulin dosage adjusted for age, sex, and diabetes duration differed significantly (T1DM: 0.79 IE per kilogram of body weight; CFRD: 0.83 IE per kilogram of body weight). Use of short-acting and long-acting insulin analogs was significantly more frequent in T1DM (47% vs. 39% and 37% vs. 28%; both P < 0.05). Metabolic control in CFRD patients without insulin was better compared with CFRD on insulin (HbA_1c: 6.00 vs. 7.12; P < 0.01), but duration of disease was significantly shorter (0.8 years [0.1–2.4] compared with 2.4 years [0.6–4.6]). There was no significant difference for BMI standard deviations scores between CFRD patients with or without insulin treatment.

CONCLUSIONS

Pediatric patients with CFRD show clear auxological and metabolic differences from those with T1DM, with different treatment choices.With improvement of therapy and increasing life expectancy of cystic fibrosis (CF) patients, secondary diabetes is becoming more frequent (1) and is recognized as the most common comorbidity, occurring in approximately 2% of children, 19% of adolescents, and 40–50% of adults (2). The reported prevalence of CF-related diabetes (CFRD) varies depending on screening methods and diagnostic criteria (3). The true burden of the disease therefore may be underestimated (4). Because CFRD is often asymptomatic, annual screening for CFRD in CF patients is recommended at 10 years of age and onward, using the oral glucose tolerance test (5). Other parameters, such as HbA_1c, fructosamine, urine glucose, or random glucose levels, have low sensitivity in the CF population (6,7). Although positive results are highly suggestive of diabetes, the use of these tests alone will miss many cases of CFRD (4).Early detection of CFRD is important, because weight loss, protein catabolism, lung function decline, and mortality are increased in CFRD (8,9). Because pediatric diabetes centers usually provide care for few patients with CFRD only, it is necessary to advance knowledge of the characteristics of this type of diabetes, which is a distinct clinical entity with unique features that has been described in a recent technical review (8).The etiology of CFRD is complex, likely consisting of a combination of insulin deficiency and insulin resistance. Additional risk factors are a genetic predisposition toward the development of diabetes (2,10,11), exocrine pancreatic insufficiency, liver disease (1), chronic inflammation, exogenous glucocorticoids, female sex, and older age (1). It is well-known that insulin therapy stabilizes lung function and improves nutritional status in patients with CFRD (12,13). Patients with CFRD are insulin-insufficient and, based on available data, insulin is the recommended therapy for these patients (14). At the onset of CFRD, most patients only need a low dose of short-acting insulin before meals to control blood glucose. With disease progression and increasing insulin deficiency, intensification of insulin therapy is necessary.Type 1 diabetes mellitus (T1DM) is the most frequent kind of diabetes in the pediatric population; therefore, its characteristics are well-described (15). In T1DM, autoimmunity leads to a destruction of β cells and finally to absolute insulin deficiency. To better define the characteristics of CFRD, we compared CFRD to T1DM in pediatric patients who were followed up in a nationwide multicenter register.     

Impaired Fasting Glucose and Risk of Cardiovascular Disease in Korean Men and Women: The Korean Heart Study

OBJECTIVE

The relationship between impaired fasting glucose (IFG) and risk of cardiovascular disease (CVD) or ischemic heart disease (IHD) varies widely according to sex and ethnicity. We evaluated the relationship between IFG and CVD or IHD among Korean men and women.

RESEARCH DESIGN AND METHODS

A total of 408,022 individuals who underwent voluntary private health examinations in 17 centers in South Korea were followed for 10 years. Data regarding CVD or IHD events were obtained from the Korean National Health Insurance database. IFG was categorized as grade 1 (fasting glucose 100–109 mg/dL) or grade 2 (110–125 mg/dL).

RESULTS

Incidence rates of CVD (per 100,000 person-years) were 2,203 for diabetes. Age-adjusted hazard ratios (HRs) for CVD were 1.17 (95% CI 1.13–1.20) for grade 1 IFG, 1.30 (1.24–1.35) for grade 2 IFG, and 1.81 (1.75–1.86) for diabetes. The increased risk for women was similar to that of men. Age-adjusted HRs for IHD and ischemic stroke were also significantly increased for men and women with IFG and diabetes. After multivariate adjustment of conventional risk factors (hypertension, dyslipidemia, smoking, obesity, and family history of CVD), the overall risk of CVD was greatly attenuated in all categories. However, the HRs for IHD and ischemic stroke remained significantly increased in men for grade 2 IFG but not in women.

