The EarlyBird Diabetes study is a longitudinal prospective cohort study of healthy children aged 5–14 years. Homeostasis model assessment (HOMA-IR), skinfolds (SSF), adiposity (percent fat, measured by dual-energy X-ray absorptiometry), serum leptin, and IGF-1 were measured annually in 235 children (134 boys). Pubertal onset was adduced from Tanner stage (TS) and from the age at which luteinizing hormone (LH) first became serially detectable (≥0.2 international units/L).

IR rose progressively from 7 years, 3–4 years before TS2 was reached or LH became detectable. Rising adiposity and IGF-1 together explained 34% of the variance in IR in boys and 35% in girls (both P < 0.001) over the 3 years preceding pubertal onset. The contribution of IGF-1 to IR was greater in boys, despite their comparatively lower IGF-1 levels.

IR starts to rise in mid-childhood, some years before puberty. Its emergence relates more to the age of the child than to pubertal onset. More than 60% of the variation in IR prior to puberty was unexplained. The demography of childhood diabetes is changing, and prepubertal IR may be important.

We identified 1,139 type 2 diabetic patients who initiated insulin therapy between 1 January 2009 and 30 June 2010. Outcomes of interest were the proportion of patients achieving A1C <7% and mean change in A1C within 3–9 months.

Mean A1C at insulin initiation was 8.2 vs. 9.2% among those who did and did not attain A1C <7% (P < 0.001). Within a mean of 5 months, 464 (40.7%) patients attained A1C <7%. In multivariable analyses controlling for insulin regimen, dose, and oral agent use, preinsulin A1C was responsible for nearly all the explained variance in A1C change. Each one percentage point of preinsulin A1C reduced the probability of attaining <7% by 26% (odds ratio 0.74 [95% CI 0.68–0.80]).

Insulin initiation at lower levels of A1C improves goal attainment and independently increases glycemic response.

Plasma VLDL of normal individuals (control subjects) (n = 13) and of those with MetS (n = 13) was resolved into subfractions with increasing negative charge (V1–V5) by anion-exchange chromatography. Human aortic endothelial cells were treated with V1–V5 or unfractionated VLDL.

Compared with the control subjects, individuals with MetS had a significantly higher percentage of V5 VLDL (V5/VLDL%) (34 ± 20 vs. 39 ± 11%, respectively; P < 0.05) and plasma V5 concentration ([V5]) (5.5 ± 4.4 vs. 15.2 ± 8.5 mg/dL, respectively; P < 0.001). Apolipoprotein (apo)B100 levels decreased and apoC levels increased from V1 to V5, indicating that V5 is apoC-rich VLDL. Regression analyses of all 26 individuals showed that [V5] was positively correlated with total cholesterol (P = 0.016), triglyceride (P < 0.000001), and V5/VLDL% (P = 0.002). Fasting plasma glucose, but not waist circumference, exhibited a positive trend (P = 0.058); plasma HDL cholesterol exhibited a weak inverse trend (P = 0.138). V5 (10 μg/mL) induced apoptosis in ~50% of endothelial cells in 24 h. V5 was the most rapidly (<15 min) internalized subfraction and induced the production of reactive oxygen species (ROS) in endothelial cells after 20 min. Unfractionated MetS VLDL, but not control VLDL, also induced ROS production and endothelial cell apoptosis.

In populations with increased risk of diabetes, the vascular endothelium is constantly exposed to VLDL that contains a high proportion of V5. The potential impact of V5-rich VLDL warrants further investigation.

This was a dynamic cohort study of 20,686 people with type 2 diabetes who had annual retinal photography up to 14 times between 1990 and 2006. Cumulative and annual incidence rates were estimated using life tables, and risk factors for progression were identified using Cox regression analysis.

Of 20,686 patients without proliferative diabetic retinopathy (PDR) or sight-threatening maculopathy at their first retinal examination (baseline), 16,444 (79%) did not have retinopathy, 3,632 (18%) had nonproliferative retinopathy, and 610 (2.9%) had preproliferative retinopathy. After 5 years, few patients without retinopathy at baseline developed preproliferative retinopathy (cumulative incidence 4.0%), sight-threatening maculopathy (0.59%), or PDR (0.68%); after 10 years, the respective cumulative incidences were 16.4, 1.2, and 1.5%. Among those with nonproliferative (background) retinopathy at baseline, after 1 year 23% developed preproliferative retinopathy, 5.2% developed maculopathy, and 6.1% developed PDR; after 10 years, the respective cumulative incidences were 53, 9.6, and 11%. Patients with nonproliferative retinopathy at baseline were five times more likely to develop preproliferative, PDR, or maculopathy than those without retinopathy at baseline (adjusted hazards ratio 5.0 [95% CI 4.4–5.6]).

