bluuebunny/crossref_metadata_2025 huggingface dataset:
Diabetes and Incidence of Functional Disability in Older Women
Authors: Gregg Edward W. , Mangione Carol M. , Cauley Jane A. , Thompson Theodore J. , Schwartz Ann V. , Ensrud Kristine E. , Nevitt Michael C. ,   for the Study of Osteoporotic Fractures Research Group
Published: March 2007

OBJECTIVE—To examine the relationship between diabetes and the incidence of functional disability and to determine the predictors of functional disability among older women with diabetes.

RESEARCH DESIGN AND METHODS—We analyzed data from 8,344 women enrolled in the Study of Osteoporotic Fractures, a prospective cohort of women aged ≥65 years. Diabetes (n = 527, 6.3% prevalence) and comorbidities (coronary heart disease, stroke, arthritis, depression, and visual impairment) were assessed by questionnaire and physical examination. Incident disability, defined as onset of inability to do one or more major functional tasks (walking 0.25 mile, climbing 10 steps, performing household chores, shopping, and cooking meals), was assessed by questionnaire over 12 years.

RESULTS—The yearly incidence of any functional disability was 9.8% among women with diabetes and 4.8% among women without diabetes. The age-adjusted hazard rate ratio (HRR) of disability for specific tasks associated with diabetes ranged from 2.12 (1.82–2.48) for doing housework to 2.50 (2.05–3.04) for walking two to three blocks. After adjustment for potential confounders at baseline (BMI, physical activity, estrogen use, baseline functional status, visual impairment, and marital status) and comorbidities (heart disease, stroke, depression, and arthritis), diabetes remained associated with a 42% increased risk of any incident disability and a 53–98% increased risk of disability for specific tasks. Among women with diabetes, older age, higher BMI, coronary heart disease, arthritis, physical inactivity, and severe visual impairment at baseline were each independently associated with disability.

CONCLUSIONS—Diabetes is associated with an increased incidence of functional disability, which is likely to further erode health status and quality of life.
The Impact of Outpatient Diabetes Management on Serum Lipids in Urban African-Americans With Type 2 Diabetes
Authors: Erdman Diane M. , Cook Curtiss B. , Greenlund Kurt J. , Giles Wayne H. , El-Kebbi Imad , Ryan Gina J. , Gallina Daniel L. , Ziemer David C. , Dunbar Virginia G. , Phillips Lawrence S.
Published: March 2007

OBJECTIVE—Treating dyslipidemia in diabetic patients is essential, particularly among minority populations with increased risk of complications. Because little is known about the impact of outpatient diabetes management on lipid outcomes, we examined changes in lipid profiles in urban African-Americans who attended a structured diabetes care program.

RESEARCH DESIGN AND METHODS—A retrospective analysis of initial and 1-year follow-up lipid values was conducted among patients selected from a computerized registry of an urban outpatient diabetes clinic. The independent effects of lipid-specific medications, glycemic control, and weight loss on serum total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels were evaluated by analysis of covariance and multiple linear regression.

RESULTS—In 345 patients (91% African-American and 95% with type 2 diabetes), HbA1c decreased from 9.3% at the initial visit to 8.2% at 1 year (P < 0.001); total and LDL cholesterol and triglyceride levels were significantly lower, and HDL cholesterol was higher. After stratifying based on use of lipid-specific therapy, different outcomes were observed. In 243 patients not taking dyslipidemia medications, average total cholesterol, LDL cholesterol, and triglyceride concentrations at 1 year were similar to initial values, whereas in 102 patients receiving pharmacotherapy, these lipid levels were all lower at 1 year relative to baseline (P < 0.001). Mean HDL cholesterol increased regardless of lipid treatment status (P < 0.001). After adjusting for other variables, changes in LDL cholesterol concentration were associated only with use of lipid-specific agents (P = 0.003), whereas improved HbA1c and weight loss had no independent effect. Lipid therapy, improved glycemic control, and weight loss were not independently related to changes in HDL cholesterol and therefore could not account for the positive changes observed. Use of lipid-directed medications, improvement in glycemic control, and weight loss all resulted in significant declines in triglyceride levels but only improved HbA1c and weight loss had an independent effect.

CONCLUSIONS—Among urban African-Americans, diabetes management led to favorable changes in HDL cholesterol and triglyceride levels, but improved glycemic control and weight loss had no independent effect on LDL cholesterol concentration. Initiation of pharmacologic therapy to treat high LDL cholesterol levels should be considered early in the course of diabetes management to reach recommended targets and reduce the risk of cardiovascular complications in this patient population.
Hormone Replacement Therapy and Its Relationship to Lipid and Glucose Metabolism in Diabetic and Nondiabetic Postmenopausal Women
Authors: Crespo Carlos J. , Smit Ellen , Snelling Anastacia , Sempos Christopher T. , Andersen Ross E.
Published: March 2007

OBJECTIVE—Among postmenopausal women, those with diabetes experience more cardiovascular diseases than those without diabetes. We examine the relationship of hormone replacement therapy (HRT) with indicators of lipid and glucose metabolism using a national sample of diabetic and nondiabetic postmenopausal women.

RESEARCH DESIGN AND METHODS—We used data from the Third National Health and Nutrition Examination Survey, conducted from 1988 to 1994. A total of 2,786 postmenopausal women aged 40–74 years participated in an oral glucose tolerance test, had blood drawn for lipid assessment, and responded to HRT questions.

RESULTS—Our results show that postmenopausal women with diabetes had increased dyslipidemia compared with nondiabetic women. Among diabetic women, current users of HRT had significant different lipid and glucose control levels than never users of HRT for the following variables: total cholesterol (225 vs. 241 mg/dl), non-HDL (169 vs. 188 mg/dl), apoA (171 vs. 147 mg/dl), fibrinogen (306 vs. 342 mg/dl), glucose (112 vs. 154 mg/dl), insulin (16.81 vs. 22.6 uU/ml), and GHb (6.03 vs. 7.13 mg/dl).

