bluuebunny/crossref_metadata_2025 huggingface dataset:
Generalizability and Persistence of a Multifaceted Intervention for Improving Quality of Care for Rural Patients With Type 2 Diabetes
Authors: Johnson Jeffrey A. , Eurich Dean T. , Toth Ellen L. , Lewanczuk Richard Z. , Lee TK , Majumdar Sumit R.
Published: March 2007

OBJECTIVE—Most quality improvement efforts for type 2 diabetes have neglected cardiovascular risk factors and are limited by a lack of information about generalizability across settings or persistence of effect over time.

RESEARCH DESIGN AND METHODS—We previously reported 6-month results of a controlled study of an intervention that improved cardiovascular risk factors for rural patients with type 2 diabetes. We subsequently provided the identical intervention to the control region after the main study was completed. The primary outcome was 10% improvement in systolic blood pressure, total cholesterol, or HbA1c. We compared the previously reported 6-month effect of the original intervention with the effect of the crossed-over intervention to the former control region and remeasured outcomes in the original intervention region 12 months later.

RESULTS—Our analysis included 200 original intervention and 181 crossed-over intervention subjects. The age of the population was 62.4 ± 12.4 years (mean ± SD), and 54.3% were women. A similar proportion of patients in the crossed-over intervention group achieved improvement in the primary composite outcome compared with the original intervention group (38 vs. 44%, respectively; P = 0.29). In adjusted analyses, we observed less improvement in blood pressure (adjusted odds ratio 0.40 [95% CI 0.17–0.75]) but greater improvements in total cholesterol (1.86 [0.93–3.7]) with the crossed-over intervention compared with the original intervention. We observed sustained improvements in total cholesterol and HbA1c levels in the original intervention group, whereas previous large gains in control of blood pressure diminished over time.

CONCLUSIONS—We found that our intervention was generalizable across settings, and its effect persisted over time. Nevertheless, without ongoing intervention or reinforcement, we noted some loss of the original benefits that had accrued. Future translational work should incorporate interventions such as ours into ongoing systems of rural care.
Increased Urinary Albumin Excretion, Insulin Resistance, and Related Cardiovascular Risk Factors in Patients With Type 2 Diabetes
Authors: De Cosmo Salvatore , Minenna Antonio , Ludovico Oznelle , Mastroianno Sandra , Di Giorgio Anna , Pirro Leonardo , Trischitta Vincenzo
Published: March 2007

OBJECTIVE—While the relevant role of insulin resistance in the pathogenesis of increased urinary albumin excretion (UAE) is well established in type 1 diabetes, its contribution in type 2 diabetes is controversial. Our aim was to investigate whether insulin resistance was associated with increased UAE in a large cohort of patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS— A total of 363 men and 349 women, aged 61 ± 9 years, with a disease duration of 11 ± 9 years and HbA1c levels of 8.6 ± 2.0% were included. Insulin resistance was derived from the homeostasis model assessment of insulin resistance (HOMAIR), and UAE was derived from the albumin-to-creatinine ratio (ACR) defined as increased if the value was ≥2.5 mg/mmol in men and ≥3.5 mg/mmol in women. ACR was correlated with HOMAIR (r = 0.15, P = 0.0001), independently of age, disease duration, blood pressure, HbA1c, triglycerides, waist circumference, and smoking.

RESULTS—When the two sexes were investigated separately, a significant correlation between ACR and HOMAIR was reached in men (n = 363; r = 0.21, P = 0.0001) but not women (n = 349; r = 0.08, P = 0.14), suggesting that insulin resistance and sex may interact (P for interaction = 0.04) in determining UAE. When men were subgrouped into quartiles of HOMAIR, those of the third and fourth quartile (i.e., the most insulin resistant) were at higher risk to have increased ACR than patients of the first quartile (third quartile: odds ratio 2.2 [95% CI 1.2–4.2], P = 0.01) (fourth quartile: 4.1 [2.2–7.9], P = 0.00002). Finally, ACR was significantly higher in men with two or more insulin resistance–related cardiovascular risk factors (i.e., abdominal obesity, dyslipidemia, and arterial hypertension) than in men with fewer than two insulin resistance–related cardiovascular risk factors (0.90 [0.2–115.1] vs. 1.56 [0.1–1367.6], respectively, P = 0.005).

CONCLUSIONS—In type 2 diabetic patients, increased UAE is strongly associated with insulin resistance and related cardiovascular risk factors. This association seems to be stronger in men than in women.
Environmental Correlates of Physical Activity Among Individuals With Diabetes in the Rural Midwest
Authors: Deshpande Anjali D. , Baker Elizabeth A. , Lovegreen Sarah L. , Brownson Ross C.
Published: March 2007

OBJECTIVE—To determine the relationship between physical and social environment attributes and levels of physical activity in a population-based sample of diabetic individuals living in rural areas.

RESEARCH DESIGN AND METHODS—Cross-sectional telephone survey data from rural communities of southeastern Missouri, Tennessee, and Arkansas were used. Logistic regression was used to calculate crude and adjusted prevalence odds ratios (PORs) and 95% CIs.

RESULTS—A total of 278 (11%) individuals with diabetes were identified. Almost 37% of this group reported no leisure-time physical activity. Individuals with diabetes who reported regular physical activity were more likely to report better general health status, normal BMI, and no physical impairment. After adjustment, regular activity was positively associated with use of three or more facilities (POR 14.3, 95% CI 3.0–67.3) in the past 30 days, the availability of many nearby places to walk (2.3, 1.1–4.8), the availability of shoulders on streets (2.4, 1.3–4.5), often walking to nearby places (4.1, 2.0–8.3), and rating the community for physical activity as generally pleasant (2.3, 1.1–4.8). Additionally, the regular activity group was more likely to report their physician had helped make a plan to increase physical activity (2.8, 1.3–5.8) and followed up on their plan (2.2, 1.1–4.4). Social environment variables were not associated with physical activity after adjustment.

