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Type 1 diabetes mellitus (T1DM) is associated with increased risk of mortality, despite improvements in management of glucose levels and treatment of cardiovascular risk factors. A population-based study of individuals with T1DM and control individuals matched for age and sex has used glycaemic control to characterize the excess risk of overall and cardiovascular mortality.

OBJECTIVE To determine whether baseline estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) independently predict coronary artery calcification (CAC) progression, and to determine how eGFR changes over 6 years in adults with type 1 diabetes compared with nondiabetic adults. RESEARCH DESIGN AND METHODS The Coronary Artery Calcification in Type 1 Diabetes study participants (n = 1,066) with complete data for eGFR assessment at baseline and 6 years were included. Three Chronic Kidney Disease Epidemiology Collaboration equations (serum creatinine, cystatin C, and both) were used to estimate eGFR. The association of baseline ACR and eGFR with CAC progression was analyzed using multiple logistic regression. RESULTS Increasing categorical baseline ACR (30 µg/mg) predicted CAC progression in participants with type 1 diabetes (odds ratio [OR], 2.15; 95% CI, 1.50–3.09; 7.19 [3.90–13.26]; and 18.09 [8.48–38.62]), respectively, compared with nondiabetic subjects. Baseline eGFR CONCLUSIONS Although increasing ACR or decreasing eGFR predicts CAC progression, coronary atherosclerosis progresses faster in people with type 1 diabetes even in the absence of diabetic kidney disease. These findings emphasize the interaction between kidney disease and cardiovascular disease in type 1 diabetes and highlight the public health importance of lowering cardiorenal risk in people with type 1 diabetes.

Cardiovascular disease (CVD) remains the leading cause of death among adults with diabetes, and CVD prevention remains a major challenge. Coronary artery calcium (CAC) score measured by electron beam tomography (EBT) or multi-slice detector computed tomography correlates closely with plaque burden and coronary angiography, and predicts coronary events independently of other risk factors. Further, progression of CAC over several years has been shown to predict increased mortality. Coronary calcification is an active process strongly associated with atherosclerotic plaque evolution and is an accepted surrogate endpoint in studies of patients with diabetes older than 30. In this review, recent findings regarding the mechanisms and implications of vascular calcification in diabetes will be discussed.

The incidence of both type 1 and type 2 diabetes is increasing globally, most likely explained by environmental changes, such as changing exposures to foods, viruses, and toxins, and by increasing obesity. While cardiovascular disease (CVD) mortality has been declining recently, this global epidemic of diabetes threatens to stall this trend. CVD is the leading cause of death in both type 1 and type 2 diabetes, with at least a two- to fourfold increased risk in patients with diabetes. In this review, the risk factors for CVD are discussed in the context of type 1 and type 2 diabetes. While traditional risk factors such as dyslipidemia, hypertension, and obesity are greater in type 2 patients than in type 1 diabetes, they explain only about half of the increased CVD risk. The role for diabetes-specific risk factors, including hyperglycemia and kidney complications, is discussed in the context of new study findings.

Background: Haptoglobin (Hp) is an abundant serum protein which binds extracorpuscular hemoglobin (Hb). Two alleles exist in humans for the Hp gene, denoted 1 and 2. Diabetic individuals with the Hp 2-2 genotype are at increased risk of developing vascular complications including heart attack, stroke, and kidney disease. Recent evidence shows that treatment with vitamin E can reduce the risk of diabetic vascular complications by as much as 50% in Hp 2-2 individuals. We sought to develop a rapid and accurate test for Hp phenotype (which is 100% concordant with the three major Hp genotypes) to facilitate widespread diagnostic testing as well as prospective clinical trials. Methods: A monoclonal antibody raised against human Hp was shown to distinguish between the three Hp phenotypes in an enzyme linked immunosorbent assay (ELISA). Hp phenotypes obtained in over 8000 patient samples using this ELISA method were compared with those obtained by polyacrylamide gel electrophoresis or the TaqMan PCR method. Results: Our analysis showed that the sensitivity and specificity of the ELISA test for Hp 2-2 phenotype is 99.0% and 98.1%, respectively. The positive predictive value and the negative predictive value for Hp 2-2 phenotype is 97.5% and 99.3%, respectively. Similar results were obtained for Hp 2-1 and Hp 1-1 phenotypes. In addition, the ELISA was determined to be more sensitive and specific than the TaqMan method. Conclusions: The Hp ELISA represents a user-friendly, rapid and highly accurate diagnostic tool for determining Hp phenotypes. This test will greatly facilitate the typing of thousands of samples in ongoing clinical studies.

Type 1 diabetes is an insulin-resistant state, but it is less clear which tissues are affected. Our previous report implicated skeletal muscle and liver insulin resistance in people with type 1 diabetes, but this occurred independently of generalized, visceral, or ectopic fat.The aim of the study was to measure adipose tissue insulin sensitivity and plasma triglyceride composition in individuals with type 1 diabetes after overnight insulin infusion to lower fasting glucose.Fifty subjects (25 individuals with type 1 diabetes and 25 controls without) were studied. After 3 d of dietary control and overnight insulin infusion, we performed a three-stage hyperinsulinemic/euglycemic clamp infusing insulin at 4, 8, and 40 mU/m(2) · min. Infusions of [1,1,2,3,3-(2)H(2)]glycerol and [1-(13)C]palmitate were used to quantify lipid metabolism.Basal glycerol and palmitate rates of appearance were similar between groups, decreased more in control subjects during the first two stages of the clamp, and similarly suppressed during the highest insulin dose. The concentration of insulin required for 50% inhibition of lipolysis was twice as high in individuals with type 1 diabetes. Plasma triglyceride saturation was similar between groups, but palmitoleic acid in plasma triglyceride was inversely related to adipocyte insulin sensitivity. Unesterified palmitoleic acid in plasma was positively related to insulin sensitivity in controls, but not in individuals with type 1 diabetes.Adipose tissue insulin resistance is a significant feature of type 1 diabetes. Palmitoleic acid is not related to insulin sensitivity in type 1 diabetes, as it was in controls, suggesting a novel mechanism for insulin resistance in this population.

OBJECTIVE Type 1 diabetes is a common chronic childhood disease, and the incidence is increasing globally. Childhood infections are considered a potential environmental trigger of type 1 diabetes. Alternatively, improved hygiene and reduced childhood infections could explain the increase in type 1 diabetes in developed countries. The association of reported illnesses during infancy and later development of islet autoimmunity (IA) were examined in the Diabetes Autoimmunity Study in the Young. RESEARCH DESIGN AND METHODS Complete illness interviews through 9 months of age were collected for 1,729 children—1,174 without a family history of type 1 diabetes and 555 with a first-degree relative with type 1 diabetes. Persistent IA was defined as positive antibodies to insulin, glutamic acid decarboxylase, or tyrosine phosphatase on at least two consecutive study visits. RESULTS There were 109 children with persistent IA among the 1,729 children with illness records. A greater number of gastrointestinal illnesses were associated with an increased risk of IA, but only among children who were exposed to gluten-containing grains (wheat or barley) either CONCLUSIONS Specific pathogens such as enteroviruses or rotavirus may increase the risk of IA in the presence of existing inflammation induced by diet.

