bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for Heterogeneous Pathogenesis of Insulin-Treated Diabetes in Black and White Children
Authors: Libman Ingrid M. , Pietropaolo Massimo , Arslanian Silva A. , LaPorte Ronald E. , Becker Dorothy J.
Published: March 2007

OBJECTIVE—We have previously reported differences in the prevalence of β-cell autoantibodies (AAs) in black and white children with insulin-treated diabetes, suggesting that the disease pathogenesis may be more heterogeneous among racial groups than previously thought. To further explore this issue, we compared clinical, biochemical, and autoimmune characteristics at disease diagnosis and follow-up treatment in an expanded number of black and white children with and without the presence of AAs.

RESEARCH DESIGN AND METHODS—The study cohort of 130 black children and adolescents, aged <19 years, diagnosed with diabetes and treated with insulin at time of diagnosis (January 1979 to December 1998) were matched with an equal number of white children by age at onset, sex, and year of diagnosis.

RESULTS—The black children had a higher prevalence of obesity (43 vs. 11%) and acanthosis nigricans (21 vs. 1%) than white children and a lower prevalence of AAs. Compared with black children who had AAs, those with no AAs were older and had a higher prevalence of obesity, acanthosis nigricans, and parental diabetes. However, one of four of the black children with AAs was obese and/or had acanthosis nigricans. Among white children, the absence of AAs was not associated with any differences in terms of obesity or acanthosis nigricans compared with those with AAs. Similar to their black counterparts, white children without antibodies were older and had a higher prevalence of parental diabetes. Although treatment with an insulin sensitizer was used, insulin therapy was rarely discontinued on follow-up.

CONCLUSIONS—These pediatric subjects, irrespective of autoimmunity, often showed characteristics associated with type 2 diabetes. These characteristics were more frequently displayed in black than in white children. Our data suggest that childhood diabetes may constitute a spectrum of pathogenic mechanisms that may overlap, including those typically associated with both type 1 and type 2 diabetes. This finding could have therapeutic implications.
Archimedes
Authors: Eddy David M. , Schlessinger Leonard
Published: March 2007

OBJECTIVE—To build a mathematical model of the anatomy, pathophysiology, tests, treatments, and outcomes pertaining to diabetes that could be applied to a wide variety of clinical and administrative problems and that could be validated.

RESEARCH DESIGN AND METHODS—We used an object-oriented approach, differential equations, and a construct we call “features.” The level of detail and realism was determined by what clinicians considered important, by the need to distinguish clinically relevant variables, and by the level of detail used in the conduct of clinical trials.

RESULTS—The model includes the pertinent organ systems, more than 50 continuously interacting biological variables, and the major symptoms, tests, treatments, and outcomes. The level of detail corresponds to that found in general medical textbooks, patient charts, clinical practice guidelines, and designs of clinical trials. The model is continuous in time and represents biological variables continuously. As demonstrated in a companion article, the equations can simulate a variety of clinical trials and reproduce their results with good accuracy.

CONCLUSIONS—It is possible to build a mathematical model that replicates the pathophysiology of diabetes at a high level of biological and clinical detail and that can be tested by simulating clinical trials.
Association of the p22phox Component of NAD(P)H Oxidase With Susceptibility to Diabetic Nephropathy in Patients With Type 1 Diabetes
Authors: Hodgkinson Andrea D. , Millward Beverley A. , Demaine Andrew G.
Published: March 2007

OBJECTIVE—Increased production of reactive oxygen species (ROS) in diabetes is thought to play a major role in the pathogenesis of diabetic microvascular complications such as nephropathy and retinopathy. The NAD(P)H oxidase complex is an important source of ROS in the vasculature. The p22 subunit is polymorphic with a C242T variant that changes histidine-72 for a tyrosine in the potential heme binding site, together with a A640G in the 3′ untranslated region. The aim was to investigate the frequency of these polymorphisms in 268 patients with type 1 diabetes with or without microvascular complications.

RESEARCH DESIGN AND METHODS—There was a highly significant increase in the frequency of the T/T242 genotype in patients with nephropathy compared with those with retinopathy alone or no microvascular disease after 20 years’ diabetes duration (uncomplicated) or normal healthy control subjects (33.3 vs. 6.5, 5.7, and 0.0%, respectively, P < 0.000001). Furthermore, the T242/G640 haplotype was found in 39.4% of the patients with nephropathy but in only 26.5% of the patients with retinopathy and 15.3 and 10.6% of the uncomplicated and normal control subjects, respectively.

RESULTS—When these variants of NAD(P)H oxidase were analyzed together with aldose reductase (5′ALR2) susceptibility genotypes, >46.0% of the patients with nephropathy possessed a T242 allele with the Z-2 5′ALR2 allele compared with only 11.2% of the uncomplicated patients (P < 0.00003).

CONCLUSIONS—In conclusion, these results suggest NAD(P)H oxidase together with the polyol pathway may contribute to the pathogenesis of diabetic nephropathy.
Effects of Stress Hyperglycemia on Acute Myocardial Infarction
Authors: Marfella Raffaele , Siniscalchi Mario , Esposito Katherine , Sellitto Ausilia , de Fanis Umberto , Romano Ciro , Portoghese Michele , Siciliano Silvio , Nappo Francesco , Sasso Ferdinando Carlo , Mininni Nicola , Cacciapuoti Federico , Lucivero Giacomo , Giunta Riccardo , Verza Mario , Giugliano Dario
Published: March 2007

OBJECTIVE—Stress hyperglycemia has been associated with increased mortality in patients with myocardial infarction (MI). We examined the association between plasma glucose levels, circulating inflammatory markers, T-cell activation, and functional cardiac outcome in patients with first MI.

