bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemodynamic Effects of Fenofibrate and Coenzyme Q10 in Type 2 Diabetic Subjects With Left Ventricular Diastolic Dysfunction
Authors: Chew Gerard T. , Watts Gerald F. , Davis Timothy M.E. , Stuckey Bronwyn G.A. , Beilin Lawrence J. , Thompson Peter L. , Burke Valerie , Currie Philip J.
Published: June 2008

OBJECTIVE—To investigate the effects of fenofibrate and coenzyme Q10 (CoQ) on diastolic function, ambulatory blood pressure (ABP), and heart rate (HR) in type 2 diabetic subjects with left ventricular diastolic dysfunction (LVDD).

RESEARCH DESIGN AND METHODS—We randomized, double-blind, 74 subjects to fenofibrate 160 mg daily, CoQ 200 mg daily, fenofibrate 160 mg plus CoQ 200 mg daily, or matching placebo for 6 months. Echocardiography (including tissue Doppler imaging) and 24-h ABP and HR monitoring were performed pre- and postintervention.

RESULTS—Neither fenofibrate nor CoQ, alone or in combination, altered early diastolic mitral annular myocardial relaxation velocity (E′), early-to-late mitral inflow velocity ratio (E/A), deceleration time, isovolumic relaxation time, or the ratio of early mitral flow velocity to early diastolic mitral annular myocardial relaxation velocity (E/E′) compared with placebo (P > 0.05). Fenofibrate and CoQ interactively (P = 0.001) lowered 24-h systolic blood pressure (−3.4 ± 0.09 mmHg, P = 0.010), with a prominent nocturnal effect (−5.7 ± 1.5 mmHg, P = 0.006). Fenofibrate (−1.3 ± 0.5 mmHg, P = 0.013) and CoQ (−2.2 ± 0.5 mmHg, P < 0.001) independently lowered 24-h diastolic blood pressure. Fenofibrate reduced 24-h HR (−3.3 ± 0.5 beats/min, P < 0.001), but CoQ had no effect on HR.

CONCLUSIONS—In type 2 diabetic subjects with LVDD, neither fenofibrate nor CoQ, alone or in combination, improved diastolic function significantly. However, fenofibrate and CoQ independently and interactively lowered 24-h blood pressure, and fenofibrate alone reduced 24-h HR.
Isolated Hyperglycemia at 1 Hour on Oral Glucose Tolerance Test in Pregnancy Resembles Gestational Diabetes Mellitus in Predicting Postpartum Metabolic Dysfunction
Authors: Retnakaran Ravi , Qi Ying , Sermer Mathew , Connelly Philip W. , Zinman Bernard , Hanley Anthony J.G.
Published: June 2008

OBJECTIVE—Gestational impaired glucose tolerance (GIGT), defined by a single abnormal value on antepartum 3-h oral glucose tolerance test (OGTT), is a metabolically heterogeneous disorder. Indeed, the antepartum metabolic phenotype of women with a single abnormal value at 1 h during the OGTT (1-h GIGT) resembles that of women with gestational diabetes mellitus (GDM), whereas GIGT at 2 or 3 h (2/3-h GIGT) is similar to normal glucose tolerance (NGT). Thus, we hypothesized that 1-h GIGT would be associated with the same adverse outcomes as GDM, i.e., increased infant birth weight and postpartum metabolic dysfunction.

RESEARCH DESIGN AND METHODS—A total of 361 women underwent an antepartum glucose challenge test (GCT) and a 3-h OGTT, assessment of obstetrical outcome at delivery, and metabolic characterization by OGTT at 3 months postpartum. The antepartum GCT/OGTT identified five study groups: GDM (n = 97), 1-h GIGT (n = 28), 2/3-h GIGT (n = 34), abnormal GCT NGT (abnormal GCT with NGT on OGTT) (n = 128), and normal GCT NGT (normal GCT with NGT on OGTT) (n = 74).

RESULTS—Caesarian section rate was higher in women with 1-h GIGT, but birth weight did not differ significantly between the non-GDM groups (P = 0.1978). At 3 months postpartum, glycemia (area under the glucose curve) progressively increased across the groups from normal GCT NGT to abnormal GCT NGT to 2/3-h GIGT to 1-h GIGT to GDM (P < 0.0001), while both insulin sensitivity (ISOGTT) and β-cell function (insulinogenic index/homeostasis model assessment of insulin resistance [HOMA-IR]) progressively decreased (P = 0.002 and P < 0.0001, respectively). The strongest independent negative predictors of insulinogenic index/HOMA-IR were GDM (t = −4.1, P < 0.0001) and 1-h GIGT (t = −3.8, P = 0.0002).

CONCLUSIONS—Like GDM, 1-h GIGT is associated with postpartum glycemia, insulin resistance, and β-cell dysfunction.
Diabetes, Glycemic Control, and Risk of Hospitalization With Pneumonia
Authors: Kornum Jette B. , Thomsen Reimar W. , Riis Anders , Lervang Hans-Henrik , Schønheyder Henrik C. , Sørensen Henrik T.
Published: June 2008

OBJECTIVE—To examine whether diabetes is a risk factor for hospitalization with pneumonia and to assess the impact of A1C level on such risk.

RESEARCH DESIGN AND METHODS—In this population-based, case-control study we identified patients with a first-time pneumonia-related hospitalization between 1997 and 2005, using health care databases in northern Denmark. For each case, 10 sex- and age-matched population control subjects were selected from Denmark's Civil Registration System. We used conditional logistic regression to compute relative risk (RR) for pneumonia-related hospitalization among subjects with and without diabetes, controlling for potential confounding factors.