The associations between elevated adiponectin and end-stage renal disease are well recognized and thought to be at least partially explained by reduced renal clearance. Conversely, the relationship between adiponectin and early diabetic kidney disease (DKD) with preserved glomerular filtration rate (GFR), including rapid GFR decline and incident chronic kidney disease (CKD) is unclear. We hypothesized that elevated adiponectin would be associated with early DKD in adults with type 1 diabetes.Adults with type 1 diabetes (n=646 at baseline, n=525 at 6years) had adiponectin and renal function by estimated GFR (eGFR) by CKD-EPI creatinine and albumin-excretion rate (AER) evaluated at baseline and 6years. Linear and logistic models evaluated the associations of baseline adiponectin with AER, macroalbuminuria (AER ≥200μg/min), eGFR, CKD (60mL/min/1.73mCompared to non-diabetics, adults with type 1 diabetes had significantly higher adiponectin, and the difference remained significant after adjusting for AER and/or eGFR (p0.0001). Adiponectin at baseline was positively associated with rapid GFR decline (OR: 1.24, 95% CI 1.00-1.53), incident CKD (OR: 1.75, 1.14-2.70), and persistent macroalbuminuria and CKD (OR: 1.61, 1.10-2.36) over 6years in adjusted models. The associations also remained significant after further adjustments for CRP, estimated insulin sensitivity and ACEi/ARB therapy.Adults with type 1 diabetes have higher adiponectin than their non-diabetic peers, and elevated adiponectin at baseline is independently associated with greater odds of developing early DKD over 6years.

Background Women with type 1 diabetes (T1D) have a four-fold increased risk for cardiovascular disease (CVD) compared to non-diabetic (non-DM) women, as opposed to double the risk in T1D men compared to non-DM men. It is unclear how early in life CVD risk differences begin in T1D females. Therefore, our objective was to compare CVD risk factors in adolescents with and without T1D to determine the effects of gender on CVD risk factors. Methods The study included 300 subjects with T1D (age 15.4±2.1 years, 50 % male, 80 % non-Hispanic White (NHW), glycated hemoglobin (A1c) 8.9±1.6 %, diabetes duration 8.8±3.0 years, BMI Z-score 0.62±0.77) and 100non-DM controls (age 15.4±2.1 years, 47 % male, 69 % NHW, BMI Z-score 0.29±1.04). CVD risk factors were compared by diabetes status and gender. Multivariate linear regression analyses were used to determine if relationships between diabetes status and CVD risk factors differed by gender independent of differences in A1c and BMI. Results Differences in CVD risk factors between T1D subjects and non-DM controls were more pronounced in girls. Compared to boys with T1D and non-DM girls, T1D girls had higher A1c (9.0 % vs. 8.6 % and 5.1 %, respectively), BMI Z-score (0.70 vs. 0.47 and 0.27), LDL-c (95 vs. 82 and 81 mg/dL), total cholesterol (171 vs. 153 and 150 mg/dL), DBP (68 vs. 67 and 63 mmHg), and hs-CRP (1.15 vs. 0.57 and 0.54 mg/dL) after adjusting for Tanner stage, smoking status, and race/ethnicity (p

Background Vasopressin exerts important cardio–renal effects, but remains problematic to measure. Copeptin is a more stable peptide derived from the same precursor molecule. We examined the associations between copeptin, coronary artery calcium (CAC), albuminuria and impaired glomerular filtration rate (GFR) in adults with type 1 diabetes (T1D). Methods Participants with (n=209) and without T1D (n=244) in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study were assessed for serum copeptin, CAC measured using 128-slice spiral CT, urinary albumin-to-creatinine ratio (UACR) and eGFR calculated by CKD-EPI creatinine. Impaired GFR was defined as eGFR 2 , albuminuria as UACR ≥30mg/g, high and very high CAC score as ≥100 and ≥300AU, and elevated copeptin as >13pmol/L (>97.5th percentile for healthy adults). Unadjusted and adjusted (age, sex, HbA1c, SBP and LDL-C) logistic models were applied to examine the relationships. Results Participants with T1D had greater ultrasensitive copeptin concentrations than non-diabetics (3.5 [95% CI 2.3–3.8] vs. 2.8 [2.7–3.1], p=0.003). In participants with T1D, elevated copeptin was associated with greater odds of impaired eGFR (OR: 18.52, 95% CI 4.03–85.02), albuminuria (10.55, 2.24–49.62), high CAC (6.61, 1.39–31.31) and very high CAC (6.24, 1.51–25.90) in multivariable models. Similar linear relationships were obtained with ultrasensitive copeptin, eGFR, UACR, CAC volume and CAC score in adjusted models. Conclusion In this cross-sectional analysis, copeptin was strongly associated with diabetic kidney disease and coronary atherosclerosis in adults with T1D. Further research is needed to determine whether these relationships hold true longitudinally in people with T1D.

In patients with type 1 diabetes mellitus (T1D), cardiovascular disease (CVD) events are more common and occur earlier in life than in non-diabetics. Reduced brachial artery distensibility (BrachD) is an independent risk factor for development of CVD. Our aim was to determine if adults with T1D have lower BrachD compared to adults without diabetes and also to determine how age and gender affect the relationship of BrachD with T1D status.BrachD was measured using the Dynapulse instrument in 829 participants (352 with T1D, 477 non-diabetics). An ANCOVA model was used to test the association of BrachD with age, sex, and T1D, and the significance of an age*sex*T1D interaction.Mean BrachD was lower in T1D patients vs. controls (6.43±1.46 vs. 7.16±1.48 % change per mmHg, p0.0001). In a model adjusted for age, T1D, and sex, the interaction of age*T1D*sex was significant (p=0.0045). Younger women both with and without T1D had higher BrachD than men with and without T1D, but older women with and without T1D had lower BrachD compared to older men with and without T1D. Women with T1D had a steeper decline in BrachD with age than nondiabetic women.BrachD is lower in T1D patients than in non-diabetics, indicating increased vascular stiffness. Younger females have higher BrachD than males, but the decline with age in BrachD is steeper for women, particularly among those with T1D. BrachD may be an inexpensive, non-invasive method to ascertain increased CVD risk in this population.

SUMMARY Diabetes causes increased mortality and healthcare costs, and prevalence is increasing worldwide. Diabetic nephropathy is the leading cause of end-stage renal disease, and is closely tied to cardiovascular disease, the main cause of death in people with diabetes. Renal function decline as measured by estimated glomerular filtration rate has emerged as a more reliable marker of kidney damage than urinary albumin, and markers for renal function decline are discussed in this review. Renal damage appears to be related to a series of effects of the hyperglycemia and insulin resistance that accompanies both Type 1 and Type 2 diabetes, including insulin resistance, accumulation of advanced glycation end products, uric acid and oxidative stress, often mediated by genetic susceptibility.