CONCLUSIONS—Diabetic and nondiabetic postmenopausal women currently taking HRT had better lipoprotein profile than never or previous users of HRT. Diabetic women currently taking HRT had better glycemic control than never or previous users of HRT.
Diabetes and Impaired Glucose Tolerance Among the Inuit Population of Greenland
Authors: Jørgensen Marit E. , Bjeregaard Peter , Borch-Johnsen Knut , Backer Vibeke , Becker Ulrik , Jørgensen Torben , Mulvad Gert
Published: March 2007

OBJECTIVE—To assess the prevalence of diabetes and impaired glucose tolerance (IGT) among the Inuit population of Greenland and to determine risk factors for developing glucose intolerance.

RESEARCH DESIGN AND METHODS—This cross-sectional study included 917 randomly selected adult Inuit subjects living in three areas of Greenland. Diabetes and IGT were diagnosed using the oral glucose tolerance test. BMI and waist-to-hip ratio were measured and blood samples were taken from each subject. Sociodemographic characteristics were investigated using a questionnaire.

RESULTS—The age-standardized prevalences of diabetes and IGT were 10.8 and 9.4% among men and 8.8 and 14.1% among women, respectively. Of those with diabetes, 70% had not been previously diagnosed. Significant risk factors for diabetes were family history of diabetes, age, BMI, and high alcohol consumption, whereas frequent intake of fresh fruit and seal meat were inversely associated with diabetic status. Age, BMI, family history of diabetes, sedentary lifestyle, and place of residence were significant predictors of IGT.

CONCLUSIONS—The prevalence of diabetes is high among the Inuit of Greenland. Heredity was a major factor, while obesity and diet were important environmental factors. The high proportion of unknown cases suggests a need for increased diabetes awareness in Greenland.
Diabetes and the Risk of Acute Urinary Tract Infection Among Postmenopausal Women
Authors: Boyko Edward J. , Fihn Stephan D. , Scholes Delia , Chen Chi-Ling , Normand Esther H. , Yarbro Patricia
Published: March 2007

OBJECTIVE—To examine whether the presence of diabetes alters the risk of acute urinary tract infection (UTI) in postmenopausal women.

RESEARCH DESIGN AND METHODS—A case-control study of the Group Health Cooperative of Puget Sound (GHC), a staff-model nonprofit health maintenance organization in Washington State, was conducted. Subjects were women aged 55–75 years who had been members of GHC for at least 1 year and who had had an acute symptomatic UTI within the preceding month. Laboratory files were used to identify women with a urine culture that grew ≥105 colonies of a urinary pathogen. Medical records were reviewed to confirm the presence of acute, clinically symptomatic UTI. Control subjects were randomly selected from the GHC enrollment file, screened to remove women with recent UTI, and frequency matched to cases by age within 2 years. An interviewer ascertained self-reported clinician-diagnosed diabetes. Diagnosis of diabetes was confirmed by the GHC diabetes registry. A subsample of women underwent measurement of postvoid residual bladder volume (n = 748) and culture of vaginal flora (n = 454).

RESULTS—Of the 901 case and 913 control subjects, diabetes was reported in 13.1 and 6.8%, respectively. The health plan diabetes registry confirmed the diagnosis in 92% of women who self-reported the condition. The age-adjusted odds ratio (OR) for UTI in relation to self-reported clinician-diagnosed diabetes was 2.2 (95% CI 1.6–3.0). Adjustment for frequency of sexual intercourse and history of UTI had little effect on this estimate. Compared with nondiabetic women, higher UTI odds were seen in subjects who used oral hypoglycemic agents (OR 2.9 [95% CI 1.7–5.1]) and insulin (2.6 [1.5–4.6]) but not in subjects with untreated diabetes or diabetes treated by lifestyle changes (1.3 [0.7–2.3]). No significant difference was seen in the OR for UTI in diabetic women with disease of shorter duration (<10 years, OR 1.9) or longer duration (≥10 years, OR 2.6) or in relation to HbA1c level. Similar microbiologic pathogens were seen in diabetic and nondiabetic women. No significant differences were seen by diabetes status in mean postvoid residual bladder volume or vaginal flora.

CONCLUSIONS—Diabetes under pharmacologic treatment is associated with increased risk of clinically apparent UTI in postmenopausal women.
Diabetic Neuropathic Foot Ulcers
Authors: Margolis David J. , Allen-Taylor Lynne , Hoffstad Ole , Berlin Jesse A.
Published: March 2007

OBJECTIVE—The goal of this study was to evaluate whether simple risk factors can be identified that successfully characterize who will heal and who will not heal among patients who have received standard therapy for diabetic neuropathic foot ulcers.

RESEARCH DESIGN AND METHODS—For this cohort study, we evaluated >31,000 individuals with a diabetic neuropathic foot ulcer seen in the Curative Health Services System. Using multivariate logistic regression, we evaluated the association between wound size, wound duration, wound grade, and other variables and their effect on whether a patient would heal by the 20th week of care.

RESULTS—We demonstrated that wound size, wound duration, and wound grade are all significantly associated with the likelihood of a wound healing by the 20th week of care. In addition, we noted that these associations were not significantly affected by the treating wound care center, whether the unit of analysis was one wound on a patient or all of their wounds, or current adjuvant therapies.

CONCLUSIONS—We have shown that three easy-to-measure risk factors are associated with a wound healing. These results should help clinicians understand the likelihood that a wound will heal and help those conducting clinical investigations to design better trials.
Small Bowel Motility Affects Glucose Absorption in a Healthy Man
Authors: Schwartz Matthijs P. , Samsom Melvin , Renooij Willem , van Steenderen Leo W. , Benninga Marc A. , van Geenen Erwin-Jan M. , van Herwaarden Margot A. , de Smet Martin B.M. , Smout André J.P.M.
Published: March 2007

OBJECTIVE—To investigate the relationship between duodenojejunal motor activity and glucose absorption and to evaluate the effect of modification of duodenojejunal motility on glucose absorption by using the prokinetic drug cisapride.