CONCLUSIONS—Physical inactivity is a significant problem in rural diabetic populations. We have identified aspects of the social and physical environment that are positively associated with physical activity. Understanding the role of the environment may result in increased physical activity for individuals with diabetes.
History of Depression Increases Risk of Type 2 Diabetes in Younger Adults
Authors: Brown Lauren C. , Majumdar Sumit R. , Newman Stephen C. , Johnson Jeffrey A.
Published: March 2007

OBJECTIVE—The purpose of this study was to assess the history of previous depression in people with incident diabetes compared with people without diabetes.

RESEARCH DESIGN AND METHODS—We conducted a population-based nested case-control study using the administrative databases of Saskatchewan Health to assess the study objective. We identified cases of type 2 diabetes based on diagnostics codes and prescription records for individuals over the age of 20 years. For each case subject, two control subjects were randomly selected from the nondiabetic population during the same index year. History of depression, based on diagnostic codes and antidepressant prescription, was ascertained up to 3 years before index date. Simple and multivariate logistic regression analysis was used to estimate the odds ratio (OR) and 95% CIs, after adjusting for age, sex, and frequency of physician visits.

RESULTS—Individuals with newly diagnosed diabetes (1,622 of 33,257; 4.9%) were 30% more likely to have had a previous history of depression compared with people without diabetes (2,279 of 59,420; 3.8%). This increased risk remained after controlling for sex and number of physician visits but was limited to subjects 20–50 years of age (adjusted OR 1.23 [95% CI 1.10–1.37]) and not in those aged ≥51 years (0.92 [0.84–1.00]).

CONCLUSIONS—Depression appears to increase the risk of developing diabetes by ∼23% in younger adults. This provides information regarding the temporality of the relationship between diabetes and depression.
Effects of Oral Insulin in Relatives of Patients With Type 1 Diabetes
Authors:   The Diabetes Prevention Trial-Type 1 Study Group
Published: March 2007

OBJECTIVE—This randomized, double-masked, placebo-controlled clinical trial tested whether oral insulin administration could delay or prevent type 1 diabetes in nondiabetic relatives at risk for diabetes.

RESEARCH DESIGN AND METHODS—We screened 103,391 first- and second-degree relatives of patients with type 1 diabetes and analyzed 97,273 samples for islet cell antibodies. A total of 3,483 were antibody positive; 2,523 underwent genetic, immunological, and metabolic staging to quantify risk of developing diabetes; 388 had a 5-year risk projection of 26–50%; and 372 (median age 10.25 years) were randomly assigned to oral insulin (7.5 mg/day) or placebo. Oral glucose tolerance tests were performed every 6 months. The median follow-up was 4.3 years, and the primary end point was diagnosis of diabetes.

RESULTS—Diabetes was diagnosed in 44 oral insulin and 53 placebo subjects. Annualized rate of diabetes was similar in both groups: 6.4% with oral insulin and 8.2% with placebo (hazard ratio 0.764, P = 0.189). In a hypothesis-generating analysis of a subgroup with insulin autoantibody (IAA) levels confirmed (on two occasions) ≥80 nU/ml (n = 263), there was the suggestion of benefit: annualized diabetes rate 6.2% with oral insulin and 10.4% with placebo (0.566, P = 0.015).

CONCLUSIONS—It is possible to identify individuals at high risk for type 1 diabetes and to enroll them in a large, multisite, randomized, controlled clinical trial. However, oral insulin did not delay or prevent type 1 diabetes. Further studies are needed to explore the potential role of oral insulin in delaying diabetes in relatives similar to those in the subgroup with higher IAA levels.
Time-Action Profile of Inhaled Insulin in Comparison With Subcutaneously Injected Insulin Lispro and Regular Human Insulin
Authors: Rave Klaus , Bott Susanne , Heinemann Lutz , Sha Sue , Becker Reinhard H.A. , Willavize Susan A. , Heise Tim
Published: March 2007

OBJECTIVE—This study compares the time-action profile of inhaled insulin (INH; Exubera) with that of subcutaneously injected insulin lispro (ILP) or regular human insulin (RHI) in healthy volunteers.

RESEARCH DESIGN AND METHODS—In this open-label, randomized, three-way, crossover study, 17 healthy male volunteers were given each of the following treatments in random order: INH (6 mg), ILP (18 units), or RHI (18 units). Glucose infusion rates and serum insulin concentrations were monitored over 10 h.

RESULTS—INH had a faster onset of action than both RHI and ILP, as indicated by shorter time to early half-maximal effect (32 vs. 48 and 41 min, respectively; P < 0.001 for IHN vs. RHI and P < 0.05 for IHN vs. ILP). Time to maximal effect was comparable between INH and ILP (143 vs. 137 min; NS) but was shorter for INH than RHI (193 min; P < 0.01). The maximal metabolic effect of INH was comparable with RHI but lower than ILP (8.7 vs. 9.8 vs. 11.2 mg · kg–1 · min–1, respectively; P < 0.01 for INH vs. ILP). The duration of action of INH, indicated by time to late half-maximal effect (387 min), was longer than ILP (313 min; P < 0.01) and comparable to RHI (415 min; NS). Total glucodynamic effect after inhalation of INH was comparable to both ILP and RHI (NS). Relative bioefficacy of INH was 10% versus RHI and 11% versus ILP. No drug-related adverse events were observed.

CONCLUSIONS—INH had a faster onset of action than RHI or ILP and a duration of action longer than ILP and comparable to RHI. These characteristics suggest that inhaled insulin is suitable for prandial insulin supplementation in patients with diabetes.
A Double-Blind, Randomized, Dose-Response Study Investigating the Pharmacodynamic and Pharmacokinetic Properties of the Long-Acting Insulin Analog Detemir
Authors: Plank Johannes , Bodenlenz Manfred , Sinner Frank , Magnes Christoph , Görzer Evelyn , Regittnig Werner , Endahl Lars A. , Draeger Eberhard , Zdravkovic Milan , Pieber Thomas R.
Published: March 2007

OBJECTIVE—To investigate the pharmacodynamic profile and duration of action for five subcutaneous doses of insulin detemir (0.1, 0.2, 0.4, 0.8, and 1.6 units/kg; 1 unit = 24 nmol) and one subcutaneous dose of NPH insulin (0.3 IU/kg; 1 IU = 6 nmol).