Type 1 diabetes is known to be a state of insulin resistance; however, the tissues involved in whole-body insulin resistance are less well known. It is unclear whether insulin resistance is due to glucose toxicity in the post-Diabetes Control and Complications Trial era of tighter glucose control.We performed this study to determine muscle and liver insulin sensitivity individuals with type 1 diabetes after overnight insulin infusion to lower fasting glucose concentration.Fifty subjects [25 controls without and 25 individuals with type 1 diabetes (diabetes duration 22.9 ± 1.7 yr, without known end organ damage] were frequency matched on age and body mass index by group and studied. After 3 d of dietary control and overnight insulin infusion to normalize glucose, we performed a three-stage hyperinsulinemic/euglycemic clamp infusing insulin at 4, 8, and 40 mU/m(2) · min. Glucose metabolism was quantified using an infusion of [6,6-(2)H(2)]glucose. Hepatic insulin sensitivity was measured using the insulin IC(50) for glucose rate of appearance (Ra), whereas muscle insulin sensitivity was measured using the glucose rate of disappearance during the highest insulin dose.Throughout the study, glucose Ra was significantly greater in individuals compared with those without type 1 diabetes. The concentration of insulin required for 50% suppression of glucose Ra was 2-fold higher in subjects with type 1 diabetes. Glucose rate of disappearance was significantly lower in individuals with type 1 diabetes during the 8- and 40-mU/m(2) · min stages.Insulin resistance in liver and skeletal muscle was a significant feature in type 1 diabetes. Nevertheless, the etiology of insulin resistance was not explained by body mass index, percentage fat, plasma lipids, visceral fat, and physical activity and was also not fully explained by hyperglycemia.

OBJECTIVE To define a panel of novel protein biomarkers of renal disease. RESEARCH DESIGN AND METHODS 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). RESULTS 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 (odds ratio 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. CONCLUSIONS 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.

People with type 1 diabetes (T1D) have markedly reduced insulin sensitivity (IS) compared to their nondiabetic counterparts, and reduced IS is linked to higher cardiovascular risk.This study aimed to develop and validate an improved method for estimating IS in people with T1D.Prospective cohort.Adults (36 with T1D, 41 nondiabetic) were recruited from the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study for measurement of IS by hyperinsulinemic-euglycemic clamp to develop a clinically useful IS prediction equation (eIS) for T1D and nondiabetic individuals. These equations were then compared with previously published equations from the SEARCH and Pittsburgh Epidemiology of Diabetes Complications studies for the ability to predict measured IS in test sets of adults and adolescents from independent clamp studies.None.Comparison of clamp-measured IS to estimated IS.The best-fit prediction model (eIS) differed by diabetes status and included waist circumference, triglycerides, adiponectin, and diastolic blood pressure in all CACTI adults and insulin dose in adults with T1D (adjusted R(2) = 0.64) or fasting glucose and hemoglobin A1c (HbA1c) in nondiabetic adults (adjusted R(2) = 0.63). The eIS highly correlated with clamp-measured IS in all of the non-CACTI comparison populations (r = 0.83, P = .0002 in T1D adults; r = 0.71, P = .01 in nondiabetic adults; r = 0.44, P = .008 in T1D adolescents; r = 0.44, P = .006 in nondiabetic adolescents).eIS performed better than previous equations for estimating IS in individuals with and without T1D. These equations could simplify point-of-care assessment of IS to identify patients who could benefit from targeted intervention.

Density of adipose tissue can be measured by CT attenuation in Hounsfield Units (HU). Increased visceral fat density has been associated with coronary artery calcification (CAC). However, the relationship between pericardial fat density and CAC is unknown. We examined the association of pericardial fat density (PAT HU) with the presence (CAC > 0) and progression of CAC in the Coronary Artery Calcification in Type 1 Diabetes study (CACTI). CACTI is a prospective cohort study of adults with and without type 1 diabetes (T1D) with a mean age of 38 years (±9) at baseline. Participants were free of CVD at the time of enrollment in the study. PAT volume was measured from baseline EBCT scans within a range of HU from -190 to -30. CAC was measured at baseline and at the follow-up exam with a mean follow-up of 6 years (±0.5). Logistic regression was used to examine the association between PAT HU and CAC. Prevalence of CAC was defined as any CAC (>0) at baseline. Progression of CAC was defined as a change in volume of ≥2.5 square-root transformed units between the baseline and followup exams. PAT volume and triglycerides were log transformed. Interaction terms for diabetes and PAT HU were tested in the models. PAT data were available on 1319 subjects for the prevalence model, and 952 for the progression model. PAT HU was significantly higher (less-negative) in those with T1D compared to those without (-75.7 ±3.7 vs -77.8 ±4.2; p

Results from the Reducing with Metformin Vascular Adverse Lesions (REMOVAL) study show for the first time that metformin has a cardiovascular benefit in patients with type 1 diabetes mellitus (T1DM), although the benefit was limited to tertiary outcomes and was modest. Additional measures are therefore needed to reduce cardiovascular disease in patients with T1DM.

Diabetic complications of nephropathy and accelerated atherosclerosis are associated with vascular remodeling and dysregulated angiogenesis. Matrix metalloproteinases (MMP) modify extracellular matrix during vascular remodeling and are excreted in urine of patients with vascular malformation or tumor angiogenesis. We hypothesized that urinary MMP activities would be sensitive biomarkers for vascular remodeling in diabetic complications. Activities of MMP-2, MMP-9, and its complex with neutrophil gelatinase-associated lipocalin (NGAL/MMP-9) were measured by substrate gel zymography in urine from nondiabetic (ND) and type 1 diabetic (T1D) rodents that were susceptible to both T1D-induced plaque angiogenesis and nephropathy, or nephropathy alone. Additionally, these urine activities were measured in ND and T1D adolescents. Urinary MMP-9, MMP-2, and NGAL/MMP-9 activities were increased and more prevalent in T1D compared with ND controls. Urinary MMP-2 activity was detected in mice with T1D-induced plaque neovascularization. In nephropathy models, urinary NGAL/MMP-9 and MMP-9 activities appeared before onset of albuminuria, whereas MMP-2 was absent or delayed. Finally, urinary MMP activities were increased in adolescents with early stages of T1D. Urinary MMP activities may be sensitive, noninvasive, and clinically useful biomarkers for predicting vascular remodeling in diabetic renal and vascular complications.

The aim was to examine whether excess weight is associated with coronary artery calcium (CAC), independent of metabolic parameters in adults with type 1 diabetes (T1D).Subjects between 19 and 56 years of age with T1D (n=621) from the Coronary Artery Calcification in Type 1 Diabetes study were classified as abnormal on four metabolic parameters: blood pressure ≥130/85 mm Hg or on antihypertensive treatment; high-density lipoprotein-cholesterol of40 mg/dL for men or50 mg/dL for women; triglycerides of ≥150 mg/dL; or C-reactive protein of ≥3 μg/mL. Study participants with two or more abnormal parameters were classified as metabolically abnormal. Weight categories by body mass index were normal (25 kg/m(2)), overweight (25 to30 kg/m(2)), and obese (≥30 kg/m(2)). CAC was measured at two visits 6.0±0.5 years apart. Progression of CAC was defined as an increase in square root transformed CAC volume of ≥2.5 mm(3) or development of clinical coronary artery disease.Among subjects with T1D, 48% of normal, 61% of overweight, and 73% of obese participants were classified as metabolically abnormal (P0.0001). Overweight and obesity were independently associated with presence of CAC, independent of presence of metabolically abnormal. Obesity but not overweight was associated with CAC progression, independent of the other cardiovascular risk factors.Although obesity is known to increase cardiovascular disease risk through inducing metabolic abnormalities such as dyslipidemia, hypertension, and inflammation, it is also a strong predictor of subclinical atherosclerosis progression in adults with T1D independent of these factors.