RESEARCH DESIGN AND METHODS—We examined seven healthy males, mean age 22 years, who were treated with cisapride 10 mg t.i.d. and placebo during 3 days in a randomized order, with a 2-week time interval. Duodenojejunal manometry was performed after each treatment on the morning of day 3, using an 18-lumen catheter. A liquid nutrient (3 kcal/min) was administered intraduodenally for 30 min, followed by a bolus of the glucose analog 3-O-methylglucose (3-OMG). Plasma 3-OMG concentrations were measured to assess absorption kinetics.

RESULTS—The area under the 3-OMG concentration curve in the first 30 min after infusion was related to the number of antegrade propagated pressure waves (r = 0.49, P < 0.05), but not to the peak concentration, time to peak, and absorption fraction. The mean amplitude of pressure waves was higher during cisapride than placebo (P < 0.05), but the reoccurrence of interdigestive motility, numbers of pressure waves, and propagated pressure waves, as well as 3-OMG absorption characteristics, were not significantly different between the two treatments. During both treatments >60% of antegrade propagated pressure waves were propagated over a very short distance (1.5 cm).

CONCLUSIONS—Glucose absorption in the human small intestine is related to short-traveling propagated intestinal contractile activity. Cisapride increases the amplitude of pressure waves, but does not affect the organization of pressure waves or the absorption of 3-OMG.
Effects of Vitamin E on Cardiovascular and Microvascular Outcomes in High-Risk Patients With Diabetes
Authors: Lonn Eva , Yusuf Salim , Hoogwerf Byrcon , Pogue Janice , Yi Qilong , Zinman Bernard , Bosch Jackie , Dagenais Gilles , Mann Johannes F.E. , Gerstein Hertzel C. ,   on behalf of the Heart Outcomes Prevention Evaluation (HOPE) Investigators
Published: March 2007

OBJECTIVES—Experimental and observational studies suggest that vitamin E may reduce the risk of cardiovascular (CV) events and of microvascular complications in people with diabetes. However, data from randomized clinical trials are limited. Therefore, we evaluated the effects of vitamin E supplementation on major CV outcomes and on the development of nephropathy in people with diabetes.

RESEARCH DESIGN AND METHODS—The Heart Outcomes Prevention Evaluation (HOPE) trial is a randomized clinical trial with a 2 × 2 factorial design, which evaluated the effects of vitamin E and of ramipril in patients at high risk for CV events. Patients were eligible for the study if they were 55 years or older and if they had CV disease or diabetes with at least one additional coronary risk factor. The study was designed to recruit a large number of people with diabetes, and the analyses of the effects of vitamin E in this group were preplanned. Patients were randomly allocated to daily treatment with 400 IU vitamin E and with 10 mg ramipril or their respective placebos and were followed for an average of 4.5 years. The primary study outcome was the composite of myocardial infarction, stroke, or CV death. Secondary outcomes included total mortality, hospitalizations for heart failure, hospitalizations for unstable angina, revascularizations, and overt nephropathy.

RESULTS—There were 3,654 people with diabetes. Vitamin E had a neutral effect on the primary study outcome (relative risk = 1.03, 95% CI 0.88–1.21; P = 0.70), on each component of the composite primary outcome, and on all predefined secondary outcomes.

CONCLUSIONS—The daily administration of 400 IU vitamin E for an average of 4.5 years to middle-aged and elderly people with diabetes and CV disease and/or additional coronary risk factor(s) has no effect on CV outcomes or nephropathy.
Acute Effect of Glimepiride on Insulin-Stimulated Glucose Metabolism in Glucose-Tolerant Insulin-Resistant Offspring of Patients With Type 2 Diabetes
Authors: Overkamp Dietrich , Volk Annette , Maerker Elke , Heide Peter E. , Wahl Hans G. , Rett Kristian , Häring Hans U.
Published: March 2007

OBJECTIVE—This study addressed whether acute infusion of glimepiride influences glucose metabolism independent of its effect on insulin secretion.

RESEARCH DESIGN AND METHODS—Ten healthy, glucose-tolerant but insulin-resistant probands were subjected to a placebo-controlled, double-blind, cross-over study. Each individual received infusions of either 0.15 mol/l saline or glimepiride in randomized order on two separate occasions. A three-step hyperinsulinemic (0.5, 1.0, and 1.5 mU · kg−1 · min−1)-euglycemic glucose clamp was performed on both occasions to determine insulin sensitivity. Glimepiride-induced insulin secretion was inhibited by octreotide. Endogenous glucose production and glucose elimination were measured with the “hot” glucose infusion method using U-[13C]glucose as tracer. Glucose oxidation was determined from indirect calorimetry. Lipolysis was evaluated by measurements of nonesterified fatty acid (NEFA) and glycerol concentration and measurement of glycerol production.

RESULTS—Plasma glucose and insulin concentrations were not significantly different between glimepiride or saline infusions. There was a significant increase in the rate of glucose infusion necessary to maintain euglycemia during infusion of glimepiride during the low- (12.2 ± 1.1 vs. 16.1 ± 1.7 μmol · kg−1· min−1) and intermediate-dose insulin infusion (24.4 ± 1.7 vs. 30.0 ± 2.8 μmol · kg−1 · min−1). This was explained by an increased rate of glucose elimination and to a lesser degree by a decrease in glucose production. Glucose oxidation rate was not different. NEFA and glycerol concentration and glycerol production were equally suppressed.