RESEARCH DESIGN AND METHODS—This single-center, randomized, double-blind, six-period, crossover study was carried out as a 24-h isoglycemic clamp (7.2 mmol/l) in 12 type 1 diabetic patients.

RESULTS—Duration of action for insulin detemir was dose dependent and varied from 5.7, to 12.1, to 19.9, to 22.7, to 23.2 h for 0.1, 0.2, 0.4, 0.8, and 1.6 units/kg, respectively. Interpolation of the dose-response relationships for AUCGIR (area under the glucose infusion rate curve) revealed that a detemir dose of 0.29 units/kg would provide the same effect as 0.3 IU/kg NPH but has a longer duration of action (16.9 vs. 12.7 h, respectively). Lower between-subject variability was observed for insulin detemir on duration of action (0.4 units/kg insulin detemir vs. 0.3 IU/kg NPH, P < 0.05) and GIRmax (maximal glucose infusion rate) (0.2 and 0.4 units/kg insulin detemir vs. 0.3 IU/kg NPH, both P < 0.05). Assessment of endogenous glucose production (EGP) and peripheral glucose uptake (PGU) resulted in an AOCEGP (area over the EGP curve) of 636 mg/kg (95% CI 279–879) vs. 584 (323–846) and an AUCPGU (area under the PGU curve) of 173 (47–316) vs. 328 (39–617) for 0.29 units/kg detemir vs. 0.3 IU/kg NPH, respectively.

CONCLUSIONS—This study shows that insulin detemir provides a flat and protracted pharmacodynamic profile.
Elevated Pregnancy Losses at High and Low Extremes of Maternal Glucose in Early Normal and Diabetic Pregnancy
Authors: Jovanovic Lois , Knopp Robert H. , Kim Haesook , Cefalu William T. , Zhu Xiao-Dong , Lee Young Jack , Simpson Joe Leigh , Mills James L. ,   for the Diabetes in Early Pregnancy Study Group
Published: March 2007

OBJECTIVE—Early pregnancy losses increase with marked hyperglycemia in diabetic pregnancy. However, mean loss rates do not differ from those of nondiabetic pregnancy. This observation might be explained by increased fetal losses at the extremes of glycemia in diabetic and nondiabetic pregnancy. To test this hypothesis, we examined relationships of proximate measures of prior glycemia, glycated protein and fructosamine, to pregnancy loss.

RESEARCH DESIGN AND METHODS—A total of 389 diabetic and 429 nondiabetic pregnant subjects participated in the Diabetes In Early Pregnancy study. Glycated protein and fructosamine measurements were standardized as multiples of control values for each center (Z score). The logarithm of odds of pregnancy loss were plotted against Z scores and tested by logistic models.

RESULTS—Mean pregnancy loss rates were 12% in diabetic and 13% in normal pregnancies. However, over six intervals of glycated protein in diabetic pregnancy, fetal loss rates at the upper and lower extremes (24 and 33%, respectively) were approximately threefold higher than the four intervening rates (8–14%). The odds ratio of pregnancy loss for these extreme intervals to the intervening intervals is 3.0 (P = 0.01). Nondiabetic losses showed a similar pattern. In confirmation, logit pregnancy losses were increased in a J-shaped curve at the glycemic extremes in normal (P < 0.019) and diabetic (P < 0.015) pregnancy. The upper glycemic extreme in diabetic pregnancy was two- to fivefold higher than in control pregnancy.

CONCLUSIONS—Pregnancy losses are increased at the extremes of glycemia in both normal and diabetic pregnancy but at higher levels in diabetic pregnancy. The data suggest defensive adaptations against hyperglycemia in diabetic pregnancy.
β-Cell Function in Mild Type 2 Diabetic Patients
Authors: Mari Andrea , Gastaldelli Amalia , Foley James E. , Pratley Richard E. , Ferrannini Ele
Published: March 2007

OBJECTIVE—We studied the effects of the oral insulin secretagogue nateglinide on insulin secretion using a modeling approach to obtain β-cell function parameters from a meal test and examined the impact of the β-cell improvement on glucose tolerance.

RESEARCH DESIGN AND METHODS—Mild type 2 diabetic men and women (n = 108; fasting glucose 7.0–8.3 mmol/l) on diet treatment alone randomly received 30, 60, or 120 mg nateglinide or placebo for 24 weeks. β-Cell function parameters were derived by modeling (based on C-peptide deconvolution) from a standardized meal test at baseline and after 24 weeks of treatment.

RESULTS—The baseline demographic and metabolic characteristics of the four groups were similar. Nateglinide treatment resulted in dose-dependent reductions in the mean postprandial glucose response and at the 120-mg dose in fasting glucose. Fasting or total insulin secretion during the meal were not different. In contrast, we found differences in the model parameters. Rate sensitivity (expressing early insulin secretion when glucose is rising) was significantly enhanced at 24 weeks with the lowest nateglinide dose, with no further stimulation at higher doses. Early potentiation (expressing an initial insulin secretion enhancement), glucose sensitivity (the slope of the glucose–insulin secretion relationship), and insulin secretion at a fixed- reference 7-mmol/l glucose concentration all showed a trend toward increasing, with increasing nateglinide dose, and were significantly greater than placebo at the 120-mg dose. In multiple regression analyses, changes in rate sensitivity, glucose sensitivity, and potentiation all contributed to the observed glucose changes.

CONCLUSIONS—The model-derived parameters are sensitive measures of β-cell function, showing improvements after nateglinide treatment and predicting changes in glucose tolerance.
Familial Aggregation of Severity of Diabetic Retinopathy in Mexican Americans From Starr County, Texas
Authors: Hallman D. Michael , Huber J. Charles , Gonzalez Victor H. , Klein Barbara E.K. , Klein Ronald , Hanis Craig L.
Published: March 2007

OBJECTIVE—Diabetic retinopathy is a major cause of blindness. To determine whether retinopathy itself or only its severity aggregates in families, we examined the occurrence and severity of diabetic retinopathy in Mexican-American siblings with type 2 diabetes.