Diabet. Med. 28, 1176–1181 (2011) Abstract Aims Patients with Type 1 diabetes have significantly elevated postprandial glucagon secretion. Dipeptidyl peptidase IV inhibitors improve HbA1c by several mechanisms, including increasing glucagon-like peptide 1 and glucose-dependent insulinotropic peptide concentrations, which decreases postprandial rises in glucagon in both Type 1 and Type 2 diabetes. This study evaluates the clinical implications of sitagliptin in adult patients with Type 1 diabetes. Methods This investigator-initiated, double-blind, randomized, crossover, 8-week, pilot study enrolled 20 adult subjects with Type 1 diabetes. Subjects received sitagliptin 100 mg/day or placebo for 4 weeks and then crossed over. Outcomes included 2-h postprandial blood glucose and 24-h area under the curve changes in glucose measurements from continuous glucose monitoring, HbA1c, fructosamine and insulin dose. Results Sitagliptin significantly reduced blood glucose (2-h postprandial and 24-h area under the curve) despite reduced total and prandial insulin dose. Based on continuous glucose monitor findings, sitagliptin improved measures of glycaemic control, including mean blood glucose (−0.6 mmol/l; P = 0.012) and time in euglycaemic range 4.4–7.8 mmol/l (0.4 ± 0.2 h; P = 0.046). Significant reductions were also observed in M100, Glycemic Risk Assessment Diabetes Equation (GRADE) and J-index. After controlling for period, treatment and insulin dose, the HbA1c was also significantly reduced [−0.27 ± 0.11% (−2.91 ± 1.16 mmol/mol); P = 0.025] when patients were taking sitagliptin. Conclusions Sitagliptin significantly improved overall glucose control, including postprandial and 24-h glucose control, in adult patients with Type 1 diabetes, while significantly reducing prandial insulin requirements. Further investigation is warranted in patients with Type 1 diabetes in a larger cohort designed to assess both clinical outcomes and mechanism of action.

Cystatin C is used increasingly as a biomarker of renal function; however, cystatin C assays are not standardized. Our objective was to compare cystatin C results within the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study over time and in repeated measures to evaluate for assay drift.Serum samples were obtained at baseline (visit 1 [V1], 2000 to 2002) and follow-up (visit 2 [V2], 2003 to 2005; visit 3 [V3], 2006 to 2008) and were assayed in 2006 (V1), 2007 to 2008 (V2), and 2010 (V3) in the same laboratory.Mean cystatin C levels measured using the Dade-Behring assay decreased over time in subjects, with measures at all three visits (V1: 0.80 ± 0.19 [0.42 to 3.41], V2: 0.75 ± 0.22 [0.39 to 3.77], and V3: 0.69 ± 0.22 [0.39 to 3.79]). Cystatin C values were lower in V1 and V2 samples remeasured in 2010 (mean differences -0.13 ± 0.04 and -0.08 ± 0.04, P0.0001 for both). Correlations for original and re-run values were strong for V1 (r = 0.99) and V2 (r = 0.99). Deming regression equations and Bland-Altman plots suggest a systematic shift in the values over time.Systematic shifts in cystatin C levels, which can be corrected by regression adjustment, occurred in our laboratory in samples measured in 2006 and 2007 to 2008 as compared with 2010. Assay standardization and measurement reliability for cystatin C must be addressed.

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a lipoprotein-associated enzyme that cleaves oxidized phosphatidylcholines, generating pro-atherosclerotic lysophosphatidylcholine and oxidized free fatty acids. Lp-PLA2 is independently associated with cardiovascular disease (CVD) in a variety of populations. Coronary calcium is a measure of subclinical CVD, and progression of coronary calcification predicts future CVD events. In type 1 diabetes there is an increase in coronary calcium and CVD despite a favorable lipid profile. Levels of Lp-PLA2 in type 1 diabetes are not known, nor is the relationship between Lp-PLA2 and progression of coronary calcification. Methods: The Coronary Artery Calcification in Type 1 Diabetes study measured coronary calcium by electron-beam computed tomography twice over a 2.6 ± 0.3-year interval. Lp-PLA2 mass and activity were measured at baseline (n = 1,097 subjects, 506 with and 591 without type 1 diabetes). Results: In type 1 diabetes Lp-PLA2 mass w...

Diabet. Med. 28, 148–155 (2011) Abstract Aims Insulin resistance and dyslipidaemia both increase cardiovascular risk in Type 1 diabetes. However, little data exist on the associations of insulin resistance to lipids in Type 1 diabetes. Our objective was to explore the associations between insulin resistance (assessed by glucose infusion rate) and lipids in people with Type 1 diabetes and determine whether adiposity and/or average glycaemia influence these associations. Methods Hyperinsulinaemic–euglycaemic clamp studies were performed in 60 subjects with Type 1 diabetes aged 12–19 years (age 15 ± 2 years, 57% female, duration of diabetes 6.3 ± 3.8 years, HbA1c 8.6 ± 1.5%, IFCC = 70 mmol/mol) and 40 subjects with Type 1 diabetes aged 27–61 years (age 45 ± 9 years, 53% female, duration of diabetes 23 ± 8 years, HbA1c 7.5 ± 0.9%, IFCC = 58 mmol/mol). Multiple linear regression models were fit to examine the association between glucose infusion rate and fasting lipid levels with adjustment for possible confounders. Results Lower glucose infusion rate was significantly associated with lower levels of HDL cholesterol in youths with Type 1 diabetes and with higher levels of triglycerides and higher triglyceride/HDL ratio in both youths and adults. The magnitude of the associations between glucose infusion rate and lipid levels translate into interquartile differences of 0.098 mmol/l for HDL cholesterol, 0.17 mmol/l for triglycerides and 1.06 for triglycerides/HDL in the adolescents and 0.20 mmol/l for triglycerides and 1.01 for triglycerides/HDL in the adults. The associations were attenuated and no longer statistically significant by adjustment for adiposity among adults, while adjustment for HbA1c had a small effect in youths and adults. Conclusions Lower insulin sensitivity is associated with a more atherogenic lipid profile in both youths and adults with Type 1 diabetes.

OBJECTIVE The objective of this study is to examine the relationship among serum levels of 25-hydroxyvitamin D (25[OH]D), polymorphisms in vitamin D-associated genes, and the presence and progression of coronary artery calcification (CAC) in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS This prospective study included 374 non-Hispanic white individuals with type 1 diabetes (mean age 40 ± 9 years; 46% were male). CAC was measured at the baseline and 3- and 6-year follow-up visits were determined by electron beam computed tomography. Serum 25[OH]D levels were measured by liquid chromatography tandem mass spectrometry at the 3-year visit. RESULTS Normal (>30 ng/mL), insufficient (20–30 ng/mL), and deficient ( CONCLUSIONS Vitamin D deficiency independently predicts prevalence and development of CAC, a marker of coronary artery plaque burden, in individuals with type 1 diabetes.

