bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammation and Activated Innate Immunity in the Pathogenesis of Type 2 Diabetes
Authors: Pickup John C.
Published: March 2007

There is increasing evidence that an ongoing cytokine-induced acute-phase response (sometimes called low-grade inflammation, but part of a widespread activation of the innate immune system) is closely involved in the pathogenesis of type 2 diabetes and associated complications such as dyslipidemia and atherosclerosis. Elevated circulating inflammatory markers such as C-reactive protein and interleukin-6 predict the development of type 2 diabetes, and several drugs with anti-inflammatory properties lower both acute-phase reactants and glycemia (aspirin and thiazolidinediones) and possibly decrease the risk of developing type 2 diabetes (statins). Among the risk factors for type 2 diabetes, which are also known to be associated with activated innate immunity, are age, inactivity, certain dietary components, smoking, psychological stress, and low birth weight. Activated immunity may be the common antecedent of both type 2 diabetes and atherosclerosis, which probably develop in parallel. Other features of type 2 diabetes, such as fatigue, sleep disturbance, and depression, are likely to be at least partly due to hypercytokinemia and activated innate immunity. Further research is needed to confirm and clarify the role of innate immunity in type 2 diabetes, particularly the extent to which inflammation in type 2 diabetes is a primary abnormality or partly secondary to hyperglycemia, obesity, atherosclerosis, or other common features of the disease.
Association of Bioavailable, Free, and Total Testosterone With Insulin Resistance
Authors: Tsai Elaine C. , Matsumoto Alvin M. , Fujimoto Wilfred Y. , Boyko Edward J.
Published: March 2007

OBJECTIVE—Previous reports of an association between low testosterone levels and diabetes risk were often confounded by covariation of sex hormone-binding globulin (SHBG) and testosterone measurements. Measurements of bioavailable and free testosterone, more reliable indexes of biologically active testosterone, were examined for their associations with markers of insulin resistance and body fat measures in 221 middle-aged nondiabetic men.

RESEARCH DESIGN AND METHODS—Bioavailable and free testosterone were calculated from the concentrations of total testosterone, SHBG, and albumin, and they were not significantly correlated with SHBG (r = 0.07–0.1). In contrast, total testosterone correlated significantly with SHBG (r = 0.63). We evaluated the relationship between these measures of circulating testosterone and markers for insulin resistance (i.e., fasting insulin, C-peptide, and homeostasis model assessment for insulin resistance [HOMA-IR]) as well as total body fat (assessed by dual-energy X-ray absorptiometry [DEXA]) and abdominal fat distribution (assessed by single-slice computed tomography [CT]).

RESULTS—Bioavailable, free, and total testosterone and SHBG all correlated significantly with fasting insulin (age-adjusted r = −0.15 [P = 0.03], −0.14 [P = 0.03], −0.32 [P < 0.0001], and −0.38 [P < 0.0001], respectively), fasting C-peptide (r = −0.18 [P = 0.009] to −0.41 [P < 0.0001]), HOMA-IR (r = −0.15 [P = 0.03] to − 0.39 [P < 0.0001]), and body fat measures (r = −0.17 [P = 0.008] to −0.44 [P < 0.0001]). Only SHBG and total testosterone were significantly associated with fasting glucose (r = −0.20 [P = 0.003] to −0.21 [P = 0.002]). In multivariate analysis, bioavailable or free testosterone was significantly and inversely associated with insulin, C-peptide, and HOMA-IR, but this was not independent of total body or abdominal fat. SHBG was a significant determinant of insulin, C-peptide, and HOMA-IR, independent of body fat. The associations between total testosterone and insulin resistance were confounded by SHBG.

CONCLUSIONS—The inverse association between testosterone and insulin resistance, independent of SHBG, was mediated through body fat.
Intraoral Tactile Sensitivity in Adults With Diabetes
Authors: Shinkai Rosemary S.A. , Hatch John P. , Cornell John E. , Yeh Chih-Ko
Published: March 2007

OBJECTIVE—The intraoral tactile sensitivity (ITS) of diabetic and nondiabetic subjects was compared. The effects of age, ethnicity, sex, and intraoral site were considered.

RESEARCH DESIGN AND METHODS—The sample comprised 589 participants of the Oral Health: San Antonio Longitudinal Study of Aging. A total of 107 subjects (61.8 ± 10.0 years; 48 women, 59 men) met American Diabetes Association diagnostic criteria for diabetes and 482 subjects (58.8 ± 11.1 years; 274 women, 208 men) did not. ITS was assessed with an oral microaesthesiometer with a cross-modality matching procedure. The dependent variable was the slope of the psychophysical function relating physical stimulus intensity (air pressure) and subjects’ judgments of stimulus intensity. Data were analyzed using ANOVA for repeated measures with between-subject factors of age, sex, ethnicity, and diabetes and the within-subject factor of intraoral site.

RESULTS—Diabetic and nondiabetic subjects showed no significant differences in ITS at any of the three test sites. European Americans demonstrated greater soft-palate sensitivity (mean ± SD 0.26 ± 0.15) compared with Mexican Americans (0.24 ± 0.16; P = 0.046). The three intraoral test sites differed in tactile sensitivity (P < 0.001); posterior tongue (0.33 ± 0.22) was most sensitive, followed by the soft palate (0.25 ± 0.15) and the anterior tongue (0.23 ± 0.13). Potentially confounding factors were not associated with ITS.

CONCLUSIONS—Our results suggest that diabetes per se may not influence ITS.
C-Reactive Protein and Incident Cardiovascular Events Among Men With Diabetes
Authors: Schulze Matthias B. , Rimm Eric B. , Li Tricia , Rifai Nader , Stampfer Meir J. , Hu Frank B.
Published: March 2007

OBJECTIVE—Several large prospective studies have shown that baseline levels of C-reactive protein (CRP) are an independent predictor of cardiovascular events among apparently healthy individuals. However, prospective data on whether CRP predicts cardiovascular events in diabetic patients are limited so far.