CONCLUSIONS

In Korea, grade 2 IFG is associated with increased risk of IHD and ischemic stroke, independent of other conventional risk factors, in men but not in women.It is well-established that type 2 diabetes is associated with a marked increase in the risk of cardiovascular disease (CVD) and ischemic heart disease (IHD) (1–4). Studies suggest that atherosclerosis develops before the onset of clinical diabetes (5,6). Supporting this possibility, many studies have reported that impaired glucose tolerance (IGT) is associated with increased cardiovascular morbidity and mortality (7,8). However, the association between impaired fasting glucose (IFG) and risk of CVD and/or IHD remains unclear (7–18). Although some studies have reported that IFG was associated with a greater risk of IHD/CVD in women than in men (17,19), others have reported similar risks for men and women (18).There has also been considerable debate regarding the threshold glucose level associated with increased CVD risk. In 2003, the American Diabetes Association (ADA) lowered the fasting plasma glucose (FPG) cutoff point for IFG from 110 to 100 mg/dL (20). Some studies have reported that FPG levels of 110–125 mg/dL were associated with significantly higher rates CVD morbidity or mortality, but that FPG levels of 100–109 mg/dL were not (12,13). However, other investigators reported that the relationship between CVD risk and fasting glucose was continuous or J-shaped rather than showing a threshold effect at high glucose levels (18,21). However, most studies were based mainly on Caucasian populations, and only a few studies have assessed the relationship between IFG and CVD risk in Asian populations (13,14,18). Furthermore, most of these studies analyzed IHD and stroke together as CVD, whereas few studies have analyzed IHD, ischemic stroke, and hemorrhagic stroke separately (14,22).The primary purpose of this study was to determine whether IFG is associated with increased risk of CVD, IHD, and/or stroke in the Korean population. We also assessed potential sex differences, which have been shown in some previous studies (17,19). Finally, we evaluated whether the CVD risk associated with fasting serum glucose (FSG) levels of 100–109 mg/dL is similar to the risk associated with FSG levels of 110–125 mg/dL (the 1997 ADA definition of IFG).     

Glucagon-Like Peptide 1 Reduces Endothelial Dysfunction,Inflammation, and Oxidative Stress Induced by Both Hyperglycemia and Hypoglycemia in Type 1 Diabetes

OBJECTIVE

Hyperglycemia and hypoglycemia currently are considered risk factors for cardiovascular disease in type 1diabetes. Both acute hyperglycemia and hypoglycemia induce endothelial dysfunction and inflammation, raising the oxidative stress. Glucagon-like peptide 1 (GLP-1) has antioxidant properties, and evidence suggests that it protects endothelial function.

RESEARCH DESIGN AND METHODS

The effect of both acute hyperglycemia and acute hypoglycemia in type 1 diabetes, with or without the simultaneous infusion of GLP-1, on oxidative stress (plasma nitrotyrosine and plasma 8-iso prostaglandin F2alpha), inflammation (soluble intercellular adhesion molecule-1 and interleukin-6), and endothelial dysfunction has been evaluated.

RESULTS

Both hyperglycemia and hypoglycemia acutely induced oxidative stress, inflammation, and endothelial dysfunction. GLP-1 significantly counterbalanced these effects.

CONCLUSIONS

These results suggest a protective effect of GLP-1 during both hypoglycemia and hyperglycemia in type 1 diabetes.Recent evidence suggests that hypoglycemia also may play an important role in favoring diabetic vascular complications (1). Hypoglycemia causes oxidative stress (2), inflammation (3,4), and endothelial dysfunction (5). Oxidative stress is considered the key player in the pathogenesis of diabetes complications (6). It is of interest that during hyperglycemia, oxidative stress is mainly produced at the mitochondrial level (6), similar to what happens in hypoglycemia (2). Therefore, oxidative stress might be considered the common factor linking hyperglycemia, hypoglycemia, and vascular complications of diabetes. Consistent with this hypothesis is the evidence that both hyperglycemia (7) and hypoglycemia produce endothelial dysfunction and inflammation through oxidative stress generation (5,8). Both endothelial dysfunction and inflammation are well-recognized pathogenic factors for vascular disease, particularly in diabetes (9).Glucagon-like peptide 1 (GLP-1) and its analogs are now being used in clinics to enhance insulin secretion and to reduce body weight in patients with type 2 diabetes (10) in whom a defect of GLP-1 secretion or action in response to the meal often has been reported (11). GLP-1 has been shown to lower postprandial and fasting glucose and HbA_1c, to suppress the elevated glucagon level, and to stimulate glucose-dependent insulin synthesis and secretion (10). Recently, a possible beneficial effect of GLP-1 analogs in the management of type 1 diabetes has been suggested (12). GLP-1, in addition to its insulin-tropic action in alleviating hyperglycemia, has beneficial effects in protecting progressive impairment of pancreatic β-cell function, preservation of β-cell mass, and suppression of glucagon secretion, gastric emptying, and appetite, which are all characteristics that could be beneficial for the management of type 1 diabetes (12).Apart from the well-documented incretin effect of GLP-1, its role in the cardiovascular system also arouses interest. GLP-1 effects on the cardiovascular system may include a direct action on the endothelium in which the presence of specific receptors for GLP-1 has been demonstrated (13). Consistently, GLP-1 has been demonstrated to improve endothelial function in diabetes (14,15). This protective effect should be exerted to improve the antioxidant defenses of the endothelium (16) and to decrease oxidative stress generation (15).The aim of this study is to test whether GLP-1 can protect endothelial function and reduce the generation of oxidative stress and inflammation during acute hyperglycemia and hypoglycemia in type 1 diabetes.     

Effects of Intraduodenal Glutamine on Incretin Hormone and Insulin Release,the Glycemic Response to an Intraduodenal Glucose Infusion,and Antropyloroduodenal Motility in Health and Type 2 Diabetes

OBJECTIVE

Glutamine reduces postprandial glycemia when given before oral glucose. We evaluated whether this is mediated by stimulation of insulin and/or slowing of gastric emptying.

