bluuebunny/crossref_metadata_2025 huggingface dataset:
Remission of Nephrotic-Range Albuminuria in Type 1 Diabetic Patients
Authors: Hovind Peter , Rossing Peter , Tarnow Lise , Toft Henrik , Parving Jeppe , Parving Hans-Henrik
Published: March 2007

OBJECTIVE—To evaluate the cumulative incidence of nephrotic-range albuminuria (NRA), the frequency of remission, and the impact on progression, we analyzed data from a prospective cohort study of type 1 diabetic patients with diabetic nephropathy.

RESEARCH DESIGN AND METHODS—All of the albuminuric type 1 diabetic patients (n = 321, 121 women), who had at least yearly measurements of glomerular filtration rate (GFR) with a 51Cr-EDTA plasma clearance technique and were followed for at least 3 years, were evaluated. NRA, defined as persistent albuminuria >2,500 mg/24 h, occurred in 126 patients (35 women) aged (mean ± SD) 34 ± 8 years, with duration of diabetes 22 ± 8 years and follow-up time from onset of NRA (median [range]) 8.7 (3.0–20.9) years. Remission of NRA was defined as sustained albuminuria <600 mg/24 h for at least 1 year.

RESULTS—The cumulative incidence of NRA was 39%. Remission was induced in 28 of 126 (22%) patients; 21 were predominantly treated with ACE inhibitors, 7 with non–ACE inhibitor medications. Remission lasted 3.6 (1.0–18.1) years. More women (37%) than men (16%) obtained remission (P = 0.01). In the remission group compared with the no-remission group, mean arterial blood pressure (mean ± SEM) was reduced (102 ± 1 vs. 106 ± 1 mmHg, P < 0.01), the rate of decline in GFR was diminished (3.8 ± 0.6 vs. 7.5 ± 0.5 ml · min–1 · year–1, P < 0.001), and serum cholesterol was lower (5.3 ± 0.2 vs. 6.1 ± 0.1 mmol/l, P < 0.01) during the whole follow-up period. No difference in glycemic control was found between groups (HbA1c 9.2 vs. 9.4%, NS).

CONCLUSIONS—In contrast to observations made before the use of antihypertensive treatment, our prospective observational study suggests that aggressive antihypertensive treatment with and without ACE inhibitors can induce long-lasting remission in a sizeable fraction of type 1 diabetic patients with NRA. The group of patients obtaining remission is characterized by slow progression of diabetic nephropathy and improved cardiovascular risk profile.
Predictive Value of Cardiac Autonomic Neuropathy in Diabetic Patients With or Without Silent Myocardial Ischemia
Authors: Valensi Paul , Sachs Régis-Nessim , Harfouche Boubakeur , Lormeau Boris , Paries Jacques , Cosson Emmanuel , Paycha Frédéric , Leutenegger Marc , Attali Jean-Raymond
Published: March 2007

OBJECTIVE— The aim of this study was to determine the predictive value of silent myocardial ischemia (SMI) and cardiac autonomic neuropathy (CAN) in asymptomatic diabetic patients.

RESEARCH DESIGN AND METHODS— We recruited 120 diabetic patients with no history of myocardial infarction or angina, a normal 12-lead electrocardiogram (ECG), and two or more additional risk factors. SMI assessment was carried out by means of an ECG stress test, a thallium-201 myocardial scintigraphy with dipyridamole, and 48-h ECG monitoring. CAN was searched for by standardized tests evaluating heart rate variations. Accurate follow-up information for 3-7 years (mean 4.5) was obtained in 107 patients.

RESULTS— There was evidence of SMI in 33 patients (30.7%). CAN was detected in 33 of the 75 patients (38.9%) who were tested, and a major cardiac event occurred in 11 of them. Among these 75 patients, the proportion of major cardiac events in the SMI+ patients was not significantly higher than that in the SMI- patients (6 of 25 vs. 5 of 50 patients), whereas it was significantly higher in the CAN+ patients than in the CAN- patients (8 of 33 vs. 3 of 42 patients; P= 0.04), with a relative risk of 4.16 (95% CI 1.01-17.19) and was the highest in the patients with both SMI and CAN (5 of 10 patients). After adjusting for SMI, there was a significant association between CAN and major cardiac events(P = 0.04).

CONCLUSIONS— In asymptomatic diabetic patients, CAN appears to be a better predictor of major cardiac events than SMI. The risk linked to CAN appears to be independent of SMI and is the highest when CAN is associated with SMI.
Therapeutic Footwear for the Neuropathic Foot: An algorithm
Authors: Dahmen Rutger , Haspels Rob , Koomen Bart , Hoeksma Agnes F.
Published: March 2007

Neuropathy may bring about changes in form and function of the foot, which may lead to ulceration and progressive deformity. These manifestations often require specially adapted footwear. A comprehensive concept of the medical, functional, and technical requirements for this type of footwear is still lacking to date. In this article, we present an algorithm that should facilitate prescription and manufacture of adequate shoes. This algorithm attempts to establish a link between the requirements from a medical and functional point of view and the technical possibilities of orthopedic shoe technology.
Improved Glycemic Control and Enhanced Insulin Sensitivity in Type 2 Diabetic Subjects Treated With Pioglitazone
Authors: Miyazaki Yoshinori , Mahankali Archana , Matsuda Masafumi , Glass Leonard , Mahankali Srikanth , Ferrannini Eleuterio , Cusi Kenneth , Mandarino Lawrence J. , DeFronzo Ralph A.
Published: March 2007

OBJECTIVE—To elucidate the effects of pioglitazone treatment on glucose and lipid metabolism in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS—A total of 23 diabetic patients (age 30–70 years, BMI < 36 kg/m2) who were being treated with a stable dose of sulfonylurea were randomly assigned to receive either placebo (n = 11) or pioglitazone (45 mg/day) (n = 12) for 16 weeks. Before and after 16 weeks of treatment, all subjects received a 75-g oral glucose tolerance test (OGTT); and hepatic and peripheral insulin sensitivity was measured with a two-step euglycemic insulin (40 and 160 mU · min−1 · m–2) clamp performed with 3-[3H]glucose and indirect calorimetry. HbA1c was measured monthly throughout the study period.