RESEARCH DESIGN AND METHODS—Echocardiographic parameters, circulating levels of interleukin-18 (IL-18), C-reactive protein (CPR), and the percent of CD16-CD56, CD4/CD8, CD152, and HLA-DR expression were investigated in 108 patients with acute MI on admission to the emergency ward.

RESULTS—Our review found that 31 new hyperglycemic patients (glycemia ≥7 mmol/l) had higher infarct segment length (P < 0.05) and myocardial performance index (P < 0.02) and reduced transmitral Doppler flow (P < 0.05), pulmonary flow analysis (P < 0.02), and ejection fraction (P < 0.05) compared with 36 hyperglycemic diabetic patients and 41 normoglycemic patients. Plasma IL-18 and CRP were higher in the hyperglycemic than in the normoglycemic patients (P < 0.005), with the highest values in patients with new hyperglycemia (P < 0.05). Hyperglycemic patients had a higher percent of CD16+/CD56+ cells and CD4/CD8 ratio (P < 0.01), whereas they had lower CD152 expression (which has a negative regulatory function in T-cell activation) compared with normoglycemic patients (P < 0.001).

CONCLUSIONS—During MI, hyperglycemia is associated with increased levels of inflammatory markers, enhanced expression of cytotoxic T-cells, and reduced expression of T-cells, which are implicated in limiting the immune process. An increased inflammatory immune process seems a likely mechanism linking acute hyperglycemia to poor cardiac outcome in MI patients.
The Metabolic Syndrome as Predictor of Type 2 Diabetes
Authors: Lorenzo Carlos , Okoloise Mayor , Williams Ken , Stern Michael P. , Haffner Steven M.
Published: March 2007

OBJECTIVE—The oral glucose tolerance test identifies high-risk subjects for diabetes, but it is costly and inconvenient. To find better predictors of type 2 diabetes, we evaluated two different definitions of the metabolic syndrome because insulin resistance, which is commonly associated with this clustering of metabolic factors, frequently precedes the onset of type 2 diabetes.

RESEARCH DESIGN AND METHODS—We compared the ability of the National Cholesterol Education Program (NCEP) definition, a modified version of the 1999 World Health Organization (WHO) definition that excludes the 2-h glucose requirement, and impaired glucose tolerance (IGT) to predict incident type 2 diabetes. In the San Antonio Heart Study, 1,734 participants completed a 7- to 8-year follow-up examination.

RESULTS—IGT and the NCEP definition had higher sensitivity than the modified WHO definition (51.9, 52.8, and 42.8%, respectively). IGT had a higher positive predictive value than the NCEP and modified WHO definitions (43.0, 30.8, and 30.4%, respectively). The combination of the IGT and NCEP definitions increased the sensitivity to 70.8% with an acceptable positive predictive value of 29.7%. Risk for incidence of type 2 diabetes using the NCEP definition was independent of other risk factors, including IGT and fasting insulin (odds ratio 3.30, 95% CI 2.27-4.80). The NCEP definition performed better with fasting glucose ≥5.4 mmol/l (sensitivity 62.0% and positive predictive value 30.9%).

CONCLUSIONS—The metabolic syndrome predicts diabetes independently of other factors. However, the NCEP definition performs better than the modified 1999 WHO definition. Lowering the fasting glucose cutoff to 5.4 mmol/l improves the prediction of diabetes by the metabolic syndrome.
Primary Prevention of Cardiovascular Events With Low-Dose Aspirin and Vitamin E in Type 2 Diabetic Patients
Authors: Sacco Michele , Pellegrini Fabio , Roncaglioni Maria C. , Avanzini Fausto , Tognoni Gianni , Nicolucci Antonio ,   on behalf of the PPP Collaborative Group
Published: March 2007

OBJECTIVE—We investigated in general practice the efficacy of antiplatelets and antioxidants in primary prevention of cardiovascular events in people with type 2 diabetes.

RESEARCH DESIGN AND METHODS—The Primary Prevention Project (PPP) is a randomized, open trial with a two-by-two factorial design aimed to investigate low-dose aspirin (100 mg/day) and vitamin E (300 mg/day) in the prevention of cardiovascular events in patients with one or more cardiovascular risk factors. The primary end point was a composite end point of cardiovascular death, stroke, or myocardial infarction. A total of 1,031 people with diabetes in the PPP, aged ≥50 years, without a previous cardiovascular event were enrolled by 316 general practitioners and 14 diabetes outpatient clinics.

RESULTS—The PPP trial was prematurely stopped (after a median of 3.7 years) by the independent data safety and monitoring board because of a consistent benefit of aspirin compared with the control group in a population of 4,495 patients with one or more major cardiovascular risk factors. In diabetic patients, aspirin treatment was associated with a nonsignificant reduction in the main end point (relative risk [RR] = 0.90, 95% CI 0.50–1.62) and in total cardiovascular events (0.89, 0.62–1.26) and with a nonsignificant increase in cardiovascular deaths (1.23, 0.69–2.19). In nondiabetic subjects, RRs for the main end point, total cardiovascular events, and cardiovascular deaths were 0.59 (0.37–0.94), 0.69 (0.53–0.90), and 0.32 (0.14–0.72), respectively. No significant reduction in any of the end points considered could be found with vitamin E in either diabetic or nondiabetic subjects.

CONCLUSIONS—Our data suggest a lower effect of primary prevention of cardiovascular disease (CVD) with low-dose aspirin in diabetic patients as opposed to subjects with other cardiovascular risk factors. If confirmed, these findings might indicate that the antiplatelet effects of aspirin in diabetic patients are overwhelmed by aspirin-insensitive mechanisms of platelet activation and thrombus formation, thus making the balance between benefits and harms of aspirin treatment unfavorable. Further large-scale trials investigating the role of aspirin in the primary prevention of CVD in diabetic patients are urgently needed.
Benefits and Risks of Solitary Islet Transplantation for Type 1 Diabetes Using Steroid-Sparing Immunosuppression
Authors: Hirshberg Boaz , Rother Kristina I. , Digon Benigno J. , Lee Janet , Gaglia Jason L. , Hines Kenneth , Read Elizabeth J. , Chang Richard , Wood Bradford J. , Harlan David M.
Published: March 2007

OBJECTIVE—The aim of this study was to describe the National Institutes of Health’s experience initiating an islet isolation and transplantation center, including descriptions of our first six recipients, and lessons learned.