RESEARCH DESIGN AND METHODS

Ten healthy subjects were studied during intraduodenal (ID) infusion of glutamine (7.5 or 15 g) or saline over 30 min, followed by glucose (75 g over 100 min), while recording antropyloroduodenal pressures. Ten patients with type 2 diabetes mellitus (T2DM) were also studied with 15 g glutamine or saline.

RESULTS

ID glutamine stimulated glucagon-like peptide 1 (GLP-1; healthy: P < 0.05; T2DM: P < 0.05), glucose-dependent insulinotropic polypeptide (GIP; P = 0.098; P < 0.05), glucagon (P < 0.01; P < 0.001), insulin (P = 0.05; P < 0.01), and phasic pyloric pressures (P < 0.05; P < 0.05), but did not lower blood glucose (P = 0.077; P = 0.5).

CONCLUSIONS

Glutamine does not lower glycemia after ID glucose, despite stimulating GLP-1, GIP, and insulin, probably due to increased glucagon. Its capacity for pyloric stimulation suggests that delayed gastric emptying is a major mechanism for lowering glycemia when glutamine is given before oral glucose.Postprandial glycemic control represents a major focus of type 2 diabetes mellitus (T2DM) management (1). The rate of gastric emptying and the release of “incretin” hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are both important determinants of postprandial glycemic excursions (2). Glucose empties from the stomach in health in the range of 1–4 kcal/min, regulated by inhibitory small-intestinal feedback via stimulation of pyloric motility and suppression of antral and duodenal contractions (3). Differences in gastric emptying account for about one-third of the variation in postprandial blood glucose levels after oral glucose (4).Glutamine reduces glucose excursions when given before oral glucose in T2DM (5), potentially by stimulating GLP-1 secretion (6) and/or slowing gastric emptying (7). The purpose of the current study was to determine whether glutamine retains its capacity to lower glycemia when glucose is delivered directly into the duodenum, thereby removing any influence of gastric emptying, while measuring antropyloroduodenal motility, gut hormones, and insulin.     

TRAF-interacting Protein (TRIP): A Novel Component of the Tumor Necrosis Factor Receptor (TNFR)- and CD30-TRAF Signaling Complexes That Inhibits TRAF2-mediated NF-κB Activation

Through their interaction with the TNF receptor–associated factor (TRAF) family, members of the tumor necrosis factor receptor (TNFR) superfamily elicit a wide range of biological effects including differentiation, proliferation, activation, or cell death. We have identified and characterized a novel component of the receptor–TRAF signaling complex, designated TRIP (TRAF-interacting protein), which contains a RING finger motif and an extended coiled-coil domain. TRIP associates with the TNFR2 or CD30 signaling complex through its interaction with TRAF proteins. When associated, TRIP inhibits the TRAF2-mediated NF-κB activation that is required for cell activation and also for protection against apoptosis. Thus, TRIP acts as a receptor–proximal regulator that may influence signals responsible for cell activation/proliferation and cell death induced by members of the TNFR superfamily.Members of the TNF receptor (TNFR)¹ superfamily play important roles in the induction of diverse signals leading to cell growth, activation, and apoptosis (1). Whether the signals induced by a given receptor leads to cell activation or death is, however, highly cell-type specific and tightly regulated during differentiation of cells. For example, the TNFRs can exert costimulatory signals for proliferation of naive lymphocytes but also induce death signals required for deletion of activated T lymphocytes (1). The cytoplasmic domains of these receptors lack intrinsic catalytic activity and also exhibit no significant homology to each other or to other known proteins. Exceptions to this include Fas(CD95) and TNFR1 that share a significant homology within an 80–amino acid region of their cytoplasmic tails (called the “death domain”; 2, 3). Therefore, it is suggested that the TNFR family members can initiate different signal transduction pathways by recruiting different types of intracellular signal transducers to the receptor complex (1).Indeed, several types of intracellular signal transducers have been identified that initiate distinct signal transduction pathways when recruited to the members of TNFR superfamily (4–19). Recent biochemical and molecular studies showed that a class of signal-transducing molecules are recruited to Fas(CD95) or TNFR1 via interaction of the death domains (2, 3, 6, 12, 17, 20). For example, Fas(CD95) and TNFR1 recruit FADD(MORT1)/RIP or TRADD/FADD (MORT1)/RIP through the interactions of their respective death domains (2, 3, 6, 12, 17, 20, 21). Clustering of these signal transducers leads to the recruitment of FLICE/ MACH, and subsequently, to cell death (13, 14).The TNFR family members can also recruit a second class of signal transducers called TRAFs (TNFR-associated factor), some of which are responsible for the activation of NF-κB or JNK (9, 20, 22). TRAF proteins were identified by their biochemical ability to interact with TNFR2, CD40, CD30, or LT-βR (4, 5, 10, 11, 15, 23–27). These receptors interact directly with TRAFs via a short stretch of amino acids within their cytoplasmic tails, but do not interact with the death domain containing proteins (4, 5, 15, 24–27). To date, five members of the TRAF family have been identified as signaling components of the TNFR family members. All TRAF members contain a conserved TRAF domain, ∼230 amino acids in length, that is used for either homo- or heterooligomerization among the TRAF family, for interactions with the cytoplasmic regions of the TNFR superfamily, or for interactions with downstream signal transducers (4, 5, 8, 10, 11, 19, 23–25, 28). In addition to the TRAF domain, most of the TRAF family members contain an NH₂-terminal RING finger and several zinc finger structures, which appear to be important for their effector functions (4, 5, 10, 11, 23–25).Several effector functions of TRAFs were revealed by recent experiments based on a transfection system. TRAF2, first identified by its interaction with TNFR2 (4), was subsequently shown to mediate NF-κB activation induced by two TNF receptors, CD40 and CD30 (9, 28–30). TRAF5 was also implicated in NF-κB activation mediated by LTβR (10), whereas TRAF3 (also known as CRAF1, CD40bp, or LAP1; references 5, 11, 24, and 25) was shown to be involved in the regulation of CD40-mediated CD23 upregulation in B cells (5). The role of other TRAF members in the TNFR family–mediated signal transduction is not clear. They may possess some effector functions as yet to be revealed, or work as adapter proteins to recruit different downstream signal transducers to the receptor complex. For example, TRAF1 is required for the recruitment of members of the cellular inhibitor of apoptosis protein (c-IAP) family to the TNFR2-signaling complex (7). In addition to the signal transduction by the TNFR family members, TRAFs may regulate other receptor-mediated signaling pathways. For example, TRAF6 is a component of IL-1 receptor (IL1R)–signaling complex, in which it mediates the activation of NF-κB by IL-1R (31). Since TRAFs form homo- or heterooligomers, it is suggested that the repertoire of TRAF members in a given cell type may differentially affect the intracellular signals triggered by these receptors. This may be accomplished by the selective interaction of TRAFs with a specific set of downstream signal transducers. Although many aspects of TRAF-mediated effector functions leading to cellular activation have been defined, it needs to be determined whether TRAF proteins will also mediate the apoptotic signals induced by the “death-domain-less” members of the TNFR superfamily (1, 27, 32–36).Here we report the isolation and characterization of a novel component of the TNFR superfamily/TRAFs signaling complex, named TRIP (TRAF-interacting protein). TRIP associates with the receptor/TRAF signaling complex, and inhibits the TRAF2-mediated NF-κB activation. Biochemical studies indicate that TRIP associates with the TNFR2 or CD30 receptor complex via its interaction with TRAF proteins, suggesting a model which can explain why the ligation of these receptors can promote different cell fates: proliferation or death.     