RESULTS—After 16 weeks of pioglitazone treatment, the fasting plasma glucose (FPG; 184 ± 15 to 135 ± 11 mg/dl, P < 0.01), mean plasma glucose during OGTT (293 ± 12 to 225 ± 14 mg/dl, P < 0.01), and HbA1c (8.9 ± 0.3 to 7.2 ± 0.5%, P < 0.01) decreased significantly without change in fasting or glucose-stimulated insulin/C-peptide concentrations. Fasting plasma free fatty acid (FFA; 647 ± 39 to 478 ± 49 μEq/l, P < 0.01) and mean plasma FFA during OGTT (485 ± 30 to 347 ± 33 μEq/l, P < 0.01) decreased significantly after pioglitazone treatment. Before and after pioglitazone treatment, basal endogenous glucose production (EGP) and FPG were strongly correlated (r = 0.67, P < 0.01). EGP during the first insulin clamp step was significantly decreased after pioglitazone treatment (P < 0.05), whereas insulin-stimulated total and nonoxidative glucose disposal during the second insulin clamp was increased (P < 0.01). The change in FPG was related to the change in basal EGP, EGP during the first insulin clamp step, and total glucose disposal during the second insulin clamp step. The change in mean plasma glucose concentration during the OGTT was strongly related to the change in total body glucose disposal during the second insulin clamp step.

CONCLUSIONS—These results suggest that pioglitazone therapy in type 2 diabetic patients decreases fasting and postprandial plasma glucose levels by improving hepatic and peripheral (muscle) tissue sensitivity to insulin.
Lower-Limb Vascularization in Diabetic Patients
Authors: Cosson Emmanuel , Paycha Frédéric , Tellier Philippe , Sachs Régis Nessim , Ramadan Arabi , Paries Jacques , Attali Jean-Raymond , Valensi Paul
Published: March 2007

OBJECTIVE—To investigate, by thallium-201 scanning, circulation in the muscles of the lower limb (LL) in diabetic patients without clinical peripheral vascular disease but with a high cardiovascular risk profile.

RESEARCH DESIGN AND METHODS—A total of 80 diabetic patients (76 patients with type 2 diabetes, mean age 57.3 years, duration of diabetes 13.0 ± 7.5 years) with more than one additional cardiovascular risk factor but no claudication were investigated. After stress testing, 1.5 MBq/kg thallium-201 was administered to perform myocardial single-photon emission computed tomography followed by LL scanning. Muscle blood flow was considered abnormal if the asymmetry in thallium-201 uptake between the two buttocks and/or thighs and/or calves was >10%.

RESULTS—Muscle perfusion defects were found in 42% of the patients, mainly in the calves. These defects correlated with retinopathy (P = 0.042) and the HbA1c level (P = 0.044). In patients with defects in the buttock and/or thigh, the prevalence of nephropathy and retinopathy was higher than in those with isolated defects in the calf (P = 0.032 and 0.023, respectively).

CONCLUSIONS—This study suggests that LL scanning coupled with myocardial scintigraphy is a convenient method of investigating peripheral muscle circulation. Proximal perfusion defects in patients without clinical arterial disease are associated with increased prevalence of retinopathy and nephropathy and, therefore, may be due to microvascular disease of LL muscle. Distal defects may indicate silent macrovascular disease of the LL.
Impaired Microvascular Vasodilatory Function in 3-Month-Old Infants of Low Birth Weight
Authors: Goh Kah Lay , Shore Angela C. , Quinn Michael , Tooke John E.
Published: March 2007

OBJECTIVE—Low birth weight has been linked to an increased risk of type 2 diabetes and cardiovascular disease in adult life. The fetal insulin hypothesis proposed that a genetic predisposition to insulin resistance may also influence vascular development. Therefore, impaired vascular function may be an intrinsic abnormality in low–birth weight infants that antedates clinical features of the insulin resistance syndrome.

RESEARCH DESIGN AND METHODS—Two groups of 3-month-old term infants were included in the study: 17 infants of lowest quartile birth weight (LQBW) and 21 infants of highest quartile birth weight (HQBW). Three aspects of skin microvascular function were examined; response to local heating, response to acetylcholine iontophoresis, and capillary density.

RESULTS—Median (interquartile ranges) birth weights of the LQBW and HQBW infants were 3,140 g (2,738–3,254) and 3,920 g (3,750–4,020), respectively. Skin maximal hyperemic response to local heating was 2.14 V (1.68–2.30) in the LQBW group vs. 2.44 V (1.96–2.90) in the HQBW group (P = 0.020), and the endothelium-dependent vasodilatory response was 1.03 V (0.62–1.32) in the LQBW group vs. 0.78 V (0.45–1.32) in the HQBW group (P = 0.297). Capillary density in the LQBW and HQBW groups were 46.3 mm−2 (40.1–53.7) and 44.1 mm−2 (41.7–56.0), respectively (P = 0.736).

CONCLUSIONS—Skin maximal hyperemic response was lower in LQBW infants, although no reduction in capillary density or defect in endothelium-dependent vasodilatation was observed. Such a lower maximal hyperemic response in early life in LQBW subjects who are at risk for type 2 diabetes and cardiovascular disease supports the hypothesis that impaired microvascular function is an early antecedent to diabetes in later life.
Windows of Opportunity to Improve Diabetes Care When Patients With Diabetes Are Hospitalized for Other Conditions
Authors: Roman Sheila H. , Chassin Mark R.
Published: March 2007

OBJECTIVE—The overwhelming majority of hospitalizations for patients with diabetes occur for treatment of comorbid conditions. This study assessed broad-based interventions to improve diabetes care for patients hospitalized with cardiac conditions.

