RESEARCH DESIGN AND METHODS—Seventy regions of elevated barefoot pressures (mean peak 834 kPa under MTHs) were identified in 20 subjects with diabetes. Foam box impressions of their feet were sent to three different orthotic supply companies for fabrication of custom insoles. One company was also given plantar pressure data, which were incorporated into the insole design. Measurements of in-shoe plantar pressures were recorded during gait for the three custom insoles in a flexible and a rocker-bottom shoe. Peak pressure and force-time integral were extracted for analysis.

RESULTS—In 64 of 70 regions, the shape-plus-pressure–based insole in the flexible shoe achieved superior unloading compared with the two shape-based insoles. On average, peak pressure was reduced by 32 and 21% (both P ≤ 0.0001) and force-time integral by 40 and 34% (both P < 0.0001) compared with the shape-based insoles. At the midfoot, force-time integral was increased by 51 and 33% (both P < 0.01). Similar trends were found using the rocker-bottom shoe.

CONCLUSIONS—Compared with insoles based only on shape, the use of foot shape with barefoot plantar pressure measurements in designing custom insoles results in enhanced offloading of high-pressure areas under the forefoot. This offloading was achieved by a greater transfer of load to the midfoot without additional loading of other forefoot structures.

RESEARCH DESIGN AND METHODS—Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures.

RESULTS—In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2–19.1) with rosiglitazone, 7.3% (4.4–10.1) with metformin, and 7.7% (3.7–11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17–2.80) and 2.13 (1.30–3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified.

CONCLUSIONS—Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings.

RESEARCH DESIGN AND METHODS—In this 24-week, multicenter, parallel-group, randomized, treat-to-target study, 321 Chinese insulin-naïve subjects with poorly controlled type 2 diabetes (fasting blood glucose ≥7.8 mmol/l and A1C ≥7.5%) were randomized (1:1) to twice- or thrice-daily (BID and TID groups, respectively) BIAsp 30 without OADs. Initial insulin doses were based on fasting blood glucose at randomization. Insulin dose was adjusted with algorithm-controlled titration to achieve premeal blood glucose of 4.4–6.1 mmol/l.

RESULTS—A1C decreased significantly in both groups (BID group –2.48 ± 0.07%; TID group –2.81 ± 0.07%). Thrice-daily BIAsp 30 showed superiority in A1C improvement (–0.33% [95% CI –0.53 to –0.13]; P < 0.01) and helped more subjects achieve A1C targets <7% (BID group 51.3% vs. TID group 65.8%; P < 0.01). Thrice-daily BIAsp 30 was more effective in subjects with baseline A1C ≥9% (<7%: BID group 41.5% vs. TID group 58.3%; P < 0.01). There was no significant difference in rates of overall and nocturnal major and minor hypoglycemia per subject year between groups. No significant differences in weight gain (BID group 3.87 ± 0.28 kg; TID group 4.09 ± 0.27 kg) and mean daily insulin doses (BID group 0.82 ± 0.28 units/kg; TID group 0.86 ± 0.34 units/kg) were observed.

CONCLUSIONS—Twice- and thrice-daily BIAsp 30 were effective in Chinese insulin-naïve subjects with poorly controlled type 2 diabetes. Thrice-daily BIAsp 30 offered greater reduction in A1C without increasing risk of hypoglycemia, insulin dose, and weight gain, especially in subjects with A1C ≥9%.

RESEARCH DESIGN AND METHODS—Overweight, middle-aged volunteers with impaired glucose tolerance were randomly assigned to intensive lifestyle intervention (n = 265) or to a control group (n = 257) for a median of 4 years. Diabetes status was ascertained annually with repeated oral glucose tolerance testing. Incidence rates of diabetes and hazard ratios (HRs) comparing the intervention group with the control group were calculated by sex and baseline tertiles of age, BMI, waist circumference, plasma glucose concentration at fasting and 2 h after a glucose load, fasting serum insulin and insulin resistance index, and categories of composite baseline Finnish Diabetes Risk Score (FINDRISC). Interactions between the intervention assignment and baseline risk factors on diabetes risk were analyzed.

RESULTS—The intervention was most effective among the oldest individuals (HRs 0.77, 0.49, and 0.36 by increasing age tertiles, respectively; P_interaction = 0.0130) and those with a high baseline FINDRISC (HRs 1.09, 0.84, 0.34, and 0.22 by increasing risk score category, respectively; P_interaction = 0.0400). The effect of the intervention on diabetes risk was not modified by other baseline characteristics or risk factors.

CONCLUSIONS—The FINDRISC may be useful in identifying high-risk groups most likely to benefit from intensive lifestyle intervention to prevent type 2 diabetes.

RESEARCH DESIGN AND METHODS—The evaluation of the SDMP in Germany represents a real-world study by using clinical data collected from participating physicians. Between 2000 and 2002 all DSPs and about 75% of the GPs in Saxony participated. Finally, 291,771 patients were included in the SDMP. Cross-sectional data were evaluated at the beginning of 2000 (group A1) and at the end of 2002 (group A2). A subcohort of 105,204 patients was followed over a period of 3 years (group B).

RESULTS—The statewide implementation of the SDMP resulted in a change in therapeutic practice and in better cooperation. The median A1C at the time of referral to DSPs decreased from 8.5 to 7.5%, and so did the overall mean. At the end, 78 and 61% of group B achieved the targets for A1C and blood pressure, respectively, recommended by the guidelines compared with 69 and 50% at baseline. Patients with poorly controlled diabetes benefited the most. Preexisting regional differences were aligned.