Epidemiology and Mortality of New-Onset Diabetes After Dialysis: Taiwan national cohort study

OBJECTIVE

We examined the predictors and risks associated with pre-existing versus new-onset diabetes mellitus (DM) after initiation of chronic dialysis therapy in end-stage renal disease (ESRD) patients.

RESEARCH DESIGN AND METHODS

In the Taiwan National Health Insurance Research Database, we examined records of ESRD patients who initiated dialysis between 1999 and 2005. Patients were followed until death, transplant, dialysis withdrawal, or 31 December 2008. Predictors of new-onset DM and mortality were calculated using Cox models.

RESULTS

A total of 51,487 incident dialysis patients were examined in this study, including 25,321 patients with pre-existing DM, 3,346 with new-onset DM, and 22,820 without DM at any time. Patients’ age (mean ± SD) was 61.8 ± 11.5, 61.6 ± 13.7, and 56.5 ± 16.6 years in pre-existing, new-onset DM, and without DM groups, respectively. The cumulative incidence rate of new-onset DM was 4% at 1 year and 21% at 9 years. Dialysis modality was not a risk factor for new-onset DM (peritoneal dialysis to hemodialysis hazard ratio [HR] of new-onset DM, 0.94 [95% CI 0.83–1.06]). Pre-existing DM was associated with 80% higher death risk (HR 1.81 [95% CI 1.75–1.87]), whereas the new-onset DM was associated with 10% increased death risk (HR 1.10 [95% CI 1.03–1.17]).