Few patients without diabetic retinopathy at the initial screening examination developed preproliferative retinopathy, PDR, or sight-threatening maculopathy after 5–10 years of follow-up. Screening intervals longer than a year may be appropriate for such patients.

We analyzed 191 kidney transplants, which had at least 1-year follow-up posttransplant. First-year posttransplant variables were collected to estimate the San Antonio Diabetes Prediction model (SADPM) and Framingham Offspring Study–Diabetes Mellitus (FOS-DM) algorithm.

Areas under the receiver operating characteristic curve of FOS-DM and SADPM scores to predict NODAT were 0.756 and 0.807 (P < 0.001), respectively. FOS-DM and SADPM scores over 75 percentile (hazard ratio 5.074 and 8.179, respectively, P < 0.001) were associated with NODAT.

Both scores can be used to identify kidney recipients at higher risk for NODAT beyond the first year. SADPM score detects some 25% of kidney transplant patients with an eightfold risk for NODAT.

Data from cardiac arrest registry supplemented with blood glucose data were analyzed in this population-based observational study. Between 2005 and 2009, a total of 170 adult patients survived to hospital admission after resuscitation from bystander-witnessed cardiac arrest of cardiac origin and ventricular fibrillation as an initial rhythm.

Sufficient data for analysis were available in 134 (79%) patients, of whom 87 (65% [95% CI 57–73]) survived to hospital discharge in Cerebral Performance Category 1 or 2. Blood glucose did not change significantly between prehospital (10.5 ± 4.1 mmol/L) and admission (10.0 ± 3.7 mmol/L) in survivors (P = 0.3483), whereas in nonsurvivors, blood glucose increased from 11.8 ± 4.6 to 13.8 ± 3.3 mmol/L (P = 0.0025).

Patients who are resuscitated from out-of-hospital ventricular fibrillation, but whose outcome is unfavorable are characterized by significant increase of blood glucose in the ultraacute postresuscitation phase.

We examined the association between serological evidence of chronic viral and bacterial infections and incident diabetes in a prospective cohort of Latino elderly. We analyzed data on 782 individuals aged >60 years and diabetes-free in 1998–1999, whose blood was tested for antibodies to herpes simplex virus 1, varicella virus, cytomegalovirus, Helicobacter pylori, and Toxoplasma gondii and who were followed until June 2008. We used Cox proportional-hazards regression to estimate the relative incidence rate of diabetes by serostatus, with adjustment for age, sex, education, cardiovascular disease, smoking, and cholesterol levels.

Individuals seropositive for herpes simplex virus 1, varicella virus, cytomegalovirus, and T. gondii did not show an increased rate of diabetes, whereas those who were seropositive for H. pylori at enrollment were 2.7 times more likely at any given time to develop diabetes than seronegative individuals (hazard ratio 2.69 [95% CI 1.10–6.60]). Controlling for insulin resistance, C-reactive protein and interleukin-6 did not attenuate the effect of H. pylori infection.

We demonstrated for the first time that H. pylori infection leads to an increased rate of incident diabetes in a prospective cohort study. Our findings implicate a potential role for antibiotic and gastrointestinal treatment in preventing diabetes.

Plasma 25(OH)D concentrations were analyzed in banked specimens in healthy youth aged 8 to 18 years who had existing data on hyperinsulinemic-euglycemic and hyperglycemic clamp to assess insulin sensitivity and secretion, and measurements of body composition, and abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT).

A total of 183 research volunteers (mean ± SD; age, 12.6 ± 2.2 years; 98 white, 98 male, 92 obese) were studied. Analysis of HbA_1c, fasting glucose and insulin, insulin sensitivity, and DI across quartiles of plasma 25(OH)D revealed no differences among whites. In blacks, the observed significance of higher insulin sensitivity and DI in the highest quartile of 25(OH)D disappeared after adjusting for any of the adiposity measures (BMI or fat mass or VAT or SAT). The difference in insulin sensitivity (9.4 ± 1.2 vs. 5.6 ± 0.5 mg/kg/min per μU/mL; P = 0.006) between 25(OH)D nondeficient (≥20 ng/mL) versus deficient (<20 ng/mL) black youth also was negated when adjusted for adiposity.