RESEARCH DESIGN AND METHODS—Using stereoscopic fundus photography of seven standard fields, we measured retinopathy in 656 type 2 diabetic patients from 282 Mexican-American families from Starr County, Texas. Retinopathy severity was scored using the Early Treatment of Diabetic Retinopathy Study system and classified as no retinopathy, early nonproliferative diabetic retinopathy (NPDR-E), moderate-to-severe nonproliferative diabetic retinopathy (NPDR-S), or proliferative diabetic retinopathy (PDR).

RESULTS—Of 249 siblings of randomly selected probands with retinopathy, 169 (67.9%) had retinopathy, compared with 95 of 125 siblings of unaffected probands (76.0%; P = 0.11). Proband retinopathy class was associated (P = 0.03) with sibling retinopathy class, with significant odds ratios (ORs) for NPDR-E versus no retinopathy (OR 0.57 [95% CI 0.35–0.93]) and PDR versus NPDR-E (2.02 [1.13–3.63]); the contrast of NPDR-S versus NPDR-E approached significance (1.78 [0.99–3.20]). With the more severe classes (PDR and NPDR-S) combined in one group and the less severe ones (none and NPDR-E) in another, more severe proband retinopathy was associated with more severe sibling retinopathy (1.72 [1.03–2.88]).

CONCLUSIONS—More severe diabetic retinopathy showed evidence of familial aggregation, but the occurrence of diabetic retinopathy per se did not. The factors involved in the onset of diabetic retinopathy may differ from those involved in its progression to more severe forms.
Magnesium Deficiency Is Associated With Insulin Resistance in Obese Children
Authors: Huerta Milagros G. , Roemmich James N. , Kington Marit L. , Bovbjerg Viktor E. , Weltman Arthur L. , Holmes Viola F. , Patrie James T. , Rogol Alan D. , Nadler Jerry L.
Published: March 2007

OBJECTIVE—Magnesium deficiency has been associated with insulin resistance (IR) and increased risk for type 2 diabetes in adults. This study was designed to determine whether obese children exhibit serum or dietary magnesium deficiency and its potential association with IR.

RESEARCH DESIGN AND METHODS—We studied 24 obese nondiabetic children (BMI ≥85th percentile) and 24 sex- and puberty-matched lean control subjects (BMI <85th percentile). We measured serum magnesium, indexes of insulin sensitivity, dietary magnesium intake (using a food frequency questionnaire), and body composition (by air displacement plethysmography).

RESULTS—Serum magnesium was significantly lower in obese children (0.748 ± 0.015 mmol/l, means ± SE) compared with lean children (0.801 ± 0.012 mmol/l) (P = 0.009). Serum magnesium was inversely correlated with fasting insulin (rs = −0.36 [95% CI −0.59 to −0.08]; P = 0.011) and positively correlated with quantitative insulin sensitivity check index (QUICKI) (0.35 [0.06–0.58]; P = 0.015). Dietary magnesium intake was significantly lower in obese children (obese: 0.12 ± 0.004 vs. lean: 0.14 ± 0.004 mg/kcal; P = 0.003). Dietary magnesium intake was inversely associated with fasting insulin (−0.43 [−0.64 to −0.16]; P = 0.002) and directly correlated with QUICKI (0.43 [0.16–0.64]; P = 0.002).

CONCLUSIONS—The association between magnesium deficiency and IR is present during childhood. Serum magnesium deficiency in obese children may be secondary to decreased dietary magnesium intake. Magnesium supplementation or increased intake of magnesium-rich foods may be an important tool in the prevention of type 2 diabetes in obese children.
Two-Year Outcome of a Combination of Weight Loss Therapies for Type 2 Diabetes
Authors: Redmon J. Bruce , Reck Kristell P. , Raatz Susan K. , Swanson Joyce E. , Kwong Christine A. , Ji Hong , Thomas William , Bantle John P.
Published: March 2007

OBJECTIVE—To evaluate the effects over 2 years of a weight loss program combining several weight loss strategies on weight loss and diabetes control in overweight subjects with type 2 diabetes.

RESEARCH DESIGN AND METHODS—A total of 59 overweight or obese individuals with type 2 diabetes were randomly assigned to either a combination therapy weight loss program for 2 years (C therapy) or a standard therapy weight loss program for 1 year followed by a combination therapy weight loss program in the 2nd year (S/C therapy). C therapy combined the use of meal replacement products, repetitive intermittent low-calorie-diet weeks, and pharmacologic therapy with sibutramine. Outcome measures included changes in weight, glycemic control, plasma lipids, blood pressure, and body composition over 2 years.

RESULTS—A total of 48 participants (23 in the C therapy group and 25 in the S/C therapy group) completed 2 years of study. After 2 years, the C therapy group had weight loss of 4.6 ± 1.2 kg (P < 0.001) and a decrease in HbA1c of 0.5 ± 0.3% (P = 0.08) from baseline. At 2 years, the C therapy group had significant reductions in BMI, fat mass, lean body mass, and systolic blood pressure. The S/C therapy group showed changes in weight and HbA1c in year 2 of the study that were similar to those demonstrated by the C therapy group in year 1.

CONCLUSIONS—This combination weight loss program resulted in significant weight loss and improved diabetes control over a 2-year period in overweight subjects with type 2 diabetes.
Diabetic Retinopathy Is Associated With Mortality and Cardiovascular Disease Incidence
Authors: van Hecke Manon V. , Dekker Jacqueline M. , Stehouwer Coen D.A. , Polak Bettine C.P. , Fuller John H. , Sjolie Anne Katrin , Kofinis Athanasios , Rottiers Raoul , Porta Massimo , Chaturvedi Nish
Published: March 2007

OBJECTIVE—To study the relationship of nonproliferative and proliferative retinopathy with all-cause mortality and cardiovascular disease (CVD) incidence in type 1 diabetic patients and, additionally, the role of cardiovascular risk factors in these associations.