CONCLUSIONS—Integrated care disease management with practicable integrated quality management including collaboration between GPs and specialist services is a significant innovation in chronic care management and an efficient way to improve diabetes care continuously.

RESEARCH DESIGN AND METHODS—Hierarchical linear models were used to investigate A1C among 1,381 patients, nested within 42 randomly assigned primary care physicians at a Veterans Affairs medical center in the southeastern U.S. The primary outcome measure was change in A1C over the course of 1 year in treatment. On average, each study physician had 33 patients with diabetes.

RESULTS—Overall, physician-related factors were associated with statistically significant but modest variability in A1C change (2%), whereas patient-level factors accounted for the majority of variation in A1C change (98%). Physician effects varied by patient characteristics, mattering more for black patients, patients aged 65 years, and patients whose glucose management improved over the treatment year.

CONCLUSIONS—The results of this study indicate that differential physician effects have minimal impact on glycemic control. Results suggest that it is logical to support policies encouraging the development of patient-level behavioral interventions because that is the level that accounts for the majority of variance in glycemic control.

RESEARCH DESIGN AND METHODS—The reliability and validity of the three HL scales were evaluated in a sample of 138 outpatients with type 2 diabetes. In addition, sociodemographic and clinical characteristics, knowledge of diabetes, information-seeking behaviors, and self-efficacy were assessed for each patient through a self-report questionnaire and review of electronic medical records.

RESULTS—Scale items were constructed to directly reflect the definition of HL. Internal consistency of functional, communicative, and critical HL scales was adequately high ( = 0.84, = 0.77, and = 0.65, respectively). Three interpretable factors were identified in exploratory factor analysis. Correlations between HL scales and other measures supported the construct validity of the scales. The three HL scales were only moderately correlated with each other, suggesting that each represents a different domain of HL abilities and skills.

CONCLUSIONS—Our newly developed HL scales are reliable and valid measures of three types of HL in diabetic patients. Exploring a patient's HL levels may provide a better understanding of the patient's potential barriers to self-management of disease and health-promoting behaviors.

RESEARCH DESIGN AND METHODS—Data on a cohort of 14,500 male veterans with type 2 diabetes were analyzed. Diagnoses of depression and diabetes were based on ICD-9 codes. Persistent recognition was defined as an ICD-9 code for depression documented in at least the second or third visit after the initial diagnosis of depression. Hazards of death were compared using Cox proportional hazards regression models adjusting for relevant covariates.

RESULTS—Over 10 years, 2,305 deaths were documented. Mortality risk was higher for depressed than nondepressed veterans with diabetes (hazard ratio [HR] 1.6 [95% CI 1.3–1.8]). Among those with depression, mortality risk was lower with persistent recognition (0–2 visits vs. ≥3 visits after initial diagnosis, HR 0.58 [0.40–0.89]) but higher for whites than blacks (1.60 [1.11–2.31]).

CONCLUSIONS—Increased mortality from depression differs by ethnicity and persistent recognition.

RESEARCH DESIGN AND METHODS—The following message was printed on the lab reports of individuals with a fasting plasma glucose (FPG) concentration between 5.5 and 6.9 mmol/l: "A FPG between 5.5 and 6.9 mmol/l is considered abnormal by the American Diabetes Association (impaired fasting glucose). An OGTT is recommended if the patient does not have a diagnosis of diabetes and suffers from conditions associated with an increased risk for having type 2 diabetes (i.e., overweight, high blood pressure, abnormal plasma lipids or family history of diabetes)." The number of educational messages printed was 81,099.

RESULTS—The intervention resulted in a significant increase in the number of OGTTs requested, from 78 ± 19 to 268 ± 48 tests per month. It also resulted in a greater proportion of case subjects that had an abnormal OGTT result.

CONCLUSIONS—Educational messages in laboratory reports aid in the diagnostic workup of hyperglycemia.

RESEARCH DESIGN AND METHODS—Random plasma glucose (RPG) was measured and 75-g oral glucose tolerance tests were performed in 1,139 individuals without known diabetes. Screening performance was assessed by logistic regression and area under the receiver operating characteristic curve (AROC).

RESULTS—NIDDK/ADA indicators age >45 years and BMI >25 kg/m² provided significant detection of both diabetes and dysglycemia (both AROCs 0.63), but screening was better with continuous-variable models of age, BMI, and race and better still with models of age, BMI, race, sex, and family history (AROC 0.78 and 0.72). However, screening was even better with RPG alone (AROCs 0.81 and 0.72). RPG >125 mg/dl could be used to prompt further evaluation with an OGTT.

CONCLUSIONS—Use of age, BMI, and race/ethnicity in guidelines for screening to detect diabetes and pre-diabetes may be less important than evaluation of RPG. RPG should be investigated further as a convenient, inexpensive screen with good predictive utility.

RESEARCH DESIGN AND METHODS—We did a population-based cohort study by linking nationwide databases in Sweden. We identified 1,840 patients in the Swedish Vascular Registry who had their first leg bypass procedure for critical lower-limb ischemia between 1 January 2001 and 31 December 2003—742 with and 1,098 without diabetes. Our primary end point was first major amputation of the limb on which bypass was done or death. Individuals were followed up until 31 December 2005 through the National Hospital Patient Registry and the Cause-of-Death Registry.