RESEARCH DESIGN AND METHODS—To investigate the association between plasma CRP levels and incidence of cardiovascular events among men with type 2 diabetes, we followed prospectively a cohort of 746 American men aged 46–81 years who were free of cardiovascular diseases at the time of blood collection in 1993–1994.

RESULTS—During an average of 5 years of follow-up (3,986 person-years), we identified 103 incident cardiovascular events (18 myocardial infarction, 70 coronary artery bypass grafting or angioplasty, and 15 stroke), confirmed by medical records. After adjustment for age, BMI, smoking, alcohol consumption, physical activity, family history of coronary heart disease, history of high blood pressure, history of high serum cholesterol, aspirin use, and fasting status as well as for fibrinogen, creatinine, HbA1c, and non-HDL cholesterol levels, CRP remained significantly associated with an increased risk of cardiovascular events. The relative risks for quartiles were 1.00, 1.51, 2.52, and 2.62 (95% CI: 1.29–5.32; P for trend: 0.011). We observed no effect modifications by plasma levels of LDL cholesterol, HDL cholesterol, non-HDL cholesterol, apolipoprotein B, HbA1c, and fibrinogen or by BMI.

CONCLUSIONS—High plasma levels of CRP were associated with an increased risk of incident cardiovascular events among diabetic men, independent of currently established lifestyle risk factors, blood lipids, and glycemic control.
Cost-Effectiveness of Prevention and Treatment of the Diabetic Foot
Authors: Ortegon Monica Maria , Redekop William Ken , Niessen Louis Wilhelmus
Published: March 2007

OBJECTIVE—To estimate the lifetime health and economic effects of optimal prevention and treatment of the diabetic foot according to international standards and to determine the cost-effectiveness of these interventions in the Netherlands.

RESEARCH DESIGN AND METHODS—A risk-based Markov model was developed to simulate the onset and progression of diabetic foot disease in patients with newly diagnosed type 2 diabetes managed with care according to guidelines for their lifetime. Mean survival time, quality of life, foot complications, and costs were the outcome measures assessed. Current care was the reference comparison. Data from Dutch studies on the epidemiology of diabetic foot disease, health care use, and costs, complemented with information from international studies, were used to feed the model.

RESULTS—Compared with current care, guideline-based care resulted in improved life expectancy, gain of quality-adjusted life-years (QALYs), and reduced incidence of foot complications. The lifetime costs of management of the diabetic foot following guideline-based care resulted in a cost per QALY gained of <$25,000, even for levels of preventive foot care as low as 10%. The cost-effectiveness varied sharply, depending on the level of foot ulcer reduction attained.

CONCLUSIONS—Management of the diabetic foot according to guideline-based care improves survival, reduces diabetic foot complications, and is cost-effective and even cost saving compared with standard care.
Diabetes and Impaired Fasting Glycemia in the Tribes of Khagrachari Hill Tracts of Bangladesh
Authors: Sayeed M. Abu , Mahtab Hajera , Khanam Parvin Akter , Ahsan Khandaker Abul , Banu Akhter , Rashid A.N.M. Bazlur , Khan A.K. Azad
Published: March 2007

OBJECTIVE—To determine the prevalence of type 2 diabetes and impaired fasting glycemia (IFG) in a tribal population of Bangladesh.

RESEARCH DESIGN AND METHODS—A cluster sampling of 1,287 tribal subjects of age ≥20 years was investigated. They live in a hilly area of Khagrachari in the far northeast of Bangladesh. Fasting plasma glucose, blood pressure, height, weight, waist girth, and hip girth were measured. Lipid fractions were also estimated. We used the 1997 American Diabetes Association diagnostic criteria.

RESULTS—The crude prevalence of type 2 diabetes was 6.6% and IFG was 8.5%. The age-standardized (20–70 years) prevalence of type 2 diabetes (95% CI) was 6.4% (4.96–7.87) and of IFG was 8.4% (6.48–10.37). Both tribesmen and women had equal risk for diabetes and IFG. Compared with the lower-income group, the participants with higher income had a significantly higher prevalence of type 2 diabetes (18.8 vs. 3.1%, P < 0.001) and IFG (17.2 vs. 4.3%, P < 0.001). Using logistic regression, we found that increased age, high-income group, and increased central obesity were the important risk factors of diabetes.

CONCLUSIONS—The prevalence of diabetes in the tribal population was higher than that of the nontribal population of Bangladesh. Older age, higher central obesity, and higher income were proven significant risk factors of diabetes. High prevalence of diabetes among these tribes indicates that the prevalence of diabetes and its complications will continue to increase. Evidently, health professionals and planners should initiate diabetes care in these tribal communities.
Are Low-Income Elderly Patients at Risk for Poor Diabetes Care?
Authors: McCall Daniel T. , Sauaia Angela , Hamman Richard F. , Reusch Jane E. , Barton Phoebe
Published: March 2007

OBJECTIVE—Diabetes is common among low-income elderly, dual-eligible (DE) Medicare/Medicaid patients resulting in significant morbidity, mortality, and cost. However, the quality of diabetes care delivered to these patients has not been evaluated. The aims of this study were to describe the quality of diabetes care provided to DE patients and compare it with non-DE patients.

RESEARCH DESIGN AND METHODS—This was a cross-sectional analysis of administrative claims from 1 January 1997 through 31 December 1998. A total of 9,453 patients aged 65–75 years with diabetes participated in the study. These were Colorado Medicare fee-for-service (FFS) outpatients. The main outcome measures consisted of a proportion of patients receiving an annual hemoglobin A1c test, biennial eye examination, biennial lipid test, and all three of these care processes.