In healthy youth, plasma 25(OH)D concentrations bear no independent relationship to parameters of glucose homeostasis and in vivo insulin sensitivity and β-cell function relative to insulin sensitivity. It remains to be determined whether in youth with dysglycemia the relationships are different and whether vitamin D optimization enhances insulin sensitivity and β-cell function.

In a cross-sectional study, an oral glucose tolerance test and demographic (age, sex, family history of diabetes, and ethnicity), clinical (BMI z score, waist circumference, and pubertal stage), and laboratory variables used in current pediatric screening criteria for type 2 diabetes mellitus were measured in 259 overweight or obese youth aged 5–17 years. Glycemic status was based on American Diabetes Association (ADA) thresholds. The performance (sensitivity and specificity) of current screening criteria and newly developed models to identify isolated IGT were compared.

Dysglycemia was present in 20.8% of the cohort. Of the 54 participants with dysglycemia, 68% had a normal fasting glucose and were identified with the 2-h glucose test. Current ADA criteria had low sensitivity (41.7% [95% CI 25.6–57.8]) and moderate specificity (69.5% [63.5–75.6]) to identify IGT. In receiver operating characteristic (ROC) analysis, the addition of hemoglobin A_1c or FPG did not improve the ROC area under the curve (AUC) (HbA_1c: 0.64 vs. 0.63; P = 0.54; HbA_1c + FPG: 0.66; P = 0.42), but adding triglyceride level did (AUC 0.72 vs. 0.63; P = 0.03). A simple model with fasting triglyceride level >1.17 mmol/L improved AUC compared with ADA screening criteria (0.68 vs. 0.57; P = 0.04).

The prevalence of IGT is high among obese children and youth. Current screening criteria have low sensitivity to detect isolated IGT. Although adding nonfasting laboratory values to history and physical measures does not improve diagnostic accuracy, adding fasting lipid profile improves predictive value.

Fasting plasma was analyzed by tandem mass spectrometry, body composition by dual energy X-ray absorptiometry and computed tomography, and total-body lipolysis and substrate oxidation by [²H₅]glycerol and indirect calorimetry, respectively. In vivo insulin sensitivity (IS) was assessed with a 3-h hyperinsulinemic-euglycemic clamp.

Long-chain AcylCNs (C18:2-CN to C14:0-CN) were similar among the three groups. Medium- to short-chain AcylCNs (except C8 and C10) were significantly lower in type 2 diabetes compared with NW, and when compared with OB, C2-, C6-, and C10-CN were lower. Amino acid concentrations were lower in type 2 diabetes compared with NW. Fasting lipolysis and FOX were higher in OB and type 2 diabetes compared with NW, and the negative association of FOX to C10:1 disappeared after controlling for adiposity, Tanner stage, and sex. IS was lower in OB and type 2 diabetes with positive associations between IS and arginine, histidine, and serine after adjusting for adiposity, Tanner stage, and sex.

These metabolomics results, together with the increased rates of in vivo FOX, are not supportive of defective fatty acid or amino acid metabolism in obesity and type 2 diabetes in youth. Such observations are consistent with early adaptive metabolic plasticity in youth, which over time—with continued obesity and aging—may become dysfunctional, as observed in adults.

To examine the relationship between retinal vascular geometry parameters and development of incident renal dysfunction in young people with type 1 diabetes.

A prospective cohort study of 511 adolescents with type 1 diabetes of at least 2 years duration, with normal albumin excretion rate (AER) and no retinopathy at baseline while attending an Australian tertiary-care hospital. AER was quantified using three overnight, timed urine specimen collections and early renal dysfunction was defined as AER >7.5 μg/min. Retinal vascular geometry (including length-to-diameter ratio [LDR] and simple tortuosity [ST]) was quantified from baseline retinal photographs. Generalized estimating equations were used to examine the relationship between incident renal dysfunction and baseline venular LDR and ST, adjusting for age, diabetes duration, glycated hemoglobin (A1C), blood pressure (BP), BMI, and cholesterol.

Diabetes duration at baseline was 4.8 (IQR 3.3–7.5) years. After a median 3.7 (2.3–5.7) years follow-up, 34% of participants developed incident renal dysfunction. In multivariate analysis, higher retinal venular LDR (odds ratio 1.7, 95% CI 1.2–2.4; quartile 4 vs. 1–3) and lower venular ST (1.6, 1.1–2.2; quartile 1 vs. 2–4) predicted incident renal dysfunction.