Renal cysts, pain, and hematuria are common presentations of autosomal dominant polycystic kidney disease (ADPKD) in children. Renal function, however, is typically preserved in these patients despite increased renal volume. Since angiogenesis has been implicated in promotion of renal cyst growth in ADPKD, we measured the serum level of various angiogenic factors and early renal structural changes and cardiovascular parameters in 71 patients with ADPKD, with a mean age of 16 years. Renal structure and left ventricular mass index were measured by magnetic resonance imaging or by echocardiogram. Renal function was assessed by creatinine clearance and urinary protein excretion. Serum growth factor levels were measured by enzyme-linked immunosorbent assay. Because of skewed distributions, the various parameters are reported as log(10). Serum log(10) vascular endothelial growth factor was positively correlated with renal and cardiac structure, but negatively with creatinine clearance. Serum angiopoietin 1 levels significantly correlated with structural change in both the kidney and the heart and with urinary protein. Thus, the correlation between angiogenic growth factors with both renal and cardiac disease severity is compatible with a possible role for angiogenesis in the early progression of disease in ADPKD.

Aim: Colesevelam is indicated to lower low density lipoprotein cholesterol (LDL-C) in hyperlipidaemia and improve glycaemic control in adults with type 2 diabetes. This short-term pilot study evaluates its effects in type 1 diabetes. Methods: This double-blind, randomized, investigator-initiated, single-centred, 12-week pilot study evaluated 40 adults (age = 36.4 ± 9.4 years) with type 1 diabetes (duration = 20.4 ± 8.5 years) and hyperlipidaemia. It was powered to show a treatment difference of >10% LDL-C reduction. Subjects received 3.75 g/day colesevelam (n = 20) or placebo (n = 20) for 12 weeks. LDL-C and haemoglobin A1c (A1c) levels were assessed at screening (week 2), baseline (week 0) and every 4 weeks throughout the treatment duration. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) levels were measured during 4-h meal (Boost Plus®, Nestle HealthCare Nutrition Inc., Florham Park, New Jersey, USA) challenge tests (MCT) at baseline and 12 weeks. Results: Colesevelam treatment resulted in a significant reduction in LDL-C values at 4 weeks [−12.1% (95% CI: −20.1 to −4.1), p = 0.004] which was sustained for the study duration (p = 0.005 at 12 weeks). The treatment group also showed a significant change in A1c from baseline at week 4; however, this was not significant for the study duration. There was a significant median increase in GLP-1 levels during the first 2 h of the baseline MCT in the treated group but no difference at 12 weeks. Conclusions: During this short-term pilot study, colesevelam treatment effectively lowered LDL-C in patients with type 1 diabetes. Improvements in A1c seen at week 4 were not sustained. Effects on glycaemic control in subjects with type 1 diabetes may be related to a postprandial rise in GLP-1 levels and require further clinical study.

Diabet. Med. 27, 1436–1442 (2010) Abstract Aims We investigated coronary artery calcium in association with glucose levels and variability measured using continuous glucose monitoring in adults with Type 1 diabetes in the Coronary Artery Calcification in Type 1 Diabetes study. Methods Coronary artery calcium was measured by electron beam tomography. The presence of any coronary artery calcium was analysed with respect to glucose levels [meanT (mean glucose), % of values 10 mmol/l and either 10 mmol/l] and glycaemic variability [sdT (sd of all glucose values); sddm (sd of the daily mean glucose levels) and sdhh:mm (glucose sd for a specified time of day, over all days)] using 3–5 days of continuous glucose monitoring from 75 subjects (45 women, 30 men), age 42 ± 9 years (mean ± sd) and diabetes duration of 29 ± 8 years using logistic regression. Results We observed significant associations between coronary artery calcium and meanT (OR = 4.4, 95% CI 1.1–18.6), % of values > 10 mmol/l (OR = 5.5, 95% CI 1.3–22.6), % of measures 10 mmol/l (OR = 5.7, 95% CI 1.3–24.9), sdT (OR = 4.7, 95% CI 1.1–19.7), sddm (OR = 6.0, 95% CI 1.2–30.4) and sdhh:mm (OR = 4.0, 95% CI 1.1–15.4), among men, but none of these variables were associated with the presence of coronary artery calcium in women. Conclusions We report the novel finding that subclinical atherosclerosis is associated with glucose levels and variability in men with Type 1 diabetes. The relationship of coronary artery calcium and glucose variability in Type 1 diabetes, and potential gender differences in this association, deserve further study.

OBJECTIVE To assess insulin action on peripheral glucose utilization and nonesterified fatty acid (NEFA) suppression as a predictor of coronary artery calcification (CAC) in patients with type 1 diabetes and nondiabetic controls. RESEARCH DESIGN AND METHODS Insulin action was measured by a three-stage hyperinsulinemic-euglycemic clamp (4, 8, and 40 mU/m2/min) in 87 subjects from the Coronary Artery Calcification in Type 1 Diabetes cohort (40 diabetic, 47 nondiabetic; mean age 45 ± 8 years; 55% female). RESULTS Peripheral glucose utilization was lower in subjects with type 1 diabetes compared with nondiabetic controls: glucose infusion rate (mg/kg FFM/min) = 6.19 ± 0.72 vs. 12.71 ± 0.66, mean ± SE, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and final clamp glucose and insulin. Insulin-induced NEFA suppression was also lower in type 1 diabetic compared with nondiabetic subjects: NEFA levels (μM) during 8 mU/m2/min insulin infusion = 370 ± 27 vs. 185 ± 25, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and time point insulin. Lower glucose utilization and higher NEFA levels, correlated with CAC volume (r = −0.42, P < 0.0001 and r = 0.41, P < 0.0001, respectively) and predicted the presence of CAC (odds ratio [OR] = 0.45, 95% CI = 0.22–0.93, P = 0.03; OR = 2.4, 95% CI = 1.08–5.32, P = 0.032, respectively). Insulin resistance did not correlate with GHb or continuous glucose monitoring parameters. CONCLUSIONS Type 1 diabetic patients are insulin resistant compared with nondiabetic subjects, and the degree of resistance is not related to current glycemic control. Insulin resistance predicts the extent of coronary artery calcification and may contribute to the increased risk of cardiovascular disease in patients with type 1 diabetes as well as subjects without diabetes.

Hyperglycaemia and dyslipidaemia are common metabolic abnormalities in adults with type 1 diabetes and both increase cardiovascular disease (CVD) risk. The hypothesis of this study was that change in HbA(1c) over 6 years would be associated with change in fasting lipids in adults with type 1 diabetes.The Coronary Artery Calcification in Type 1 Diabetes (CACTI) study examined 652 patients with type 1 diabetes (54% female); 559 and 543 had follow-up visits at 3 and 6 years. Baseline age (mean ± SD) was 37 ± 9 years, diabetes duration 23 ± 9 years, and HbA(1c) 8.0 ± 1.3%. Use of dyslipidaemia medication was 17%, 32%, and 46% at the three visits. Separate longitudinal mixed models were fitted to examine the relationship between change in HbA(1c) and change in fasting total cholesterol (TC), HDL-cholesterol (HDL-c), LDL-cholesterol (LDL-c), log triacylglycerols (TG), and non-HDL-cholesterol (non-HDL-c). Because of an interaction between dyslipidaemia medication use and association of HbA(1c) with lipids, results were stratified by dyslipidaemia medication use.Among patients not using dyslipidaemia medication, a higher HbA(1c) was associated with significantly worse levels of the lipids TC, LDL-c, TG and non-HDL-c (per 1% change in HbA1c, TC 0.101 mmol/l, 95% CI 0.050, 0.152; LDL-c 0.103 mmol/l, 95% CI 0.058, 0.148; TG 0.052 mmol/l, 95% CI 0.024, 0.081; and non-HDL-c 0.129 mmol/l, 95% CI 0.078, 0.180) but not HDL-c (-0.20 mmol/l, 95% CI -0.047, 0.007). The associations between HbA(1c) and any lipid outcome among those on dyslipidaemia medication were in the same direction, but attenuated compared with persons not on medication.Change in HbA(1c) is significantly associated with change in fasting lipids, but dyslipidaemia medications may be required to optimise lipid and cardiovascular health.