RESULTS—The study included 34,239 patients with a pneumonia-related hospitalization and 342,390 population control subjects. The adjusted RR for pneumonia-related hospitalization among subjects with diabetes was 1.26 (95% CI 1.21–1.31) compared with nondiabetic individuals. The adjusted RR was 4.43 (3.40–5.77) for subjects with type 1 diabetes and 1.23 (1.19–1.28) for subjects with type 2 diabetes. Diabetes duration ≥10 years increased the risk of a pneumonia-related hospitalization (1.37 [1.28–1.47]). Compared with subjects without diabetes, the adjusted RR was 1.22 (1.14–1.30) for diabetic subjects whose A1C level was <7% and 1.60 (1.44–1.76) for diabetic subjects whose A1C level was ≥9%.

CONCLUSIONS—Type 1 and type 2 diabetes are risk factors for a pneumonia-related hospitalization. Poor long-term glycemic control among patients with diabetes clearly increases the risk of hospitalization with pneumonia.
Two-Year Pulmonary Safety and Efficacy of Inhaled Human Insulin (Exubera) in Adult Patients With Type 2 Diabetes
Authors: Rosenstock Julio , Cefalu William T. , Hollander Priscilla A. , Belanger Andre , Eliaschewitz Freddy G. , Gross Jorge L. , Klioze Solomon S. , St. Aubin Lisa B. , Foyt Howard , Ogawa Masayo , Duggan William T.
Published: June 2008

OBJECTIVE—The purpose of this study was to evaluate the 2-year pulmonary safety of inhaled human insulin (Exubera [EXU]) in 635 nonsmoking adults with type 2 diabetes.

RESEARCH DESIGN AND METHODS—Patients were randomly assigned to receive prandial EXU or subcutaneous insulin (regular or short-acting) plus basal (intermediate- or long-acting) insulin. The primary end points were the annual rate of decline in forced expiratory volume in 1 s (FEV1) and carbon monoxide diffusing capacity (DLCO).

RESULTS—Small differences in FEV1 favoring subcutaneous insulin developed during the first 3 months but did not progress. Adjusted treatment group differences in FEV1 annual rate of change were −0.007 l/year (90% CI −0.021 to 0.006) between months 0 and 24 and 0.000 l/year (−0.016 to 0.016) during months 3–24. Treatment group differences in DLCO annual rate of change were not significant. Both groups sustained similar reductions in A1C by month 24 (last observation carried forward) (EXU 7.7–7.3% vs. subcutaneous insulin 7.8–7.3%). Reductions in fasting plasma glucose (FPG) were greater with EXU than with subcutaneous insulin (adjusted mean treatment difference −12.4 mg/dl [90% CI −19.7 to −5.0]). Incidence of hypoglycemia was comparable in both groups. Weight increased less with EXU than with subcutaneous insulin (−1.3 kg [−1.9 to −0.7]). Adverse events were comparable, except for a higher incidence of mild cough and dyspnea with EXU.

CONCLUSIONS—Two-year prandial EXU therapy showed a small nonprogressive difference in FEV1 and comparable sustained A1C improvement but lower FPG levels and less weight gain than seen in association with subcutaneous insulin in adults with type 2 diabetes.
Is the Combination of Sulfonylureas and Metformin Associated With an Increased Risk of Cardiovascular Disease or All-Cause Mortality?
Authors: Rao Ajay D. , Kuhadiya Nitesh , Reynolds Kristi , Fonseca Vivian A.
Published: June 2008

OBJECTIVE—Observational studies assessing the association of combination therapy of metformin and sulfonylurea on all-cause and/or cardiovascular mortality in type 2 diabetes have shown conflicting results. We therefore evaluated the effects of combination therapy of sulfonylureas and metformin on the risk of all-cause mortality and cardiovascular disease (CVD) among people with type 2 diabetes.

RESEARCH DESIGN AND METHODS—A MEDLINE search (January 1966–July 2007) was conducted to identify observational studies that examined the association between combination therapy of sulfonylureas and metformin on risk of CVD or all-cause mortality. From 299 relevant reports, 9 were included in the meta-analysis. In these studies, combination therapy of metformin and sulfonylurea was assessed, the risk of CVD and/or mortality was reported, and adjusted relative risk (RR) or equivalent (hazard ratio and odds ratio) and corresponding variance or equivalent was reported.

RESULTS—The pooled RRs (95% CIs) of outcomes for individuals with type 2 diabetes prescribed combination therapy of sulfonylureas and metformin were 1.19 (0.88–1.62) for all-cause mortality, 1.29 (0.73–2.27) for CVD mortality, and 1.43 (1.10–1.85) for a composite end point of CVD hospitalizations or mortality (fatal or nonfatal events).

CONCLUSIONS—The combination therapy of metformin and sulfonylurea significantly increased the RR of the composite end point of cardiovascular hospitalization or mortality (fatal and nonfatal events) irrespective of the reference group (diet therapy, metformin monotherapy, or sulfonylurea monotherapy); however, there were no significant effects of this combination therapy on either CVD mortality or all-cause mortality alone.
Retinal Arteriolar Dilation Predicts Retinopathy in Adolescents With Type 1 Diabetes
Authors: Cheung Ning , Rogers Sophie L. , Donaghue Kim C. , Jenkins Alicia J. , Tikellis Gabriella , Wong Tien Yin
Published: June 2008

OBJECTIVE—Alterations in retinal vascular caliber may reflect early subclinical microvascular dysfunction. In this study, we examined the association of retinal vascular caliber to incident retinopathy in young patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS—This was a prospective cohort study of 645 initially retinopathy-free type 1 diabetic patients, aged 12–20 years. Participants had seven-field stereoscopic retinal photographs taken of both eyes at baseline and follow-up. Retinal vascular caliber was measured from baseline photographs using a computer-based program following a standardized protocol. Incident retinopathy was graded according to the modified Airlie House classification from follow-up photographs.

RESULTS—Over a median follow-up of 2.5 years, 274 participants developed retinopathy (14.8 per 100 person-years). After adjustments for age, sex, diabetes duration, glycemia, mean arterial blood pressure, BMI, and cholesterol levels, larger retinal arteriolar caliber (fourth versus first quartile) was associated with a more than threefold higher risk of retinopathy (hazard rate ratio 3.44 [95% CI 2.08–5.66]). Each SD increase in retinal arteriolar caliber was associated with a 46% increase in retinopathy risk (1.46 [1.22–1.74]). This association was stronger in female than in male participants. After similar adjustments, retinal venular caliber was not consistently associated with incident retinopathy.