RESEARCH DESIGN AND METHODS—Six females with chronic type 1 diabetes, hypoglycemia unawareness, and no endogenous insulin secretion (undetectable serum C-peptide) were transplanted with allogenic islets procured from brain dead donors. To prevent islet rejection, patients received daclizumab, sirolimus, and tacrolimus.

RESULTS—All patients noted less frequent and less severe hypoglycemia, and one-half were insulin independent at 1 year. Serum C-peptide persists in all but one patient (follow-up 17–22 months), indicating continued islet function. Two major procedure-related complications occurred: partial portal vein thrombosis and intra-abdominal hemorrhage. While we observed no cytomegalovirus infection or malignancy, recipients frequently developed transient mouth ulcers, diarrhea, edema, hypercholesterolemia, weight loss, myelosuppression, and other symptoms. Three patients discontinued immunosuppressive therapy: two because of intolerable toxicity (deteriorating kidney function and sirolimus-induced pneumonitis) while having evidence for continued islet function (one was insulin independent) and one because of gradually disappearing islet function.

CONCLUSIONS—We established an islet isolation and transplantation program and achieved a 50% insulin-independence rate after at most two islet infusions. Our experience demonstrates that centers not previously engaged in islet transplantation can initiate a program, and our data and literature analysis support not only the promise of islet transplantation but also its remaining hurdles, which include the limited islet supply, procedure-associated complications, imperfect immunosuppressive regimens, suboptimal glycemia control, and loss of function over time.
Contribution of Visceral Adiposity to the Exaggerated Postprandial Lipemia of Men With Impaired Glucose Tolerance
Authors: Blackburn Patricia , Lamarche Benoît , Couillard Charles , Pascot Agnés , Tremblay Angelo , Bergeron Jean , Lemieux Isabelle , Després Jean-Pierre
Published: March 2007

OBJECTIVE—Impaired glucose tolerance (IGT) has been associated with alterations in numerous coronary heart disease risk factors, including postprandial hyperlipidemia. An excess visceral adipose tissue accumulation is also predictive of IGT and of an exaggerated postprandial lipemia. The objective of the present study was therefore to compare the respective contributions of visceral adipose tissue accumulation versus IGT with the variation in postprandial lipemia.

RESEARCH DESIGN AND METHODS—Potential differences in postprandial triglyceride (TG)-rich lipoprotein (TRL) levels following a standardized breakfast with a high fat content were examined among men characterized by normal glucose tolerance (NGT) or IGT. Sixty-seven men were classified according to their glucose tolerance status (<7.8 mmol/l [NGT] or between 7.8 and 11.1 mmol/l [IGT] 2 h after a 75-g oral glucose test).

RESULTS—Men with IGT showed the highest TRL-TG concentrations (P < 0.05) at the 4-, 6-, and 8-h time points compared with men with NGT. These higher postprandial TRL-TG levels among men with IGT were also accompanied by a greater postprandial TG total area under the incremental curve in all TRL fractions (large, medium, and small) (P < 0.05). Furthermore, subjects characterized by IGT had also the highest visceral adipose tissue accumulation (P < 0.009). When subgroups of IGT and NGT men were individually matched (n = 11) for similar visceral adipose tissue accumulation, no significant difference was found in postprandial responses of all TRL-TG fractions between the two groups.

CONCLUSIONS—These results provide evidence that visceral adipose tissue accumulation is an important factor involved in the deterioration of postprandial lipemia noted among men with IGT.
Diagnosing Insulin Resistance by Simple Quantitative Methods in Subjects With Normal Glucose Metabolism
Authors: Ascaso Juan F. , Pardo Susana , Real José T. , Lorente Rosario I. , Priego Antonia , Carmena Rafael
Published: March 2007

OBJECTIVE—To identify a reliable yet simple indirect method for detection of insulin resistance (IR).

RESEARCH DESIGN AND METHODS—A total of 65 subjects (44 men and 21 women aged 30–60 years) were selected by a simple random sampling method. Inclusion criteria were voluntary participation from staff and hospital personnel, absence of abnormal glucose tolerance, and normal results of lipid profile and basic blood chemistry. A blood sample was taken after a 12-h overnight fast to determine plasma lipid, glucose, and insulin levels. An intravenous glucose tolerance test with administration of insulin after 20 min and extraction of multiple blood samples for glucose and insulin measurements and calculation of the minimal model approximation of the metabolism of glucose (MMAMG) Si value were performed. Three indirect indexes used to predict insulin sensitivity or IR were calculated, and metabolic syndrome was diagnosed using the Adult Treatment Panel III (ATP III) criteria. All results were correlated with those of the MMAMG.

RESULTS—The 75th percentile value as the cutoff point to define IR corresponded with a fasting plasma glucose level of 12 mU/l, a homeostasis model assessment of 2.6, a 25th percentile for Si value of 21, and QUICKI (quantitative insulin sensitivity check index) and McAuley indexes of 0.33 and 5.8, respectively. The Si index correlated (P < 0.001) with all the indirect indexes and parameters of the metabolic syndrome.