RESEARCH DESIGN AND METHODS—A pre-post quasi-experimental study design was used to evaluate the implementation of two quality improvement interventions: 1) revision of the hospital’s capillary blood glucose monitoring form into a color-coded process control chart and 2) a clinical path for type 2 diabetes as a secondary diagnosis. Interventions were implemented on the medical and surgical cardiac care units (not including the intensive care units on these services) of a tertiary academic medical center. A chart abstraction sample included 328 subjects with no exposure to the interventions and 336 subjects hospitalized after both interventions were implemented. Telephone surveys were conducted after discharge on 446 patients.

RESULTS—The frequency of patients with severe hyperglycemia (at least one glucose level >400 mg/dl) and prolonged hyperglycemia (at least three consecutive glucose levels >250 mg/dl) decreased from 12 and 17% preintervention to 6.6 and 10% postintervention (P = 0.017 and P = 0.013, respectively). We found that 9% of the patients preintervention and 5% of the patients postintervention (P = 0.05) had nosocomial infections. Patient-reported receipt of self-care instruction varied from 44 to 69% on nine survey items preintervention. Postintervention linear regression slopes for receipt of self-care instruction were all greater than preintervention slopes, but the differences did not achieve statistical significance. We found that 40% of the patients had important diabetes knowledge deficits.

CONCLUSIONS—Our broad-based interventions were associated with a decreased frequency of prolonged and severe hyperglycemia and a decreased frequency of nosocomial infections. We also identified opportunities to improve diabetes self-care instruction before discharge and to address important knowledge deficits of patients.
The Marital Relationship and Psychosocial Adaptation and Glycemic Control of Individuals With Diabetes
Authors: Trief Paula M. , Himes Christine L. , Orendorff Rebecca , Weinstock Ruth S.
Published: March 2007

OBJECTIVE—To explore the relationship between marital relationship domains (i.e., intimacy and adjustment) and glycemic control and psychosocial adaptation to diabetes.

RESEARCH DESIGN AND METHODS—A total of 78 insulin-treated adults with both type 1 and type 2 diabetes were assessed on a single occasion. They completed two marital quality measures (Spanier Dyadic Adjustment Scale and Personal Assessment of Intimacy in Relationships Scale) and four quality-of-life measures (Diabetes Quality of Life Scale, Medical Outcomes Study Health Survey, Problem Areas in Diabetes Scale, and Positive and Negative Affect Scale). Glycemic control was assessed by HbA1c. Demographic data (age, sex, type and duration of diabetes, years married, other medical conditions, family history, disability, and years of education) were gathered from the chart and questionnaires.

RESULTS—Concerning psychosocial adaptation, both of the marital quality measures were predictors of aspects of adaptation. Better marital satisfaction was related to higher levels of diabetes-related satisfaction and less impact, as well as less diabetes-related distress and better general quality of life. Higher levels of marital intimacy were related to better diabetes-specific and general quality of life. Concerning glycemic control, there was a nonsignificant trend for marital adjustment scores to relate to HbA1c (P = 0.0568).

CONCLUSIONS—For insulin-treated adults with diabetes, quality of marriage is associated with adaptation to diabetes and other aspects of health-related quality of life. The suggestive finding that marital adjustment may relate to glycemic control warrants further study. Future work should also explore the impact of couples-focused interventions on adaptation, adherence, and glycemic control.
The Sulfonylurea Glyburide Induces Impairment of Glucagon and Growth Hormone Responses During Mild Insulin-Induced Hypoglycemia
Authors: ter Braak Edith W.M.T. , Appelman Alexander M.M.F. , van der Tweel Ingeborg , Erkelens D. Willem , van Haeften Timon W.
Published: March 2007

OBJECTIVE—The sulfonylurea (SU) glyburide may cause severe and prolonged episodes of hypoglycemia. We aimed at investigating the impact of glyburide on glucose counterregulatory hormones during stepwise hypoglycemic clamp studies.

RESEARCH DESIGN AND METHODS—We performed stepwise hypoglycemic clamp studies in 16 healthy volunteers (7 women and 9 men aged 44 ± 10 years). We investigated counterregulatory hormonal and symptom responses at arterialized venous plasma glucose levels (PG) of 3.8, 3.2, and 2.6 mmol/l, comparing 10 mg glyburide orally and placebo in a double-blind, randomized crossover fashion.

RESULTS—The increase in plasma glucagon with time from PG = 3.8 onward was smaller for glyburide than for placebo (P = 0.014). Plasma glucagon area under the curve (AUC)60–180 was lower after glyburide than after placebo (1,774 ± 715 vs. 2,161 ± 856 pmol · l–1 · min, P = 0.014). From PG = 3.8 onward, plasma growth hormone (GH) levels with placebo were nearly two times (1.9 [95% CI 1.2–2.9]) as high as with glyburide (P = 0.011). AUC60–180 for GH was lower after glyburide than after placebo (geometric mean [range] 665 [356–1,275] and 1,058 [392–1,818] mU · l–1 · min, respectively; P = 0.04). No significant differences were observed for plasma cortisol, epinephrine and norepinephrine, or incremental symptom scores.

CONCLUSIONS—The SU glyburide induces multiple defects in glucose counterregulatory hormonal responses, notably decreases in both glucagon and GH release.
Endogenous Sex Hormones and the Development of Type 2 Diabetes in Older Men and Women: the Rancho Bernardo Study
Authors: Oh Jee-Young , Barrett-Connor Elizabeth , Wedick Nicole M. , Wingard Deborah L.
Published: March 2007

OBJECTIVE—To determine the prospective association between endogenous sex hormones and the development of type 2 diabetes in older men and women.