CONCLUSIONS—Retinal arteriolar dilatation predicts retinopathy development in young patients with type 1 diabetes. Our data suggest that arteriolar dysfunction may play a critical role in the pathogenesis of early diabetic retinopathy and that computer-based retinal vascular caliber measurements may provide additional prognostic information regarding risk of diabetes microvascular complications.
Sex Disparities in the Treatment and Control of Cardiovascular Risk Factors in Type 2 Diabetes
Authors: Gouni-Berthold Ioanna , Berthold Heiner K. , Mantzoros Christos S. , Böhm Michael , Krone Wilhelm
Published: June 2008

OBJECTIVE—To assess whether sex differences exist in the effective control and medication treatment intensity of cardiovascular disease (CVD) risk factors.

RESEARCH DESIGN AND METHODS—We performed a cross-sectional analysis including 44,893 patients with type 2 diabetes (51% women). End points included uncontrolled CVD risk factors (LDL cholesterol ≥130 mg/dl, systolic blood pressure [SBP] ≥140 mmHg, and A1C ≥8%) and the intensity of medical management in patients with uncontrolled CVD risk factors. Multiple-adjusted odds ratios were calculated after stratification for the presence of CVD (present in 39% of the patients).

RESULTS—Women with CVD were less likely to have SBP, LDL cholesterol, and A1C controlled and less likely to receive intensive lipid-lowering treatment. Women without CVD were less likely than men to have LDL cholesterol controlled with no differences in SBP or A1C control.

CONCLUSIONS—Women with diabetes and CVD have poorer control of important modifiable risk factors than men and receive less intensified lipid-lowering treatment.
Diabetes and Other Disorders of Glycemia in a Rural South African Community
Authors: Motala Ayesha A. , Esterhuizen Tonya , Gouws Eleanor , Pirie Fraser J. , Omar Mahomed A.K.
Published: June 2008

OBJECTIVE—The purpose of this study was to determine the prevalence of diabetes, impaired glucose tolerance (IGT), impaired fasting glycemia (IFG), and associated risk factors in a rural South African black community.

RESEARCH DESIGN AND METHODS—This was a cross-sectional survey conducted by random cluster sampling of adults aged >15 years. Participants had a 75-g oral glucose tolerance test using the 1998 World Health Organization criteria for disorders of glycemia.

RESULTS—Of 1,300 subjects selected, 1,025 subjects (815 women) participated (response rate 78.9%). The overall age-adjusted prevalence of diabetes was 3.9%, IGT 4.8%, and IFG 1.5%. The prevalence was similar in men and women for diabetes (men 3.5%; women 3.9%) and IGT (men 4.6%; women 4.7%) but higher in men for IFG (men 4.0%; women 0.8%). The prevalence of diabetes and IGT increased with age both in men and women, with peak prevalence in the 55- to 64-year age-group for diabetes and in the ≥65-year age-group for IGT. Of the cases of diabetes, 84.8% were discovered during the survey. In multivariate analysis, the significant independent risk factors associated with diabetes included family history (odds ratio 3.5), alcohol ingestion (2.8), waist circumference (1.1), systolic blood pressure (1.0), serum triglycerides (2.3), and total cholesterol (1.8); hip circumference was protective (0.9).

CONCLUSIONS—There is a moderate prevalence of diabetes and a high prevalence of total disorders of glycemia, which suggests that this community, unlike other rural communities in Africa, is well into an epidemic of glucose intolerance. There is a low proportion of known diabetes and a significant association with potentially modifiable risk factors.
Tumor Necrosis Factor-α Antagonism Improves Vasodilation During Hyperinsulinemia in Metabolic Syndrome
Authors: Tesauro Manfredi , Schinzari Francesca , Rovella Valentina , Melina Domenico , Mores Nadia , Barini Angela , Mettimano Marco , Lauro Davide , Iantorno Micaela , Quon Michael J. , Cardillo Carmine
Published: June 2008

OBJECTIVE—Obesity is associated with chronic inflammation due to overproduction of proinflammatory cytokines, including tumor necrosis factor (TNF)-α. We assessed the effects of TNF-α neutralization by infliximab on vascular reactivity during hyperinsulinemia in obesity-related metabolic syndrome.

RESEARCH DESIGN AND METHODS—Vascular responses to intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in patients with metabolic syndrome, before and after administration of infliximab.

RESULTS—Patients had blunted vasodilator responses to ACh and SNP during hyperinsulinemia compared with control subjects; a potentiation of the responsiveness to both ACh and SNP, however, was observed in patients following infliximab. The antioxidant vitamin C improved the vasodilator response to ACh in patients with metabolic syndrome, but its effect was not further enhanced by concurrent administration of infliximab.

CONCLUSIONS—TNF-α neutralization ameliorates vascular reactivity in metabolic syndrome during hyperinsulinemia, likely in relation to decreased oxidative stress, thereby suggesting an involvement of inflammatory cytokines in vascular dysfunction of these patients.
One-Hour Plasma Glucose Concentration and the Metabolic Syndrome Identify Subjects at High Risk for Future Type 2 Diabetes
Authors: Abdul-Ghani Muhammad A. , Abdul-Ghani Tamam , Ali Nibal , DeFronzo Ralph A.
Published: June 2008

OBJECTIVE—To assess the efficacy of 1-h plasma glucose concentration and the metabolic syndrome in predicting future risk of type 2 diabetes.