RESULTS—Incidence of ipsilateral amputation or death was higher in patients with diabetes than in patients without (30.2 vs. 22 events/100 person-years; crude hazard ratio [HR] 1.32 [95% CI 1.17–1.50]). Similarly, individuals with diabetes had a shorter amputation-free survival period than individuals without (2.3 years, range 1.9–2.8 vs. 3.4 years, range 3.1–3.7). Adjustment for demographic characteristics, comorbidities, and risk factors for amputation or death did not substantially affect the risk (HR 1.46 [95% CI 1.26–1.69]). The effect was more pronounced in male (1.75 [1.47–2.08]) than in female (1.35 [1.11–1.64]) patients after adjustment for age.

CONCLUSIONS—Diabetes is associated with lower amputation–free survival after leg bypass for critical limb ischemia. Patients with diabetes and limb ischemia need intensified treatment of diabetes-related risk factors to improve outcome.

RESEARCH DESIGN AND METHODS—Subjects aged ≥20 years were studied in Tamilnadu, India, in Chennai (city, n = 2,192; 1,053 men and 1,138 women), Kanchipuram (town, n = 2,290; 988 men and 1,302 women), and Panruti (PUVs, n = 2,584; 1,280 men and 1,304 women) in 2006. Demographic, socioeconomic, and anthropometric details; blood pressure; physical activity; diet habits; and lipids were studied. Risk associations with diabetes were analyzed using multiple logistic regression analyses. Present and previous data in the city and the PUVs were compared.

RESULTS—Mean BMI, waist circumference, and family history of diabetes were significantly lower in the PUVs. The PUVs had a lower prevalence of diabetes (9.2 [95% CI 8.0–10.5], P < 0.0001) than the city (18.6 [16.6–20.5]) and town (16.4 [14.1–18.6]). Approximately 40% of subjects were newly diagnosed. Prevalence of impaired glucose tolerance (IGT) was higher (P < 0.0001) in the city (7.4 [6.2–8.5]) than in the town (4.3 [3.3–5.3]) and the PUVs (5.5 [4.6–6.5]). Prevalence of IFG was generally low. Age, family history, and waist circumference were significantly associated with diabetes, while physical activity was not. Overweight, elevated waist circumference, hypertension, and dyslipidemia were more prevalent in the city.

CONCLUSIONS—In the city, diabetes increased from 13.9 to 18.6% in 6 years and IGT decreased significantly. The town and city had similar prevalences; the PUVs had lower diabetes prevalence, but prevalence had increased compared with that in a previous survey. Cardiometabolic abnormalities were more prevalent in urban populations.

RESEARCH DESIGN AND METHODS—In this retrospective study of 175,249 women aged 13–58 years with 209,287 singleton deliveries of ≥20 weeks’ gestation from 1999 through 2005 in all Kaiser Permanente hospitals in southern California, information from clinical databases and birth certificates was used to estimate the prevalence of preexisting diabetes and GDM.

RESULTS—Preexisting diabetes was identified in 2,784 (1.3%) of all pregnancies, rising from an age- and race/ethnicity-adjusted prevalence of 0.81 per 100 in 1999 to 1.82 per 100 in 2005 (P_trend < 0.001). Significant increases were observed in all age-groups and all racial/ethnic groups. After women with preexisting diabetes were excluded, GDM was identified in 15,121 (7.6%) of 199,298 screened pregnancies. The age- and race/ethnicity-adjusted GDM prevalence remained constant at 7.5 per 100 in 1999 to 7.4 per 100 in 2005 (P_trend = 0.07). Among all deliveries to women with either form of diabetes, 10% were due to preexisting diabetes in 1999, rising to 21% in 2005, with GDM accounting for the remainder.

CONCLUSIONS—The stable prevalence of GDM and increase in the prevalence of preexisting diabetes were independent of changes in the age and race/ethnicity of the population. The increase in preexisting diabetes, particularly among younger women early in their reproductive years, is of concern.

RESEARCH DESIGN AND METHODS—We related diabetes and TCF7L2 variation with occurrence of several common cancers in a prospective cohort study of 13,117 middle-aged adults initially free of cancer in 1987–1989. We assessed five single nucleotide polymorphisms (SNPs) in TCF7L2 including the putative SNP (rs7903146) for diabetes. We identified incident cancers through 2000 via cancer registries, supplemented by hospital records.

RESULTS—Diabetes was associated marginally inversely with incidence of prostate cancer but not with incidence of colorectal, colon, lung, or breast cancer. The T allele of rs7903146 (frequency 30%) was associated with increased risk of colorectal cancer and, more specifically, colon cancer, with adjusted hazard ratios (95% CI) of 1.0 for CC, 1.25 (0.85–1.83) for CT, and 2.15 (1.27–3.64) for TT genotypes (P_trend = 0.009). TCF7L2 variation also was associated with lung cancer incidence in whites but not blacks, but residual confounding by smoking may be present.

CONCLUSIONS—Subjects who were initially cancer-free and carrying certain genetic variants of TCF7L2, most notably the T allele of rs7903146, have an increased risk of colon cancer. This association appears to be an independent gene effect not explained by diabetes. Because the T allele of rs7903146 is common, if a causal link is established, this variant could account for a sizable proportion (~17% here) of cases of colon cancer in the general population.

RESEARCH DESIGN AND METHODS—We examined the association of CRP single nucleotide polymorphisms (SNPs) (m772A>G, m301G>A >T, i178T>A, 3u1273C>T, and 3u2131C>T) with baseline plasma CRP levels among 1,123 white U.S. participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study and the modulating effect of these SNPs on CRP response to a 3-week fenofibrate treatment among 290 participants with the metabolic syndrome.