OBJECTIVEIndividuals with type 1 diabetes have a less atherogenic fasting lipid profile than those without diabetes but paradoxically have increased rates of cardiovascular disease (CVD). We investigated differences in lipoprotein subfraction cholesterol distribution and insulin resistance between subjects with and without type 1 diabetes to better understand the etiology of increased CVD risk.RESEARCH DESIGN AND METHODSFast protein liquid chromatography was used to fractionate lipoprotein cholesterol distribution in a substudy of the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study (n = 82, age 46 ± 8 years, 52% female, 49% with type 1 diabetes for 23 ± 8 years). Insulin resistance was assessed by a hyperinsulinemic-euglycemic clamp.RESULTSAmong men, those with type 1 diabetes had less VLDL and more HDL cholesterol than control subjects (P < 0.05), but among women, those with diabetes had a shift in cholesterol to denser LDL, despite more statin use. Among control subjects, men had more cholesterol distributed as VLDL and LDL but less as HDL than women; however, among those with type 1 diabetes, there was no sex difference. Within sex and diabetes strata, a more atherogenic cholesterol distribution by insulin resistance was seen in men with and without diabetes, but only in women with type 1 diabetes.CONCLUSIONSThe expected sex-based less atherogenic lipoprotein cholesterol distribution was not seen in women with type 1 diabetes. Moreover, insulin resistance was associated with a more atherogenic lipoprotein cholesterol distribution in all men and in women with type 1 diabetes. This lipoprotein cholesterol distribution may contribute to sex-based differences in CVD in type 1 diabetes.

Aims/hypothesis Microalbuminuria is common in type 1 diabetes and is associated with an increased risk of renal and cardiovascular disease. We aimed to develop and validate a clinical prediction rule that estimates the absolute risk of microalbuminuria. Methods Data from the European Diabetes Prospective Complications Study (n = 1115) were used to develop the prediction rule (development set). Multivariable logistic regression analysis was used to assess the association between potential predictors and progression to microalbuminuria within 7 years. The performance of the prediction rule was assessed with calibration and discrimination (concordance statistic [c-statistic]) measures. The rule was validated in three other diabetes studies (Pittsburgh Epidemiology of Diabetes Complications [EDC] study, Finnish Diabetic Nephropathy [FinnDiane] study and Coronary Artery Calcification in Type 1 Diabetes [CACTI] study). Results Of patients in the development set, 13% were microalbuminuric after 7 years. Glycosylated haemoglobin, AER, WHR, BMI and ever smoking were found to be the most important predictors. A high-risk group (n = 87 [8%]) was identified with a risk of progression to microalbuminuria of 32%. Predictions showed reasonable discriminative ability, with c-statistic of 0.71. The rule showed good calibration and discrimination in EDC, FinnDiane and CACTI (c-statistic 0.71, 0.79 and 0.79, respectively). Conclusions/interpretation We developed and validated a clinical prediction rule that uses relatively easily obtainable patient characteristics to predict microalbuminuria in patients with type 1 diabetes. This rule can help clinicians to decide on more frequent check-ups for patients at high risk of microalbuminuria in order to prevent long-term chronic complications. Electronic supplementary material The online version of this article (doi:10.1007/s00125-009-1585-3) contains a list of the members of the EURODIAB, EDC, FinnDiane and CACTI Study Groups and other contributors to the study, which is available to authorised users.

In this study we sought to validate urinary biomarkers for diabetes and two common complications, coronary artery disease (CAD) and diabetic nephropathy (DN).A CAD score calculated by summing the product of a classification coefficient and signal amplitude of 15 urinary polypeptides was previously developed. Five sequences of biomarkers in the panel were identified as fragments of collagen alpha-1(I) and alpha-1(III). Prospectively collected urine samples available for analysis from 19 out of 20 individuals with CAD (15 with type 1 diabetes [T1D] and four without diabetes) and age-, sex-, and diabetes-matched controls enrolled in the Coronary Artery Calcification in Type 1 Diabetes study were analyzed for the CAD score using capillary electrophoresis and electrospray ionization mass spectrometry. Two panels of biomarkers that were previously defined to distinguish diabetes status were analyzed to determine their relationship to T1D. Three biomarker panels developed to distinguish DN (DNS) and two biomarker panels developed to distinguish renal disease (RDS) were examined to determine their relationship with renal function.The CAD score was associated with CAD (odds ratio with 95% confidence interval, 2.2 [1.3-5.2]; P = 0.0016) and remained significant when adjusted individually for age, albumin excretion rate (AER), blood pressure, waist circumference, intraabdominal fat, glycosylated hemoglobin, and lipids. DNS and RDS were significantly correlated with AER, cystatin C, and serum creatinine. The biomarker panels for diabetes were both significantly associated with T1D status (P0.05 for both).We validated a urinary proteome pattern associated with CAD and urinary proteome patterns associated with T1D and DN.

Coronary artery disease is increased in women with type 1 diabetes (T1D), compared with nondiabetic (Non-DM) women. Women with T1D have more menstrual dysfunction and are less likely to use hormonal birth control (BC) than Non-DM women.The purpose of this study was to determine whether coronary artery calcium (CAC) is associated with menstrual dysfunction and BC use in women with T1D.This was a prospective cohort study, and participants were followed up for an average of 2.4 yr.Patients included 612 women (293 T1D, 319 Non-DM) between the ages of 19 and 55 yr who had CAC measured twice by electron beam tomography.Irregular menses and amenorrhea were more common in T1D than Non-DM women (22.1 vs. 14.9%, P0.05 and 16.6 vs. 7.0%, P0.001). T1D women reported less BC use than Non-DM women (79.8 vs. 89.9%, P0.001) and reached menarche at an older age (13.1 +/- 1.8 vs. 12.8 +/- 1.5 yr, P0.05). Use of BC was associated with less CAC progression in all women, but this association was stronger in T1D women (P value for interaction = 0.02). Irregular menses were associated with greater CAC progression only among T1D women.A prior history of BC use is associated with reduced CAC progression among all women, with a stronger association in T1D than in Non-DM women. Women with T1D who report irregular menses have increased CAC progression, compared with those with regular menses.