RESEARCH DESIGN AND METHODS—This prospective study included 2,237 type 1 diabetic patients from 31 centers in 16 European countries at baseline, aged 15–60 years, who were examined for retinopathy by taking two-field 45° fundus photographs, which were centrally graded. Mortality and cardiovascular morbidity follow-up was assessed 6–8 years after baseline examination according to a standardized protocol.

RESULTS—After 7.9 years of follow-up, 64 patients had died and 128 patients had incident CVD. The age- and sex-adjusted hazard ratios (HRs) of all-cause mortality were 1.45 (95% CI 0.71–2.96) and 4.16 (1.96–8.84) in patients with nonproliferative and proliferative retinopathy at baseline, respectively. Adjustments for cardiovascular risk factors completely obliterated the association with nonproliferative retinopathy, whereas the association with proliferative retinopathy remained twofold increased, although nonsignificant. The age- and sex-adjusted HRs of incident CVD were 1.73 (1.15–2.60) and 2.05 (1.22–3.45) in patients with nonproliferative and proliferative retinopathy, respectively. After adjustments for cardiovascular risk factors, both associations were attenuated and lost statistical significance.

CONCLUSIONS—This study shows that type 1 diabetic patients with nonproliferative or proliferative retinopathy have an increased risk for all-cause mortality and incident CVD. The presence of cardiovascular risk factors explained the associations to a large extent, except for the associations with proliferative retinopathy, which suggests that other shared mechanisms may be involved.
Serum Adiponectin Is Increased in Type 1 Diabetic Patients With Nephropathy
Authors: Saraheimo Markku , Forsblom Carol , Fagerudd Johan , Teppo Anna-Maija , Pettersson-Fernholm Kim , Frystyk Jan , Flyvbjerg Allan , Groop Per-Henrik ,   on behalf of the FinnDiane Study Group
Published: March 2007

OBJECTIVE—To elucidate whether serum adiponectin is associated with renal function, low-grade inflammatory markers, metabolic control, and insulin resistance in type 1 diabetic patients with and without nephropathy.

RESEARCH DESIGN AND METHODS—A total of 189 type 1 diabetic patients from the Finnish Diabetic Nephropathy Study were divided into three groups based on their urinary albumin excretion rate (AER): patients with normal AER (n = 66) had no antihypertensive medication, while patients with microalbuminuria (n = 63) or macroalbuminuria (n = 60) were all treated with an ACE inhibitor. Renal function was estimated with the Cockcroft-Gault formula. Adiponectin was measured by an in-house time-resolved immunofluorometric assay.

RESULTS—Adiponectin concentrations were higher in women than in men, but since there was no significant difference in sex distribution between the groups, data were pooled. Adiponectin concentrations were higher in patients with macroalbuminuria (19.8 ± 12.0 mg/l) than in patients with microalbuminuria (13.1 ± 4.8 mg/l) or normoalbuminuria (11.8 ± 4.2 mg/l). In a univariate analysis, adiponectin was positively associated with creatinine (r = 0.41; P < 0.0001), AER (r = 0.33; P < 0.0001), interleukin-6 (r = 0.22; P = 0.002), systolic blood pressure (r = 0.22; P = 0.004), HbA1c (r = 0.17; P = 0.02), total cholesterol (r = 0.16; P = 0.03), and HDL cholesterol (r = 0.16; P = 0.03) and negatively with estimated glomerular filtration rate (GFR; r = −0.52; P < 0.0001) and waist-to-hip ratio (WHR; r = −0.16; P = 0.03). In a multiple linear regression analysis including the above variables, estimated GFR, AER, and WHR were independently associated with adiponectin levels (r2 = 0.32).

CONCLUSIONS—Serum adiponectin concentrations are increased in type 1 diabetic patients with nephropathy, and levels are further associated with renal insufficiency.
Foot Small Muscle Atrophy Is Present Before the Detection of Clinical Neuropathy
Authors: Greenman Robert L. , Khaodhiar Lalita , Lima Christina , Dinh Thanh , Giurini John M. , Veves Aristidis
Published: March 2007

OBJECTIVE—To characterize structural changes and the metabolic profile of foot muscles and correlate them with diabetic neuropathy measurements using phosphorus-31 (31P) rapid acquisition with relaxation enhancement (RARE) magnetic resonance imaging (MRI).

RESEARCH DESIGN AND METHODS—We studied 12 control subjects, 9 nonneuropathic diabetic patients, and 12 neuropathic diabetic patients using 31P RARE and proton (1H) MRI at 3 Tesla. The ratio of the total cross-sectional area of the foot to that of the muscle tissue was calculated from transaxial 1H and 31P images. The average 31P concentration across the metatarsal head region was measured from the 31P images.

RESULTS—The muscle area−to−total area ratio differed among all three groups (means ± SD): 0.55 ± 0.04 vs. 0.44 ± 0.05 vs. 0.06 ± 0.06 for control, nonneuropathic, and neuropathic subjects, respectively (P < 0.0001). The average 31P concentration also differed among all groups: 27.7 ± 3.8 vs. 21.7 ± 4.8 vs. 7.9 ± 8.8 mmol/l for control, nonneuropathic, and neuropathic subjects (P < 0.0001). The muscle area−to−total area ratio strongly correlated with clinical measurements: Neuropathy Disability Score, r = −0.83, P < 0.0001; vibration perception threshold, r = −0.79, P < 0.0001; and Semmes-Weinstein monofilaments, r = −0.87, P < 0.0001.

CONCLUSIONS—Small muscle atrophy is present in diabetes before clinical peripheral neuropathy can be detected using standard clinical techniques. The 31P RARE MRI method evaluates the severity of muscle atrophy, even in the early stages when neuropathy is absent. This technique may prove to be a useful diagnostic tool in identifying early-stage diabetic foot problems.
Vital Capacity as a Predictor of Incident Type 2 Diabetes
Authors: Yeh Hsin-Chieh , Punjabi Naresh M. , Wang Nae-Yuh , Pankow James S. , Duncan Bruce B. , Brancati Frederick L.
Published: March 2007

OBJECTIVE—To test the hypothesis that lower vital capacity is cross-sectionally associated with features of insulin resistance and is an independent predictor of incident type 2 diabetes.