RESULTS—There were strong associations of m301G>A>T (rs3091244; P = 0.003), i178T>A (rs1417938; P = 0.001), 3u1273C>T (rs1130864; P = 0.001), and 3u2131C>T (rs1205; P < 0.001) with baseline CRP levels. Moreover, among subjects with the metabolic syndrome, fenofibrate induced the greatest reduction in CRP levels for TT subjects of the i178T>A compared with TA and AA subjects (–30 for TT, –19 for TA, and –11% for AA; P = 0.004). Similarly, for the m301G>A>T, major allele carriers displayed maximal reduction of CRP over noncarriers (–20 for GG, –15 for GA and GT, and –0.3% for TA and AA; P = 0.020).

CONCLUSIONS—Our results demonstrate that common genetic variants within the CRP gene affect baseline CRP levels and further modulate CRP response in subjects with the metabolic syndrome treated with fenofibrate. This knowledge could contribute to a better prediction of therapeutic success.

RESEARCH DESIGN AND METHODS—We used a retrospective, longitudinal repeated-measures design to model the contribution of medication adherence to black-white differences in A1C among type 2 diabetic patients at a large multispecialty group practice. We identified 1,806 adult (aged ≥18 at diagnosis) patients (467 black and 1,339 white) with newly initiated oral hypoglycemic therapy between 1 December 1994 and 31 December 2000. Race was identified using an electronic medical record and patient self-report. Baseline was defined as the 13 months preceding and included the month of therapy initiation. All patients were required to have at least 12 months of follow-up.

RESULTS—At initiation of therapy, black patients had higher average A1C values compared with whites (9.8 vs. 8.9, a difference of 0.88; P < 0.0001). Blacks had lower average medication adherence during the first year of therapy (72 vs. 78%; P < 0.0001). Although more frequent medication refills were associated with lower average A1C values, adjustment for adherence did not eliminate the black-white gap.

CONCLUSIONS—We found persistent racial differences in A1C that were not explained by differences in medication adherence. Our findings suggest that targeting medication adherence alone is unlikely to reduce disparities in glycemic control in this setting. Further research is needed to explore possible genetic and environmental determinants of higher A1C among blacks at diagnosis, which may represent a critical period for more intensive intervention.

RESEARCH DESIGN AND METHODS— Subjects with type 1 diabetes from a population-based register in Yorkshire, U.K., diagnosed between 1978 and 2004 were linked to the U.K. National Health Service Central Register for death notifications. Deaths were coded using ICD-9 (1979–2000) and ICD-10 (2001–2005). Standardized mortality ratios (SMRs) were calculated using expected numbers of deaths from U.K. mortality rates by cause of death and age at diagnosis.

RESULTS—A total of 4,246 individuals were followed up, providing 50,471 person-years of follow-up. Mean follow-up length was 12.8 years for individuals aged 0–14 years and 8.3 for those aged 15–29 years. Overall, 108 patients died, of whom 77 (71%) were male. A total of 74 (1.7/1,000 person-years) deaths occurred in inidividuals aged 0–14 years and 34 (4.6/1,000 person-years) in those aged 15–29 years. The SMR was 4.7 (95% CI 3.8–5.6) overall, similar for males and females, but higher for individuals aged 15–29 years (SMR 6.2 [95% CI 4.3–8.6]) compared with those aged 0–14 years (4.2 [3.3–5.3]). The SMR rose with increasing disease duration. A total of 47 of 108 deaths (44%) occurred from diabetes complications, 32 of which were acute and 15 chronic. Twenty-two percent (n = 24) of deaths were attributed to accidents or violence (SMR 2.1 [95% CI 1.4–3.2]), including six suicides. Sixteen percent of all deaths were related to drug misuse (including insulin but excluding tobacco and alcohol) (SMR 6.4 [95% CI 3.7–10.2]).

CONCLUSIONS—Subjects with type 1 diabetes diagnosed under 30 years of age had a 4.7-fold excess mortality risk. Nearly half of the deaths were due to acute or chronic complications of diabetes. Drug misuse–related deaths may be an emerging trend in this population warranting further investigation.

RESEARCH DESIGN AND METHODS—Data from 18,651 clinical outpatient visits (1,033 girls and 1,147 boys) at 20 pediatric clinics during 2001 and 2002 registered in the Swedish Childhood Diabetes Registry SWEDIABKIDS, a national quality registry, were analyzed.

RESULTS—A1C was <7.0% (target value ~8% per Diabetes Control and Complications Trial/National Glycohemoglobin Standardization Program standards) at 35% of the visits. Girls had significantly higher mean A1C than boys during adolescence. High mean A1C was correlated with high mean insulin dose, long duration of diabetes, and older age. Mean A1C varied between clinics (6.8–8.2%). Differences between centers could not be explained by differences in diabetes duration, age, BMI, or insulin dose.

CONCLUSIONS—Adolescents with a high insulin dose and a long duration of diabetes, especially girls, need to be focused on. Differences in mean values between centers remained inexplicable and require further investigation.

RESEARCH DESIGN AND METHODS—We compared the serum PSA levels in 224 diabetic men with those in 1,293 healthy men and investigated the relationships between serum PSA levels and various variables.

RESULTS—Except for men aged 40–49 years, serum PSA levels were lower in diabetic men than in healthy men. Multiple regression analysis demonstrated that age, BMI, and presence of diabetes were independent determinants of serum PSA level.

CONCLUSIONS—Serum PSA levels were lower in diabetic men compared with those in healthy men, which is in line with previous reports that patients with type 2 diabetes are at a decreased risk of prostate cancer.