CONCLUSIONS

Whereas dialysis modality does not appear to associate with new-onset DM, both pre-existing and new-onset DM are related to higher long-term mortality in maintenance dialysis patients.The increasing prevalence of diabetes mellitus (DM) is a global health issue in the obese and aging (1). Chronic kidney disease is an important complication of DM. Diabetic nephropathy, the leading cause of end-stage renal disease (ESRD) (2), accounts for ∼40% of patients on maintenance dialysis (3).Many studies (2,4) report an association between pre-existing DM at the initiation of dialysis and a poor outcome in ESRD patients undergoing dialysis. However, few published studies have focused on postdialysis new-onset DM (4–7). Glucose is one of the contents of hemodialysates (8) and peritoneal dialysates (9). Peritoneal dialysis (PD) patients, who received 24-h continuous high-glucose–concentration peritoneal dialysates, can develop hyperglycemia and transient hyperinsulinism (10). Woodward et al. (6), examining the U.S. Renal Data System, showed the incidence of new-onset DM to be ∼6% per year in dialysis patients. In Asia, Chinese patients in Hong Kong have been observed to have a high prevalence of hyperglycemia with a daily exchange of 1.5% glucose dialysate (7). Some epidemiological studies of glycemic load in relation to incident DM report inconsistent results. For example, although high intake of foods with high glycemic load has been found to increase the risk of type 2 DM in Chinese (11), Mosdøl et al. (12) did not find such an association in the Whitehall II study. Nevertheless, one meta-analysis of prospective cohort studies enrolling 13 trials concluded that there was a positive association between glycemic load and type 2 DM (13). Pure glucose has the highest glycemic index, but few long-term follow-up studies have investigated the glucose load and the risk of DM, especially in patients with ESRD. In addition, it has been demonstrated that increased plasma glucose levels are an independent risk factor for mortality among dialysis patients, even a minor degree of hyperglycemia (7). It has also been reported that the cumulative advanced atherosclerotic change in DM could be responsible for the increased further cardiovascular mortality thereafter.The worldwide number of ESRD patients undergoing dialysis has grown significantly in recent decades. The incidence and prevalence rates of ESRD are high in Taiwan (14). However, studies on new-onset DM are scarce, especially studies with epidemiological data from a national cohort of Asians with ESRD on maintenance dialysis. Therefore, this study investigates whether there is an association between dialysis modality and new-onset DM and whether new-onset DM is a risk factor for long-term mortality. To find out, we used a large dataset from the Taiwan National Health Insurance Research Database (NHIRD) from 1999 to 2008 to evaluate the epidemiology, incidence, and mortality of new-onset DM in ESRD patients undergoing dialysis.     

Endothelial Progenitor Cells Are Related to Glycemic Control in Children With Type 1 Diabetes Over Time

OBJECTIVE

The risk of cardiovascular death before the age of 40 is 20-fold higher in patients with type 1 diabetes mellitus (T1DM). Endothelial progenitor cells (EPCs) predict cardiovascular morbidity and mortality in patients without diabetes. We hypothesized that EPCs are modified in children with T1DM and are related to characteristics of T1DM such as glycemic control.

RESEARCH DESIGN AND METHODS

Children (n = 190; 156 T1DM subjects and 34 control subjects) were included in an observational cohort study and matched for age and sex. EPCs were enumerated by flow cytometry at the beginning (cross-sectional) and 1 year later (longitudinal). To analyze changes of variables during the observation, Δ values were calculated.

RESULTS

EPCs were significantly reduced in T1DM children versus control subjects (609 ± 359 vs. 1,165 ± 484, P < 0.001). Multivariate regression modeling revealed that glycated hemoglobin A_1c (HbA_1c) was the strongest independent predictor of EPCs (β = −0.355, P < 0.001). Overall glycemic control at the beginning and end of study did not differ (7.8 ± 1.2 vs. 7.8 ± 1.2 relative %, P = NS), but we observed individual HbA_1c changes of −4.30/+3.10 relative %. The strongest EPC increase was observed in the patients with the most favorable HbA_1c lowering during the 1-year follow-up. Accordingly, the strongest EPC decrease was demonstrated in the patients with the strongest HbA_1c worsening during the time period.

CONCLUSIONS

This is the first prospective study demonstrating diminished EPCs in children with T1DM. The association of better glycemic control with an increase in EPC numbers within 1 year suggests that a reduction of the high cardiovascular disease burden might be mediated likewise.Over the last 30 years, a marked improvement in diabetic nephropathy, retinopathy, and neuropathy was observed in patients with type 1 diabetes mellitus (T1DM) (1–3). However, no difference for the incidence of cardiovascular disease (CVD) was observed in those patients (1–3). Thus, one can assume that late improvements in diabetes care do not reduce cardiovascular risk (1–3).Even more, despite dramatic improvement in CVD therapy, such as interventional therapy, statins, and clopidogrel, CVD mortality did not improve in T1DM over the last 10 years (1–3). In fact, the mortality of CVD before 40 years of age is 20-fold higher in patients with T1DM compared with age- and sex-adjusted healthy subjects. Between 30–40 years of age, CVD is already the first cause of death in those patients (4,5).The main contributor to the increased cardiovascular risk might be unsatisfactory glycemic control, which emerges from the very beginning of T1DM (childhood) (6–8). Other mechanisms speculated to be associated or involved independently might be endothelial dysfunction (9) and/or systemic vascular inflammation (10).Recent analysis of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) trial strengthened the suspicion that endothelial dysfunction and vascular inflammation might be involved in the increased susceptibility to vascular disease (11,12) in T1DM. However, the exact mechanisms linking those pathophysiological findings to manifest clinical disease are not understood.A possible link might be vascular progenitor cells, which are involved in vascular hemostasis and counteract the aberrances of vascular inflammation. Werner and Nickenig (13) argued that endothelial progenitor cells (EPCs) are the common feature of atherosclerosis, from its beginning as endothelial dysfunction to its result as end-stage ischemic heart disease. EPCs measured by colony-forming assays were demonstrated to correlate with the Framingham Risk Score and endothelial function (14), and furthermore, when measured by flow cytometry, EPCs were found to be associated with cardiovascular outcome (15).In accordance with the theory of endothelial continuum of EPCs (13), EPCs were demonstrated to be reduced in adults with T1DM in a pilot study (16). We have added that EPCs are directly related to stages of retinopathy in adults with T1DM (17) and also T2DM (18). Recently, three very interesting cross-sectional pilot-like studies have been reported. First, Sibal et al. (19) showed an association of EPCs and premature atherosclerosis in young adults with T1DM by investigating flow-mediated dilatation in those patients. However, they did not obtain a significant difference for CD34⁺/CD309⁺ cells between T1DM and control subjects. Second, DiMeglio et al. (20) demonstrated a reduction of EPCs already in young adults (mean age 20.3 ± 1.4 years) with T1DM compared with those without. Third, Palombo et al. (21) confirmed a reduction of EPCs in 16 young adults with T1DM and added an association of EPCs and intima media thickness. All three studies failed to identify any association of EPCs with characteristics of T1DM, such as glycemic control or total insulin dosage.It is tempting to speculate that diminished EPCs could be one of the pathophysiological mechanisms linking the elevated CVD risk to young patients with T1DM. We assumed that elevated inflammation and/or impaired glucose control might be associated cross-sectionally and longitudinally with diminished levels of EPCs, thereby leading to the increased risk for CVD at such a young age.     