RESEARCH DESIGN AND METHODS—A total of 1,611 subjects from the San Antonio Heart Study, who were free of type 2 diabetes at baseline; who had plasma glucose and insulin concentrations measured at time 0, 30, 60, and 120 min during the oral glucose tolerance test (OGTT); and who had their diabetes status determined with an OGTT after 7–8 years of follow-up, were evaluated. Two models, based on glucose tolerance status, 1-h plasma glucose concentration, and presence of the metabolic syndrome, were tested in predicting the risk for type 2 diabetes at 7–8 years of follow-up.

RESULTS—A cutoff point of 155 mg/dl for the 1-h plasma glucose concentration during the OGTT was used to stratify subjects in each glucose tolerance group into low, intermediate, and high risk for future type 2 diabetes. A model based upon 1-h plasma glucose concentration, Adult Treatment Panel (ATP) III criteria for the metabolic syndrome, and fasting plasma glucose, independent of 2-h plasma glucose, performed equally well in stratifying nondiabetic subjects into low, intermediate, and high risk for future type 2 diabetes and identified a group of normal glucose-tolerant subjects who were at very high risk for future type 2 diabetes.

CONCLUSIONS—The plasma glucose concentration at 1 h during the OGTT is a strong predictor of future risk for type 2 diabetes. A plasma glucose cutoff point of 155 mg/dl and the ATP III criteria for the metabolic syndrome can be used to stratify nondiabetic subjects into three risk groups: low, intermediate, and high risk.
GAD65 Autoantibody Responses in Japanese Latent Autoimmune Diabetes in Adult Patients
Authors: Maruyama Taro , Oak Shilpa , Shimada Akira , Hampe Christiane S.
Published: June 2008

OBJECTIVE—To determine whether development of insulin requirement in patients with latent autoimmune diabetes in adults (LADA) is accompanied with the emergence of a type 1 diabetes–like autoimmune response.

RESEARCH DESIGN AND METHODS—We correlated β-cell–specific autoimmunity reflected in autoantibodies to the 65-kDa isoform of GAD (GAD65) with insulin requirement. We determined GAD65Ab epitope specificities in type 1 diabetic patients, LADA patients without insulin requirement (nonprogressed), and LADA patients that had developed insulin requirement (progressed).

RESULTS—Recognition of a type 1 diabetes–specific GAD65Ab epitope was more pronounced in type 1 diabetic patients than in nonprogressed (P < 0.001) or progressed (P < 0.01) LADA patients, with no significant differences between the two LADA cohorts. These differences were particularly pronounced in samples with GAD65Ab titers <1,000 units/ml, with no differences in epitope specificities in samples with higher GAD65Ab titers. Disease duration (initial diabetes diagnosis until sample collection or development of insulin requirement) in nonprogressed and progressed LADA patients, respectively, was not correlated with epitope specificity, suggesting lack of epitope maturation. This was supported by epitope analyses of longitudinal samples from LADA patients during progression to insulin requirement.

CONCLUSIONS—First, the GAD65Ab-specific autoimmune reaction in type 1 diabetic patients with low and moderate GAD65Ab titers differs from that in LADA patients, irrespective of insulin requirement. Second, the GAD65Ab-specific autoimmune response in LADA patients does not change after their initial diabetes diagnosis. Finally, LADA patients with high GAD65Ab titers resemble type 1 diabetic patients in their GAD65Ab epitope specificity.
The Rising Incidence of Type 1 Diabetes Is Accounted for by Cases With Lower-Risk Human Leukocyte Antigen Genotypes
Authors: Fourlanos Spiros , Varney Michael D. , Tait Brian D. , Morahan Grant , Honeyman Margo C. , Colman Peter G. , Harrison Leonard C.
Published: June 2008

OBJECTIVE—The rising incidence of type 1 diabetes has been attributed to environment, implying a lesser role for genetic susceptibility. However, the rise could be accounted for by either more cases with classic high-risk genes or by cases with other risk genes. Separately, for any degree of genetic susceptibility, age at presentation may decrease in a permissive environment. To examine these possibilities, human leukocyte antigen (HLA) class II DRB1 genes known to confer risk for type 1 diabetes were analyzed in relation to year of birth and age at diagnosis over the last five decades.

RESEARCH DESIGN AND METHODS—Caucasoid subjects (n = 462) diagnosed with type 1 diabetes before age 18 between 1950 and 2005 were DRB1 genotyped.

RESULTS—Mean ± SD age at diagnosis, 8.5 ± 4.5 years, did not differ across decades. Recent diagnosis was associated with a lower proportion but unchanged incidence of the highest-risk DRB1 genotype DR3,4 (2000–2005, 28% vs. 1950–1969, 79%; P < 0.0001) and a higher proportion of lower-risk genotypes DR4,X and DR3,X (2000–2005, 48% vs. 1950–1969, 20%; P = 0.0002). The frequency of the DRX,X genotype was low (≤3%) across decades. Recent birth was associated with a lower age at diagnosis for lower risk DR3,3 and DR4,4 (P < 0.0001) and DR4,X (P < 0.0001) and DR3,X (P = 0.015) genotypes but not for DR3,4.

CONCLUSIONS—The rising incidence and decreasing age at diagnosis of type 1 diabetes is accounted for by the impact of environment on children with lower-risk HLA class II genes, who previously would not have developed type 1 diabetes in childhood.
Prevalence and Risk Factors for Neuropathy in a Canadian First Nation Community
Authors: Bruce Sharon G. , Young T. Kue
Published: June 2008

OBJECTIVE—The purpose of this study was to determine the prevalence of and risk factors for diabetic neuropathy in a Canadian First Nation population.

RESEARCH DESIGN AND METHODS—This was a community-based screening study of 483 adults. Measures included glucose, A1C, cholesterol, triglycerides, homocysteine, hypertension, waist circumference, height, weight, and foot examinations. Neuropathy was defined as loss of protective sensation determined through application of a 10-g monofilament.