RESEARCH DESIGN AND METHODS—In 1998, 1,143 primary care patients with type 2 diabetes participated in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study. At baseline, HRQOL was assessed with the RAND-36 and, after almost 6 years, life status was retrieved. Cox proportional hazards modeling was used to investigate the association between HRQOL (continuous data) and mortality with adjustment for selected confounders (smoking, age, sex, diabetes duration, A1C, renal function, BMI, blood pressure, HDL cholesterol, and macrovascular complications).

RESULTS—The Physical Component Summary of the RAND-36 was inversely associated with mortality (hazard ratio [HR] 0.979 [95% CI 0.966–0.992]), as were two separate RAND-36 dimensions.

CONCLUSIONS—This study found that HRQOL is an independent marker of mortality and emphasizes the importance of looking beyond clinical parameters in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS—We studied the feasibility of the Medtronic ePID system in youth with type 1 diabetes and hypothesized that small manual premeal "priming" boluses would reduce postprandial excursions during closed-loop control. Seventeen adolescents (aged 15.9 ± 1.6 years; A1C 7.1 ± 0.8%) underwent 34 h of closed-loop control; 8 with full closed-loop (FCL) control and 9 with hybrid closed-loop (HCL) control (premeal priming bolus).

RESULTS—Mean glucose levels were 135 ± 45 mg/dl in the HCL group versus 141 ± 55 mg/dl in the FCL group (P = 0.09); daytime glucose levels averaged 149 ± 47 mg/dl in the HCL group versus 159 ± 59 mg/dl in the FCL group (P = 0.03). Peak postprandial glucose levels averaged 194 ± 47 mg/dl in the HCL group versus 226 ± 51 mg/dl in the FCL group (P = 0.04). Nighttime control was similar in both groups (111 ± 27 vs. 112 ± 28 mg/dl).

CONCLUSIONS—Closed-loop glucose control using an external sensor and insulin pump provides a means to achieve near-normal glucose concentrations in youth with type 1 diabetes during the overnight period. The addition of small manual priming bolus doses of insulin, given 15 min before meals, improves postprandial glycemic excursions.

RESEARCH DESIGN AND METHODS—A double-blind study was performed on 24 male patients with type 2 diabetes and hypertension divided into two groups of 12 patients that randomly received either an oral supplementation of placebo or NAC + ARG for 6 months.

RESULTS—The NAC + ARG treatment caused a reduction of both systolic (P < 0.05) and diastolic (P < 0.05) mean arterial blood pressure, total cholesterol (P < 0.01), LDL cholesterol (P < 0.005), oxidized LDL (P < 0.05), high-sensitive C-reactive protein (P < 0.05), intracellular adhesion molecule (P < 0.05), vascular cell adhesion molecule (P < 0.01), nitrotyrosine (P < 0.01), fibrinogen (P < 0.01), and plasminogen activator inhibitor-1 (P < 0.05), and an improvement of the intima-media thickness during endothelial postischemic vasodilation (P < 0.02). HDL cholesterol increased (P < 0.05). No changes in other parameters studied were observed.

CONCLUSIONS—NAC + ARG administration seems to be a potential well-tolerated antiatherogenic therapy because it improves endothelial function in hypertensive patients with type 2 diabetes by improving NO bioavailability via reduction of oxidative stress and increase of NO production. Our study's results give prominence to its potential use in primary and secondary cardiovascular prevention in these patients.

RESEARCH DESIGN AND METHODS—We measured circulating levels of amylin and pancreatic polypeptide after 1) a 75-g glucose load in 28 healthy, normal-weight women, 2) 72-h complete energy deficiency (severe hypoleptinemia) with administration of either placebo or replacement-dose recombinant methionyl human leptin (r-metHuLeptin) in normal-weight men (n = 6) and women (n = 7), and 3) chronic mild energy deficiency (mild hypoleptinemia) in 7 women with hypothalamic amenorrhea before and after r-metHuLeptin administration for 3 months.

RESULTS—Amylin and pancreatic polypeptide levels increased 15 min after a 75-g glucose load and remained elevated at 60 and 120 min (P < 0.0001). Fasting for 72 h decreased leptin (to 21%) and amylin (to 67%) of baseline but not pancreatic polypeptide levels. Normalizing leptin levels with r-metHuLeptin did not alter the fasting-induced decrease in amylin and had no effect on pancreatic polypeptide levels. Neither amylin nor pancreatic polypeptide levels were different in leptin-deficient women with hypothalamic amenorrhea compared with weight-matched control subjects, and normalization of leptin levels with r-metHuLeptin treatment did not alter amylin or pancreatic polypeptide levels.

CONCLUSIONS—Circulating amylin levels increase after a glucose load and decrease in response to short-term complete fasting, but these changes are not mediated by leptin.

RESEARCH DESIGN AND METHODS—The cross-sectional association between CAC and retinopathy was assessed on a Veteran Affairs Diabetes Trial subsample of 204 subjects with a mean duration of type 2 diabetes of 12.3 ± 8.3 years.

RESULTS—Retinopathy was correlated with CAC (r = 0.19, P = 0.006). Median CAC increased across retinopathy categories: 197 in those with no retinopathy, 229 in those with microaneurysms only, 364 in those with mild nonproliferative diabetic retinopathy (NPDR), 300 in those with moderate to severe NPDR, and 981 in those with proliferative diabetic retinopathy (PDR). Stepwise multivariable linear regression analysis was performed to find a parsimonious subset of relevant risk factors to include along with PDR in predicting CAC. After adjustment for either this subset of standard factors (P = 0.047) or a more extensive panel of risk factors (P = 0.035), PDR was significantly associated with CAC. Moreover, using logistic regression, individuals with PDR were approximately sixfold more likely to have CAC >400 than those with no PDR, even after adjustment for other CVD risk factors.