CONCLUSIONS—Glimepiride improves peripheral glucose uptake and decreases endogenous glucose production independent of its insulin secretagogue action. The effects shown in this acute study are, however, too small to be considered therapeutically beneficial for the individual patient.
Bimodality in Blood Glucose Distribution
Authors: Lim Teck-Onn , Bakri Rugayah , Morad Zaki , Hamid Maimunah A.
Published: March 2007

OBJECTIVE—Bimodality in blood glucose (BG) distribution has been demonstrated in several populations with a high prevalence of diabetes and obesity. However, other population studies had not found bimodality, thus casting doubt on its universality. We address this question in four ethnic populations—namely Malay, Chinese, Indian, and the indigenous people of Borneo.

RESEARCH DESIGN AND METHODS—A national health survey was conducted in Malaysia in 1996. A total of 18,397 subjects aged ≥30 years had post-challenge BG measurements taken. To test whether BG was consistent with a bimodal distribution, we fitted unimodal normal and skewed distribution as well a mixture of two normal distributions to the data by age and ethnic groups.

RESULTS—Age-specific prevalence of diabetes varied from 1.3 to 26.3%. In all ethnic/age groups, the bimodal model fitted the log BG data better (likelihood ratio tests, all P values <0.001).

CONCLUSIONS—Bimodality in BG distribution is demonstrable even in populations with a very low prevalence of diabetes and obesity. Previous studies that found unimodality had failed to detect the second mode because of inadequate sample size, bias due to treatment of subjects with known diabetes, and inclusion of subjects with type 1 diabetes in the sample. Bimodality implies that diabetes is a distinct entity rather than an arbitrarily defined extreme end of a continuously distributed measurement.
Reduction of Blood Glucose Variability in Type 1 Diabetic Patients Treated By Pancreatic Islet Transplantation
Authors: Kessler Laurence , Passemard Raphael , Oberholzer Jose , Benhamou Pierre Yves , Bucher Pascal , Toso Christian , Meyer Pierre , Penfornis Alfred , Badet Lionel , Wolf Philippe , Colin Cyrille , Morel Philippe , Pinget Michel ,   on behalf of the GRAGIL Group
Published: March 2007

OBJECTIVE—To compare the glycemic profiles of patients with type 1 diabetes treated with either an implantable insulin pump or pancreas or islet transplantation by the means of the continuous glucose monitoring system (CGMS; Minimed, Sylmar, CA).

RESEARCH DESIGN AND METHODS—The CGMS enabled recording of subcutaneous glucose concentrations (range 2.2–22 mmol/l) over 72 h (288 measurements per day). Over 3 days, 26 patients with type 1 diabetes were connected to a CGMS: 10 patients were treated with intraperitoneal insulin infusion through an implantable pump (IPII), 9 patients were treated with simultaneous pancreas-kidney transplantation (SPK), and 7 patients were treated with pancreatic islet transplantation after kidney grafting (IAK). All SPK patients and four IAK patients were insulin independent, whereas three IAK patients had partial graft function and reduced exogenous insulin needs. Glucose control was evaluated by the mean glucose concentration, glucose variability, and the number and duration of hypoglycemic events (<3.3 mmol/l) over 3 days.

RESULTS—The mean glucose concentration and the glucose variability in SPK and IAK patients were significantly lower than those observed in patients treated with IPII: 5.38 ± 1.12 and 5.83 ± 0.81 vs. 7.81 ± 1.55 mmol/l (P < 0.001) and 1.40 ± 0.42 and 1.32 ± 0.53 vs. 3.47 ± 1.66 mmol/l (P < 0.001), respectively. Furthermore, the mean glucose concentration and the glucose variability were comparable between SPK and IAK patients. Over 3 days, no hypoglycemic events were observed in SPK patients and insulin-independent IAK patients. A total of 4.12 ± 1.66 hypoglycemic events were detected in the IPII patient group, whereas only 0.66 ± 0.57 events were observed in IAK patients with partial graft function (P < 0.001). The duration of the hypoglycemic events was significantly longer in IPII patients as compared with IAK patients: 64 ± 33 vs. 30 ± 15 min for the day period and 130 ± 62 vs. 30 ± 27 min for the night period (P < 0.001).

CONCLUSIONS—Use of subcutaneous CGMS confirms that islet transplantation can be as efficient as pancreas transplantation in restoring good metabolic control and reducing blood glucose variability. Metabolic improvement due to use of an implantable insulin pump requires insulin delivery by a closed loop.
Effects of Energy-Restricted Diets Containing Increased Protein on Weight Loss, Resting Energy Expenditure, and the Thermic Effect of Feeding in Type 2 Diabetes
Authors: Luscombe N.D. , Clifton P.M. , Noakes M. , Parker B. , Wittert G.
Published: March 2007

OBJECTIVE—To determine the effect of a high-protein (HP) diet compared with a low-protein (LP) diet on weight loss, resting energy expenditure (REE), and the thermic effect of food (TEF) in subjects with type 2 diabetes during moderate energy restriction.

RESEARCH DESIGN AND METHODS—In this study, 26 obese subjects with type 2 diabetes consumed a HP (28% protein, 42% carbohydrate) or LP diet (16% protein, 55% carbohydrate) during 8 weeks of energy restriction (1,600 kcal/day) and 4 weeks of energy balance. Body weight and composition and REE were measured, and the TEF in response to a HP or LP meal was determined for 2 h, at weeks 0 and 12.

RESULTS—The mean weight loss was 4.6 ± 0.4 kg (P < 0.001), of which 4.5 ± 0.4 kg was fat (P < 0.001), with no effect of diet (P = 0.6). At both weeks 0 and 12, TEF was greater after the HP than after the LP meal (0.064 vs. 0.050 kcal · kcal−1 energy consumed · 2 h−1, respectively; overall diet effect, P = 0.003). REE and TEF were reduced similarly with each of the diets (time effects, P = 0.02 and P < 0.001, respectively).