RESULTS—The mean patient age was 71 ± 2.8 years. Over 22% of patients were identified as dual eligible, and they were significantly more likely to be younger, female, and of minority race/ethnicity; reside in a rural location; and have comorbid conditions compared with the non-DE population. DE patients had more visits to primary care physicians, emergency departments, and hospitalizations but were less likely to visit endocrinologists. DE patients were significantly less likely to receive an annual A1c test (73 vs. 81%; P < 0.0001), biennial ophthalmologic examination (63 vs. 75%; P < 0.0001), and biennial lipid testing (43 vs. 57%; P < 0.0001). The adjusted odds ratio of urban DE patients receiving all three care measures was 0.60 (95% CI 0.52–0.69) compared with urban non-DE patients. Minority race/ethnicity and emergency department use were significantly associated with not receiving diabetes care, whereas endocrinology visits were associated with an increased odds of receiving diabetes care.

CONCLUSIONS—DE Medicare/Medicaid status was independently associated with not receiving diabetes care, especially among those in urban areas.
An Explanation for the Increase in Heart Disease Mortality Rates in Diabetic Pima Indians
Authors: Pavkov Meda E. , Sievers Maurice L. , Knowler William C. , Bennett Peter H. , Nelson Robert G.
Published: March 2007

OBJECTIVE—Diabetic nephropathy (DN) became the leading cause of death in diabetic Pima Indians in the 1970s, but was superseded by ischemic heart disease (IHD) in the 1980s. This study tests the hypothesis that the rise in the IHD death rate between 1965 and 1998 is attributable to access to renal replacement therapy (RRT).

RESEARCH DESIGN AND METHODS—Underlying causes of death were determined among 2,095 diabetic Pima Indians ≥35 years old during four 8.5-year time intervals. To assess the effect of access to RRT on IHD death rates, trends were reexamined after subjects receiving RRT were classified as if they had died of DN.

RESULTS—During a median follow-up of 11.1 years (range 0.01–34), 818 subjects died. The age- and sex-adjusted DN death rate decreased over the 34-year study (P = 0.05), whereas the IHD death rate increased from 3.3 deaths/1,000 person-years (95% CI 1.4–5.2) to 6.3 deaths/1,000 person-years (95% CI 4.5–8.0; P = 0.03). After 151 subjects on RRT were reclassified as if they had died of DN, the death rate for DN increased from 4.8 deaths/1,000 person-years (95% CI 2.6–7) to 11.3 deaths/1,000 person-years (95% CI 9–13.6; P = 0.0007), whereas the increase in the IHD death rate disappeared (P = 0.57).

CONCLUSIONS—The incidence rate of renal failure attributable to diabetes has increased rapidly over the past 34 years in Pima Indians. IHD has emerged as the leading cause of death due largely to the availability of RRT and to changes in the pattern of death among those with DN.
High Prevalence of Glucose Abnormalities in Patients With Hepatitis C Virus Infection
Authors: Lecube Albert , Hernández Cristina , Genescà Joan , Esteban Joan I. , Jardí Rosend , Simó Rafael
Published: March 2007

OBJECTIVE—The aim of this study was to compare the prevalence of both impaired fasting glucose (IFG) and diabetes between hepatitis C virus (HCV)-infected patients and patients with other liver diseases but anti-HCV−, taking into account the degree of liver damage.

RESEARCH DESIGN AND METHODS—A total of 642 consecutive patients attending the outpatient liver unit of a university hospital (498 anti-HCV+ and 144 anti-HCV−) were prospectively recruited. Patients were classified as having chronic hepatitis (n = 472) or cirrhosis (n = 170) by means of the result of either a liver biopsy or by typical clinical features. A logistic regression model was used to determine independent associations of covariates (age, sex, BMI, HCV antibody status, and triglycerides) with the presence of glucose abnormalities.

RESULTS—A threefold increase in the prevalence of glucose abnormalities was observed in HCV+ patients with chronic hepatitis in comparison with HCV− subjects (32 vs. 12%; P = 0.0003). In contrast, among patients with cirrhosis, although both diabetes and IFG were more prevalent in anti-HCV+ patients (40%) than in anti-HCV− patients (36%), the differences were not statistically significant. Finally, the logistic regression analysis showed that HCV infection was independently related to glucose abnormalities in those patients with chronic hepatitis (odds ratio 4.26 [95% CI 2.03–8.93]). In contrast, HCV was not an independent predictor of glucose abnormalities in cirrhotic patients.

CONCLUSIONS—The high prevalence of IFG and diabetes found in HCV-infected patients observed in our study suggests that screening for glucose abnormalities should be indicated in these patients. In addition, we provide evidence that the genuine connection between HCV infection and diabetes is initiated at early stages of hepatic disease.
Parallel Increase in Urinary Excretion Rates of Immunoglobulin G, Ceruloplasmin, Transferrin, and Orosomucoid in Normoalbuminuric Type 2 Diabetic Patients
Authors: Narita Takuma , Sasaki Hiroshi , Hosoba Mihoko , Miura Takeshi , Yoshioka Naomi , Morii Tsukasa , Shimotomai Takashi , Koshimura Jun , Fujita Hiroki , Kakei Masafumi , Ito Seiki
Published: March 2007

OBJECTIVE—Increased urinary excretions of several plasma proteins with different molecular radii <55 Å and different isoelectric points (pI), such as IgG, ceruloplasmin, transferrin, and orosomucoid, have been independently reported to precede the development of microalbuminuria in diabetic patients. We examined whether increases in urinary excretions of these proteins would be in parallel in the same patient.

RESEARCH DESIGN AND METHODS—Urinary excretion rates of proteins mentioned above in timed overnight urine samples were evaluated in 61 normoalbuminuric type 2 diabetic patients (group D) aged 40–60 years and in 17 age-matched control subjects (group C).