Circulating adiponectin is elevated in human type 1 diabetes (T1D) and nonobese diabetic (NOD) mice without the expected indications of adiponectin action, consistent with tissue resistance.Adiponectin stimulates hepatocyte production of the suppressor of glucose from autophagy (SOGA), a protein that inhibits glucose production. We postulated that due to tissue resistance, the elevation of adiponectin in T1D should fail to increase the levels of a surrogate marker for liver SOGA, the circulating C-terminal SOGA fragment.Liver and plasma SOGA were measured in NOD mice (n = 12) by Western blot. Serum adiponectin and SOGA were measured in T1D and control (Ctrl) participants undergoing a three-stage insulin clamp for the Coronary Artery Calcification in T1D study (n = 20). Glucose turnover was measured using 6,6[(2)H2]glucose (n = 12).In diabetic NOD mice, the 13%-29% decrease of liver SOGA (P = .003) and the 30%-37% reduction of circulating SOGA (P.001) were correlated (r = 0.826; P = .001). In T1D serum, adiponectin was 50%-60% higher than Ctrl, SOGA was 30%-50% lower and insulin was 3-fold higher (P.05). At the low insulin infusion rate (4 mU/m(2)·min), the resulting glucose appearance correlated negatively with adiponectin in T1D (r = -0.985, P = .002) and SOGA in Ctrl and T1D (r = -0.837, P = .001). Glucose disappearance correlated with adiponectin in Ctrl (r = -0.757, P = .049) and SOGA in Ctrl and T1D (r = -0.709, P = .010). At 40 mU/m(2)·min, the lowered glucose appearance was similar in Ctrl and T1D. Glucose disappearance increased only in Ctrl (P = .005), requiring greater glucose infusion to maintain euglycemia (8.58 ± 1.29 vs 3.09 ± 0.87 mg/kg·min; P = .009).The correlation between liver and plasma SOGA in NOD mice supports the use of the latter as surrogate marker for liver concentration. Reduced SOGA in diabetic NOD mice suggests resistance to adiponectin. The dissociation between adiponectin and SOGA in T1D raises the possibility that restoring adiponectin signaling and SOGA might improve the metabolic response to insulin therapy.

Apolipoprotein B (apoB) and non–high-density lipoprotein cholesterol (non-HDL-C) are cardiovascular disease risk markers, although data in adults with type 1 diabetes mellitus (DM) are limited. We hypothesized that elevated apoB and non-HDL-C would be associated with greater odds of coronary artery calcification progression (CACp), a measure of coronary atherosclerosis, than either category alone in adults with type 1 DM. We grouped subjects with type 1 DM (n = 652) into 4 groups: elevated apoB (≥90 mg/dl) and elevated non-HDL-C (≥130 mg/dl), elevated non-HDL-C alone, elevated apoB alone, and normal apoB and non-HDL-C. We used logistic regression to examine the associations between the groups and CACp for a period of 6 years. We performed sensitivity analyses with elevated apoB and non-HDL-C redefined as at or more than the cohort means (91.4 and 119.0 mg/dl, respectively). Subjects with elevated apoB and non-HDL-C had greater odds of CACp compared with those with normal apoB and non-HDL-C (odds ratio 1.90, 95% confidence interval 1.15 to 3.15) and compared with subjects with elevated apoB alone (odds ratio 2.86, 95% confidence interval 1.43 to 5.74) adjusting for age, gender, duration, hemoglobin A1c, and statins. Similar results were obtained with elevated apoB and non-HDL-C defined as at or more than the cohort means. In conclusion, elevated apoB and non-HDL-C carry a greater risk of atherosclerosis than elevated apoB in the absence of elevated non-HDL-C in adults with type 1 DM. These data suggest that apoB and non-HDL-C should be viewed as complementary rather than competitive indexes of cardiovascular disease risk in type 1 DM.

Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9-23) mimotopes engineered to bind the mouse MHCII molecule, IA(g7), in an unfavorable position or register. Because of the similarities between IA(g7) and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9-23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-γ response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9-23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulin-specific therapies to prevent diabetes onset.

Pericardial adipose tissue (PAT) is ectopic fat deep (epicardial adipose tissue) and superficial (paracardial adipose tissue) to the pericardium of the heart. PAT has been cross-sectionally associated with diabetes, but the association with development of diabetes is unclear. Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), we tested whether PAT at baseline was associated with incident diabetes over nearly 10 years of follow-up. The baseline visit (visit 1) was conducted between 2000-2002. Four follow-up visits were conducted at 2 year intervals with visit 5 between 2010 and 2012. Diabetes was defined as a fasting glucose ≥126 mg/dl or the use of antidiabetic medication. Diabetes-free participants at baseline were followed for incident diabetes at any subsequent visit (visits 2-5). Volume of PAT was measured from computed tomographic (CT) scans taken at visits 1 - 4. CT scans were completed on all participants at baseline. Repeat scans were performed on random halves at visits 2 and 3, and a subset at visit 4. Multivariable Cox proportional hazards models were used to assess the association between PAT and incident diabetes. The figure presents the mean PAT by visit and the mean PAT at baseline among those without diabetes at any time during the study period and those that develop diabetes over the 10 years of follow-up. In Cox regression models adjusted for age, race, and sex, each SD increment of baseline PAT (42.0 mL) was associated with a hazard ratio (HR) for incident diabetes of 1.6 (95% CI 1.5-1.7, p We found that PAT was highly stable over time, accumulating very slowly. Its baseline value strongly predicts incident diabetes independent of overall body mass and central fatness.

People with type 1 diabetes mellitus (T1D) have reduced insulin sensitivity (IS), which partially explains their increased risk of cardiovascular disease. However, there is limited data on how weight gain alters IS in T1D, and so this study aimed to analyze the effect of weight change on IS components in T1D and non-diabetic (non-DM) adults. This study included 1133 adults (T1D=528 and non-DM n=605) with a mean ± SD age of 38 ± 9 years from the Coronary Artery Calcification in Type 1 Diabetes cohort, examined at baseline and after 6.2±0.6 years. Weight change was categorized as follows: weight loss (WL), lost > 2%), weight stable (WS), within 2% of baseline, and weight gain (WG), > 2%. Estimated IS (eIS) was calculated by a model derived from a clamp study (Table) at each visit. Multiple age and sex adjusted least squares means were calculated by weight change group and diabetes status, and progression of coronary artery calcium (CAC) was examined by logistic regression. There was a significant improvement in eIS in the T1D WL group, along with a greater reduction in triglycerides and insulin dose and increase in adiponectin compared to the other weight change groups (Table). There was significant increase in eIS among the non-DM WL group, along with a reduction in triglycerides, fasting glucose, HbA1c and DBP and an increase in adiponectin. For each 2% increase in weight, the odds ratio (OR) for progression of CAC was 1.23 (95% CI 1.1-1.4, p=0.002), after adjusting for age, sex, diabetes status, and baseline BMI and CAC. The odds of CAC progression were decreased by 40% (OR 0.6, 95% CI 0.5-0.8, p=0.0007) for each SD increase in eIS, adjusting for the same variables. In conclusion, over 6 years of follow-up, weight loss increased eIS and related factors in both people with and without T1D, but was not associated with improved Hba1c in T1D. Additionally, weight gain was associated with a greater risk and eIS with a lower risk for CAC progression, demonstrating the importance of avoiding weight gain in prevention of subclinical cardiovascular disease.