CONCLUSIONS—In patients with type 2 diabetes, a low-fat diet with an increased protein-to-carbohydrate ratio does not significantly increase weight loss or blunt the fall in REE.
Morning Hyperglycemic Excursions
Authors: Monnier Louis , Colette Claude , Rabasa-Lhoret Rémy , Lapinski Hélène , Caubel Cécile , Avignon Antoine , Boniface Hélène
Published: March 2007

OBJECTIVE—To determine whether, over daytime, one or several hyperglycemic excursions exist that can be general failures in the glycemic control of patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS—In 200 non–insulin-using patients with type 2 diabetes, diurnal plasma glucose and insulin profiles were studied. Plasma glucose concentrations were measured after an overnight fast (at 8:00 a.m. immediately before breakfast), during the postprandial period (at 11:00 a.m. and 2:00 p.m.), and during the postabsorptive period (at 5:00 p.m., extended postlunch time).

RESULTS—In the population considered as a whole, prelunch glucose concentrations (12.0 mmol/l) were found to be significantly increased (P < 0.0001) when compared with those observed at 8:00 a.m. (8.8 mmol/l), at 2:00 p.m. (10.5 mmol/l), and at 5:00 p.m. (8.6 mmol/l). Similar significant excursions (P < 0.0001) in prelunch glucose were observed within subsets of patients selected from the following criteria: 1) body weight, 2) HbA1c, 3) categories of treatment, and 4) residual β-cell function. From the calculation of areas under the daytime glucose curves, the relative contributions of postprandial and fasting glucose to the total glucose increment were found to be similar.

CONCLUSIONS—High plasma glucose excursions over morning periods seem to be a permanent failure in non–insulin-using patients with type 2 diabetes, whatever the clinical (BMI), biological (HbA1c), therapeutic, and pathophysiological (residual β-cell function) status. Midmorning glucose testing should be recommended for detecting such abnormalities and for correcting them with appropriate therapies.
Immune Responses to Insulin Aspart and Biphasic Insulin Aspart in People With Type 1 and Type 2 Diabetes
Authors: Lindholm Anders , Jensen Lisbeth B. , Home Philip D. , Raskin Philip , Boehm Bernhard O. , Råstam Jacob ,   for the European and North American Study Groups on Insulin Aspart
Published: March 2007

OBJECTIVE—The antibody responses to a novel rapid-acting insulin analog, insulin aspart (IAsp), and their potential clinical correlates were studied with a specifically developed method in 2,420 people with diabetes treated for up to 1 year with preprandial subcutaneous injections of IAsp.

RESEARCH DESIGN AND METHODS—Circulating insulin antibodies were analyzed by radioimmunoassay with 125I insulin or IAsp tracers and polyethylene glycol precipitation. Four multinational, open, parallel group studies were conducted in Europe and North America, with a total of 1,534 people with diabetes exposed to IAsp and 886 people exposed to human insulin (HI) as meal-related insulin for 6–12 months.

RESULTS—Insulin antibodies specific to HI or IAsp were absent in a majority of patients throughout the 6- to 12-month study periods. A majority of the patients (64–68%) had antibodies cross-reacting between HI and IAsp when entering the studies, with baseline levels (means ± SD of percent bound/total) of 16.6 ± 16.3% in study 1 and 10.3 ± 14.0% in study 4. In all four studies, cross-reactive antibodies increased in patients exposed to IAsp, with a maximum at 3 months, and thereafter there was a decline toward baseline levels at 9–12 months (levels at 3 and 12 months: 22.3 ± 19.7 and 16.8 ± 16.5% in study 1 and 21.5 ± 21.9 and 16.9 ± 17.4% in study 4). Antibody levels showed similar changes in people with type 1 and type 2 diabetes, and there was no consistent relationship between antibody formation and glycemic control or between antibody formation and safety in terms of adverse events.

CONCLUSIONS—Treatment with IAsp is associated with an increase in cross-reactive insulin antibodies, with a subsequent fall toward baseline values, without any indication of clinical relevance because no effect on efficacy or safety could be identified.
Oral Contraceptive Use and Association With Glucose, Insulin, and Diabetes in Young Adult Women
Authors: Kim Catherine , Siscovick David S. , Sidney Stephen , Lewis Cora E. , Kiefe Catarina I. , Koepsell Thomas D.
Published: March 2007

OBJECTIVE— We studied the associations between 1) current use of oral contraceptives (OCs) and 2) glucose levels, insulin levels, and diabetes in young women.

RESEARCH DESIGN AND METHODS—Subjects were women (n = 1,940) in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective observational study of African-Americans and whites aged 18–30 years at enrollment in 1985–1986. We analyzed the cross-sectional associations between 1) current use of OCs and 2) fasting glucose, fasting insulin, and presence of diabetes using generalized estimating equations to adjust for repeated measures. We also examined the effect of current use of OCs on incident diabetes at year 10 of the study.

RESULTS—In unadjusted analyses, current use was associated with lower fasting glucose levels [–3.1 mg/dl, 95% CI (−3.7, −2.5)] and reduction in the odds of diabetes [odds ratio 0.56 (0.32, 0.97)], but not lower fasting insulin levels [−0.01 μU/ml (−0.03, 0.02)], compared with nonuse in both African-American and white women. After adjustment for covariates, current use of OCs was still associated with lower fasting glucose levels [–1.8 mg/dl (−2.4, –1.3)] and lower odds of diabetes [odds ratio 0.56 (0.33, 0.95)], although the associations were attenuated. After adjustment, current use of OCs was associated with higher insulin levels [0.12 μU/ml (0.006, 0.23)]. No association existed between pattern of use of OCs and incident diabetes at year 10, although the total number of new persons with diabetes at year 10 was small (n = 17).