RESULTS—The excretion rates of these proteins were significantly higher in group D than in group C. These exhibited a strong linear correlation with each other and had a weak correlation with the excretion rate of N-acethylglucosaminidase. The excretion rate of α2-macroglobulin with large molecular radii of 88 Å was not different between groups C and D, nor did they have any correlations with the excretion rates of the other proteins. Creatinine clearance and blood pressure levels in group D were significantly higher than those in group C.

CONCLUSIONS—In normoalbuminuric diabetic patients, excretion rates of plasma proteins with molecular radii <55 Å increased in parallel with each other. In view of our previous finding that urinary excretions of these plasma proteins selectively increased in parallel with enhanced glomerular filtration rate after acute protein loading, the present finding may be explained by renal hemodynamic changes, such as increased intraglomerular hydraulic pressure.
Improvements in Patient-Reported Outcomes Associated With an Intervention to Enhance Quality of Care for Rural Patients With Type 2 Diabetes
Authors: Maddigan Sheri L. , Majumdar Sumit R. , Guirguis Lisa M. , Lewanczuk Richard Z. , Lee T. K. , Toth Ellen L. , Johnson Jeffrey A.
Published: March 2007

OBJECTIVE—The aim of this study was to examine patient-reported outcomes in a controlled trial of a multifaceted provider-level intervention to improve quality of care for rural patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS—We conducted a before/after intervention study with concurrent controls in two rural regions in Alberta, Canada. The intervention consisted of six monthly visits by a multidisciplinary health care team and was primarily directed at primary care providers. Clinical and patient-reported outcomes were assessed after 6 months. Patient-reported outcomes included changes in health-related quality of life (Health Utilities Index Mark 3 [HUI3]), satisfaction with care, lifestyle (Diabetes Lifestyle Form), and adherence to self-care activities. Analysis of covariance was used to assess differences over time between the control and intervention regions.

RESULTS—A total of 200 intervention and 172 control subjects were included in this analysis. After adjusting for important clinical and demographic differences, a statistically significant and clinically important improvement in the overall HUI3 score was seen at the 6-month follow-up in the intervention region (0.06 [95% CI 0.02–0.10]) compared with the control region (0.01 [−0.04 to 0.04]) (P = 0.03 for the difference between groups). Satisfaction with general medical care (P < 0.001 between groups) and diabetes care (P < 0.001 between groups) increased among patients in the intervention region compared with the control region. Self-efficacy, attitudes, and beliefs about diabetes control all increased in the intervention region when compared with the control region, but adherence to self-care activities did not.

CONCLUSIONS—A provider-level intervention directed at improving quality of clinical care for patients with type 2 diabetes also had a favorable impact on overall health-related quality of life, satisfaction with care, and other humanistic outcomes.
Patient Satisfaction and Glycemic Control After 1 Year With Inhaled Insulin (Exubera) in Patients With Type 1 or Type 2 Diabetes
Authors: Rosenstock Julio , Cappelleri Joseph C. , Bolinder Björn , Gerber Robert A.
Published: March 2007

OBJECTIVE—The aim of this study was to determine patient satisfaction in patients with type 1 or type 2 diabetes receiving an inhaled insulin or subcutaneous insulin regimen, as assessed by pooled analysis of two 12-week parent studies and 1-year extension studies.

RESEARCH DESIGN AND METHODS—In the 12-week parent studies, patients with type 1 (n = 70) or type 2 (n = 51) diabetes were randomized to an inhaled insulin or subcutaneous insulin regimen. In the 1-year extension studies, patients were allowed to select either treatment regimen. Patient satisfaction was assessed at baseline, week 12, and 1 year using the Patient Satisfaction with Insulin Therapy questionnaire.

RESULTS—Of the 60 patients who received inhaled insulin during the parent studies, 85.0% (n = 51) chose to continue treatment, 13.3% (n = 8) switched to subcutaneous insulin, and 1.7% (n = 1) did not continue. Of the 61 patients who received subcutaneous insulin, 21.3% (n = 13) chose to continue treatment, 75.4% (n = 46) switched to inhaled insulin, and 3.3% (n = 2) did not continue. From baseline (parent studies) to 1 year (extension studies), HbA1c reductions of 0.8% were sustained, and greater improvements were observed in the inhaled insulin group compared with the subcutaneous insulin group in terms of overall satisfaction (37.9 vs. 3.1%; P < 0.01) and ease of use (43.2 vs. −0.9%; P < 0.01).

CONCLUSIONS—Inhaled insulin was preferred over subcutaneous insulin, which resulted in greater patient satisfaction up to 1 year in patients with type 1 or type 2 diabetes with durable effects on HbA1c levels.
Reduced Mortality Associated With the Use of ACE Inhibitors in Patients With Type 2 Diabetes
Authors: Eurich Dean T. , Majumdar Sumit R. , Tsuyuki Ross T. , Johnson Jeffrey A.
Published: March 2007

OBJECTIVE—ACE inhibitor therapy is widely used in lower-risk patients with type 2 diabetes to reduce mortality, despite limited evidence to support this clinical strategy. The aim of this study was to evaluate the association between ACE inhibitor use and mortality in patients with diabetes and no cardiovascular disease.

RESEARCH DESIGN AND SETTINGS—Using the Saskatchewan health databases, 12,272 new users of oral hypoglycemic agents were identified between the years of 1991 and 1996. We excluded 3,202 subjects with previous cardiovascular disease. Of the remaining subjects, 1,187 “new users” of ACE inhibitors were identified (ACE inhibitor cohort). Subjects not receiving ACE inhibitor therapy throughout the follow-up period served as the control cohort (n = 4,989). Subjects were prospectively followed until death or the end of 1999. Multivariate Cox proportional hazards models were used to assess differences in all-cause and cardiovascular-related mortality between cohort groups.