CONCLUSIONS—When compared with the Si index, the most sensitive and specific indirect method was the score proposed by McAuley et al. (specificity 0.91, sensitivity 0.75, 9.2 probability ratio of a positive test), followed by the existence of metabolic syndrome (specificity 0.91, sensitivity 0.66, 7.8 probability ratio of a positive test).
Dietary Fat Intake as Risk Factor for the Development of Diabetes
Authors: Thanopoulou Anastasia C. , Karamanos Basil G. , Angelico Francesco V. , Assaad-Khalil Samir H. , Barbato Alfredo F. , Del Ben Maria P. , Djordjevic Predrag B. , Dimitrijevic-Sreckovic Vesna S. , Gallotti Cristina A. , Katsilambros Nikolaos L. , Migdalis Ilias N. , Mrabet Mansouria M. , Petkova Malina K. , Roussi Demetra P. , Tenconi Maria-Teresa P.
Published: March 2007

OBJECTIVE—To investigate the role of dietary factors in the development of type 2 diabetes.

RESEARCH DESIGN AND METHODS—In the context of the Multinational MGSD Nutrition Study, three groups of subjects were studied: 204 subjects with recently diagnosed diabetes (RDM), 42 subjects with undiagnosed diabetes (UDM) (American Diabetes Association criteria—fasting plasma glucose [FPG] ≥126 mg/dl), and 55 subjects with impaired fasting glucose (IFG) (FPG ≥110 and <126 mg/dl). Each group was compared with a control group of nondiabetic subjects, matched one by one for center, sex, age, and BMI. Nutritional habits were evaluated by a dietary history method, validated against the 3-day diet diary. In RDM, the questionnaire referred to the nutritional habits before the diagnosis of diabetes. Demographic data were collected, and anthropometrical and biochemical measurements were taken.

RESULTS—Compared with control subjects, RDM more frequently had a family history of diabetes (49.0 vs. 14.2%; P < 0.001), exercised less (exercise index 53.5 vs. 64.4; P < 0.01), and more frequently had sedentary professions (47.5 vs. 27.4%; P < 0.001). Carbohydrates contributed less to their energy intake (53.5 vs. 55.1%; P < 0.05), whereas total fat (30.2 ± 0.5 vs. 27.8 ± 0.5%; P < 0.001) and animal fat (12.2 ± 0.3 vs. 10.8 ± 0.3%; P < 0.01) contributed more and the plant-to-animal fat ratio was lower (1.5 ± 0.1 vs. 1.8 ± 0.1; P < 0.01). UDM more frequently had a family history of diabetes (38.1 vs. 19.0%; P < 0.05) and sedentary professions (58.5 vs. 34.1%; P < 0.05), carbohydrates contributed less to their energy intake (47.6 ± 1.7 vs. 52.8 ± 1.4%; P < 0.05), total fat (34.7 ± 1.5 vs. 30.4 ± 1.2%; P < 0.05) and animal fat (14.2 ± 0.9 vs. 10.6 ± 0.7%; P < 0.05) contributed more, and the plant-to-animal fat ratio was lower (1.6 ± 0.2 vs. 2.3 ± 0.4; P < 0.05). IFG differed only in the prevalence of family history of diabetes (32.7 vs. 16.4%; P < 0.05).

CONCLUSIONS—Our data support the view that increased animal fat intake is associated with the presence of diabetes.
Quality of Care for Patients Diagnosed With Diabetes at Screening
Authors: Edelman David , Olsen Maren K. , Dudley Tara K. , Harris Amy C. , Oddone Eugene Z.
Published: March 2007

OBJECTIVE—Screening for diabetes has the potential to be an effective intervention, especially if patients have intensive treatment of their newly diagnosed diabetes and comorbid hypertension. We wished to determine the process and quality of diabetes care for patients diagnosed with diabetes by systematic screening.

RESEARCH DESIGN AND METHODS—A total of 1,253 users of the Durham Veterans Affairs Medical Center aged 45–64 years who did not report having diabetes were screened for diabetes with an HbA1c test. All subjects with an HbA1c level ≥6.0% were invited for follow-up blood pressure and fasting plasma glucose (FPG) measurements. A case of unrecognized diabetes was defined as HbA1c ≥7.0% or FPG ≥126 mg/dl. For each of the 56 patients for whom we made a new diagnosis of diabetes, we notified the patient’s primary care provider of this diagnosis. One year after diagnosis, we reviewed these patients’ medical records for traditional diabetes performance measures as well as blood pressure. Follow-up blood pressure was also ascertained from medical record review for all subjects with HbA1c ≥6.0% who did not have diabetes. We compared blood pressure changes between patients with and without diabetes.

RESULTS—Among patients diagnosed with diabetes at screening, 34 of 53 (64%) had evidence of diet or medical treatment for their diabetes, 42 of 53 (79%) had HbA1c measured within the year after diagnosis, 32 of 53 (60%) had cholesterol measured, 25 of 53 (47%) received foot examinations, 29 of 53 (55%) had eye examinations performed by an eye specialist, and 16 of 53 (30%) had any measure of urine protein. The mean blood pressure decline over the year after diagnosis for patients with diabetes was 2.3 mmHg; this decline was similar to that found for 183 patients in the study without diabetes (change in blood pressure, −3.6 mmHg). At baseline, 48% of patients with diabetes had blood pressure <140/90, compared with 40% of patients without diabetes; 1 year later, the same 48% of patients with diabetes had blood pressure <140/90, compared with 56% of patients without diabetes (P = 0.31 for comparing the change in percent in control between groups).

CONCLUSIONS—Patients with diabetes diagnosed at screening achieve less tight blood pressure control than similar patients without diabetes. Primary care providers do not appear to manage diabetes diagnosed at screening as intensively as long-standing diabetes and do not improve the management of hypertension given the new diagnosis of diabetes.
Prevalence and Predictors of Sexual Dysfunction in Patients With Type 1 Diabetes
Authors: Enzlin Paul , Mathieu Chantal , Van den Bruel Annick , Vanderschueren Dirk , Demyttenaere Koen
Published: March 2007

OBJECTIVE—This study aimed to 1) measure the prevalence of sexual dysfunction in patients with diabetes; 2) describe how descriptive variables, psychological variables, diabetic complications, and sexual dysfunction relate in patients with diabetes; and 3) describe the predictors of sexual dysfunction in patients with diabetes.