CONCLUSIONS—Current use of OCs is associated with lower glucose levels in young African-American and white women and may be associated with lower odds of diabetes.
Clinical Efficacy of Orlistat Therapy in Overweight and Obese Patients With Insulin-Treated Type 2 Diabetes
Authors: Kelley David E. , Bray George A. , Pi-Sunyer F. Xavier , Klein Samuel , Hill James , Miles John , Hollander Priscilla
Published: March 2007

OBJECTIVE—Weight loss improves glycemic control, lipid profiles, and blood pressure in patients with type 2 diabetes. However, successful long-term weight loss is difficult for these patients, particularly those treated with insulin. The aim of this study was to assess the effect of orlistat, a gastrointestinal lipase inhibitor, on weight loss, glycemic control, and cardiovascular risk factors in overweight or obese insulin-treated type 2 diabetic patients.

RESEARCH DESIGN AND METHODS—This study was a 1-year multicenter, randomized, double-blind, placebo-controlled trial of orlistat (120 mg three times a day) or placebo combined with a reduced-calorie diet in overweight or obese adults (BMI 28–40 kg/m2) with type 2 diabetes treated with insulin alone or combined with oral agents, but with suboptimal metabolic control (HbA1c 7.5–12.0%). Outcome measurements included changes in body weight, glycemic control, blood pressure, and serum lipids.

RESULTS—After 1 year, the orlistat group lost significantly more weight (−3.89 ± 0.3% of baseline body weight, means ± SE) than the placebo group (−1.27 ± 0.3%, P < 0.001). Orlistat treatment, compared with placebo, produced greater decreases in HbA1c (−0.62 ± 0.08 vs. −0.27 ± 0.08%, P = 0.002), fasting serum glucose (−1.63 ± 0.3 vs. −1.08 ± 0.3 mmol/l, P = 0.02), and the required doses of insulin and other diabetic medications. Orlistat also produced greater improvements than placebo in serum total cholesterol (P = 0.0002) and LDL cholesterol concentrations (P = 0.001) and LDL/HDL ratio (P = 0.01).

CONCLUSIONS—Orlistat therapy produces clinically significant weight loss, with improvements in glycemic control and cardiovascular disease risk factors, in overweight or obese patients with type 2 diabetes who have suboptimal metabolic control with insulin therapy.
Elimination of Dietary Gluten Does Not Reduce Titers of Type 1 Diabetes-Associated Autoantibodies in High-Risk Subjects
Authors: Hummel Michael , Bonifacio Ezio , Naserke Heike E. , Ziegler Anette G.
Published: March 2007

OBJECTIVE—Removal of the dietary wheat protein gluten protects against autoimmune diabetes in animal models. Furthermore, elimination of dietary gluten reduces the frequency of type 1 diabetes in patients with celiac disease. Herein we test the hypothesis that gluten is the driving antigen for type 1 diabetes-associated islet autoimmunity.

RESEARCH DESIGN AND METHODS—Seven autoantibody-positive, first-degree relatives of patients with type 1 diabetes were placed on a gluten-free diet for 12 months followed by gluten reexposure for 12 months. Gliadin antibodies as well as the diabetes-related antibodies insulin autoantibody (IAA), GAD antibody (GADA), and tyrosin phosphatase IA2 antibody (IA-2A) were measured every 3 months; oral glucose tolerance tests were performed every 6 months. Changes in autoantibody titers were compared with those observed in a matched historical cohort.

RESULTS—A reduction in IgG gliadin antibody titers was observed during the gluten-free period, but titers of diabetes-associated autoantibodies changed independently of gluten exposure. Type 1 diabetes-associated islet autoantibody levels at the end of the gluten-free diet period were not significantly different from those before commencement of the diet (P = 0.2) or at the end of the gluten reexposure period (P = 0.4). Changes in individual subjects were identified, but no differences were noted between the gluten-free and the gluten re-exposure periods, and the changes were similar to those observed in the historical control cohort (P = 1.0). Major titer reductions (>50%) in the gluten-free period were observed in only one subject for all antibodies. Type 1 diabetes developed in this subject and in a second subject during the gluten reexposure period.

CONCLUSIONS—The findings do not support the hypothesis that gluten is a driving antigen in type 1 diabetes.
A Longitudinal Study of the Effects of a Gluten-Free Diet on Glycemic Control and Weight Gain in Subjects With Type 1 Diabetes and Celiac Disease
Authors: Amin Rakesh , Murphy Nuala , Edge Julie , Ahmed Marion L. , Acerini Carlo L. , Dunger David B.
Published: March 2007

OBJECTIVE—To describe the longitudinal growth characteristics and glycemic control in type 1 diabetic children diagnosed with celiac disease and started on a gluten-free diet (GFD).

RESEARCH DESIGN AND METHODS—Data on growth and glycemic control for 11 case subjects diagnosed with celiac disease (cd+ group) and started on a GFD were collected prospectively, and two control subjects without celiac disease matched for age, sex, and duration of diabetes (cd− group) were selected for comparison.

RESULTS—In the period between diagnosis of type 1 diabetes and start of a GFD in the cd+ compared with the cd− group, BMI standard deviation score (SDS) was lower (–0.2 vs. 0.7, P = 0.015), as was HbA1c (8.9 vs. 9.8%, P = 0.002). In a regression model the cd+ group had lower BMI SDS (P < 0.001) and lower HbA1c (P = 0.04), independent of other variables. On a GFD, BMI SDS increased by 12 months in the cd+ group and then was no different than the cd− group (1.1 vs. 1.0, P = 0.11), whereas HbA1c improved further within case subjects compared with pre-GFD (8.9 vs. 8.3%, P = 0.002). On a GFD, case subjects in contrast to control subjects showed no deterioration in HbA1c during the years of puberty (8.3 vs. 10.0%, P = 0.022)

CONCLUSIONS—In children with type 1 diabetes, untreated celiac disease resulted in lower BMI SDS and lower HbA1c. Recovery of BMI SDS with a GFD was associated with further improvement in HbA1c as compared with pre-GFD, with no expected deterioration in glycemic control during puberty. These apparent clinical benefits need confirming by larger studies.
Elevated Risk of Cardiovascular Disease Prior to Clinical Diagnosis of Type 2 Diabetes
Authors: Hu Frank B. , Stampfer Meir J. , Haffner Steven M. , Solomon Caren G. , Willett Walter C. , Manson JoAnn E.
Published: March 2007

OBJECTIVE—To examine whether the risk of cardiovascular disease (CVD) is elevated before clinical diagnosis of type 2 diabetes in women.