RESULTS—Subjects were 60.7 ± 13.7 years old, 43.6% female, and were followed for an average of 5.3 ± 2.1 years. Mean duration of ACE inhibitor therapy was 3.6 ± 1.8 years. We observed significantly fewer deaths in the ACE inhibitor group (102 [8.6%]) compared with the control cohort (853 [17.1%]), with an adjusted hazard ratio (HR) and 95% CI of 0.49 (0.40–0.61) (P < 0.001). Cardiovascular-related mortality was also reduced (40 [3.4%] vs. 261 [5.2%], adjusted HR, 0.63 [0.44–0.90]; P = 0.012).

CONCLUSIONS—The use of ACE inhibitors was associated with a significant reduction in all-cause and cardiovascular-related mortality in a broad spectrum of patients with type 2 diabetes and no cardiovascular disease.
Improved Glycemic Control With No Weight Increase in Patients With Type 2 Diabetes After Once-Daily Treatment With the Long-Acting Glucagon-Like Peptide 1 Analog Liraglutide (NN2211)
Authors: Madsbad Sten , Schmitz Ole , Ranstam Jonas , Jakobsen Grethe , Matthews David R. ,   on behalf of the NN2211-1310 International Study Group
Published: March 2007

OBJECTIVE—Liraglutide is a long-acting glucagon-like peptide 1 analog designed for once daily injection. This study assessed the efficacy and safety of liraglutide after 12 weeks of treatment in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS—A double-blind, randomized, parallel-group, placebo-controlled trial with an open-label comparator arm was conducted among 193 outpatients with type 2 diabetes. The mean age was 56.6 years and the mean HbA1c was 7.6% across the treatment groups. Patients were randomly assigned to one of five fixed-dosage groups of liraglutide (0.045, 0.225, 0.45, 0.60, or 0.75 mg), placebo, or open-label sulfonylurea (glimepiride, 1–4 mg). The primary end point was HbA1c after 12 weeks; secondary end points were fasting serum glucose, fasting C-peptide, fasting glucagon, fasting insulin, β-cell function, body weight, adverse events, and hypoglycemic episodes.

RESULTS—A total of 190 patients were included in the intention-to-treat (ITT) analysis. HbA1c decreased in all but the lowest liraglutide dosage group. In the 0.75-mg liraglutide group, HbA1c decreased by 0.75 percentage points (P < 0.0001) and fasting glucose decreased by 1.8 mmol/l (P = 0.0003) compared with placebo. Improvement in glycemic control was evident after 1 week. Body weight decreased by 1.2 kg in the 0.45-mg liraglutide group (P = 0.0184) compared with placebo. The proinsulin-to-insulin ratio decreased in the 0.75-mg liraglutide group (−0.18; P = 0.0244) compared with placebo. Patients treated with glimepiride had decreased HbA1c and fasting glucose, but slightly increased body weight. No safety issues were raised for liraglutide; observed adverse events were mild and transient.

CONCLUSIONS—A once-daily dose of liraglutide provides efficacious glycemic control and is not associated with weight gain. Adverse events with the drug are mild and transient, and the risk of hypoglycemia is negligible.
Comparative Roles of Microvascular and Nerve Function in Foot Ulceration in Type 2 Diabetes
Authors: Krishnan Singhan T.M. , Baker Neil R. , Carrington Anne L. , Rayman Gerry
Published: March 2007

OBJECTIVE—To determine the relative roles of different modalities of sensory nerve function (large and small fiber) and the role of microvascular dysfunction in foot ulceration in type 2 diabetic subjects.

RESEARCH DESIGN AND METHODS—A total of 20 control subjects and 18 type 2 diabetic subjects with foot ulceration and 20 without were studied. None of the subjects had clinical features of peripheral vascular disease. The Computer-Aided Sensory Evaluator IV (CASE IV) was used to determine vibration detection threshold (VDT), cold detection threshold (CDT), warm detection threshold (WDT), and heat pain onset threshold (HPO). Vibration perception threshold (VPT) was also assessed by a neurothesiometer. Microvascular function (maximum hyperemia to skin heating to 44°C) was assessed using laser Doppler flowmetry (mean maximum hyperemia using laser Doppler flowmeter [LDFmax]), laser Doppler imaging (mean maximum hyperemia using laser Doppler imager [LDImax]), and skin oxygenation with transcutaneous oxygen tension (TcpO2).

RESULTS—VPT, VDT, CDT, and HPO were all significantly higher in individuals with ulceration than in those without (VPT and VDT: P < 0.0001) (CDT and HPO: P = 0.01). LDFmax, LDImax, and TcpO2 were significantly lower in the two diabetic groups than in the control subjects, but there was no difference between individuals with and without ulceration. Univariate logistic regression analysis revealed similar odds ratios for foot ulceration for VDT, CDT, HPO, and VPT (OR 1.97 [95% CI 1.30–2.98], 1.58 [1.20–2.08], 2.30 [1.21–4.37], and 1.24 [1.08–1.42], respectively). None of the microvascular parameters yielded significant odds ratios for ulceration.

CONCLUSIONS—This study found that there was no additional value in measuring small-fiber function with the CASE IV over measuring vibration by either CASE IV or the inexpensive neurothesiometer in discriminating between individuals with and without ulceration. Furthermore, none of the tests of microvascular function including the TcpO2 were able to discriminate between individuals with and without ulceration, suggesting that such tests may not be of benefit in identifying subjects at greater risk of foot ulceration.
Using Metabolic Syndrome Traits for Efficient Detection of Impaired Glucose Tolerance
Authors: Meigs James B. , Williams Ken , Sullivan Lisa M. , Hunt Kelly J. , Haffner Steven M. , Stern Michael P. , González Villalpando Clicerio , Perhanidis Jessica S. , Nathan David M. , D’Agostino Ralph B. , D’Agostino Ralph B. , Wilson Peter W.F.
Published: March 2007

OBJECTIVE—Efficient detection of impaired glucose tolerance (IGT) is needed to implement type 2 diabetes prevention interventions.