RESEARCH DESIGN AND METHODS—A total of 240 adult type 1 diabetic patients visiting the outpatient diabetes clinic of a university hospital completed questionnaires evaluating psychological adjustment to diabetes and sexual functioning. Medical records were used to obtain HbA1c values as well as information on microvascular diabetic complications.

RESULTS—Sexual dysfunction was reported by 27% of women and 22% of men. No differences were found between sexes in type of reported sexual dysfunction. In men, but not in women, sexual dysfunction was related to age, BMI, duration of diabetes, and diabetic complications. No correlation with HbA1c was found in either sex. In women, but not in men, sexual dysfunction was related to depression and the quality of the partner relationship. Binary logistic regression demonstrated that, in men, the significant predictors of sexual dysfunction were higher age and presence of complications, whereas, in women, sexual dysfunction was related to depression.

CONCLUSIONS—Both women and men with diabetes are at increased risk for sexual dysfunction. This study suggests that in men with diabetes, sexual dysfunction is related to somatic and psychological factors, whereas in women with diabetes, psychological factors are more predominant.
Urinary Cadmium, Impaired Fasting Glucose, and Diabetes in the NHANES III
Authors: Schwartz Gary G. , Il’yasova Dora , Ivanova Anastasia
Published: March 2007

OBJECTIVE—Increasing rates of type 2 diabetes worldwide suggest that diabetes may be caused by environmental toxins. Cadmium is a widespread environmental pollutant that accumulates in the pancreas and exerts diabetogenic effects in animals. To test the hypothesis that exposure to cadmium is associated with impaired fasting glucose and type 2 diabetes, we examined the associations between urinary cadmium and the prevalence of impaired fasting glucose (prediabetes) and diabetes in the Third National Health and Nutrition Examination Survey (NHANES III).

RESEARCH DESIGN AND METHODS—We analyzed data on 8,722 adults ≥40 years of age from the NHANES III (1988–1994), a cross-sectional health survey of a nationally representative sample of the noninstitutionalized civilian U.S. population. We studied urinary levels of cadmium (adjusted for urine creatinine) in relation to the prevalence of impaired fasting glucose and diabetes, using the criteria of the American Diabetes Association.

RESULTS—After adjustment for age, ethnicity, sex, and BMI, the odds of impaired fasting glucose and diabetes increased dose-dependently with elevations in urinary cadmium from 0–0.99 to 1.00–1.99 and ≥2 μg/g creatinine (impaired fasting glucose, odds ratio [OR] 1.48, 95% CI 1.21–1.82 and OR 2.05, 95% CI 1.42–2.95; diabetes, OR 1.24, 95% CI 1.06–1.45 and OR 1.45, 95% CI 1.07–1.97).

CONCLUSIONS—In this large cross-sectional study, urinary cadmium levels are significantly and dose-dependently associated with both impaired fasting glucose and diabetes. These findings, which require confirmation in prospective studies, suggest that cadmium may cause prediabetes and diabetes in humans.
Lifestyle Modification to Improve Blood Pressure Control in Individuals With Diabetes
Authors: Egede Leonard E.
Published: March 2007

OBJECTIVE—To determine the effectiveness of physician advice on hypertension-related lifestyle modification in individuals with diabetes.

RESEARCH DESIGN AND METHODS—Data on adults with one or more physician visit in the 1998 National Health Interview Survey (NHIS) were analyzed (diabetes, n = 1,609; no diabetes, n = 19,672). The proportion with hypertension who received physician advice to lose weight, increase physical activity, or take antihypertensive medications and the proportion who reported adhering to advice were compared by diabetes status. Logistic regression was used to identify factors associated with receipt of physician advice and adherence to advice by diabetes status controlling for covariates. Then, logistic regression was also used to determine the extent to which patient adherence among people with diabetes differed by age, sex, and race/ethnicity, controlling for other covariates. STATA statistical software was used for all analyses to account for the complex survey design of NHIS.

RESULTS—Controlling for covariates, individuals with diabetes were more likely to receive advice (odds ratio [OR] 1.94 for weight loss, 1.99 for exercise, and 2.16 for medications). Adherence was more likely in individuals with diabetes (OR 1.40 for losing weight and 2.16 for taking medications). Adherence in people with diabetes did not differ by sex or race/ethnicity. Subjects 18–44 years old were least likely to report losing weight (OR 0.15) or taking medications (0.31) compared with subjects ≥65 years old.

CONCLUSIONS—Physician advice appears effective at changing hypertension-related lifestyles in people with diabetes regardless of sex or race/ethnicity. However, advice on increasing physical activity does not seem as effective.
The Effect of Alcohol Intake on Insulin Sensitivity in Men
Authors: Zilkens Renate R. , Burke Valerie , Watts Gerald , Beilin Laurence J. , Puddey Ian B.
Published: March 2007

OBJECTIVE—Population data suggest that alcohol consumption may influence the risk of diabetes in a biphasic manner, but this has not been tested by any controlled interventions. The object of this study was to determine whether reducing alcohol intake in moderate-to-heavy drinkers (40–110 g/day) results in improvement in insulin sensitivity.