RESULTS—Twenty-two percent of participants had a previous diagnosis of diabetes, and 14% had new diabetes or impaired fasting glucose (IFG). The prevalence of neuropathy increased by glucose level: 5% among those with normal glucose levels, 8% among those with new IFG and diabetes, and 15% among those with established diabetes (P < 0.01). Those with neuropathy were more likely to have foot deformities (P < 0.01) and callus (P < 0.001) than those without neuropathy. Among those with dysglycemia (≥6.1 mmol/l), the mean number of foot problems for those with insensate feet was 3 compared with 0.3 among those with sensation (P < 0.001). In multivariate logistic regression female sex, low education, A1C, smoking, and homocysteine were independently associated with neuropathy, after controls for age.

CONCLUSIONS—Neuropathy prevalence is high, given the young age of our participants (mean 40 years) and was present among those with undiagnosed diabetes. The high number and type of foot problems places this population at increased risk for ulceration; the low level of foot care in the community increases the risk. Homocysteine is a risk factor that may be related to lifestyle and requires further investigation.
Differences in the Contribution of the CTLA4 Gene to Susceptibility to Fulminant and Type 1A Diabetes in Japanese Patients
Authors: Kawasaki Eiji , Imagawa Akihisa , Makino Hideichi , Uga Miho , Abiru Norio , Hanafusa Toshiaki , Uchigata Yasuko , Eguchi Katsumi
Published: June 2008

OBJECTIVE—To examine the contribution of the CTLA4 gene in the susceptibility to fulminant type 1 diabetes and compare it with classic type 1A diabetes.

RESEARCH DESIGN AND METHODS—We genotyped the +49G>A and CT60G>A variants of the CTLA4 gene in fulminant type 1 diabetic patients (n = 55), classic type 1A diabetic patients (n = 91), and healthy control subjects (n = 369). We also assessed serum levels of the soluble form of CTLA4 (sCTLA4).

RESULTS—The +49GG and CT60GG genotypes were associated with type 1A diabetes (P < 0.001). In contrast, the CT60AA genotype, but not the +49G>A variation, was associated with fulminant type 1 diabetes (P < 0.05), especially in patients carrying HLA-DR4 (P < 0.01). Serum levels of sCTLA4 were significantly decreased in patients with fulminant type 1 diabetes (P < 0.05).

CONCLUSIONS—These results suggest that CTLA4 CT60 affects the genetic susceptibility to fulminant type 1 diabetes. Furthermore, the contribution of CTLA4 to disease susceptibility is distinct between fulminant type 1 diabetes and classic type 1A diabetes.
Hyperglycemia Is Associated With Enhanced Thrombin Formation, Platelet Activation, and Fibrin Clot Resistance to Lysis in Patients With Acute Coronary Syndrome
Authors: Undas Anetta , Wiek Ilona , Stêpień Ewa , Zmudka Krzysztof , Tracz Wiesława
Published: June 2008

OBJECTIVE—Acute hyperglycemia on admission for acute coronary syndrome worsens the prognosis in patients with and without known diabetes. Postulated mechanisms of this observation include prothrombotic effects. The aim of this study was to evaluate the effect of elevated glucose levels on blood clotting in acute coronary syndrome patients.

RESEARCH DESIGN AND METHODS—We studied 60 acute coronary syndrome patients within the first 12 h after pain onset, including 20 subjects with type 2 diabetes, 20 subjects with no diagnosed diabetes but with glucose levels >7.0 mmol/l, and 20 subjects with glucose levels <7.0 mmol/l. We determined generation of thrombin-antithrombin complexes (TATs) and soluble CD40 ligand (sCD40L), a platelet activation marker, at the site of microvascular injury, together with ex vivo plasma fibrin clot permeability and lysis time.

RESULTS—The acute coronary syndrome patients with no prior diabetes but elevated glucose levels had increased maximum rates of formation and total production of TATs (by 42.9%, P < 0.0001, and by 25%, P < 0.0001, respectively) as well as sCD40L release (by 16.2%, P = 0.0011, and by 16.3%, P < 0.0001, respectively) compared with those with normoglycemia, whereas diabetic patients had the highest values of TATs and sCD40L variables (P < 0.0001 for all comparisons). Patients with hyperglycemia, with no previously diagnosed diabetes, had longer clot lysis time (by ∼18%, P < 0.0001) similar to that in diabetic subjects, but not lower clot permeability compared with that in normoglycemic subjects.

CONCLUSIONS—Hyperglycemia in acute coronary syndrome is associated with enhanced local thrombin generation and platelet activation, as well as unfavorably altered clot features in patients with and without a previous history of diabetes.
Colesevelam HCl Improves Glycemic Control and Reduces LDL Cholesterol in Patients With Inadequately Controlled Type 2 Diabetes on Sulfonylurea-Based Therapy
Authors: Fonseca Vivian A. , Rosenstock Julio , Wang Antonia C. , Truitt Kenneth E. , Jones Michael R.
Published: June 2008

OBJECTIVE—Hyperglycemia is a risk factor for microvascular complications and may increase the risk of cardiovascular disease in patients with type 2 diabetes. This study tested the LDL cholesterol–lowering agent colesevelam HCl (colesevelam) as a potential novel treatment for improving glycemic control in patients with type 2 diabetes on sulfonylurea-based therapy.

RESEARCH DESIGN AND METHODS—A 26-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study was carried out between August 2004 and August 2006 to evaluate the efficacy and safety of colesevelam for reducing A1C in adults with type 2 diabetes whose glycemic control was inadequate (A1C 7.5–9.5%) with existing sulfonylurea monotherapy or sulfonylurea in combination with additional oral antidiabetes agents. In total, 461 patients were randomized (230 given colesevelam 3.75 g/day and 231 given placebo). The primary efficacy measurement was mean placebo-corrected change in A1C from baseline to week 26 in the intent-to-treat population (last observation carried forward).