RESEARCH DESIGN AND METHODS—We conducted a prospective cohort study of vital capacity as a predictor of incident type 2 diabetes using 9-year follow-up data on 11,479 middle-aged adults without diabetes at baseline from the Atherosclerosis Risk in Communities (ARIC) Study.

RESULTS—Forced vital capacity (FVC) and forced expiratory volume in 1 s were measured at baseline using standard spirometry. Incident type 2 diabetes cases were ascertained during follow-up. At baseline, low FVC (% predicted) was independently associated with indicators of the insulin resistance syndrome, including higher fasting levels of glucose, insulin, and triglycerides; lower fasting HDL cholesterol; and higher systolic blood pressure. In prospective analyses, there were graded associations between low FVC (% predicted) and incidence of type 2 diabetes in men and women. These associations persisted in multivariable analyses that adjusted for age, race, adiposity, smoking, physical activity, and ARIC center. Compared with individuals in the highest quartile of FVC (% predicted), the fully adjusted hazard ratio (95% CI) of diabetes in individuals in the lowest quartile was 1.6 (1.3–2.0) in men and 1.7 (1.3–2.1) in women. These relationships were stronger in those who have never smoked.

CONCLUSIONS—Lower vital capacity is an independent predictor of incident type 2 diabetes. Pulmonary factors related to vital capacity deserve attention as possible risk factors for insulin resistance and diabetes.
A Clinical Trial of Continuous Subcutaneous Insulin Infusion Versus Multiple Daily Injections in Older Adults With Type 2 Diabetes
Authors: Herman William H. , Ilag Liza L. , Johnson Susan L. , Martin Catherine L. , Sinding Joyce , Al Harthi Abdulaziz , Plunkett Cynthia D. , LaPorte Frankie B. , Burke Ray , Brown Morton B. , Halter Jeffery B. , Raskin Philip
Published: March 2007

OBJECTIVE—To compare the efficacy and safety of continuous subcutaneous insulin infusion (CSII) and multiple daily injection (MDI) in older adults with insulin-treated type 2 diabetes and to assess treatment satisfaction and quality of life.

RESEARCH DESIGN AND METHODS—Adults (n = 107) ≥60 years of age (mean age 66 years) with insulin-treated type 2 diabetes (mean duration 16 years, BMI 32 kg/m2, and HbA1C [A1C] 8.2%) were randomized to CSII (using insulin lispro) or MDI (using insulin lispro and insulin glargine) in a two-center, 12-month, prospective, randomized, controlled clinical trial. Efficacy was assessed with A1C, safety by frequency of hypoglycemia, and treatment satisfaction and quality of life with the Diabetes Quality of Life Clinical Trial Questionnaire and the 36-item short-form health survey, version 2.

RESULTS—Forty-eight CSII subjects (91%) and 50 MDI subjects (93%) completed the study. Mean A1C fell by 1.7 ± 1.0% in the CSII group to 6.6% and by 1.6 ± 1.2% in the MDI group to 6.4%. The difference in A1C between treatment groups was not statistically significant (P = 0.20). Eighty-one percent of CSII subjects and 90% of MDI subjects experienced at least one episode of minor (self-treated) hypoglycemia (P = 0.17), and three CSII and six MDI subjects experienced severe hypoglycemia (P = 0.49). Rates of severe hypoglycemia were similarly low in the two groups (CSII 0.08 and MDI 0.23 events per person-year, P = 0.61). Weight gain did not differ between groups (P = 0.70). Treatment satisfaction improved significantly with both CSII and MDI (P < 0.0001), and the difference between groups was not statistically significant (P = 0.58).

CONCLUSIONS—In older subjects with insulin-treated type 2 diabetes, both CSII and MDI achieved excellent glycemic control with good safety and patient satisfaction.
Use of Inhaled Insulin in a Basal/Bolus Insulin Regimen in Type 1 Diabetic Subjects
Authors: Skyler Jay S. , Weinstock Ruth S. , Raskin Philip , Yale Jean-François , Barrett Eugene , Gerich John E. , Gerstein Hertzel C. ,   the Inhaled Insulin Phase III Type 1 Diabetes Study Group
Published: March 2007

OBJECTIVE—Despite the demonstrated benefits of glycemic control, patient acceptance of basal/bolus insulin therapy for type 1 diabetes has been slow. We investigated whether a basal/bolus insulin regimen involving rapid-acting, dry powder, inhaled insulin could provide glycemic control comparable with a basal/bolus subcutaneous regimen.

RESEARCH DESIGN AND METHODS—Patients with type 1 diabetes (ages 12–65 years) received twice-daily subcutaneous NPH insulin and were randomized to premeal inhaled insulin (n = 163) or subcutaneous regular insulin (n = 165) for 6 months.

RESULTS—Mean glycosylated hemoglobin (A1C) decreased comparably from baseline in the inhaled and subcutaneous insulin groups (−0.3 and −0.1%, respectively; adjusted difference −0.16% [CI −0.34 to 0.01]), with a similar percentage of subjects achieving A1C <7%. Although 2-h postprandial glucose reductions were comparable between the groups, fasting plasma glucose levels declined more in the inhaled than in the subcutaneous insulin group (adjusted difference −39.5 mg/dl [CI −57.5 to −21.6]). Inhaled insulin was associated with a lower overall hypoglycemia rate but higher severe hypoglycemia rate. The overall hypoglycemia rate (episodes/patient-month) was 9.3 (inhaled) vs. 9.9 (subcutaneous) (risk ratio [RR] 0.94 [CI 0.91–0.97]), and the severe hypoglycemia rate (episodes/100 patient-months) was 6.5 vs. 3.3 (RR 2.00 [CI 1.28–3.12]). Increased insulin antibody serum binding without associated clinical manifestations occurred in the inhaled insulin group. Pulmonary function between the groups was comparable, except for a decline in carbon monoxide−diffusing capacity in the inhaled insulin group without any clinical correlates.