RESEARCH DESIGN AND METHODS—A 4-week run-in period where subjects maintained their usual drinking pattern was followed by randomization to a two-way cross-over intervention study. In each of two 4-week treatment interventions, subjects either substituted their usual alcohol intake with a 0.9% alcohol beer or maintained their usual alcohol intake. At the end of each 4-week period, insulin sensitivity as determined by the low-dose insulin glucose infusion test and the homeostasis model assessment (HOMA) score, and biomarkers of alcohol consumption (γ-glutamyl transpeptidase [γ-GT] and HDL cholesterol) were measured.

RESULTS—A total of 16 healthy men aged 51.0 ± 2.7 (mean ± SEM) years with a BMI of 26.4 ± 0.61 kg/m2 completed the study. There was a large reduction in alcohol intake (72.4 ± 5.0 vs. 7.9 ± 1.6 g/day, P < 0.001) and significant reductions in γ-GT (geometric mean 24.4 units/l [95% CI 19.7–30.2] vs. 18.6 units/l [15.5–22.2], P < 0.01) and HDL cholesterol (1.36 ± 0.07 vs. 1.13 ± 0.07 mmol/l, P < 0.001). There was no effect of alcohol on insulin sensitivity index (ISI), fasting insulin, glucose, or HOMA score.

CONCLUSIONS—A substantial reduction in alcohol intake from 7.2 to 0.8 standard drinks per day in healthy men did not change insulin sensitivity as measured by ISI or HOMA score.
Pramlintide as an Adjunct to Insulin Therapy Improves Long-Term Glycemic and Weight Control in Patients With Type 2 Diabetes
Authors: Hollander Priscilla A. , Levy Philip , Fineman Mark S. , Maggs David G. , Shen Larry Z. , Strobel Susan A. , Weyer Christian , Kolterman Orville G.
Published: March 2007

OBJECTIVE—Mealtime amylin replacement with the human amylin analog pramlintide, as an adjunct to mealtime insulin replacement, reduces postprandial glucose excursions in patients with type 2 diabetes. The aim of the present study was to assess the long-term efficacy and safety of pramlintide in this patient population.

RESEARCH DESIGN AND METHODS—In a 52-week, double-blind, placebo-controlled, parallel-group, multicenter study, 656 patients with type 2 diabetes (age 57 ± 10 years, diabetes duration 12 ± 7 years, BMI 34.0 ± 7.0 kg/m2, HbA1c 9.1 ± 1.2%, mean ± SD) treated with insulin (alone or in combination with sulfonylureas and/or metformin) were randomized to receive additional preprandial subcutaneous injections of either placebo or pramlintide (60 μg TID, 90 μg BID, or 120 μg BID).

RESULTS—Treatment with pramlintide 120 μg BID led to a sustained reduction from baseline in HbA1c (−0.68 and −0.62% at weeks 26 and 52, respectively), which was significantly greater than that seen with placebo (P < 0.05). The proportion of patients achieving an HbA1c <8% was approximately twofold greater with pramlintide (120 μg BID) than with placebo (46 vs. 28%, P < 0.05). The glycemic improvement with pramlintide 120 μg BID was accompanied by a mean weight loss (−1.4 kg vs. +0.7 kg with placebo at week 52, P < 0.05) and occurred without an overall increase in the severe hypoglycemia event rate. The most common adverse event associated with pramlintide use was transient, mild-to-moderate nausea.

CONCLUSIONS—Mealtime amylin replacement with pramlintide 120 μg BID, as an adjunct to insulin therapy, improves long-term glycemic and weight control in patients with type 2 diabetes.
Serum Lipoproteins in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications Cohort
Authors: Jenkins Alicia J. , Lyons Timothy J. , Zheng Deyi , Otvos James D. , Lackland Daniel T. , McGee Daniel , Garvey W. Timothy , Klein Richard L. ,   The DCCT/EDIC Research Group
Published: March 2007

OBJECTIVE—To relate the nuclear magnetic resonance (NMR)-determined lipoprotein profile, conventional lipid and apolipoprotein measures, and in vitro oxidizibility of LDL with gender and glycemia in type 1 diabetes.

RESEARCH DESIGN AND METHODS—In the 1997–1999 Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) cohort, serum from 428 women and 540 men were characterized by conventional lipids, NMR, apolipoprotein levels, and LDL susceptibility to in vitro oxidation. Simple and partial correlation coefficients were calculated for each lipoprotein-related parameter versus gender, with and without covariates (age, diabetes duration, concurrent HbA1c, DCCT randomization, hypertension, BMI, waist-to-hip ratio, and albuminuria). For concurrent HbA1c, data were analyzed as above, exchanging gender for HbA1c. Associations were significant if P < 0.05.

RESULTS—Although men and women had similar total and LDL cholesterol and triglycerides, men exhibited the following significant percent differences in NMR profiles versus women: small VLDL 41; IDL −30; medium LDL 39; small LDL 21; large HDL −32; small HDL 35; LDL particle concentration 4; VLDL and HDL diameters −8 and −4, respectively. Small VLDL, small HDL, medium LDL (women only), small LDL (men only), and LDL particle concentration were positively correlated, and HDL size was inversely correlated, with concurrent HbA1c. NMR profile was unrelated to prior DCCT randomization. Susceptibility of LDL to oxidation was unrelated to gender and glycemia.

CONCLUSIONS—Male gender and poor glycemia are associated with a potentially more atherogenic NMR lipoprotein profile. Neither gender nor glycemia influence LDL oxidation in vitro.
Safety and Efficacy of Repaglinide in Type 2 Diabetic Patients With and Without Impaired Renal Function
Authors: Hasslacher Christoph ,   for the Multinational Repaglinide Renal Study Group
Published: March 2007

OBJECTIVE—To evaluate the influence of renal impairment on the safety and efficacy of repaglinide in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS—This multinational, open-label study comprised a 6-week run-in period, continuing prestudy antidiabetic medication, followed by a titration period (1–4 weeks) and a 3-month maintenance period. Patients with normal renal function (n = 151) and various degrees of renal impairment (n = 130) were treated with repaglinide (maximal dose of 4 mg, three times daily). Safety and efficacy assessments were performed at baseline (end of run-in) and at the end of study treatment.