RESEARCH DESIGN AND METHODS—A standardized medical history was obtained, an oral glucose tolerance test was performed, and plasma samples for sex hormones and covariates were collected from ambulatory, community-dwelling men and women at baseline from 1984 to 1987. Approximately 8 years later (1992–1996), another medical history was obtained, an oral glucose tolerance test was performed, fasting and 2-h insulin levels were measured, and the homeostasis model assessment for insulin resistance (HOMA-IR) was evaluated. This report is based on the 294 men and 233 women, aged 55–89 years, who completed both visits and who did not have diabetes as determined by history or glucose tolerance test at baseline, as well as women who were postmenopausal and not taking replacement estrogen.

RESULTS—In age-adjusted correlation analyses, total testosterone was inversely and significantly related to subsequent levels of fasting and postchallenge glucose and insulin in men, whereas bioavailable testosterone and bioavailable estradiol were positively and significantly related to fasting and postchallenge glucose and insulin in women (all P <0.05). There was similar significant association with insulin resistance (HOMA-IR) in unadjusted and multiply adjusted analyses (P <0.05). There were 26 men and 17 women with new (incident) diabetes. The odds for new diabetes were 2.7 (95% CI 1.1–6.6) for men in the lowest quartile of total testosterone and 2.9 (1.1–8.4) for women in the highest quartile of bioavailable testosterone.

CONCLUSIONS—Low testosterone levels in men and high testosterone levels in women predict insulin resistance and incident type 2 diabetes in older adults.
Evaluating Once- and Twice-Daily Self-Monitored Blood Glucose Testing Strategies for Stable Insulin-Treated Patients With Type 2 Diabetes
Authors: Hoffman Richard M. , Shah Jayendra H. , Wendel Christopher S. , Duckworth William C. , Adam Karen D. , Bokhari Syed U. , Dalton Cheri , Murata Glen H.
Published: March 2007

OBJECTIVE—To evaluate once- and twice-daily self-monitored blood glucose testing strategies in assessing glycemic control and detecting hypoglycemia or hyperglycemia in patients with stable insulin-treated type 2 diabetes.

RESEARCH DESIGN AND METHODS—Subjects with stable insulin-treated type 2 diabetes monitored blood glucose four times daily (prebreakfast, prelunch, predinner, and bedtime) for 8 weeks. We correlated mean blood glucose values with HbA1c measured after 8 weeks and determined the number of hypoglycemic (≤3.33 mmol/l) and hyperglycemic (≥22.20 mmol/l) readings captured at the various testing times.

RESULTS—A total of 150 subjects completed the monitoring period; their average age was 67 years, 90% were men, and the mean HbA1c at baseline was 8.0 ± 1.8%. The overall correlation of glucose testing and HbA1c was 0.79 (P < 0.0001). Mean blood glucose values for each of the four once-daily testing strategies were significantly correlated with HbA1c (r = 0.65–0.70, P < 0.0001), as were mean blood glucose values for each of the six twice-daily testing strategies (r = 0.73–0.75, P < 0.0001). The prebreakfast/prelunch measurements captured the largest proportion (63.6%) of the hypoglycemic readings, the predinner/bedtime measurements captured the largest proportion (66.2%) of hyperglycemic readings, and the prelunch/predinner measurements captured the largest proportion (57.7%) of all out-of-range readings.

CONCLUSIONS—Twice-daily testing strategies, particularly prelunch/predinner, effectively assess glycemic control and capture a substantial proportion of out-of-range readings. However, personal testing strategies will vary depending on an individual’s risk for hypoglycemia and hyperglycemia.
Predicting Future Cardiovascular Disease
Authors: Stern Michael P. , Fatehi Pedram , Williams Ken , Haffner Steven M.
Published: March 2007

OBJECTIVE—Our objective was to compare the performance of oral glucose tolerance tests (OGTTs) and multivariate models incorporating commonly available clinical variables in their ability to predict future cardiovascular disease (CVD).

RESEARCH DESIGN AND METHODS—We randomly selected 2,662 Mexican-Americans and 1,595 non-Hispanic whites, 25–64 years of age, who were free of both CVD and known diabetes at baseline from several San Antonio census tracts. Medical history, cigarette smoking history, BMI, blood pressure, fasting and 2-h plasma glucose and serum insulin levels, triglyceride level, and fasting serum total, LDL, and HDL cholesterol levels were obtained at baseline. CVD developed in 88 Mexican-Americans and 71 non-Hispanic whites after 7–8 years of follow-up. Stepwise multiple logistic regression models were developed to predict incident CVD. The areas under receiver operator characteristic (ROC) curves were used to assess the predictive power of these models.

RESULTS—The area under the 2-h glucose ROC curve was modestly but not significantly greater than under the fasting glucose curve, but both were relatively weak predictors of CVD. The areas under the ROC curves for the multivariate models incorporating readily available clinical variables other than 2-h glucose were substantially and significantly greater than under the glucose ROC curves. Addition of 2-h glucose to these models did not improve their predicting power.

CONCLUSIONS—Better identification of individuals at high risk for CVD can be achieved with simple predicting models than with OGTTs, and the addition of the latter adds little if anything to the predictive power of the model.
Incidence of Falls, Risk Factors for Falls, and Fall-Related Fractures in Individuals With Diabetes and a Prior Foot Ulcer
Authors: Wallace Carolyn , Reiber Gayle E. , LeMaster Joseph , Smith Douglas G. , Sullivan Katrina , Hayes Shane , Vath Christy
Published: March 2007

OBJECTIVE—To describe the incidence of falls, risk factors for falls, and the frequency of fall-related fractures in a cohort of individuals with diabetes and a prior foot ulcer.

RESEARCH DESIGN AND METHODS—A total of 400 individuals with diabetes and a prior foot ulcer were recruited from two western Washington State health care organizations and followed prospectively for 2 years. Diabetes, demographic, and health information was collected at baseline, 1 year, and 2 years. Data on falls were collected at baseline, 4 weeks, and every 17 weeks thereafter. Medical records were abstracted to confirm fall-related morbidity.