Adverse Outcomes After Noncardiac Surgery in Patients With Diabetes: A nationwide population-based retrospective cohort study

OBJECTIVE

To investigate whether diabetes affects perioperative complications or mortality and to gauge its impact on medical expenditures for noncardiac surgeries.

RESEARCH DESIGN AND METHODS

With the use of reimbursement claims from the Taiwan National Health Insurance system, we performed a population-based cohort study of patients with and without diabetes undergoing noncardiac surgeries. Outcomes of postoperative complications, mortality, hospital stay, and medical expenditures were compared between patients with and without diabetes.

RESULTS

Diabetes increased 30-day postoperative mortality (odds ratio 1.84 [95% CI 1.46–2.32]), particularly among patients with type 1 diabetes or uncontrolled diabetes and patients with preoperative diabetes-related comorbidities, such as eye involvement, peripheral circulatory disorders, ketoacidosis, renal manifestations, and coma. Compared with nondiabetic control patients, coexisting medical conditions, such as renal dialysis (5.17 [3.68–7.28]), liver cirrhosis (3.59 [2.19–5.88]), stroke (2.87 [1.95–4.22]), mental disorders (2.35 [1.71–3.24]), ischemic heart disease (2.08 [1.45–2.99]), chronic obstructive pulmonary disease (1.96 [1.29–2.97]), and hyperlipidemia (1.94 [1.01–3.76]) were associated with mortality for patients with diabetes undergoing noncardiac surgery. Patients with diabetes faced a higher risk of postoperative acute renal failure (3.59 [2.88–4.48]) and acute myocardial infarction (3.65 [2.43–5.49]). Furthermore, diabetes was associated with prolonged hospital stay (2.30 [2.16–2.44]) and increased medical expenditures (1.32 [1.25–1.40]).

CONCLUSIONS

Diabetes increases postoperative 30-day mortality, complications, and medical expenditures in patients undergoing in-hospital noncardiac surgeries.Diabetes is a common chronic disease that causes widespread disability and death, with a global prevalence of 2.8% in 2000 and an estimated prevalence of 4.4% in 2030 (1). In the U.S., the national burden of diabetes was estimated to be $245 billion in 2012 (2). The epidemiology, pathogenesis, prevention, and treatment of diabetes have been well established over the past 2 centuries (3).Diabetes is an independent determinant of increased risk of perioperative complications and mortality in cardiovascular surgeries (4,5), yet how extensively diabetes affects postoperative mortality and complications in noncardiac surgeries has not been determined. Some studies indicated that survival outcomes and perioperative complications in noncardiac surgeries do not differ between patients with and without diabetes (6,7), whereas other research showed conflicting data about whether diabetes increased perioperative complications, mortality, hospital stay, and health care expenditures (8–16).Previous studies were limited by several factors, including a focus on a single type of noncardiac surgery (6,8,10,12,14), small sample size (6,7,9,13), inappropriate selection of nondiabetes control subjects (6–16), inadequate adjustment for potential confounders (7,9–12,15), and reporting of a single outcome after surgery (10,16). It remains unclear whether coexisting medical conditions, types of diabetes, glycemic control, and diabetes-related comorbidities affect postoperative outcomes in patients with diabetes.This study used Taiwan National Health Insurance Program reimbursement claims to investigate postoperative complications, 30-day mortality, length of hospital stay, and medical expenditures after adjustment by propensity score-matched pair method in patients with diabetes undergoing noncardiac surgeries. We also investigated the impact of coexisting medical conditions and diabetes-related comorbidities on postoperative 30-day mortality among patients with diabetes.     