RESULTS—The least squares (LS) mean change in A1C from baseline to week 26 was −0.32% in the colesevelam group and +0.23% in the placebo group, resulting in a treatment difference of −0.54% (P < 0.001). The LS mean percent change in LDL cholesterol from baseline to week 26 was −16.1% in the colesevelam group and +0.6% in the placebo group, resulting in a treatment difference of −16.7% (P < 0.001). Furthermore, significant reductions in fasting plasma glucose, fructosamine, total cholesterol, non–HDL cholesterol, and apolipoprotein B were demonstrated in the colesevelam relative to placebo group at week 26.

CONCLUSIONS—Colesevelam improved glycemic control and reduced LDL cholesterol levels in patients with type 2 diabetes receiving sulfonylurea-based therapy.
A New Luminescence Assay for Autoantibodies to Mammalian Cell–Prepared Insulinoma-Associated Protein 2
Authors: Burbelo Peter D. , Hirai Hiroki , Leahy Hannah , Lernmark Ake , Ivarsson Sten A. , Iadarola Michael J. , Louis Notkins Abner
Published: June 2008

OBJECTIVE—Insulinoma-associated protein 2 (IA-2) is a major autoantigen in type 1 diabetes, and IA-2 autoantibodies are routinely detected by a liquid-phase radioimmunoprecipitation assay. The present experiments were initiated to develop a new assay that does not require the use of radioisotopes or autoantigens prepared in bacteria or by in vitro transcription/translation.

RESEARCH DESIGN AND METHODS—IA-2 luciferase fusion protein was expressed in mammalian cells and assayed for autoantibodies by liquid-phase luciferase immunoprecipitation.

RESULTS—Our study showed that there was no significant difference between the luciferase immunoprecipitation and the radioimmunoprecipitation assays in sensitivity and specificity, and comparison of the two assays revealed a high correlation coefficient (R2 = 0.805).

CONCLUSIONS—The luciferase system offers a robust, inexpensive, nonradioactive method for the detection of autoantibodies to mammalian cell–prepared IA-2 and could be of practical value at the clinical level.
Dietary Patterns and A1C in Japanese Men and Women
Authors: Nanri Akiko , Mizoue Tetsuya , Yoshida Daigo , Takahashi Ryota , Takayanagi Ryoichi
Published: June 2008

OBJECTIVE—Dietary patterns in Western populations have been linked to type 2 diabetes, but the role of diet in Japanese remains unclear. We investigated the association between major dietary patterns and glucose tolerance status as measured by A1C in Japanese adults.

RESEARCH DESIGN AND METHODS—The groups of subjects were comprised of 3,243 men and 4,667 women who participated in the baseline survey of an ongoing cohort study on lifestyle-related diseases in Fukuoka, Japan. Dietary patterns were derived by using principal-component analysis of the consumption of 49 food items, ascertained by a food-frequency questionnaire. Logistic regression analysis was used to estimate sex-specific odds ratios (ORs) of elevated A1C (≥5.5%), with adjustment for potential confounding variables.

RESULTS—The Westernized breakfast pattern characterized by frequent intake of bread but infrequent intake of rice was inversely related to A1C concentrations (Ptrend = 0.02 in both men and women); the multivariate-adjusted ORs for the highest versus lowest quintiles were 0.60 (95% CI 0.43–0.84) and 0.64 (0.46–0.90) for men and women, respectively. The seafood dietary pattern was positively associated with A1C concentrations in men only (Ptrend = 0.01). Neither the healthy nor high-fat dietary pattern was related to A1C.

CONCLUSIONS—A dietary pattern featuring frequent intake of white rice may deteriorate glucose metabolism in Japanese men and women, and the salty seafood dietary pattern may have a similar effect in men.
Increased Daily Walking Improves Lipid Oxidation Without Changes in Mitochondrial Function in Type 2 Diabetes
Authors: Trenell Michael I. , Hollingsworth Kieren G. , Lim Ee Lin , Taylor Roy
Published: June 2008

OBJECTIVE—To determine whether increased daily physical activity improves mitochondrial function and/or lipid oxidation in type 2 diabetes.

RESEARCH DESIGN AND METHODS—Volunteers with (n = 10) and without (n = 10) type 2 diabetes were matched for habitual physical activity, age, sex, and weight. Basal and maximal mitochondrial activity, physical activity, and resting substrate oxidation were measured at baseline and after 2 and 8 weeks of increased physical activity.

RESULTS—Baseline physical activity (6,450 ± 851 vs. 7,638 ± 741 steps/day), basal ATP use (12 ± 1 vs. 12 ± 1 μmol · ml−1 · min−1), phosphocreatine recovery from exercise (31 ± 5 vs. 29 ± 3 s), and basal lipid oxidation (0.57 ± 0.07 vs. 0.65 ± 0.06 mg · kg body wt−1 · min−1) were similar in people with and without type 2 diabetes. There was a significant increase in physical activity after 8 weeks (12,322 ± 1,979 vs. 9,187 ± 1,159 steps/day, respectively). Following increased physical activity, there were no changes in basal ATP use or phosphocreatine recovery after exercise in either group. Basal lipid oxidation increased after 8 weeks of increased physical activity in people with type 2 diabetes (0.79 ± 0.08 mg · kg−1 · min−1) but not people without (0.68 ± 0.13 mg · kg body wt−1 · min−1).

CONCLUSIONS—Resting and maximal ATP turnover are not impaired in people with well-controlled type 2 diabetes compared with control subjects matched for physical activity as well as age and weight. Increased unsupervised daily physical activity is sustainable and improves lipid oxidation independent of change in mitochondrial activity in people with type 2 diabetes.
Optimizing Postprandial Glycemia in Pediatric Patients With Type 1 Diabetes Using Insulin Pump Therapy
Authors: O'Connell Michele A. , Gilbertson Heather R. , Donath Susan M. , Cameron Fergus J.
Published: June 2008

OBJECTIVE—Postprandial glycemic excursions may contribute to the development of diabetes-related complications. Meals of high and low glycemic index (GI) have distinct effects on postprandial glycemia (PPG). Insulin pump therapy offers the potential to tailor insulin delivery to meal composition; however, optimal bolus types for meals of different glycemic loads have not been defined. We sought to compare the impact of GI combined with varying prandial bolus types on PPG.