RESEARCH DESIGN AND METHODS—A total of 117,629 female nurses aged 30–55 years who were free of diagnosed CVD at baseline were recruited in 1976 and followed for 20 years.

RESULTS—A total of 1,508 women had diagnosed type 2 diabetes at baseline in 1976. During 20 years of follow-up, 110,227 women remained free of diabetes diagnosis and 5,894 women developed type 2 diabetes. During 2.2 million person-years of follow-up, we documented 1,556 new cases of myocardial infarction (MI), 1,405 strokes, 815 fatal coronary heart disease (CHD), and 300 fatal strokes. Among women who developed type 2 diabetes during follow-up, the age-adjusted RRs of MI were 3.75 (95% CI 3.10–4.53) for the period before the diagnosis and 4.57 (3.87–5.39) for the period after the diagnosis, compared with women who remained free of diabetes diagnosis. The multivariate RRs further adjusting for BMI, smoking, and other cardiovascular risk factors were 3.17 (2.61–3.85) and 3.97 (3.35–4.71). The risk of stroke was also significantly elevated before diagnosis of diabetes (multivariate RR = 2.30 [1.76–2.99]). Further adjustment for history of hypertension or hypercholesterolemia did not appreciably alter the results.

CONCLUSIONS—Our data indicate a substantially elevated risk of CVD before clinical diagnosis of type 2 diabetes in women. These findings suggest that aggressive management of cardiovascular risk factors is warranted in individuals at increased risk for diabetes.
Acute and Prolonged Effects of Sildenafil on Brachial Artery Flow-Mediated Dilatation in Type 2 Diabetes
Authors: Desouza Cyrus , Parulkar Akhil , Lumpkin David , Akers Donald , Fonseca Vivian A.
Published: March 2007

OBJECTIVE—Flow-mediated dilatation (FMD), induced by occlusion of the brachial artery, is an index of nitric oxide-dependent endothelial function that is impaired in patients with type 2 diabetes. Sildenafil (Viagra) is an inhibitor of phosphodiesterase 5 (PDE-5), which is used for management of erectile dysfunction in a broad range of patients, including those with type 2 diabetes. Its effects on endothelial function in these patients have not been previously assessed.

RESEARCH DESIGN AND METHODS—We assessed the acute and prolonged effects of a low dose of sildenafil (25 mg) on FMD in patients with type 2 diabetes. We performed a double-blind, placebo-controlled cross-over trial in 16 patients (14 of whom completed the study) with type 2 diabetes who had erectile dysfunction without overt clinical heart disease.

RESULTS—In these patients, the mean ± SD brachial artery diameter (BAD) measured by ultrasound was 4.33 ± 0.6 mm. After inducing FMD, the BAD increased 8% to 4.66 ± 0.6 mm (P = 0.2). One hour after oral administration of sildenafil 25 mg, FMD increased the BAD significantly by 15% to 4.99 ± 0.5 mm (P ≤ 0.01), whereas it did not change with placebo (4.6 ± 0.6 mm, P = 0.1). After treatment with sildenafil 25 mg daily for 2 weeks and testing 24 h after the last dose, the mean FMD was 14% (P = 0.01). In contrast, the mean FMD with placebo was 9% (P = 0.45).

CONCLUSIONS—We conclude that acute and prolonged sildenafil treatment has a favorable effect on brachial artery flow-mediated dilatation that persists for at least 24 h after the last dose. Further investigation is needed to determine whether this prolonged effect has clinical implications in patients with type 2 diabetes.
Heterogeneity in the Relationship Between Ethnicity, BMI, and Fasting Insulin
Authors: Palaniappan Latha P. , Carnethon Mercedes R. , Fortmann Stephen P.
Published: March 2007

OBJECTIVE—To determine whether the association of BMI and fasting insulin is modified by ethnicity.

RESEARCH DESIGN AND METHODS—Non-Hispanic black (black), non-Hispanic white (white), and Mexican-American men and women aged 20–80 years from the Third National Health and Nutrition Examination Survey (1988–1994) were included in this study. Linear regression models with an interaction term were used to test whether ethnicity modified the association between BMI and fasting insulin.

RESULTS—Fasting insulin was 19, 26, 20, and 19% higher in black women than white women with BMI levels of <22, 22–24, 25–27, and 28–30 kg/m2, respectively. These differences between black and white women converged at BMI levels >30 kg/m2. Mexican-American women had fasting insulin levels that were 17, 22, 20, and 16% higher than those of white women at BMI levels of 25–27, 28–30, 31–33, and >34 kg/m2, respectively, but were not different in individuals with BMI levels <25 kg/m2. Adjusting for established risk factors did not attenuate these associations in women. Differences in fasting insulin among men were not as apparent.

CONCLUSIONS—These findings suggest that the effect of obesity on insulin sensitivity is different for Americans in ethnic minorities. In black subjects, fasting insulin is higher at lean weight when compared with white and Mexican-American subjects. In Mexican-American subjects, fasting insulin is higher in overweight individuals when compared with white and black subjects. These findings are more pronounced in women than in men. This result reinforces the importance of designing prevention programs that are tailored to meet the needs of specific populations. Investigation of possible explanations for these differences seems warranted.
Diabetes Contributes to Cholesterol Metabolism Regardless of Obesity
Authors: Simonen Piia P. , Gylling Helena K. , Miettinen Tatu A.
Published: March 2007

OBJECTIVE—To investigate cholesterol metabolism in obesity with and without diabetes.