CONCLUSIONS—Inhaled insulin may provide an alternative for the management of type 1 diabetes as part of a basal/bolus strategy in patients who are unwilling or unable to use preprandial insulin injections.
Race-Specific Differences in Antioxidant Enzyme Activity in Patients With Type 2 Diabetes
Authors: Zitouni Karima , Nourooz-Zadeh Jaffar , Harry Diane , Kerry Sally M. , Betteridge D. John , Cappuccio Francesco P. , Earle Kenneth A.
Published: March 2007

OBJECTIVE—Lipid hydroperoxide, a marker of oxidative stress, is linked to the development of nephropathy and is reportedly higher in patients of African origin compared with Caucasians. This may be relevant to race-specific differences in susceptibility to nephropathy. We investigated whether alterations in antioxidant enzyme activity could account for this biochemical phenotype and examined the relationship with conventional markers of renal disease.

RESEARCH DESIGN AND METHODS—Two hundred seventeen individuals were studied. Patients with type 2 diabetes (n = 75) of African and Caucasian origin were matched by sex and racial origin with healthy control subjects (n = 142). Plasma total superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity were spectrophotometrically measured, and total cholesterol and triglycerides were measured by enzymatic methods.

RESULTS—SOD activity was higher and GPx activity lower in patients with diabetes than in healthy control subjects (573 ± 515 vs. 267 ± 70 units/l, P < 0.001 and 150 ± 93 vs. 178 ± 90 units/l, P = 0.019, respectively). Patients of African origin with diabetes had lower GPx and higher SOD activity compared with Caucasian patients (126 ± 82 vs. 172 ± 97 units/l, P = 0.03 and 722 ± 590 vs. 445 ± 408 units/l, P = 0.002, respectively). Patients of African origin with normal urinary albumin excretion had significantly higher plasma creatinine concentrations (100.7 ± 14.2 vs. 88.1 ± 14.9 μmol/l, P = 0.007) and lower GPx activity (99.0 ± 72.4 vs. 173.7 ± 107.4 units/l, P = 0.02) compared with those of Caucasian origin. African origin was an independent predictor of elevated SOD (P = 0.007) and reduced GPx activity (P = 0.02) in regression analysis.

CONCLUSIONS—SOD and GPx enzyme activities vary according to race and could account for differences in lipid hydroperoxide. In patients of African origin, susceptibility to renal disease may be associated with lowered GPx activity.
Peripheral Total and Differential Leukocyte Count in Diabetic Nephropathy
Authors: Chung Fu-Mei , Tsai Jack C.-R. , Chang Dao-Ming , Shin Shyi-Jang , Lee Yau-Jiunn
Published: March 2007

OBJECTIVE—Because of increasing evidence that white blood cells (WBCs) play a role in the development and progression of diabetes complications, this study aimed to investigate the relation of circulating total and differential leukocyte counts to nephropathy in patients with type 2 diabetes. Plasma leptin levels were also measured to investigate their role in peripheral leukocytosis.

RESEARCH DESIGN AND METHODS—For this study, 1,480 subjects with type 2 diabetes who were enrolled in a disease management program were stratified according to urinary microalbumin and serum creatinine measurements. The total and differential leukocyte profiles of peripheral blood were measured and plasma leptin was examined by enzyme-linked immunosorbent assay. Demographic and potential metabolic confounding factors were analyzed with linear and logistic regression to calculate the effects of leukocyte count on diabetic nephropathy.

RESULTS—The peripheral total WBC, monocyte, and neutrophil counts increased in parallel with the advancement of diabetic nephropathy. In contrast, the lymphocyte count decreased. When WBC counts were analyzed per quartile and as continuous variables after adjusting for age, sex, and other known risk factors with multiple regression analysis, peripheral total WBC, monocyte, neutrophil, and lymphocyte counts were independently and significantly associated with diabetic nephropathy. Plasma leptin levels increased in patients with nephropathy and correlated significantly with total WBC count (r = 0.194, P = 0.014).

CONCLUSIONS—Because leukocytes are activated and secrete cytokines in the diabetic state and leptin stimulates leukocyte proliferation and differentiation, our results suggest that circulating leukocytes contribute to the development and progression of nephropathy, partially through the effects of leptin, in patients with type 2 diabetes.
Urinary Albumin Excretion Rate Is Associated With Increased Ambulatory Blood Pressure in Normoalbuminuric Type 2 Diabetic Patients
Authors: Leitão Cristiane B. , Canani Luís H. , Bolson Patrícia B. , Molon Marcel P. , Pinotti Antônio F. , Gross Jorge L.
Published: March 2007

OBJECTIVE—To evaluate the 24-h blood pressure profile in normoalbuminuric type 2 diabetic patients.

RESEARCH DESIGN AND METHODS—A cross-sectional study was conducted in 90 type 2 diabetic patients with a urinary albumin excretion rate (UAER) <20 μg/min on two occasions, 6 months apart (immunoturbidimetry). Patients underwent clinical and laboratory evaluations. Ambulatory blood pressure monitoring and echocardiograms were also performed.

RESULTS—UAER was found to correlate positively with systolic doctor’s office blood pressure measurements (r = 0.243, P = 0.021) and ambulatory blood pressure (24 h: r = 0.280, P = 0.008) and left ventricular posterior wall thickness (r = 0.359, P = 0.010). Patients were divided into four groups according to UAER (<5, ≥5–10, ≥10–15, and ≥15–20 μg/min). Systolic blood pressure parameters for the 1st, 2nd, 3rd, and 4th groups, respectively, were 123.0 ± 10.6, 132.5 ± 15.0, 139.0 ± 23.4, and 130.7 ± 8.0 mmHg for 24-h blood pressure (ANOVA P = 0.004) and 48.4 ± 6.0, 54.5 ± 11.2, 58.8 ± 15.6, and 57.6 ± 8.0 mmHg for 24-h pulse pressure (ANOVA P = 0.003). A progressive increase in the prevalence of diabetic retinopathy was observed from the 1st to the 4th UAER group: 27.3, 43.8, 45.5, and 66.7% (P = 0.029 for trend).