CONCLUSIONS—These data indicate an important relationship between retinopathy and extent of CAC and suggest the potential to identify and treat shared risk factors for these common micro- and macrovascular complications.

RESEARCH DESIGN AND METHODS—Circulating SP-A concentration and metabolic variables (including insulin sensitivity by minimal model method, n = 89) were measured in 164 nonsmoking men.

RESULTS—Circulating SP-A concentration was significantly higher among patients with glucose intolerance and type 2 diabetes than in subjects with normal glucose tolerance, even after adjustment for BMI, age, and smoking status (ex/never). The most significant differences were found in overweight and obese subjects with altered glucose tolerance (n = 59) who showed significantly increased serum SP-A concentrations (by a mean of 24%) compared with obese subjects with normal glucose tolerance (n = 58) (log SP-A 1.54 ± 0.13 vs. 1.44 ± 0.13; P < 0.0001). Insulin sensitivity (P = 0.003) contributed independently to 22% of SP-A variance among all subjects. In subjects with altered glucose tolerance, insulin sensitivity (P = 0.01) and fasting triglycerides (P = 0.02) contributed to 37% of SP-A variance. Controlling for serum creatinine or C-reactive protein in these models did not significantly change the results.

CONCLUSIONS—Lung-derived SP-A protein was associated with altered glucose tolerance and insulin resistance in 164 nonsmoking men.

RESEARCH DESIGN AND METHODS—Data from a series of 449 patients with diabetic foot ulcers managed in the U.K. were used to evaluate the new simplified system of classification and to derive an aggregate score. The use of the score was then explored using data from series managed in Germany (n = 239), Tanzania (n = 479), and Pakistan (n = 173).

RESULTS—A highly significant difference was found in time to healing between ulcers of increasing score in the U.K. series (Kruskal-Wallis test; P = 0). When data from all centers were examined, a step-up in days to healing was noted for those with scores of ≥3 (out of 6). Examination of baseline variables contributing to outcome revealed the following differences among centers: ischemia, ulcer area, and depth contributing to outcome in the U.K.; ischemia, area, depth, and infection in Germany; depth, infection, and neuropathy in Tanzania; and depth alone in Pakistan.

CONCLUSIONS—Any system of classification designed for general implementation must encompass all the variables that contribute to outcome in different communities. Adoption of a simple score based on these variables, the Site, Ischemia, Neuropathy, Bacterial Infection, and Depth (SINBAD) score, may prove useful in predicting ulcer outcome and enabling comparison among different centers.

RESEARCH DESIGN AND METHODS—In a cross-sectional study, all patients with type 1 diabetes underwent cardiovascular magnetic resonance imaging. We included 63 patients with diabetic nephropathy and 73 patients with normoalbuminuria.

RESULTS—All patients had normal global LVF. LVM was increased in patients with diabetic nephropathy compared with patients with persistent normoalbuminuria. Patients with nephropathy had smaller left ventricular volumes and increased levels of NT-proBNP. Linear regression analysis in patients with diabetic nephropathy showed that NT-proBNP and creatinine were associated with LVM.

CONCLUSIONS—Increased LVM is identified in asymptomatic type 1 diabetic patients with nephropathy compared with normoalbuminuric patients. Elevated levels of NT-proBNP were associated with increased LVM, which are both markers of increased cardiovascular risk.

RESEARCH DESIGN AND METHODS—Glomerular filtration rate (GFR) was monitored over a mean of 10.1 years in 85 subjects with type 1 diabetes (with an average of 5.6 measurements per individual). Baseline mean ± SD iGFR of the cohort was 106.1 ± 2.6 ml/min per 1.73 m². The rates of decline in GFR (GFR) were derived using linear regression.

RESULTS—In 19 of 85 subjects with declining renal function (i.e., iGFR >3.3 ml/min per 1.73 m² per year), GFR (ml/min per 1.73 m² per year) was 6.5 by iGFR, 4.2 by 10⁴/creatinine, 3.6 by Cockcroft-Gault formula, 3.4 by the Modification of Diet in Renal Disease (MDRD)-6 equation, and 3.5 by the MDRD-4 variable equation (P < 0.01 vs. iGFR). In comparison, GFR was 6.1 using the formula Cys-GFR = (86.7/cystatin C concentration) – 4.2 (not significant).

CONCLUSIONS—Cystatin C was more accurate in detecting decline in renal function than creatinine-based methods in this population of subjects with type 1 diabetes and a normal mean baseline GFR.

RESEARCH DESIGN AND METHODS—hs-CRP was measured in 329 blood samples collected from 49 subjects with type 1 diabetes with MA and 49 normoalbuminuric subjects matched for age, sex, and duration of diabetes.

RESULTS—In subjects developing MA, a progressive rise in hs-CRP was detected with levels significantly higher in the years after the onset of MA when compared with levels before MA onset (P = 0.003; age-adjusted P = 0.06). After the onset of MA, hs-CRP levels were significantly higher in subjects with MA when compared with normoalbuminuric subjects (median 1.9 mg/l [range 0.2–9.8] vs. 1.1 mg/l [0.2–6.4]; P = 0.02; adjusted P = 0.036).

CONCLUSIONS—In this population of young subjects with type 1 diabetes, there was a significant increase in hs-CRP levels after the onset of MA, likely reflecting a general state of inflammation.

RESEARCH DESIGN AND METHODS—Receiver operating characteristics analysis was used to determine diagnostic thresholds for insulin receptoropathy in severe insulin resistance for adiponectin and for the insulin-regulated hepatic proteins sex hormone–binding globulin (SHBG) and IGF binding protein-1 (IGFBP-1).