RESEARCH DESIGN AND METHODS—An open crossover study examining the effects of four different meal and bolus-type combinations on 3-h PPG (measured by continuous glucose-monitoring system [CGMS]) was conducted. A total of 20 young people aged 8–18 years with type 1 diabetes using insulin-pump therapy participated. Meals had equal macronutrient, energy, and fiber content and differed only in GI (low vs. high). Participants consumed meals of the same GI on consecutive days and were randomized to receive either a standard (100%) or a dual-wave (DW) (50:50% over 2 h) bolus each day. CGMS data from 10 healthy control participants established the target response to each meal.

RESULTS—A DW bolus before low-GI meals decreased PPG area under the curve (AUC) by up to 47% (P = 0.004) and lowered the risk of hypoglycemia for the same premeal glucose (P = 0.005) compared with standard bolus. High-GI meals resulted in significant upward PPG excursions with greater AUC (P = 0.45), regardless of bolus type.

CONCLUSIONS—These data support the use of a DW bolus with low GI meals to optimize PPG in patients with type 1 diabetes using insulin pump therapy.
Improving Treatment of Depression Among Latinos With Diabetes Using Project Dulce and IMPACT
Authors: Gilmer Todd P. , Walker Chris , Johnson Elizabeth D. , Philis-Tsimikas Athena , Unützer Jürgen
Published: June 2008

OBJECTIVE—To assess the feasibility and cost of integrating diabetes and depression care management in three community clinics serving a low-income and predominately Spanish-speaking Latino population.

RESEARCH DESIGN AND METHODS—We screened diabetes patients for depression, and for those with depressive symptoms, we provided depression care management. We assessed changes in depressive symptoms using the Patient Health Questionnaire-9 (PHQ-9), diabetes self-care activities (nutrition, exercise, and medication adherence), and costs.

RESULTS—Thirty-three percent of patients with diabetes had symptoms of major depression. Among 99 patients completing the study, PHQ-9 scores declined by an average of 7.5 points from 14.8 to 7.3 (P < 0.001). Clients averaged 6.7 visits with the care manager during the study period. Costs of depression care management were estimated to be $512 per participant.

CONCLUSIONS—Adding a depression care manager to an existing diabetes management team was effective at reducing depressive symptoms at a reasonable cost.
Influence of and Optimal Insulin Therapy for a Low–Glycemic Index Meal in Children With Type 1 Diabetes Receiving Intensive Insulin Therapy
Authors: Ryan Rochelle L. , King Bruce R. , Anderson Donald G. , Attia John R. , Collins Clare E. , Smart Carmel E.
Published: June 2008

OBJECTIVE—The purpose of this study was to quantify the effects of glycemic index on postprandial glucose excursion (PPGE) in children with type 1 diabetes receiving multiple daily injections and to determine optimal insulin therapy for a low–glycemic index meal.

RESEARCH DESIGN AND METHODS—Twenty subjects consumed test breakfasts with equal macronutrient contents on 4 consecutive days; high–and low–glycemic index meals (glycemic index 84 vs. 48) were consumed with preprandial ultra-short-acting insulin, and the low–glycemic index meal was also consumed with preprandial regular insulin and postprandial ultra-short-acting insulin. Each child's insulin dose was standardized. Continuous glucose monitoring was used.

RESULTS—The PPGE was significantly lower for the low–glycemic index meal compared with the high–glycemic index meal at 30–180 min (P < 0.02) when preprandial ultra-short-acting insulin was administered. The maximum difference occurred at 60 min (4.2 mmol/l, P < 0.0001). Regular insulin produced a 1.1 mmol/l higher PPGE at 30 min compared with ultra-short-acting insulin (P = 0.015) when the low–glycemic index meal was consumed. Postprandial ultra-short-acting insulin produced a higher PPGE at 30 and 60 min compared with preprandial administration when the low–glycemic index meal was consumed. The maximum difference was 2.5 mmol/l at 60 min (P < 0.0001).

CONCLUSIONS—Low–glycemic index meals produce a lower PPGE than high–glycemic index meals. Preprandial ultra-short-acting insulin is the optimal therapy for a low–glycemic index meal.
Risks of Nontraumatic Lower-Extremity Amputations in Patients with Type 1 Diabetes
Authors: Jonasson Junmei Miao , Ye Weimin , Sparén Pär , Apelqvist Jan , Nyrén Olof , Brismar Kerstin
Published: June 2008

OBJECTIVE—The purpose of this study was to estimate the risks of nontraumatic lower-extremity amputations (LEAs) in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS—We identified 31,354 patients with type 1 diabetes (15,001 women and 16,353 men) in the Swedish Inpatient Register between 1975 and 2004. The incidence of nontraumatic LEAs was followed up until 31 December 2004 by cross-linkage in the Inpatient Register and linkage to the Death and Migration registers. Poisson regression modeling was used to compare the risks of nontraumatic LEAs during different calendar periods of follow-up, with adjustment for both sex and attained age at follow-up. Standardized incidence ratios (SIRs) were used to estimate the relative risks (RRs) with the age-, sex-, and calendar period–matched general Swedish population as reference. The cumulative probability of nontraumatic LEAs was calculated by the Kaplan-Meier method.

RESULTS—In total, 465 patients with type 1 diabetes underwent nontraumatic LEAs. The risk was lower during the most recent calendar period (2000–2004) than during the period before 2000 (RR 0.6 [95% CI 0.5–0.8]). However, even in this most recent period, the risk for nontraumatic LEAs among these relatively young patients was 86-fold higher than that in the matched general population (SIR 85.8 [72.9–100.3]). By age 65 years, the cumulative probability of having a nontraumatic LEA was 11.0% for women with type 1 diabetes and 20.7% for men with type 1 diabetes.