RESULTS—The average age of the study population was 62 years, with 77% male and 23% female. Approximately 32% had fixed foot deformities, 58% had insensate feet, and 76% had comorbid conditions. Of the participants, 252 (64%) reported at least one fall during the 2-year study period. The overall incidence of falls in this cohort was 1.25 falls/person-year (95% CI 1.17–1.33). For the 164 participants (41%) who reported two or more falls, a BMI ≥30 kg/m2, the presence of one or more comorbid conditions, and insensate feet increased the risk. Two or more falls of any type were associated with a higher fracture risk. Although women were not at significantly greater risk for falls than men, their fracture incidence was 3.6 times higher.

CONCLUSIONS—Falls are very common in individuals with diabetes and prior foot ulcers. A small percentage of falls resulted in fractures. The risk of a fall-related fracture was significantly higher in women than in men. Increased attention to falls and fall prevention is indicated for diabetes care providers.
Effects of Tadalafil on Erectile Dysfunction in Men With Diabetes
Authors: Sáenz de Tejada Iñigo , Anglin Greg , Knight James R. , Emmick Jeffrey T.
Published: March 2007

OBJECTIVE—To evaluate the efficacy and safety of tadalafil taken as needed before sexual activity by men with diabetes and erectile dysfunction (ED).

RESEARCH DESIGN AND METHODS—Men with type 1 or type 2 diabetes and a minimum 3-month history of ED were randomly allocated to one of three groups: placebo (n = 71), tadalafil 10 mg (n = 73), or tadalafil 20 mg (n = 72) taken up to once daily for 12 weeks. Changes from baseline in mean scores on the erectile function domain of the International Index of Erectile Function (IIEF) and changes from baseline in the proportion of “yes” responses to question 2, “Were you able to penetrate?,” and 3, “Were you able to complete intercourse?,” of the Sexual Encounter Profile were coprimary outcome measures.

RESULTS—A total of 191 (88%) of 216 patients completed the study. Treatment with tadalafil significantly improved all primary efficacy variables, regardless of baseline HbA1c level. Therapy with tadalafil also significantly improved a number of secondary outcome measures, including changes in other IIEF domains, individual IIEF questions, and percentage of positive responses to a global assessment question measuring erection improvement. Treatment with tadalafil did not alter mean HbA1c levels. Tadalafil was well tolerated, with headache and dyspepsia being the most frequent adverse events with active treatment.

CONCLUSIONS—Tadalafil therapy significantly enhanced erectile function and was well tolerated by men with diabetes and ED.
Diabetes in Ontario
Authors: Hux Janet E. , Ivis Frank , Flintoft Virginia , Bica Adina
Published: March 2007

OBJECTIVE—Accurate information about the magnitude and distribution of diabetes can inform policy and support health care evaluation. We linked physician service claims (PSCs) and hospital discharge abstracts (HDAs) to determine diabetes prevalence and incidence.

RESEARCH DESIGN AND METHODS—A retrospective cohort was constructed using administrative data from the national HDA database, PSCs for Ontario (population 11 million), and registries carrying demographics and vital statistics. All HDAs and PSCs bearing a diagnosis of diabetes (ICD9-CM 250) were selected for 1991–1999. Two previously reported algorithms for identification of diabetes were applied as follows: “1-claim” (any HDA or PSC showing diabetes) and “2-claim” (one HDA or two PSCs within 2 years showing diabetes). Incident cases were defined as individuals who met the criteria for diabetes for the first time after at least 2 years of observation. For validation, diagnostic data abstracted from primary care charts (n=3,317) of 57 randomly selected physicians were linked to the administrative data cohort, and sensitivity and specificity were calculated.

RESULTS—In 1998, 696,938 individuals met the 1-claim criteria and 528,280 met the 2-claim criteria. Sensitivity for diabetes was 90 and 86%; for the 1- and 2-claim algorithms, specificity was 92 and 97%, respectively, and positive predictive values were 61 and 80%, respectively. Using the 2-claim algorithm, the all-age prevalence increased from 3.2% in 1993 to 4.5% in 1998 (6.1% in adults). Incidence remained stable.

CONCLUSIONS—Administrative data can be used to establish population-based incidence and prevalence of diabetes. Diabetes prevalence is increasing in Ontario and is considerably higher than self-reported rates.
The Gly972Arg Polymorphism in Insulin Receptor Substrate-1 Is Associated With Decreased Birth Weight in a Population-Based Sample of Brazilian Newborns
Authors: Bezerra Rosângela M.N. , de Castro Vagner , Sales Teresa , Passini Renato , Marba Sergio T.M. , Saad Sara T.O. , Saad Mario J.A.
Published: March 2007

OBJECTIVE—We studied the association between the Gly972Arg polymorphism in insulin receptor substrate-1 (IRS-1) and birth weight in a population-based sample of Brazilian newborns.

RESEARCH DESIGN AND METHODS—We studied 194 newborn children with adequate gestational age to identify the association between the Gly972Arg polymorphism and birth weight using PCR—restriction fragment length polymorphism analysis.

RESULTS—The data showed that the birth weight was lower in the newborns with the Gly972Arg polymorphism in IRS-1 compared with control subjects (3,141 ±31.8 vs. 3,373 ±80.3 g, P < 0.008). The results also showed that the frequency of this polymorphism was increased in newborns with a birth weight <3,000 g (P=0.041).

CONCLUSIONS—These results suggest that the genotype Gly972Arg may influence birth weight, reinforcing the hypothesis that genetically determined insulin resistance and/or reduced insulin secretion can result in impaired insulin-mediated growth in the fetus.
Elevated Remnant-Like Particle Cholesterol and Triglyceride Levels in Diabetic Men and Women in the Framingham Offspring Study
Authors: Schaefer Ernst J. , McNamara Judith R. , Shah Paulesh K. , Nakajima Katsuyuki , Cupples L. Adrienne , Ordovas Jose M. , Wilson Peter W.F.
Published: March 2007

OBJECTIVE—Remnants of triglyceride-rich lipoproteins are thought to be atherogenic. A new antibody-based assay allows for the isolation of remnant-like particles (RLPs) from plasma or serum, and the subsequent measurement of RLP cholesterol (RLPC) and triglycerides (RLPTGs). We hypothesized that diabetic patients would have higher remnant levels than nondiabetic patients.