RESULTS—Adiponectin >7 mg/l in severe insulin resistance had a 97% positive predictive value for insulin receptoropathy and <5 mg/l a 97% negative predictive value. IGFBP-1 and SHBG had lesser, though still significant, utility.

CONCLUSIONS—Use of these markers is likely to have significant value in accelerating the diagnosis of insulin receptoropathies.

RESEARCH DESIGN AND METHODS—Twenty-six diabetic subjects (12 with and 14 without chronic neuropathic pain) were compared, with 18 subjects without diabetes and pain. The left thalamus, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC) were assessed using ¹H-MRS.

RESULTS—In the DLPFC, diabetic subjects had a decrease in N-acetyl aspartate (NAA) and creatine relative to the control group. In the thalamus, there was a reduction of NAA in the diabetic group with pain compared with that in patients with diabetes and no pain.

CONCLUSION—Subjects with diabetes have metabolite differences in the brain compared with control subjects. Subjects with painful neuropathy showed reduced NAA in the thalamus, which may explain the genesis of pain in some cases.

RESEARCH DESIGN AND METHODS—Among 19,257 hypertensive patients in the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA) who were randomly assigned to receive one of two antihypertensive regimens (atenolol ± thiazide or amlodipine ± perindopril), 14,120 were at risk of developing diabetes at baseline. Of these, 1,366 (9.7%) subsequently developed NOD during median follow-up of 5.5 years. A multivariate Cox model was developed to identify the independent predictors of NOD and individual risk scores.

RESULTS—NOD was significantly associated with an increase in baseline fasting plasma glucose (FPG), BMI, serum triglycerides, and systolic blood pressure. In contrast, amlodipine ± perindopril in comparison with atenolol ± thiazide treatment (hazard ratio 0.66 [95% CI 0.59–0.74]), high HDL cholesterol, alcohol use, and age >55 years were found to be significantly protective factors. FPG was the most powerful predictor with risk increasing by 5.8 times (95% CI 5.23–6.43) for each millimole per liter rise >5 mmol/l. The risk of NOD increased steadily with increasing quartile of risk score, with a 19-fold increase (95% CI 14.3–25.4) among those in the highest compared with those in the lowest quartile. The model showed excellent internal validity and discriminative ability.

CONCLUSIONS—Baseline FPG >5 mmol/l, BMI, and use of an atenolol ± diuretic regimen were among the major determinants of NOD in hypertensive patients. The model developed from these data allows accurate prediction of NOD among hypertensive subjects.

RESEARCH DESIGN AND METHODS—Adiponectin is an adipocyte-derived protein with antiatherogenic and insulin-sensitizing properties. To date, the relationship between adiponectin and plaque composition is unknown. Fasting blood samples were collected from 185 patients undergoing coronary angiography and intravascular ultrasound (IVUS). Plaque composition was categorized as fibrous, fibrofatty, necrotic core, or dense calcium and further classified as IVUS-derived adaptive or pathological intimal thickening, fibroatheroma, fibrocalcific, or thin cap fibroatheroma.

RESULTS—Adiponectin correlated with normalized plaque volume (r = –0.16, P = 0.025) and atheroma lipid content as measured by normalized fibrofatty volume (r = –0.19, P = 0.009). Low adiponectin levels were associated with IVUS-derived pathological intimal thickening (r = –0.18, P = 0.01). With increasing quartiles (Q) of adiponectin, the normalized volume of fibrofatty plaque decreased (P = 0.03), which was driven by reductions in the nondiabetic cohort (Q1 44.2 mm³; Q2 28.2 mm³; Q3 24.7 mm³; and Q4 23.4 mm³; P = 0.01). No similar association was present in diabetic patients. Low adiponectin levels were also associated with IVUS-derived pathological intimal thickening in nondiabetic (r = –0.20, P = 0.03) but not diabetic patients.

CONCLUSIONS—Low adiponectin levels are associated with atherogenic lipoproteins (elevated triglycerides, small dense LDL cholesterol, and low HDL cholesterol), increased plaque volume, lipid-rich plaque, and IVUS-derived pathological intimal thickening in the total cohort that was driven by the nondiabetic population, suggesting an antiatherogenic role in the early stages of lesion development.

RESEARCH DESIGN AND METHODS—This was a prospective study of 3,562 nondiabetic men aged 60–79 years followed up for an average of 7 years during which there were 162 incident cases of type 2 diabetes.

RESULTS—Elevated t-PA (top third) was associated with a near threefold increase in risk of diabetes compared with the risk in those in the bottom third after adjustment for lifestyle factors and waist circumference (relative risk [RR] 2.98 [95%CI 1.79–5.00]; P_trend < 0.0001); weaker but significant (marginal) associations were seen with vWF (1.24 [0.83–1.85]; P = 0.05 for trend). Both biomarkers of endothelial dysfunction correlated significantly with markers of inflammation (interleukin-6 [IL-6] and C-reactive protein [CRP]), hepatic function (-glutamyl transferase [GGT]), and insulin resistance, with t-PA showing stronger associations with adiposity, hepatic function, and insulin resistance than vWF. t-PA was also significantly and inversely associated with adiponectin. Adjustment for IL-6, adiponectin, and GGT attenuated the association of incident diabetes with vWF (1.06 [0.71–1.60]), but the relationship seen with t-PA remained significant (adjusted RR 2.19 [1.29–3.70]). Subsequent adjustment for insulin attenuated the association further, but t-PA was still associated with a significant increase in risk (1.66 [0.96–2.85]; P_trend = 0.02).