HLA-DM Interactions with Intermediates in HLA-DR Maturation and a Role for HLA-DM in Stabilizing Empty HLA-DR Molecules

Major histocompatibility complex (MHC) class II–positive cell lines which lack HLA-DM expression accumulate class II molecules associated with residual invariant (I) chain fragments (class II–associated invariant chain peptides [CLIP]). In vitro, HLA-DM catalyzes CLIP dissociation from class II–CLIP complexes, promoting binding of antigenic peptides. Here the physical interaction of HLA-DM with HLA-DR molecules was investigated. HLA-DM complexes with class II molecules were detectable transiently in cells, peaking at the time when the class II molecules entered the MHC class II compartment. HLA-DR αβ dimers newly released from I chain, and those associated with I chain fragments, were found to associate with HLA-DM in vivo. Mature, peptide-loaded DR molecules also associated at a low level. These same species, but not DR-I chain complexes, were also shown to bind to purified HLA-DM molecules in vitro. HLA-DM interaction was quantitatively superior with DR molecules isolated in association with CLIP. DM-DR complexes generated by incubating HLA-DM with purified DR αβCLIP contained virtually no associated CLIP, suggesting that this superior interaction reflects a prolonged HLA-DM association with empty class II dimers after CLIP dissociation. Incubation of peptide-free αβ dimers in the presence of HLA-DM was found to prolong their ability to bind subsequently added antigenic peptides. Stabilization of empty class II molecules may be an important property of HLA-DM in facilitating antigen processing.The recognition of antigen by CD4⁺ T helper cells requires the presentation of short peptides displayed in the binding groove of MHC class II molecules (1, 2). MHC class II molecules are cell surface expressed heterodimeric (αβ) glycoproteins. Newly synthesized class II α and β chains assemble in the ER with a third transmembrane glycoprotein, the invariant (I) chain (3, 4). With the aid of the molecular chaperone calnexin, three αβ dimers bind sequentially to a trimer of the I chain in the ER (5, 6). The nonameric complex moves through the Golgi apparatus and is sorted by signals in the cytoplasmic domain of the I chain (7) and the class II β chain (8) to endosomal compartments with late endosomal (class II–containing vesicles, CIIV; 9) or lysosome-like characteristics (MHC class II compartment [MIIC]¹; 10–13) where the I chain is proteolytically cleaved by aspartic and cysteine proteases (14–17). The released αβ dimers are loaded with peptides derived from internalized pathogen-derived or endogenous proteins present in the endocytic system and transported to the cell surface.The expression of HLA-DM, encoded by MHC-linked genes (18, 19), is required for class II–restricted processing and presentation of most protein antigens but not for the presentation of exogenously added antigenic peptides (reviewed in reference 20). Class II molecules in DM-negative B-lymphoblastoid cell lines (B-LCL) are expressed on the cell surface at wild-type levels but are associated with a set of peptides derived from residues 81-104 of the I chain (class II–associated invariant chain peptides, or CLIP) instead of antigenic peptides (21, 22). Similar complexes accumulate in class II–positive cell lineages in mice in which the Ma (DMA) gene is disrupted (23–25). The ability to isolate αβCLIP complexes from wild-type APCs (2), their transient appearance during pulse–chase analysis of class II transport (26–27), and the proteolytic generation of αβCLIP complexes from αβI in vitro (27), all indicate that αβCLIP complexes are an intermediate in the class II processing pathway and that CLIP probably represents the end product of I chain proteolysis. Recent x-ray crystallographic analysis of HLA-DR3-CLIP complexes has demonstrated that CLIP binds in the antigen binding groove of the class II molecules (28) indicating that CLIP must first be removed before endocytically generated peptides can bind.Recently, we and others have shown that CLIP removal and peptide loading are directly catalyzed by DM in vitro (29–31), suggesting that DM also removes CLIP from αβCLIP complexes in vivo. For DM to catalyze the release of CLIP, it seemed likely that a DM–class II interaction must occur and, indeed, Sanderson et al. (32) have shown by coprecipitation that DM and DR associate under steady state conditions in vivo. The association is favored by low pH in the nonionic detergent digitonin, and occurs in dense compartments, probably in MIICs. In this study, using biosynthetic labeling and coprecipitation of DR with DM, we show that in vivo the DM-DR association is transient, and that DM associates with peptide loaded αβ dimers, extending the initial observations reported by Sanderson et al. (32). Additionally, we examine the in vitro interaction of affinity-purified DM with DR molecules associated with I chain, fragments of I chain, CLIP, or the normal complement of peptides expressed in wild-type cells. The results indicate a degree of specificity for αβCLIP in the interaction, and suggest that one function of HLA-DM is to prolong the survival of empty class II molecules in the MIIC, a chaperone-like function which is likely to be important in antigen processing.     

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

The Relative Contribution of Prepregnancy Overweight and Obesity,Gestational Weight Gain,and IADPSG-Defined Gestational Diabetes Mellitus to Fetal Overgrowth

OBJECTIVE

The International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria for diagnosis of gestational diabetes mellitus (GDM) identifies women and infants at risk for adverse outcomes, which are also strongly associated with maternal overweight, obesity, and excess gestational weight gain.

RESEARCH DESIGN AND METHODS

We conducted a retrospective study of 9,835 women who delivered at ≥20 weeks’ gestation; had a prenatal, 2-h, 75-g oral glucose tolerance test; and were not treated with diet, exercise, or antidiabetic medications during pregnancy. Women were classified as having GDM based on IADPSG criteria and were categorized into six mutually exclusive prepregnancy BMI/GDM groups: normal weight ± GDM, overweight ± GDM, and obese ± GDM.

RESULTS

Overall, 5,851 (59.5%) women were overweight or obese and 1,892 (19.2%) had GDM. Of those with GDM, 1,443 (76.3%) were overweight or obese. The prevalence of large-for-gestational-age (LGA) infants was significantly higher for overweight and obese women without GDM compared with their normal-weight counterparts. Among women without GDM, 21.6% of LGA infants were attributable to maternal overweight and obesity, and the combination of being overweight or obese and having GDM accounted for 23.3% of LGA infants. Increasing gestational weight gain was associated with a higher prevalence of LGA in all groups.