DESIGN AND METHODS—We compared RLPC and RLPTG levels of diabetic subjects (68 women, 121 men) participating in the Framingham Heart Study with those of nondiabetic subjects (1,499 women, 1,357 men).

RESULTS—Mean RLPC values for diabetic women were 106% higher than those for nondiabetic women (0.367 ± 0.546 mmol/l [14.2 ± 21.1 mg/dl] vs. 0.179 ± 0.109 mmol/l [6.9 ± 4.2 mg/dl]; P < 0.0001), and RLPTG values for diabetic women were 385% higher than those for nondiabetic women (1.089 ± 2.775 mmol/l [93.1 ± 245.6 mg/dl] vs. 0.217 ± 0.235 mmol/l [19.2 ± 20.8 mg/dl]; P < 0.0001). Similar but less striking differences were observed in diabetic men, who had mean RLPC values 28% higher than those seen in nondiabetic men (0.285 ± 0.261 mmol/l [11.0 ± 10.1 mg/dl] vs. 0.223 ± 0.163 mmol/l [8.6 ± 6.3 mg/dl]; P < 0.001) and mean RLPTG values 70% higher than those seen in nondiabetic men (0.606 ± 1.019 mmol/l [53.6 ± 90.2 mg/dl] vs. 0.357 ± 0.546 mmol/l [31.6 ± 48.3 mg/dl]; P < 0.001). Moreover, diabetic men and women had significantly higher total triglycerides and lower HDL cholesterol levels than nondiabetic subjects.

CONCLUSIONS—The data indicate that RLP particles are elevated in diabetic subjects. To achieve optimal reduction of risk for cardiovascular disease, treatment of elevated RLP values, along with the control of LDL cholesterol levels, should be considered.
Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of a Single-Dose of NN2211, a Long-Acting Glucagon-Like Peptide 1 Derivative, in Healthy Male Subjects
Authors: Elbrønd Bodil , Jakobsen Grethe , Larsen Søren , Agersø Henrik , Jensen Lisbeth Bjerring , Rolan Paul , Sturis Jeppe , Hatorp Vibeke , Zdravkovic Milan
Published: March 2007

OBJECTIVE—The primary objective of the present study was to investigate the safety, tolerability, and pharmacokinetics of a single dose of NN2211, a long-acting glucagon-like peptide 1 (GLP-1) derivative, in healthy male subjects. The secondary objective was to investigate the pharmacodynamics of NN2211.

RESEARCH DESIGN AND METHODS—In a double-blind, randomized dose, escalation, placebo-controlled study, healthy male subjects were enrolled at eight consecutive dose levels (1.25, 2.5, 5.0, 10.0, 12.5, 15.0, 17.5, and 20.0 μg/kg) with eight subjects per dose level at a 3:1 active:placebo randomization. After subcutaneous dosing with NN2211, 48-h pharmacokinetic, and 24-h glucose, insulin and glucagon profiles were assessed. In addition, three subjects at each dose level were randomly assigned (one placebo/two active) to an intravenous glucose tolerance test (IVGTT) 9 h after the dose (corresponding to the time to maximal plasma concentration of NN2211).

RESULTS—After subcutaneous administration, the half-life of NN2211 was found to be 11–15 h. Overall, although there were no statistically significant differences compared with placebo in the area under the curve (0–9 h for insulin or glucagon), there was a borderline- significant lowering of glucose levels (P = 0.066). During the IVGTT, there was a statistically significant increase in insulin secretion (P = 0.0002), but there was no significant effect on glucagon levels. Although no significant effect was observed on glucose levels during the IVGTT, there was a dose-dependent increase in the glucose disappearance constant. Whereas no serious adverse events were observed, there was a higher incidence of adverse events after active treatment compared with placebo treatment (notably headache, dizziness, nausea, and vomiting).

CONCLUSIONS—This study provides evidence that NN2211 has a pharmacokinetic profile consistent with once-daily dosing in humans.
Pupil Signs of Sympathetic Autonomic Neuropathy in Patients With Type 1 Diabetes
Authors: Pittasch Daniel , Lobmann Ralf , Behrens-Baumann Wolfgang , Lehnert Hendrik
Published: March 2007

OBJECTIVE—Pupillary autonomic neuropathy is considered an early sign of the development of systemic autonomic neuropathy. Sympathetic denervation is related to the duration of diabetes and the development of systemic autonomic dysfunction. We investigated pupil responsiveness to directly and indirectly acting sympathomimetics in type 1 diabetic patients with and without long-term complications, defined as cardiac autonomic neuropathy (CAN), peripheral sensomotor neuropathy, retinopathy, and nephropathy, and in healthy subjects.

RESEARCH DESIGN AND METHODS—A total of 47 randomly chosen type 1 diabetic patients and 20 healthy subjects were selected for this study. Patients were divided into groups determined by whether they had long-term diabetic complications. Pharmacological tests were performed with cocaine 4%, epinephrine 1%, and pholedrine 5% eye drops. Horizontal pupil diameter (HPD) was measured at the beginning of the pharmacological tests and at defined time points after instillation of the eye drops.