RESEARCH DESIGN AND METHODS—We assessed the capacity of the metabolic syndrome (MetS) to identify IGT in a cross-sectional analysis of 3,326 Caucasian Framingham Offspring Study (FOS), 1,168 Caucasian and 1,812 Mexican-American San Antonio Heart Study (SAHS), 1,983 Mexico City Diabetes Study (MCDS), and 452 Caucasian, 407 Mexican-American, and 290 African-American Insulin Resistance Atherosclerosis Study (IRAS) men and women aged 30–79 years who had a clinical examination and an oral glucose tolerance test (OGTT) during 1987–1996. Those with diabetes treatment or fasting plasma glucose ≥7.0 mmol/l were excluded (MetS was defined by Third Report of the National Cholesterol Education Program’s Adult Treatment Panel criteria and IGT as 2-h postchallenge glucose [2hPG] ≥7.8 mmol/l). We calculated positive (PPV) and negative predictive values (NPV), population attributable risk percentages (PAR%), age- and sex-adjusted odds ratios (ORs), and areas under the receiver operating characteristic curve (AROCs) associated with MetS traits.

RESULTS—Among FOS, SAHS, and MCDS subjects, 24–43% had MetS and 15–23% had IGT (including 2–5% with 2hPG ≥11.1 mmol/l). Among those with MetS, OR for IGT were 3–4, PPV were 0.24–0.41, NPV were 0.84–0.91, and PAR% were 30–40%. Among subjects with MetS defined by impaired fasting glucose (IFG) and any two other traits, OR for IGT were 9–24, PPV were 0.62–0.89, NPV were 0.78–0.87, and PAR% were 3–12%. Among IRAS subjects, 24–34% had MetS and 37–41% had IGT. Among those with MetS, ORs for IGT were 3–6, PPVs were 0.57–0.73, and NPVs were 0.67–0.72. In logistic regression models, IFG, large waist, and high triglycerides were independently associated with IGT (AROC 0.71–0.83) in all study populations.

CONCLUSIONS—The MetS, especially defined by IFG, large waist, and high triglycerides, efficiently identifies subjects likely to have IGT on OGTT and thus be eligible for diabetes prevention interventions.
The Burden of Treatment Failure in Type 2 Diabetes
Authors: Brown Jonathan B. , Nichols Gregory A. , Perry Andrew
Published: March 2007

OBJECTIVE—In type 2 diabetes, therapies to maintain blood glucose control usually fail after several years. We estimated the glycemic burden that accumulates from treatment failure and describe the time course and predictors of failure.

RESEARCH DESIGN AND METHODS—A prospective, population-based study using retrospective observational data. We identified all 7,208 complete courses of treatment with nondrug therapy, sulfonylurea monotherapy, metformin monotherapy, and combination oral antihyperglycemic therapy between 1994 and 2002, inclusive, among members of the Kaiser Permanente Northwest Region. We calculated mean cumulative glycemic burden, defined as HbA1c-months >8.0 or 7.0% for each treatment. We then measured the likelihood that the next HbA1c would exceed 8.0 and 7.0% after HbA1c exceeded each of ten hypothetical treatment thresholds. Finally, we estimated multivariate logistic regression models to predict when HbA1c would continue to deteriorate.

RESULTS—In this well-controlled population, the average patient accumulated nearly 5 HbA1c-years of excess glycemic burden >8.0% from diagnosis until starting insulin and about 10 HbA1c-years of burden >7.0%. Whenever patients crossed the American Diabetes Association-recommended treatment threshold of 8.0%, their next HbA1c result was as likely to be <8.0 as >8.0%. Multivariate prediction models had highly statistically significant coefficients, but predicted <10% of the variation in future HbA1c results.

CONCLUSIONS—Clinicians should change glucose-lowering treatments in type 2 diabetes much sooner or use treatments that are less likely to fail. An action point at 7.0% or lower is more likely to prevent additional deterioration than the traditional action point of 8.0%.
Albumin Excretion Rate Is Not Affected by Asymptomatic Urinary Tract Infection
Authors: Hernández Cristina , Simó Rafael
Published: March 2007

OBJECTIVE—The aim of the study was to evaluate whether asymptomatic urinary tract infection (UTI) significantly influences the level of albumin excretion rate (AER) in diabetic patients.

RESEARCH DESIGN AND METHODS—We screened prospectively for UTI and AER in 765 type 2 diabetic subjects. AER was determined before and after antimicrobial therapy in those patients in whom an asymptomatic UTI was diagnosed (n = 59). To interpret the clinical significance of AER changes, the coefficient of biological variation (CVb) of the AER (CVb-AER) was assessed in a control group of type 2 diabetic patients without UTI (n = 56).

RESULTS—AER did not change after antimicrobial treatment either in the whole group of patients with UTI (pre: 13.8 μg/min [0.1–195] vs. post: 8.5 μg/min [0.1–185]; P = 0.1) or in those patients in whom the infection was eradicated (pre: 11.7 μg/min [0.1–195] vs. post: 7.1 μg/min [0.1–185]; NS). The CVb-AER was 64% in the control group and was inversely correlated with AER (r = −0.44; P = 0.001). The decrease of AER after antimicrobial therapy (55%) did not exceed the biological variation of AER (64%). Finally, UTI did not significantly influence the classification of diabetic patients as normo- or microalbuminuric.

CONCLUSIONS—Asymptomatic UTI does not increase AER in type 2 diabetic patients. Therefore, our results suggest that testing for UTI is not necessary when AER is measured in diabetic patients.
A Multinational Comparison of Complications Assessment in Type 1 Diabetes
Authors: Walsh Michael G. , Zgibor Janice , Borch-Johnsen Knut , Orchard Trevor J. ,   on behalf of the DiaComp Investigators
Published: March 2007

OBJECTIVE—To describe the global geographic variation of micro- and macrovascular complications in childhood-onset type 1 diabetes assessed by both reported and measured disease and risk factors and relate any such variation to diabetes control and health care activities.