CONCLUSIONS

Prepregnancy overweight and obesity account for a high proportion of LGA, even in the absence of GDM. Interventions that focus on maternal overweight/obesity and gestational weight gain, regardless of GDM status, have the potential to reach far more women at risk for having an LGA infant.Both International Association of Diabetes in Pregnancy Study Groups (IADPSG)–defined gestational diabetes mellitus (GDM) (1,2) and maternal overweight and obesity (2–4) are associated with increased risk for adverse maternal and perinatal outcomes, such as fetal overgrowth, shoulder dystocia and birth injury, pre-eclampsia, and preterm delivery. Although most studies addressing the effects of maternal BMI on adverse outcomes include women with GDM (2–6), a few have reported these associations in overweight or obese women with normal glucose tolerance (7–9). Scant data exist that demonstrate associations between GDM and adverse outcomes in the absence of overweight or obesity (9).Although it is currently estimated that 10–25% of pregnant women develop GDM by IADPSG criteria (1,2,10), 50–60% of women are overweight or obese at the start of their pregnancies (6,7,11,12). Prepregnancy overweight and obesity are also associated with GDM development, as 65–75% of women with GDM are also overweight or obese (11,13). As such, the relative impact of prepregnancy BMI and maternal glycemia during pregnancy on adverse maternal and perinatal outcomes is difficult to tease apart. Moreover, excess gestational weight gain complicates a large number of pregnancies and is highly correlated with maternal overweight and obesity, as well as the development of GDM (14–16). Despite the fact that studies have reported increases in the risk of adverse outcomes with increasing gestational weight gain (13,15–18), many studies examining the effects of maternal obesity and/or glucose levels have not accounted for this important factor.The purpose of this study was to examine the effects of prepregnancy overweight and obesity among women with and without IADPSG-defined GDM on clinically important adverse outcomes, focusing primarily on fetal overgrowth, one of the most prevalent adverse conditions associated with maternal and neonatal morbidity. In addition to magnitude of association, we determine the proportion of large-for-gestational-age (LGA) infants attributable to each risk factor and combinations thereof. We also examine the relative contribution of increasing gestational weight gain to the development of LGA.     

Estimating the Population Prevalence of Diagnosed and Undiagnosed Diabetes

OBJECTIVE

Health administrative data are frequently used for diabetes surveillance, but validation studies are limited, and undiagnosed diabetes has not been considered in previous studies. We compared the test properties of an administrative definition with self-reported diabetes and estimated prevalence of undiagnosed diabetes by measuring glucose levels in mailed-in capillary blood samples.

RESEARCH DESIGN AND METHODS

A stratified random sample of 6,247 individuals (Quebec province) was surveyed by telephone and asked to mail in fasting blood samples on filter paper to a central laboratory. An administrative definition was applied (two physician claims or one hospitalization for diabetes within a 2-year period) and compared with self-reported diabetes alone and with self-reported diabetes or elevated blood glucose level (≥7 mmol/L). Population-level prevalence was estimated with the use of the administrative definition corrected for its sensitivity and specificity.

RESULTS

Compared with self-reported diabetes, sensitivity and specificity were 84.3% (95% CI 79.3–88.5%) and 97.9% (97.4–98.4%), respectively. Compared with diabetes by self-report and/or glucose testing, sensitivity was lower at 58.2% (52.2–64.6%), whereas specificity was similar at 98.7% (98.0–99.3%). Adjusted for sampling weights, population-level prevalence of physician-diagnosed diabetes was 7.2% (6.3–8.0%). Prevalence of total diabetes (physician-diagnosed and undiagnosed) was 13.4% (11.7–15.0%), indicating that ∼40% of diabetes cases are undiagnosed.

CONCLUSIONS

A substantial proportion of diabetes cases are missed by surveillance methods that use health administrative databases. This finding is concerning because individuals with undiagnosed diabetes are likely to have a delay in treatment and, thus, a higher risk for diabetes-related complications.The rapid rise in diabetes incidence and prevalence is placing substantial strains on health care systems in terms of management of both the disease itself and its complications (1). Accurate disease surveillance, therefore, is critical to making proper projections of health care needs and costs. In Canada, the National Diabetes Surveillance System (NDSS) tracks diabetes prevalence through physician billing and hospital admissions databases (2–4). Similar algorithms have been used in the U.S. and other countries (3,5–12). Although these administrative health database definitions have been validated through medical record (4,13), survey (4,6,8,14,15), and medication use data (4,10,16), no validation study of claims-based administrative algorithms has accounted for previously undiagnosed diabetes.In the current study, we validated an administrative database diabetes definition and estimated the prevalence of physician-diagnosed diabetes through a population-based health survey. We used a novel approach to estimate the prevalence of undiagnosed diabetes that involved mailed-in capillary blood samples in which fasting glucose levels were measured at a central laboratory. Finally, by using survey data and glucose levels to correct the administrative database diabetes definition, we estimated the actual diabetes prevalence and compared this with what would have been estimated by the uncorrected definition.