RESULTS—Statistical analysis showed a significantly smaller HPD in the patients before instillating eye drops (P = 0.011). In particular, the HPD was significantly smaller in the patient group without CAN when compared with healthy subjects (P = 0.004). Maximal cocaine reaction was diminished in the complication group (P < 0.001). Epinephrine test, visual acuity, ocular pressure, and HbA1c did not differ in patients with or without long-term complications. The noncomplication group showed no significant differences in pupillary responses as compared with healthy subjects. The complication group showed a smaller HPD (P = 0.022), reduced pupillary responses in the cocaine (P = 0.037) and pholedrine tests (P < 0.001), and anisocor pupil sizes after instillation of the eye drops (P = 0.034).

CONCLUSIONS—Our results clearly show that sympathetic denervation does exist in the pupil of diabetic patients and that it can be rapidly assessed using the cocaine test. These data and the results of the epinephrine test suggest a mixed pre- and postganglionic dysfunction of the sympathetic plexus. The significant smaller HPD in patients without CAN compared with that of healthy subjects could be a sign for early involvement of the pupil function before cardiac manifestation of systemic autonomic diabetic neuropathy.
Effect of Long-Term Exposure to Insulin Lispro on the Induction of Antibody Response in Patients With Type 1 or Type 2 Diabetes
Authors: Fineberg S. Edwin , Huang Jie , Brunelle Rocco , Gulliya K. S. , Anderson James H.
Published: March 2007

OBJECTIVE—To determine the long-term effects of insulin lispro on inducing lispro-specific, insulin-specific, and cross-reactive (reactive with both insulin lispro and human insulin) antibodies.

RESEARCH DESIGN AND METHODS—A multinational, multicenter combination of controlled and noncontrolled, open-label studies of 4.5 years’ duration was designed to evaluate the long-term immunologic profile of subcutaneously administered insulin lispro. A total of 1,221 patients (men and women; 12–81 years of age) with type 1 or type 2 diabetes were enrolled. Circulating anti-insulin antibodies were measured using radioimmunoassays.

RESULTS—Insulin-specific and lispro-specific antibody responses were within the background noise levels of the assays. Significant elevations of antibody were confined to a cross-reactive antibody response. Antibody levels resulting from prior exposure to long- and short-acting insulins changed little after transfer to insulin lispro and remained within or near the baseline levels. De novo exposure to insulin lispro resulted in increases in cross-reactive but not insulin- or lispro-specific antibody levels. Cross-reactive insulin antibodies developed more readily in patients with type 1 diabetes than in those with type 2 diabetes. Long-term antibody responses tended to decrease over time and returned to baseline or near-baseline levels by the end of the long-term studies. No evidence of an anamnestic antibody response could be found in individuals treated intermittently with insulin lispro.

CONCLUSIONS—The immunogenic profile of patients treated with insulin lispro was comparable to that of patients treated with recombinant human insulin. Inductions of significant levels of specific or cross-reactive antibodies were not observed in patients who had received insulin previously. No significant antibody-dependent increases in insulin dosage requirements were noted in these patients. The incidence of insulin allergy was not different from that in patients treated with recombinant regular human insulin.
Predictive Properties of Impaired Glucose Tolerance for Cardiovascular Risk Are Not Explained by the Development of Overt Diabetes During Follow-Up
Authors: Qiao Qing , Jousilahti Pekka , Eriksson Johan , Tuomilehto Jaakko
Published: March 2007

OBJECTIVE—To evaluate the relationship of impaired glucose tolerance (IGT) at baseline to coronary heart disease (CHD) incidence, and cardiovascular disease (CVD) and total mortality at follow-up, and to analyze whether the relationship is independent of the subsequent development of diabetes during follow-up.

RESEARCH DESIGN AND METHODS—A baseline screening survey for diabetes was performed in 1987 using a 2-h 75-g oral glucose tolerance test. A total of 1,234 men and 1,386 women aged 45–64 years, who were free of diabetes at baseline, were followed up for 10 years. During the follow-up, 153 subjects had an incident CHD event, 224 died, and 100 deaths were due to cardiovascular causes. Multivariate adjusted (adjusted for age, sex, waist-to-hip ratio, systolic blood pressure, cholesterol, HDL cholesterol, and smoking) hazard ratio (HR) was estimated using Cox regression analysis.

RESULTS—In subjects who had IGT at baseline and who did not progress to diabetes during the follow-up, the multivariate adjusted HR (95% CI) was 1.49 (0.95–2.34) for CHD incidence, 2.34 (1.42–3.85) for CVD mortality, and 1.65 (1.13–2.40) for all-cause mortality.

CONCLUSIONS—Baseline IGT was an independent risk predictor for cardiovascular morbidity and mortality and for total mortality, which was not confounded by the subsequent development of overt diabetes.
Progression of Coronary Artery Calcification in Type 1 Diabetes
Authors: Snell-Bergeon Janet K. , Hokanson John E. , Jensen Lisa , MacKenzie Todd , Kinney Gregory , Dabelea Dana , Eckel Robert H. , Ehrlich James , Garg Satish , Rewers Marian
Published: March 2007

OBJECTIVE—Coronary artery disease (CAD) occurs earlier in life and is more often fatal in people with type 1 diabetes. This excess risk seems to be higher than in those with type 2 diabetes and is poorly explained by conventional risk factors. The role of glycemic control is controversial and has not been previously addressed in a prospective manner using a reliable marker for subclinical CAD, such as coronary artery calcification (CAC), measured by electron beam computed tomography (EBCT).

RESEARCH DESIGN AND METHODS—We measured CAC twice during an interval of 2.7 years in 109 men and women with type 1 diabetes (aged 22–50 years). Progression of CAC was found in 21 patients, based on change in the square root-transformed volume score.

RESULTS—In multiple logistic regression, CAC progression was associated with baseline hyperglycemia (odds ratio [OR] 7.11, 95% CI 1.38–36.6, P = 0.02), adjusted for the presence of CAC at baseline (P = 0.01), duration of diabetes (P = 0.02), sex (P = 0.09), and age (P = 0.27). There was also a significant interactive effect of higher insulin dose and higher BMI (P = 0.03).