RESEARCH DESIGN AND METHODS—We performed cross-sectional metabolic studies in obese individuals with and without type 2 diabetes. The study population consisted of 16 obese (BMI >30 kg/m2) diabetic subjects with a mean age of 52 ± 2 years (SE) and 16 nondiabetic control subjects of similar age and weight. Cholesterol absorption efficiency was measured with peroral dual isotopes and cholesterol synthesis with sterol balance.

RESULTS—Serum total cholesterol did not differ between the groups, but LDL and HDL cholesterol were significantly lower and VLDL cholesterol and serum total and VLDL triglycerides were higher in the diabetic group than in the control group. Cholesterol absorption efficiency was 29 ± 1% in diabetic subjects vs. 42 ± 2% in the control subjects (P < 0.01). Cholesterol synthesis was higher (17 ± 1 vs. 14 ± 1 mg · kg−1 · day−1; P < 0.05) and neutral sterol and bile acid excretion and cholesterol turnover tended to be higher in the diabetic group than in the control group. Blood glucose was positively related to cholesterol synthesis in the diabetic group (r = +0.663, P < 0.01) and in the control group (r = +0.590, P < 0.05), suggesting that the higher blood glucose level, the higher the cholesterol synthesis. In addition, blood glucose was significantly positively related to fecal neutral sterol excretion in both groups.

CONCLUSIONS—Cholesterol absorption efficiency was lower and cholesterol synthesis was higher in obese subjects with diabetes than in those without diabetes, suggesting that diabetes modulates cholesterol metabolism more than obesity alone.
Prognostic Value of Dobutamine-Atropine Stress Myocardial Perfusion Imaging in Patients With Diabetes
Authors: Schinkel Arend F.L. , Elhendy Abdou , van Domburg Ron T. , Bax Jeroen J. , Vourvouri Eleni C. , Sozzi Fabiola B. , Valkema Roelf , Roelandt Jos R.T.C. , Poldermans Don
Published: March 2007

OBJECTIVE—Exercise tolerance in patients with diabetes is frequently impaired due to noncardiac disease such as claudication and polyneuropathy. This study assesses the prognostic value of dobutamine stress myocardial perfusion imaging in patients with diabetes.

RESEARCH DESIGN AND METHODS—A total of 207 consecutive diabetic patients who were unable to undergo exercise stress testing underwent dobutamine-atropine stress myocardial perfusion imaging. Follow-up was successful in 206 of 207 (99.5%) patients. A total of 12 patients underwent early (<60 days) revascularization and were excluded from the analysis. End points during follow-up were hard cardiac events, defined as cardiac death and nonfatal myocardial infarction.

RESULTS—Abnormal myocardial perfusion was detected in 125 (64%) patients. During 4.1 ± 2.4 years of follow-up, 73 (38%) deaths occurred, 36 (49%) of which were due to cardiac causes. Nonfatal myocardial infarction occurred in 7 (4%) patients, and 45 (23%) patients underwent late coronary revascularization. Cardiac death occurred in 2 of 69 (3%) patients with normal myocardial perfusion and in 34 of 125 (27%) patients with perfusion abnormalities (P < 0.0001). A multivariable Cox proportional hazard model demonstrated that, in addition to clinical and stress test data, an abnormal scan had an incremental prognostic value for prediction of cardiac death (hazard ratio 7.2, 95% CI 1.7–30). The summed stress score was an important predictor of cardiac death; the hazard ratio was 1.2 (95% CI 1.07–1.34) per one-unit increment.

CONCLUSIONS—Dobutamine-atropine stress myocardial perfusion imaging provides additional prognostic information incremental to clinical data in patients with diabetes who are unable to undergo exercise stress testing.
l-Arginine: An Ultradian-Regulated Substrate Coupled With Insulin Oscillations in Healthy Volunteers
Authors: Schaefer Adrien , Simon Chantal , Viola Antoine , Piquard François , Geny Bernard , Brandenberger Gabrielle
Published: March 2007

OBJECTIVE—Coupled oscillations of 50–110 min in insulin and glucose have been found previously in healthy men under continuous enteral nutrition. Because l-arginine induces insulin release as glucose does, we tested the hypothesis that l-arginine can also display such an ultradian rhythm.

RESEARCH DESIGN AND METHODS—Seven healthy male subjects participated in one experimental night during which blood was sampled every 10 min from 2300 to 0700. Plasma glucose, C-peptide, and l-arginine levels were measured simultaneously. The insulin secretion rate (ISR) was calculated from plasma C-peptide levels by a deconvolution procedure.

RESULTS—Plasma glucose followed the recognizable profiles, with oscillations closely linked to similar changes in the ISR. Pulse analysis of l-arginine profiles revealed significant oscillations linked to glucose and ISR oscillations, with the highest cross-correlation coefficients at time lag 0 ranging from 0.380 to 0.680 for glucose and l-arginine and from 0.444 to 0.726 for ISR and l-arginine (P < 0.01). The mean period of l-arginine oscillations was 77.2 ± 6.2 min, and their mean amplitude was 19.9 ± 1.7%, similar to that of glucose (17.0 ± 1.9%), when expressed as the percentage of mean overnight levels.

CONCLUSIONS—This newly discovered ultradian rhythm of l-arginine and its coupling with glucose and ISR oscillations sheds new light on the regulation of l-arginine, the substrate of numerous metabolic pathways, including nitric oxide synthesis. These oscillations may be of significance in conditions of hyperinsulinemia or abnormal glucose tolerance.