RESEARCH DESIGN AND METHODS—The DiaComp study is a multinational (17 countries) cross-sectional study of complications in type 1 diabetes and is comprised of two levels (level 1 includes survey only and level 2 includes survey plus examination). This report concerns level 2, representing 12 countries (n = 892). All participants were diagnosed at <15 years of age and had a diabetes duration of 5–24 years when surveyed. All complications were assessed by self-report and for microalbuminuria by Micral II dipstick, neuropathy by the Michigan Neuropathy Screening Instrument exam, and hypertension using the Hypertension Detection and Follow-up Program (HDFP) protocol. HbA1c was determined by using the DCA analyzer.

RESULTS—A wide variation in neuropathy, reported renal disease/proteinuria, and hypertension among those of short diabetes duration was noted, with central Europe (Romania and Lithuania) standing out for both self-reported renal disease and measured microalbuminuria and for both self-reported and examined neuropathy. The Caribbean (Puerto Rico) also had high rates of microalbuminuria and examined neuropathy. For those of long duration, variation was more moderate. We found generally good agreement between the reported and clinically determined measures for neuropathy (r = 0.5, P = 0.01) and hypertension (r = 0.61, P = 0.001) as demonstrated by the high overall correlation between examination and self-report for these two complications. However, the agreement between examination and self-report for renal disease/proteinuria was less, with low overall correlation (r = −0.05, P = 0.86) and incongruous centers (Slovakia and Finland). Geographic variation in prevalence was not consistently explained for all complications, even with strong independent prediction by systolic blood pressure, although the variation in microalbuminuria was largely accounted for by self-monitored blood glucose, which was significantly protective.

CONCLUSIONS—This report has identified wide variation and geographic patterns in complication prevalence, with a further indication that self-report is generally in agreement with examined prevalence, though less for renal disease/proteinuria. However, this level of DiaComp, with more complete assessment of risk factors and health care practice, was still not able to completely explain the variation in complication prevalence, except for microalbuminuria.
The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive)
Authors: Charbonnel Bernard , Dormandy John , Erdmann Erland , Massi-Benedetti Massimo , Skene Allan ,   PROactive Study Group
Published: March 2007

OBJECTIVE—The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) assesses the effect of pioglitazone, a peroxisome proliferator-activated receptor agonist, with anti-inflammatory and vascular properties, on the secondary prevention of macrovascular events in type 2 diabetes.

RESEARCH DESIGN AND METHODS—PROactive is an on-going randomized, double-blind outcome study in patients with type 2 diabetes managed with diet and/or oral blood glucose-lowering drugs (combination of oral agents with insulin is permitted) who have a history of macrovascular disease. Patients are randomized to receive pioglitazone (forced titration from 15 to 30 to 45 mg, depending on tolerability) or placebo in addition to existing therapy. The primary end point is the time from randomization to occurrence of a new macrovascular event or death. Follow-up is estimated to span 4 years.

RESULTS—A total of 5,238 patients have been randomized from 19 countries. At entry into the study, patients enrolled are a mean age of 61.8 years, with type 2 diabetes for a mean of 9.5 years; 60.9 and 61.5% are taking metformin or a sulfonylurea, respectively; and 33.6% are using insulin in addition to oral glucose-lowering drugs. The majority of patients are men (66.1%). Patients are required to meet one or more of entry criteria, as follows: >6 months’ history of myocardial infarction (46.7%); coronary artery revascularization (30.8%), stroke (18.8%), or acute coronary syndrome for >3 months (13.7%); other evidence of coronary artery disease (48.1%); or peripheral arterial occlusive disease (19.9%). One-half (48.5%) of the patients have two or more of these risk factors. Three-quarters (75.4%) have hypertension, and 58.8% are current or previous smokers.

CONCLUSIONS—The cohort of patients enrolled in PROactive is a typical type 2 diabetic population at high risk of further macrovascular events. The characteristics of this population are ideal for assessing the ability of pioglitazone to reduce the cardiovascular risk of patients with type 2 diabetes.
Disturbed Eating Behavior and Eating Disorders in Preteen and Early Teenage Girls With Type 1 Diabetes
Authors: Colton Patricia , Olmsted Marion , Daneman Denis , Rydall Anne , Rodin Gary
Published: March 2007

OBJECTIVE—To compare the prevalence of eating disturbances in preteen and early teenage girls with type 1 diabetes to their nondiabetic peers.

RESEARCH DESIGN AND METHODS—A cross-sectional, case-controlled study of 101 girls with type 1 diabetes, ages 9–14 years, and 303 age-matched, female nondiabetic control subjects was conducted. Participants completed a Children’s Eating Disorder Examination interview. Socioeconomic status, BMI, and diabetes-related variables were assessed. Groups were compared using χ2 analyses.

RESULTS—Binge eating; the use of intense, excessive exercise for weight control; the combination of two disturbed eating-related behaviors; and subthreshold eating disorders were all more common in girls with type 1 diabetes. Metabolic control was not related to eating behavior in this study population.

CONCLUSIONS—Eating disturbances, though mostly mild, were significantly more common in preteen and early teenage girls with type 1 diabetes. Screening and prevention programs for this high-risk group should begin in the preteen years.
Cooling Detection Thresholds in the Assessment of Diabetic Sensory Polyneuropathy
Authors: Zinman Lorne H. , Bril Vera , Perkins Bruce A.
Published: March 2007

OBJECTIVE—Cooling detection threshold testing may be an important quantitative method for assessing polyneuropathy, in that it has traditionally been viewed as a measure of small-fiber involvement. The present study sought to determine the agreement between two common testing devices and to determine whether these are concordant in their association with predictor variables for diabetic sensory polyneuropathy.