CONCLUSIONS—In conclusion, in this young cohort with type 1 diabetes, suboptimal glycemic control (HbA1c >7.5%) was a strong risk factor for progression of CAC. Insulin resistance may also play a role.
Prevalence of Delayed Gastric Emptying in Diabetic Patients and Relationship to Dyspeptic Symptoms
Authors: Samsom M. , Vermeijden J.R. , Smout A.J.P.M. , van Doorn E. , Roelofs J. , van Dam P.S. , Martens E.P. , Eelkman-Rooda S.J. , van Berge-Henegouwen G.P.
Published: March 2007

OBJECTIVE—Data on the prevalence of abnormal gastric emptying in diabetic patients are still lacking. The relation between gastric emptying and dyspeptic symptoms assessed during gastric emptying measurement has not yet been investigated. The aim was to investigate the prevalence of delayed gastric emptying in a large cohort of unselected diabetic patients and to investigate the relation between gastric emptying and gastrointestinal sensations experienced in the 2 weeks before and during the test meal, prospectively.

RESEARCH DESIGN AND METHODS—Gastric emptying was evaluated in 186 patients (106 with type 1 diabetes, mean duration of diabetes 11.6 ± 11.3 years) using 100 mg 13C-enriched octanoic acid added to a solid meal.

RESULTS—Gastric emptying was significantly slower in the diabetic subjects than in the healthy volunteers (T50: 99.5 ± 35.4 vs. 76.8 ± 21.4 min, P < 0.003; Ret120 min: 30.6 ± 17.2 vs. 20.4 ± 9.7%, P < 0.006). Delayed gastric emptying was observed in 51 (28%) diabetic subjects. The sensations experienced in the 2 weeks before the test were weakly correlated with the sensation scored during the gastric emptying test. Sensations assessed during the gastric emptying test did predict gastric emptying to some extent (r = 0.46, P < 0.0001), whereas sensations experienced in the previous 2 weeks did not.

CONCLUSIONS—This prospective study shows that delayed gastric emptying can be observed in 28% of unselected patients with diabetes. Upper gastrointestinal sensations scored during the gastric emptying tests do predict the rate of gastric emptying to some extent and sensation experienced during daily life does not.
Insulin Suppresses Plasma Concentration of Vascular Endothelial Growth Factor and Matrix Metalloproteinase-9
Authors: Dandona Paresh , Aljada Ahmad , Mohanty Priya , Ghanim Husam , Bandyopadhyay Arindam , Chaudhuri Ajay
Published: March 2007

OBJECTIVE—We recently demonstrated a potent anti-inflammatory and thus a potential antiatherogenic effect of insulin in human aortic endothelial cells and mononuclear cells at physiologically relevant concentrations. We have now further investigated the anti-inflammatory suppressive action of insulin on vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9. VEGF and MMP-9 play a central regulatory role in angiogenesis, contribute to the pathogenesis of proliferative retinopathy, and have also been found to accelerate atherosclerosis.

RESEARCH DESIGN AND METHODS—Insulin was infused (2 IU/h) in 5% dextrose (100 ml/h) and KCl (8 mmol/h) into 10 fasting, obese, nondiabetic subjects for 4 h. Subjects were also infused with 5% dextrose without insulin and with saline on two separate occasions. Blood samples were obtained at 0, 2, 4, and 6 h.

RESULTS—Plasma insulin concentrations increased from a basal level of 12.5 ± 2.2 to 28.2 ± 3.3 μU/ml at 2 h and 24.4 ± 3.7 μU/ml at 4 h after insulin infusion. VEGF concentration decreased from 307.2 ± 163.8 pg/ml (100%) at 0 h to 73.5 ± 20.9% of the basal level at 2 h and 67.1 ± 23.2% at 4h. Plasma MMP-9 concentrations decreased from 375 ± 196.3 ng/ml (100%) at 0 h to 83 ± 22% of the basal level at 2 h and to 82 ± 21% of the basal level at 4 h (P < 0.05). Dextrose infusion alone did not change plasma VEGF concentration. However, plasma MMP-9 concentration increased significantly at 4 h following dextrose infusion alone (P < 0.05). Saline infusions without insulin caused no alteration in glucose, insulin, VEGF, or MMP-9.

CONCLUSIONS—These observations may have implications for a potential antiretinopathic and antiatherosclerotic effect of insulin in the long term.
A Prospective Study of Self-Reported Sleep Duration and Incident Diabetes in Women
Authors: Ayas Najib T. , White David P. , Al-Delaimy Wael K. , Manson JoAnn E. , Stampfer Meir J. , Speizer Frank E. , Patel Sanjay , Hu Frank B.
Published: March 2007

Short-term sleep restriction results in impaired glucose tolerance. To test whether habitually short sleep duration increases the risk of developing diabetes, we studied a cohort of 70,026 women enrolled in the Nurses Health Study, without diabetes at baseline, and who responded to a question about daily sleep duration in 1986. Subjects were followed until 1996 for the diagnosis of diabetes (1,969 cases). Long and short sleep durations were associated with an increased risk of diabetes diagnosis. The relative risks (RRs) for short (slept ≤5 h per day) and long (slept ≥9 h per day) sleepers were 1.57 (95% CI 1.28–1.92) and 1.47 (1.19–1.80), respectively. After adjustment for BMI and a variety of confounders, the RR was not significantly increased for short sleepers (1.18 [0.96–1.44]) but remained modestly increased for long sleepers (1.29 [1.05–1.59]). We then performed a similar analysis using only symptomatic cases (n = 1,187). Adjusted RRs for symptomatic diabetes were modestly elevated in both short (1.34 [1.04–1.72]) and long (1.35 [1.04–1.75]) sleepers. Our data suggest that the association between a reduced self-reported sleep duration and diabetes diagnosis could be due to confounding by BMI, or sleep restriction may mediate its effects on diabetes through weight gain. Sleep restriction may be an independent risk factor for developing symptomatic diabetes.