Retinal venular geometry independently predicted incident renal dysfunction in young people with type 1 diabetes. These noninvasive retinal measures may help to elucidate early mechanistic pathways for microvascular complications. Retinal venular geometry may be a useful tool to identify individuals at high risk of renal disease early in the course of diabetes.

To define a panel of novel protein biomarkers of renal disease.

Adults with type 1 diabetes in the Coronary Artery Calcification in Type 1 Diabetes study who were initially free of renal complications (n = 465) were followed for development of micro- or macroalbuminuria (MA) and early renal function decline (ERFD, annual decline in estimated glomerular filtration rate of ≥3.3%). The label free proteomic discovery phase was conducted in 13 patients who progressed to MA by the 6-year visit and 11 control subjects, and four proteins (Tamm-Horsfall glycoprotein, α-1 acid glycoprotein, clusterin, and progranulin) identified in the discovery phase were measured by enzyme-linked immunosorbent assay in 74 subjects: group A, normal renal function (n = 35); group B, ERFD without MA (n = 15); group C, MA without ERFD (n = 16); and group D, both ERFD and MA (n = 8).

In the label free analysis, a model of progression to MA was built using 252 peptides, yielding an area under the curve (AUC) of 84.7 ± 5.3%. In the validation study, ordinal logistic regression was used to predict development of ERFD, MA, or both. A panel including Tamm-Horsfall glycoprotein (odd ratio [OR] 2.9, 95% CI 1.3–6.2, P = 0.008), progranulin (1.9, 0.8–4.5, P = 0.16), clusterin (0.6, 0.3–1.1, P = 0.09), and α-1 acid glycoprotein (1.6, 0.7–3.7, P = 0.27) improved the AUC from 0.841 to 0.889.

A panel of four novel protein biomarkers predicted early renal damage in type 1 diabetes. These findings require further validation in other populations for prediction of renal complications and treatment monitoring.

To evaluate the ability of certified retinal imagers to identify presence versus absence of sight-threatening diabetic retinopathy (stDR) (moderate nonproliferative diabetic retinopathy or worse or diabetic macular edema) at the time of retinal imaging in a telemedicine program.

Diabetic patients in a primary care setting or specialty diabetes clinic received Joslin Vision Network protocol retinal imaging as part of their care. Trained nonphysician imagers graded the presence versus absence of stDR at the time of imaging. These gradings were compared with masked gradings of certified readers.

Of 158 patients (316 eyes) imaged, all cases of stDR (42 eyes [13%]) were identified by the imagers at the time of imaging. Six eyes with mild nonproliferative diabetic retinopathy were graded by the imagers to have stDR (sensitivity 1.00, 95% CI 0.90–1.00; specificity 0.97, 0.94–0.99).

Appropriately trained imagers can accurately identify stDR at the time of imaging.

In young-onset diabetes, insulin therapy status is a rough marker of diabetes type. We describe the mortality experience of a low-income, predominantly minority population with diabetes diagnosed before age 30 years, stratified by insulin therapy.

A total of 1,098 adults aged 40–79 years (median 49) diagnosed with diabetes before age 30 years and 49,914 without diabetes were recruited from community health centers. Individuals with diabetes were categorized by insulin therapy at baseline: group A, insulin therapy only; group B, insulin therapy and an oral hypoglycemic agent; and group C, no insulin therapy. Cox models were used to compute hazard ratios (HRs) and 95% CI for cause-specific mortality based on both underlying and contributing causes of death from death certificates.

During follow-up (mean 3.9 years), 15.0, 12.5, and 7.3% of groups A, B, and C, respectively, and 4.6% without diabetes died. Compared with individuals without diabetes, HRs (CI) for all-cause mortality were 4.3 (3.4–5.6), 4.2 (2.8–6.3), and 2.0 (1.4–2.8) in groups A, B, and C, respectively. The leading cause of death was renal failure (end-stage renal disease [ESRD]) in group A, ESRD and coronary artery disease (CAD) in group B, and CAD in group C and individuals without diabetes. HRs for these conditions were at least twice as high as the HRs for all-cause mortality, reaching 17.3 (10.2–29.3), 17.9 (8.3–38.7), and 5.1 (2.3–11.7) in groups A, B, and C, respectively, for ESRD.