RESEARCH DESIGN AND METHODS—A total of 83 patients with diabetes (10 patients with type 1 diabetes and 73 patients with type 2 diabetes) and a wide spectrum of diabetic sensory polyneuropathy severity underwent concurrent cooling detection threshold testing using the Medoc and CASE IV instruments. Common predictor variables for diabetic sensory polyneuropathy were measured on the same day.

RESULTS—Measurements of cooling detection thresholds by both instruments were highly correlated (Spearman’s correlation coefficient 0.81, P < 0.001) and demonstrated a high degree of agreement by the method of Bland and Altman (95% distribution critical values for the difference in cooling detection thresholds, +7.5 and −5.6°C). Cooling detection thresholds by both instruments were strongly correlated with clinical indicators of large-fiber neuropathy but not with the symptoms of small-fiber neuropathy (pain).

CONCLUSIONS—These two instruments available for assessment of cooling detection thresholds are interchangeable for research in diabetic sensory polyneuropathy. However, this modality is equivalent to other modalities of quantitative sensory threshold testing in its association with indicators of large-fiber neuropathy and does not seem to provide an advantage for the prediction of small-fiber involvement.
The Effect of Trandolapril and Its Fixed-Dose Combination With Verapamil on Proteinuria in Normotensive Adults With Type 2 Diabetes
Authors: Rubio-Guerra Alberto Francisco , Arceo-Navarro Adalberto , Vargas-Ayala German , Rodriguez-Lopez Leticia , Lozano-Nuevo Jose Juan , Gomez-Harper Carlos Treviño
Published: March 2007

OBJECTIVE—To compare the effect of fixed-dose trandolapril-verapamil (FDTV) with that of trandolapril on proteinuria in normotensive, type 2 diabetic patients.

RESEARCH DESIGN AND METHODS—A total of 60 normotensive, type 2 diabetic patients with 24-h proteinuria >300 mg were randomly assigned to two groups for open-label treatment. One group received 2 mg trandolapril/180 mg verapamil FDTV once daily; the other group received 2 mg trandolapril once daily. Study drugs were administered for 6 months in both groups. Creatinine clearance and 24-h urinary protein excretion were measured at the beginning and the end of the study. Patients were evaluated monthly for blood pressure, fasting blood glucose level, heart rate, and adverse events. Statistical analysis was performed using ANOVA.

RESULTS—Both groups experienced a statistically significant (P < 0.005) mean decrease in mean proteinuria from baseline: FDTV ([mean ± SD] 1,200 ± 200 to 540 ± 79 mg; P < 0.001) and trandolapril (1,105 ± 212 to 750.9 ± 134 mg; P < 0.005). A significantly greater reduction from baseline in proteinuria was observed in the FDTV group compared with the trandolapril group. Patients who received trandolapril experienced a statistically significant (P < 0.05) decrease in mean creatinine clearance (91.1 ± 3.4 to 75.3 ± 3 ml/min; P < 0.05) compared with patients who received FDTV (88.3 ± 3.6 to 82.9 ± 3.5 ml/min; P > 0.05). Final fasting blood glucose was significantly lower in the FDTV group (139 ± 19) compared with the trandolapril group (154 ± 22; P < 0.001). No significant differences were observed between the two groups in mean baseline or final measurements of blood pressure, mean heart rate, or frequency of adverse events.

CONCLUSIONS—Our results suggest that FDTV is more effective than trandolapril in reducing proteinuria in normotensive, type 2 diabetic patients. This effect on proteinuria is not related with blood pressure reduction.
Reductions in Plasma Cytokine Levels With Weight Loss Improve Insulin Sensitivity in Overweight and Obese Postmenopausal Women
Authors: Ryan Alice S. , Nicklas Barbara J.
Published: March 2007

OBJECTIVE—The purpose of this study was to determine whether improvements in insulin sensitivity with weight loss are mediated by changes in inflammation in obese, postmenopausal women.

RESEARCH DESIGN AND METHODS—We studied 58 sedentary, overweight, and obese (BMI 33 ± 1 kg/m2, means ± SEM) postmenopausal (58 ± 1 year) women at baseline and 37 women who completed 6 months of weight loss induced by diet and exercise. The women underwent 3-h hyperinsulinemic-euglycemic clamps (40 mU · m−2 · min−1) to determine glucose utilization (M). Insulin sensitivity was determined as M/I, the amount of glucose metabolized per unit of plasma insulin (I). Visceral adipose tissue (VAT) and plasma concentrations of C-reactive protein (CRP), cytokines interleukin (IL)-6, and tumor necrosis factor (TNF)-α, as well as their soluble receptors, were measured.

RESULTS—At baseline, CRP concentration was a predictor of both glucose utilization and insulin sensitivity, independent of adiposity, race, and aerobic fitness (M: partial r = −0.30, P = 0.03, and M/I: partial r = −0.32, P = 0.02). Weight loss resulted in significant reductions in body weight, fat mass, VAT, and fasting glucose and insulin levels (P < 0.05). Both glucose utilization and insulin sensitivity increased by 16% (P < 0.05). CRP, IL-6, and soluble TNF receptor (sTNFR)-1 concentrations decreased (P < 0.05), but concentrations of TNF-α, sTNFR-2, and soluble IL-6 receptor (IL-6sR) did not change. In stepwise regression models to predict changes in glucose homeostasis, changes in VAT and sTNF-R1 independently predicted changes in glucose utilization (r = −0.49 and cumulative r = −0.64, P < 0.01), while changes in VAT and IL-6 were both independent predictors of changes in insulin sensitivity (r = −0.57 and cumulative r = −0.68, P < 0.01).

CONCLUSIONS—Improvements in glucose metabolism with weight loss programs are independently associated with decreases in cytokine concentrations, suggesting that a reduction in inflammation is a potential mechanism that mediates improvements in insulin sensitivity.