RESULTS—The type and severity of adverse events during repaglinide treatment were similar to the run-in period. The number of patients with adverse events was not significantly related to renal function during run-in or repaglinide treatment. Percentage of patients with hypoglycemic episodes increased significantly (P = 0.007) with increasing severity of renal impairment during run-in but not during repaglinide treatment (P = 0.074). Metabolic control (HbA1c and fasting blood glucose) with repaglinide was unchanged from that on previous antidiabetic medication. Final repaglinide dose tended to be lower for patients with severe and extreme renal impairment than for patients with less severe renal impairment or normal renal function (P = 0.032).

CONCLUSIONS—Repaglinide has a good safety and efficacy profile in type 2 diabetic patients complicated by renal impairment and is an appropriate treatment choice, even for individuals with more severe degrees of renal impairment.
RANTES Promoter Genotype Is Associated With Diabetic Nephropathy in Type 2 Diabetic Subjects
Authors: Nakajima Kunihiro , Tanaka Yasushi , Nomiyama Takashi , Ogihara Takeshi , Ikeda Fuki , Kanno Rei , Iwashita Noseki , Sakai Ken , Watada Hirotaka , Onuma Tomio , Kawamori Ryuzo
Published: March 2007

OBJECTIVE—To evaluate the effect of RANTES gene promoter polymorphism and RANTES receptor (CCR5 gene) promoter polymorphism on diabetic nephropathy in Japanese type 2 diabetic subjects.

RESEARCH DESIGN AND METHODS—A total 616 Japanese subjects with type 2 diabetes were recruited. Polymorphisms of −28 C/G and −403 G/A in the RANTES gene promoter region, and of 59029 G/A in the CCR5 gene promoter region were detected by PCR-RFLP (restriction fragment length polymorphism). The association of these genotypes with nephropathy was analyzed.

RESULTS—While the RANTES −403 genotype showed no association with nephropathy, the frequency of the −28G allele was significantly higher in the DN2 group (urinary albuminuria-to-creatinine ratio [ACR] ≧300 mg/g creatinine, serum creatinine <2.0 mg/dl) than in the DN0 (ACR <30 mg/g creatinine) and DN1 (ACR ≥30 mg/g creatinine and <300 mg/g creatinine) groups. The frequency of a RANTES −28G-positive genotype (C/G or G/G) was higher in the DN2 group than in the DN0 and DN1 groups (34% vs. 25 and 20%, P = 0.0268, χ2 = 4.905), and the frequency of a CCR5 59029 A-positive genotype (G/A or A/A) was higher in the DN1 and DN2 groups than in the DN0 group (84 and 85% vs. 76%, P = 0.0123, χ2 = 6.269). Discriminant analysis showed that the RANTES −28G-positive genotype and CCR5 59029A-positive genotype were independently associated with nephropathy. The percentage of macroalbuminuria was twofold higher in the subjects having −28G or 59029A and threefold higher in the subjects having −28G and 59029A than in the subjects without −28G and 59029A.

CONCLUSIONS—The RANTES promoter −28G genotype and CCR5 promoter 59029A genotype may be independent risk factors for diabetic nephropathy in patients with type 2 diabetes and may have an additive effect on nephropathy.
Frequency of Severe Hypoglycemia Requiring Emergency Treatment in Type 1 and Type 2 Diabetes
Authors: Leese Graham P. , Wang Jixian , Broomhall Janice , Kelly Paul , Marsden Andrew , Morrison William , Frier Brian M. , Morris Andrew D. ,   For the DARTS/MEMO Collaboration
Published: March 2007

OBJECTIVE—To determine the incidence, predisposing factors, and costs of emergency treatment of severe hypoglycemia in people with type 1 and type 2 diabetes.

RESEARCH DESIGN AND METHODS—Over a 12-month period, routinely collected datasets were analyzed in a population of 367,051 people, including 8,655 people with diabetes, to measure the incidence of severe hypoglycemia that required emergency assistance from Ninewells Hospital and Medical School (NHS) personnel including those in primary care, ambulance services, hospital accident and emergency departments, and inpatient care. Associated costs with these episodes were calculated.

RESULTS—A total of 244 episodes of severe hypoglycemia were recorded in 160 patients, comprising 69 (7.1%) people with type 1 diabetes, 66 (7.3%) with type 2 diabetes treated with insulin, and 23 (0.8%) with type 2 diabetes treated with sulfonylurea tablets. Incidence rates were 11.5 and 11.8 events per 100 patient-years for type 1 and type 2 patients treated with insulin, respectively. Age, duration, and socioeconomic status were identified as risk factors for severe hypoglycemia. One in three cases were treated solely by the ambulance service with no other contact from health care professionals. The total estimated cost of emergency treatment of severe hypoglycemia was ≤£92,078 in one year.

CONCLUSIONS—Hypoglycemia requiring emergency assistance from health service personnel is as common in people with type 2 diabetes treated with insulin as in people with type 1 diabetes. It is associated with considerable NHS resource use that has a significant economic and personal cost.
Increasing Physical Activity in People With Type 2 Diabetes
Authors: Kirk Alison , Mutrie Nanette , MacIntyre Paul , Fisher Miles
Published: March 2007

OBJECTIVE—To evaluate effect of exercise consultation on physical activity and resultant physiological and biochemical variables at 6 months in people with type 2 diabetes.