CONCLUSIONS—In type 2 diabetic patients, UAER in the normoalbuminuric range is positively associated with systolic ambulatory blood pressure indexes, left ventricular posterior wall thickness, and diabetic retinopathy, suggesting that intensive blood pressure treatment may prevent diabetes complications in these patients.
Risks for All-Cause Mortality, Cardiovascular Disease, and Diabetes Associated With the Metabolic Syndrome
Authors: Ford Earl S.
Published: March 2007

OBJECTIVE—In recent years, several major organizations have endorsed the concept of the metabolic syndrome and developed working definitions for it. How well these definitions predict the risk for adverse events in people with the metabolic syndrome is only now being learned. The purpose of this study was to summarize the estimates of relative risk for all-cause mortality, cardiovascular disease, and diabetes reported from prospective studies in samples from the general population using definitions of the metabolic syndrome developed by the National Cholesterol Education Program (NCEP) and World Health Organization (WHO).

RESEARCH DESIGN AND METHODS—The author reviewed prospective studies from July 1998 through August 2004.

RESULTS—For studies that used the exact NCEP definition of the metabolic syndrome, random-effects estimates of combined relative risk were 1.27 (95% CI 0.90–1.78) for all-cause mortality, 1.65 (1.38–1.99) for cardiovascular disease, and 2.99 (1.96–4.57) for diabetes. For studies that used the most exact WHO definition of the metabolic syndrome, the fixed-effects estimates of relative risk were 1.37 (1.09–1.74) for all-cause mortality and 1.93 (1.39–2.67) for cardiovascular disease; the fixed-effects estimate was 2.60 (1.55–4.38) for coronary heart disease.

CONCLUSIONS—These estimates suggest that the population-attributable fraction for the metabolic syndrome, as it is currently conceived, is ∼6–7% for all-cause mortality, 12–17% for cardiovascular disease, and 30–52% for diabetes. Further research is needed to establish the use of the metabolic syndrome in predicting risk for death, cardiovascular disease, and diabetes in various population subgroups.
Foot Ulcer Risk Is Lower in South-Asian and African-Caribbean Compared With European Diabetic Patients in the U.K.
Authors: Abbott Caroline A. , Garrow Adam P. , Carrington Anne L. , Morris Julie , Van Ross Ernest R. , Boulton Andrew J.
Published: March 2007

OBJECTIVE—To determine 1) foot ulcer rates for European, South-Asian, and African-Caribbean diabetic patients in the U.K and 2) the contribution of neuropathy and peripheral arterial disease (PAD) differences to altered ulcer risk between the groups.

RESEARCH DESIGN AND METHODS—In this U.K. population–based study, we screened 15,692 type 1 and type 2 diabetic patients in the community health care setting for foot ulcers, foot deformities, neuropathy, and PAD plus other characteristics. In total, 13,409 were European (85.5%), 1,866 were South Asian (11.9%), and 371 were African Caribbean (2.4%).

RESULTS—The age-adjusted prevalence of diabetic foot ulcers (past or present) for Europeans, South Asians, and African Caribbeans was 5.5, 1.8, and 2.7%, respectively (P < 0.0001). Asians and African Caribbeans had less neuropathy, PAD, and foot deformities than Europeans (P = 0.003). The unadjusted risk of ulcer (odds ratio [OR]) for Asians versus Europeans was 0.29 (95% CI 0.20–0.41) (P < 0.0001). PAD, neuropathy, foot deformities, and insulin use attenuated the age-adjusted OR from 0.32 to 0.52 (0.35–0.76) (P < 0.0001). African-Caribbean versus European ulcer risk in males was attenuated from 0.60 to 0.71 by vibration sensation.

CONCLUSIONS—South Asians with diabetes in the U.K. have about one-third the risk of foot ulcers of Europeans. The lower levels of PAD, neuropathy, insulin usage, and foot deformities of the Asians account for approximately half of this reduced foot ulcer risk. Lower neuropathy is the main contributor to the reduced African-Caribbean ulcer rate, particularly in men. The reasons for these ethnic differences warrant further investigation.
Pharmacokinetics, Prandial Glucose Control, and Safety of Insulin Glulisine in Children and Adolescents With Type 1 Diabetes
Authors: Danne Thomas , Becker Reinhard H. A. , Heise Tim , Bittner Claudia , Frick Annke D. , Rave Klaus
Published: March 2007

OBJECTIVE—The aim of this study was to investigate the pharmacokinetics, postprandial blood glucose excursions, and safety of insulin glulisine as compared with regular human insulin (RHI), both administered immediately before meals in pediatric patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS—A total of 10 children (aged 5–11 years) and 10 adolescents (aged 12–17 years) were enrolled in a randomized, single-center, single-dose, double-blind, cross-over study. The blood glucose of fasting patients was stabilized with intravenous insulin, following which patients received 0.15 IU/kg of subcutaneously injected insulin glulisine or RHI 2 min before a weight-adjusted standardized liquid meal.

RESULTS—For insulin glulisine versus RHI, maximum insulin concentrations (58 vs. 33 μIU/ml, P < 0.05) and initial insulin concentrations (insulin [area under the curve] AUC0–2h 5,232 vs. 2,994 μIU · min−1 · ml−1, P < 0.05; data are geometric means) were higher after insulin glulisine than RHI. Both time to maximum insulin concentration (54 vs. 66 min) and mean residence time (88 vs. 137 min, P < 0.05) were shorter with insulin glulisine versus RHI. Postprandial glucose excursions after insulin glulisine were lower than after RHI (glucose AUC0–6h 641 vs. 801 mg · h−1 · dl−1, P < 0.05). The pharmacokinetic profile for insulin glulisine was similar for children and adolescents, whereas the pharmacokinetic profile for RHI demonstrated a 64% higher concentration in adolescents. Insulin glulisine was safe and well tolerated.

CONCLUSIONS—The rapid-acting properties of insulin glulisine that have been previously demonstrated in adults are also observed in children and adolescents with type 1 diabetes. Further, these initial data indicate that insulin glulisine is safe and well tolerated in this patient population.