Excess mortality persists among people with young-onset diabetes of long duration, with ESRD and CAD as the leading contributors to mortality.

Newly diagnosed patients with type 2 diabetes were recruited and treated with continuous subcutaneous insulin infusion (CSII) for 2–3 weeks. They were also invited to participate in diabetes self-management intervention during hospitalization and complete a DCP questionnaire on attitudes toward diabetes at baseline and 3, 6, and 12 months after suspension of CSII.

Near normoglycemia was achieved by 118 patients after short-term CSII, with 65 remaining in drug-free remission for >1 year. They had significantly better glycemic control and greater restoration of acute insulin response after CSII as well as higher educational attainment compared with patients experiencing relapse. They also achieved higher scores in positive attitude, (belief in) importance of care, care ability, self-care adherence, and less negative attitude. Differences between the two groups became greater over time. Cox proportional hazards model analysis indicated that greater self-care adherence (hazard ratio 0.184, P < 0.001) and homeostasis model assessment of insulin resistance before treatment (0.854, P = 0.053) were independent predictors for long-term remission, whereas elevated 2-h postprandial plasma glucose after CSII (1.156, P = 0.015) was a risk factor for relapse.

Attitudes toward diabetes affect long-term drug-free remission in newly diagnosed patients with type 2 diabetes after short-term CSII.

To determine the incremental prognostic value of dobutamine stress echocardiography (DSE) at 13-year follow-up (SD 3.2 years) for predicting mortality and cardiac events in diabetic patients.

A total of 396 diabetic patients (mean age 61 ± 11 years; 252 men [64%]) with limited exercise capacity who underwent DSE for evaluation of ischemia were studied. End points were all causes of mortality, cardiac death, and hard cardiac events (cardiac death and nonfatal myocardial infarction).

During a mean follow-up of 13 years, 230 patients (58%) died (121 cardiac deaths), and 30 patients had nonfatal myocardial infarction. Cumulative survival in patients with an abnormal DSE at 5, 10, and 15 years was 68, 49, and 41%, respectively. In patients with a normal DSE, these respective numbers were 74, 57, and 44%. Multivariate analyses showed that DSE provided incremental value over clinical characteristics and stress test parameters for prediction of mortality and cardiac events. Survival analysis showed that DSE provided optimal risk stratification up to 7 years after initial testing; after that period, the risk of adverse outcome increased comparably in both normal and abnormal DSE patients.

DSE provided restricted predictive value of adverse outcome in patients with diabetes who were unable to perform an adequate exercise stress test. DSE provided optimal risk stratification up to 7 years after initial testing. Repeated DSE at that time might add to its prognostic value.

It is unclear whether coronary artery calcium (CAC) is effective for risk stratifying patients with diabetes in whom treatment decisions are uncertain.

Of 44,052 asymptomatic individuals referred for CAC testing, we studied 2,384 individuals with diabetes. Subjects were followed for a mean of 5.6 ± 2.6 years for the end point of all-cause mortality.

There were 162 deaths (6.8%) in the population. CAC was a strong predictor of mortality across age groups (age <50, 50–59, ≥60), sex, and risk factor burden (0 vs. ≥1 additional risk factor). In individuals without a clear indication for aspirin per current guidelines, CAC stratified risk, identifying patients above and below the 10% risk threshold of presumed aspirin benefit.

CAC can help risk stratify individuals with diabetes and may aid in selection of patients who may benefit from therapies such as low-dose aspirin for primary prevention.

Standard NCSs were performed on healthy control (HC), DM, and IGT groups (N = 147). The bilateral NCS parameters of the MDC, DS, and MP nerves were investigated. The Toronto Clinical Scoring System (TCSS) was assessed for the DM and IGT groups.

The mean TCSS scores of the IGT and DM groups were 2.5 ± 2.3 and 2.8 ± 2.2, respectively. No significant differences between the two groups were observed. After adjustment of age and BMI, the DM group showed significant NCS differences in DS and MDC nerves compared with the HC group (P < 0.05). These differences were also exhibited in the left DS of the IGT group (P = 0.0003). More advanced NCS findings were observed in the DM group. Bilateral abnormal NCS responses in these distal sensory nerves were found in 40 and 16% of DM and IGT patients, respectively.

These results showed that the simultaneous assessment of the most distal sensory nerves allowed the detection of early NCS changes in the IGT and DM groups, even when the routine NCS showed normal findings.