RESEARCH DESIGN AND METHODS—A total of 70 inactive people with type 2 diabetes were given standard exercise information and were randomized to receive an exercise consultation (n = 35) or not (n = 35). Exercise consultation, based on the transtheoretical model, combines motivational theory and cognitive behavioral strategies into an individualized intervention to promote physical activity. Changes from baseline to 6 months were assessed in 1) physical activity (7-day recall, accelerometer, cardiorespiratory fitness, stage, and processes of change), 2) physiological variables (blood pressure and BMI), and 3) biochemical variables (HbA1c, lipid profile, and fibrinogen).

RESULTS—Between-group differences were recorded for the change in minutes of moderate activity (P < 0.001) and activity counts (P < 0.001) per week. Experimental participants recorded an increase in activity counts per week and minutes of moderate activity per week (P < 0.001). The control group recorded no significant changes. More experimental participants increased stage of change (χ2 = 22.6, P < 0.001). Between-group differences were recorded for the change in total exercise duration and peak gradient (P < 0.005), HbA1c (P = 0.02), systolic BP (P = 0.02), and fibrinogen (P = 0.03).

CONCLUSIONS—Exercise consultation increased physical activity and improved glycemic control and cardiovascular risk factors in people with type 2 diabetes.
Do All Prepubertal Years of Diabetes Duration Contribute Equally to Diabetes Complications?
Authors: Donaghue Kim C. , Fairchild Jan M. , Craig Maria E. , Chan Albert K. , Hing Stephen , Cutler Lucy R. , Howard Neville J. , Silink Martin
Published: March 2007

OBJECTIVE—This study was designed to explore the timeline of protection against complications in prepubertal children with diabetes, in particular the effects of diabetes duration before age 5 years.

RESEARCH DESIGN AND METHODS—In this study, 193 adolescents with prepubertal diabetes onset were followed longitudinally for retinopathy (early background and clinical) and microalbuminuria (albumin excretion rate >7.5 μg/min and >20 μg/min). Multiple logistic regression analysis was used to compare the effect of pre- and postpubertal diabetes duration on the risk of each complication in 90 subjects reassessed as young adults. For the entire cohort, Kaplan-Meier estimates were used to determine time free of each complication, and survival was compared in those diagnosed before and after age 5 years. Accelerated failure time modeling was used to estimate the effect of covariates, including diabetes duration before puberty, on the risk of complications.

RESULTS—Prepubertal duration improved the prediction for retinopathy over postpubertal duration alone in the young adults. The survival-free period of retinopathy and microalbuminuria was significantly longer (2–4 years) for those diagnosed before age 5 years compared with those diagnosed after age 5 years. Time to onset of all complications increased progressively with longer diabetes duration before gonadarche. Higher HbA1c during adolescence had an independent effect on the risk of retinopathy and microalbuminuria.

CONCLUSIONS—Prepubertal diabetes duration remains a significant predictor of retinopathy in young adults. The effect of time on the risk of retinopathy and microalbuminuria is nonuniform, with an increasing delay in the onset of complications in those with longer prepubertal duration. These findings are of major clinical importance when setting targets of glycemic control in young children who are at greatest risk of hypoglycemia.
Insulin Resistance, Inflammation, and Serum Fatty Acid Composition
Authors: Fernández-Real José-Manuel , Broch Montserrat , Vendrell Joan , Ricart Wifredo
Published: March 2007

OBJECTIVE—Fatty acids (FAs) have been involved in the development of chronic inflammatory conditions such as insulin resistance and obesity. However, the relation among insulin resistance, obesity, inflammatory activity (circulating interleukin [IL]-6) and dietary FAs has been scarcely studied in otherwise healthy subjects.

RESEARCH DESIGN AND METHODS—We aimed to study these interactions in 123 overweight (BMI 26.9 ± 2.4 kg/m2 [means ± SD]) subjects and 109 lean (BMI 21.7 ± 1.7 kg/m2, P < 0.000001) subjects. IL-6 was measured by immunoassay and FA by gas liquid cromatography.

RESULTS—The percentage of saturated FAs (r = 0.30, P = 0.01) and ω-6 FAs (r = −0.32, P = 0.001) were significantly associated with circulating IL-6, whereas the percentage of ω-3 FAs correlated negatively with C-reactive protein in overweight subjects (P = 0.04). Saturated-to-ω-3 and saturated-to-ω-6 FA ratios were significantly and positively associated with C-reactive protein (P < 0.0001) and IL-6 (P < 0.001), respectively. In contrast, none of these associations reached statistical significance in lean subjects. Those subjects in the most insulin-sensitive quintile (homeostasis model assessment value) showed a significantly higher percentage of linoleic acid (C18:2 ϖ6) (P = 0.03) and a significantly lower level of araquidic (C20:0) (P = 0.04), behenic (C22:0) (P = 0.009), lignoceric (C24:0) (P = 0.02), and nervonic (C24:1 ϖ9) (P = 0.001) FAs than the remaining subjects. In parallel, the most insulin-sensitive subjects showed significantly decreased C-reactive protein (P = 0.03). Serum C-reactive protein was significantly associated with percent linoleic acid and eicosapentaenoic acid in nonsmoking men (P = 0.03 and P = 0.04, respectively) and with docosahexaenoic acid in nonsmoking women (r = −0.46, P < 0.0001). We constructed a multivariant regression analysis to predict circulating IL-6. Age, BMI, waist-to-hip ratio (WHR), smoking status, and the relation of saturated to ω-6 or saturated to ω-3 FAs were considered as independent variables separately in men and women. In overweight men, the ratio of saturated to ω-3 FAs (P = 0.01), but not age, sex, BMI, WHR, or smoking status, independently contributed to 17% of IL-6 variance. In lean men, smoking status (P = 0.02), but not the remaining variables, contributed to 8% of IL-6 variance.

CONCLUSIONS—Dietary FAs (as inferred from plasma FA concentration) seem to be linked to inflammatory activity in overweight subjects and in subjects with insulin resistance. Being overweight modulates the relation of FAs to inflammatory markers.