CONCLUSIONS—Although the risks appeared to have declined in recent years, patients with type 1 diabetes still have a very high risk for nontraumatic LEAs.
Sex-Specific Association of the Putative Fructose TransporterSLC2A9Variants With Uric Acid Levels Is Modified by BMI
Authors: Brandstätter Anita , Kiechl Stefan , Kollerits Barbara , Hunt Steven C. , Heid Iris M. , Coassin Stefan , Willeit Johann , Adams Ted D. , Illig Thomas , Hopkins Paul N. , Kronenberg Florian
Published: June 2008

OBJECTIVE—High serum uric acid levels lead to gout and have been reported to be associated with an increased risk of hypertension, obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Recently, the putative fructose transporter SLC2A9 was reported to influence uric acid levels. The aim of the present study was to examine the association of four single nucleotide polymorphisms within this gene with uric acid levels and to determine whether this association is modified by obesity.

RESEARCH DESIGN AND METHODS—Four single nucleotide polymorphisms within SLC2A9 (rs6855911, rs7442295, rs6449213, and rs12510549) were genotyped in the population-based prospective Bruneck Study (n = 800) and in a case-control study from Utah including 1,038 subjects recruited for severe obesity and 831 control subjects.

RESULTS—We observed highly significant associations between all four polymorphisms and uric acid levels in all study groups. Each copy of the minor allele decreased age- and sex-adjusted uric acid levels by 0.30–0.35 mg/dl on average, which translates to a relative decrease of 5–6% with P values ranging from 10−9 to 10−11 in the combined analysis. An extended adjustment for BMI, creatinine, gout medication, and alcohol intake improved P values to a range of 10−14 to 10−20. The association was more pronounced in women and the population-based Bruneck Study and was significantly modified by BMI, with stronger effect sizes in individuals with high BMI.

CONCLUSIONS—Genetic variants within SLC2A9 have significant effects on uric acid levels and are modified by sex and BMI.
Dose-Dependent Effect of Rosuvastatin on VLDL–Apolipoprotein C-III Kinetics in the Metabolic Syndrome
Authors: Ooi Esther M.M. , Watts Gerald F. , Chan Dick C. , Chen Meifania M. , Nestel Paul J. , Sviridov Dmitri , Barrett P. Hugh R.
Published: June 2008

OBJECTIVE—Dysregulated apolipoprotein (apo)C-III metabolism may account for hypertriglyceridemia and increased cardiovascular risk in the metabolic syndrome. This study investigated the dose-dependent effect of rosuvastatin on VLDL apoC-III transport in men with the metabolic syndrome.

RESEARCH DESIGN AND METHODS—Twelve men with the metabolic syndrome were studied in a randomized double-blind crossover trial of 5-week intervention periods with placebo, 10 mg rosuvastatin, or 40 mg rosuvastatin, with 2-week placebo washouts between each period. VLDL apoC-III kinetics were examined using a stable isotope method and compartmental modeling at the end of each intervention period.

RESULTS—Compared with placebo, there was a significant dose-dependent reduction with rosuvastatin in plasma triglyceride and VLDL apoC-III concentrations. Rosuvastatin significantly (P < 0.05) increased VLDL apoC-III fractional catabolic rate (FCR) and decreased its production rate, with a significant (P < 0.05) dose-related effect. With 40 mg rosuvastatin, changes in VLDL apoC-III concentration were inversely associated with changes in VLDL apoC-III FCR and positively associated with VLDL apoC-III production rate (P < 0.05). Changes in VLDL apoC-III concentration and production rate were positively correlated with changes in VLDL apoB concentration and production rate and inversely correlated with VLDL apoB FCR (P < 0.05). Similar associations were observed with 10 mg rosuvastatin but were either less or not statistically significant.

CONCLUSIONS—In this study, rosuvastatin decreased the production and increased the catabolism of VLDL apoC-III, a mechanism that accounted for the significant reduction in VLDL apoC-III and triglyceride concentrations. This has implications for the management of cardiometabolic risk in obese subjects with the metabolic syndrome.
Insulin Sensitivity Measured With Euglycemic Clamp Is Independently Associated With Glomerular Filtration Rate in a Community-Based Cohort
Authors: Nerpin Elisabet , Risérus Ulf , Ingelsson Erik , Sundström Johan , Jobs Magnus , Larsson Anders , Basu Samar , Ärnlöv Johan
Published: June 2008

OBJECTIVE—To investigate the association between insulin sensitivity and glomerular filtration rate (GFR) in the community, with prespecified subgroup analyses in normoglycemic individuals with normal GFR.

RESEARCH DESIGN AND METHODS—We investigated the cross-sectional association between insulin sensitivity (M/I, assessed using euglycemic clamp) and cystatin C–based GFR in a community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men [ULSAM], n = 1,070). We also investigated whether insulin sensitivity predicted the incidence of renal dysfunction at a follow-up examination after 7 years.

RESULTS—Insulin sensitivity was directly related to GFR (multivariable-adjusted regression coefficient for 1-unit higher M/I 1.19 [95% CI 0.69–1.68]; P < 0.001) after adjusting for age, glucometabolic variables (fasting plasma glucose, fasting plasma insulin, and 2-h glucose after an oral glucose tolerance test), cardiovascular risk factors (hypertension, dyslipidemia, and smoking), and lifestyle factors (BMI, physical activity, and consumption of tea, coffee, and alcohol). The positive multivariable-adjusted association between insulin sensitivity and GFR also remained statistically significant in participants with normal fasting plasma glucose, normal glucose tolerance, and normal GFR (n = 443; P < 0.02). In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function (GFR <50 ml/min per 1.73 m2) during follow-up independently of glucometabolic variables (multivariable-adjusted odds ratio for 1-unit higher of M/I 0.58 [95% CI 0.40–0.84]; P < 0.004).

CONCLUSIONS—Our data suggest that impaired insulin sensitivity may be involved in the development of renal dysfunction at an early stage, before the onset of diabetes or prediabetic glucose elevations. Further studies are needed in order to establish causality.