CONCLUSION—t-PA antigen, but not vWF antigen, is independently associated with risk of type 2 diabetes.

RESEARCH DESIGN AND METHODS—Cross-sectional analysis of 2,588 participants (aged 52–96 years; 46% men) without known diabetes. SDB was defined as respiratory disturbance index ≥10 events/h. IFG, IGT, occult diabetes, and body weight were classified according to recent accepted guidelines. Participants with and without SDB were compared on prevalence and odds ratios for measures of impaired glucose metabolism (IGM), adjusting for age, sex, race, BMI, and waist circumference.

RESULTS—SDB was observed in 209 nonoverweight and 1,036 overweight/obese participants. SDB groups had significantly higher adjusted prevalence and adjusted odds of IFG, IFG plus IGT, and occult diabetes. The adjusted odds ratio for all subjects was 1.3 (95% CI 1.1–1.6) for IFG, 1.2 (1.0–1.4) for IGT, 1.4 (1.1–2.7) for IFG plus IGT, and 1.7 (1.1–2.7) for occult diabetes.

CONCLUSIONS—SDB was associated with occult diabetes, IFG, and IFG plus IGT, after adjusting for age, sex, race, BMI, and waist circumference. The magnitude of these associations was similar in nonoverweight and overweight participants. The consistency of associations across all measures of IGM and body habitus groups and the significant association between SDB and IFG plus IGT, a risk factor for rapid progression to diabetes, cardiovascular disease, and mortality, suggests the importance of SDB as a risk factor for clinically important levels of metabolic dysfunction.

RESEARCH DESIGN AND METHODS—A total of 5,269 people aged ≥30 years, with IGT and/or IFG without known CVD or renal insufficiency, were randomized to 15 mg/day ramipril versus placebo and 8 mg/day rosiglitazone versus placebo. A composite cardiorenal outcome and its CVD and renal components were assessed during the 3-year follow-up.

RESULTS—Compared with placebo, neither ramipril (15.7% [412 of 2,623] vs. 16.0% [424 of 2,646]; hazard ratio [HR] 0.98 [95% CI 0.84–1.13]; P = 0.75) nor rosiglitazone (15.0% [394 of 2,635] vs. 16.8% [442 of 2,634]; 0.87 [0.75–1.01]; P = 0.07) reduced the risk of the cardiorenal composite outcome. Ramipril had no impact on the CVD and renal components. Rosiglitazone increased heart failure (0.53 vs. 0.08%; HR 7.04 [95% CI 1.60–31.0]; P = 0.01) but reduced the risk of the renal component (0.80 [0.68–0.93]; P = 0.005); prevention of diabetes was independently associated with prevention of the renal component (P < 0.001).

CONCLUSIONS—Ramipril did not alter the cardiorenal outcome or its components. Rosiglitazone, which reduced diabetes, also reduced the development of renal disease but not the cardiorenal outcome and increased the risk of heart failure.

RESEARCH DESIGN AND METHODS—We examined 993 healthy children and adolescents aged 12–19 years with reliable measures of cardiovascular fitness from the National Health and Nutrition Examination Survey 1999–2002. HRR parameters 1–3 min after exercise were calculated from exercise test results. Anthropometric and metabolic risk factors as well as metabolic Z score were obtained.

RESULTS—The HRR parameters were inversely correlated with most of the metabolic risks, including waist circumference, systolic blood pressure (SBP), serum triglycerides, and serum C-reactive protein (CRP) levels, and were positively correlated with serum HDL levels. In multiple linear regression analysis, among the metabolic risks, waist circumference was the only parameter associated with HRR parameters (P = 0.038, 0.001, and 0.001 for 1-, 2-, and 3-min HRR, respectively) in boys. In girls, waist circumference (P = 0.001 and <0.001 for 2- and 3-min HRR, respectively), SBP (P = 0.029 for 1-min HRR), serum glucose (P = 0.021 for 2-min HRR), and serum CRP (P = 0.007 for 2-min HRR) levels were the most important determinants of HRR parameters. The adjusted 1-min HRR did not change across four quartiles of metabolic Z score, while the adjusted 3-min HRR decreased significantly with four quartiles of metabolic Z score.

CONCLUSIONS—Metabolic risks are inversely associated with HRR in healthy children and adolescents. Our finding suggests that there is a link between metabolic risks and autonomic nervous system functions in healthy young ages.

RESEARCH DESIGN AND METHODS—A total of 15 patients with type 2 diabetes received insulin glulisine or human insulin before a liquid meal test. Thereafter, skin microvascular blood flow was measured by laser Doppler fluxmetry and blood samples were taken for measurement of plasma levels of glucose, insulin, intact proinsulin, asymmetric dimethylarginine, nitrotyrosine, interleukin-18, matrix metalloproteinase-9, oxidized LDL, and free fatty acids.

RESULTS—Insulin glulisine injections resulted in higher postprandial insulin levels (means ± SEM area under the curve [AUC]_0–120 51.0 ± 6.8 vs. 38.2 ± 5.4 mU/l; P = 0.004), while plasma glucose (AUC_0–240 158 ± 9 vs. 180 ± 9 mg/dl; P < 0.05) and intact proinsulin (AUC_0–240 26.2 ± 3.5 vs. 31.2 ± 4.3 pmol/l; P = 0.002) were lower. Microvascular blood flow increased after insulin glulisine injection (27.9 ± 3.1 to 51.7 ± 9.9 arbitrary units [AU]; P < 0.05), while only a minor increase was found during human insulin (27.9 ± 3.1 to 34.4 ± 7.8 AU; not si