LDL cholesterol (LDL-C) is the current lipid standard for cardiovascular disease (CVD)-risk assessment in type 1 diabetes. Apolipoprotein B (apoB) may be helpful to further stratify CVD risk. We explored the association between apoB and pulse wave velocity (PWV) to determine if apoB would improve CVD-risk stratification, especially in type 1 diabetes adolescents with borderline LDL-C (100-129 mg/dL). We hypothesized that type 1 diabetes adolescents with borderline LDL-C and elevated apoB (≥90 mg/dL) would have increased PWV compared to those with borderline LDL-C and normal apoB (90 mg/dL), and that apoB would explain more of the variability of PWV than alternative lipid indices.Fasting lipids, including apoB, were collected in 267 adolescents, age 12-19 years, with diabetes duration5 years and HbA1c 8.9 ± 1.6 %. Triglyceride to HDL-C ratio (TG/HDL-C) and nonHDL-cholesterol (nonHDL-C) were calculated. PWV was measured in the carotid-femoral segment.ApoB, nonHDL-C and TG/HDL-C correlated with PWV (p 0.0001). ApoB, nonHDL-C and TG/HDL-C remained significantly associated with PWV in fully adjusted models. In adolescents with borderline LDL-C (n = 61), PWV was significantly higher in those with elevated apoB than in those with normal apoB (5.6 ± 0.6 vs. 5.2 ± 0.6 m/s, p 0.01) and also remained significant after adjustment for CVD-risk factors (p = 0.0002). Moreover, in those with borderline LDL-C, apoB explained more of the variability of PWV than nonHDL-C and TG/HDL-C.Elevated apoB is associated with increased arterial stiffness in type 1 diabetes adolescents. Measurement of apoB in addition to LDL-C may be helpful in stratifying CVD risk in type 1 diabetes adolescents, especially in those with borderline LDL-C.

Current and former smokers are at an increased risk for lung cancer and cardiovascular disease (CVD). We investigated two methods of visual scoring of coronary artery calcium on lung cancer screening computed tomography (CT) to predict cardiovascular and all-cause mortality.Cases were 1000 participants, age 55-74 years, enrolled in the National Lung Screening Trial CT arm who died during the study. An equal number of participants alive at the end of the study (controls) were matched in terms of sex, CT scanner vendor, and model, and 5-year age and smoking pack-years group. Coronary calcium was measured visually by three readers using two semiquantitative scoring schemes. Conditional logistic regression was used to analyze the association between the presence and the extent of coronary calcium and all-cause and cardiovascular mortality, stratified on matching criteria.Cases and controls were well matched for age (64±6 vs. 64±5, P=0.95) and mean pack-years smoking (61±24 vs. 62±24, P=1.0). Cases were significantly more likely to have coronary calcium than controls (85 vs. 77%, P0.001). Having any calcium was associated with an increased risk for CVD mortality using either visual scoring method (odds ratio 3.4, 95% confidence interval 2.0-5.6, P0.001, and odds ratio 3.3, 95% confidence interval 2.0-5.6, P0.001).Visual scoring of coronary calcium predicts all-cause and CVD mortality in National Lung Screening Trial participants, independent of current versus former smoking status. Visual coronary calcium scoring in low-dose CT scans helps identify individuals at high risk for mortality who may benefit from further CVD prevention.

OBJECTIVE—Dyslipidemia is a preventable major risk factor for coronary heart disease (CHD). Despite an increased risk of CHD in type 1 diabetes, little is known concerning awareness and adequacy of dyslipidemia treatment in this population. In this report, we describe the prevalence of dyslipidemia and adequacy of pharmacological treatment in patients with type 1 diabetes and comparable nondiabetic subjects. RESEARCH DESIGN AND METHODS—From 2000 to 2002, the Coronary Artery Calcification in Type 1 Diabetes study obtained fasting lipid profiles in 1,416 individuals aged 19–56 years with no history of CHD: 652 type 1 diabetic patients (46% men, mean age 37 ± 9 years) and 764 nondiabetic control subjects (50% men, mean age 39 ± 9 years). These data combined with patient questionnaire results were used to determine prevalence of dyslipidemia and adequacy of pharmacological treatment. For all subjects, dyslipidemia was defined using National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS—Type 1 diabetic subjects had significantly less dyslipidemia than nondiabetic control subjects (47 vs. 58%, P < 0.001), and a higher percentage of those with abnormal lipids were aware of (52 vs. 34%, P < 0.0001), on medication for (36 vs. 9%, P < 0.0001), and in control of their lipid levels (15 vs. 1.4%, P < 0.001). Of those on treatment, control was achieved in 41% of type 1 diabetic subjects and 15% of nondiabetic participants (P < 0.01). CONCLUSIONS—Dyslipidemia, a major risk factor for CHD, remains largely undiagnosed and undertreated in high-risk populations, such as patients with type 1 diabetes.

OBJECTIVE—The prevalence of gestational diabetes mellitus (GDM) varies in direct proportion with the prevalence of type 2 diabetes in a given population or ethnic group. Given that the number of people with diabetes worldwide is expected to increase at record levels through 2030, we examined temporal trends in GDM among diverse ethnic groups. RESEARCH DESIGN AND METHODS—Kaiser Permanente of Colorado (KPCO) has used a standard protocol to universally screen for GDM since 1994. This report is based on 36,403 KPCO singleton pregnancies occurring between 1994 and 2002 and examines trends in GDM prevalence among women with diverse ethnic backgrounds. RESULTS—The prevalence of GDM among KPCO members doubled from 1994 to 2002 (2.1–4.1%, P < 0.001), with significant increases in all racial/ethnic groups. In logistic regression, year of diagnosis (odds ratio [OR] and 95% CI per 1 year = 1.12 [1.09–1.14]), mother’s age (OR per 5 years = 1.7 [1.6–1.8]) and ethnicity other than non-Hispanic white (OR = 2.1 [1.9–2.4]) were all significantly associated with GDM. Birth year remained significant (OR = 1.06, P = 0.006), even after adjusting for prior GDM history. CONCLUSIONS—This study shows that the prevalence of GDM is increasing in a universally screened multiethnic population. The increasing GDM prevalence suggests that the vicious cycle of diabetes in pregnancy initially described among Pima Indians may also be occurring among other U.S. ethnic groups.

OBJECTIVE: To evaluate the association between standard and computed tomography (CT)-based measures of obesity and subclinical atherosclerosis, defined as coronary artery calcium (CAC) by Electron Beam Computed Tomography (EBCT). DESIGN: Cross-sectional, observational study of anthropometric and CT obesity measures and presence of CAC. SUBJECTS: Participants were 383 men and 379 women, aged 20–58 y and asymptomatic for coronary artery disease (CAD). MEASUREMENTS: Intra-abdominal fat (IAF) and subcutaneous fat (SQF) were measured at the level of lumbar 2–3 and 4–5 spaces, using EBCT. Body mass index (BMI) was calculated from height and weight, and minimum waist circumference and maximum hip circumference were measured. CAC was measured by EBCT. RESULTS: In both men and women, BMI, waist circumference, IAF, and SQF were significantly related to CAC. However, BMI or waist circumference explained variation in the presence of CAC as well as IAF or SQF, univariately and after adjustment for additional cardiovascular risk factors. CONCLUSION: CT-based obesity exposure measures are not superior to BMI or waist circumference in association studies of subclinical CAD.

The objective of this is study was to examine whether estimated insulin resistance and insulin resistance-related factors are associated with coronary artery calcification (CAC) in 1,420 asymptomatic participants in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. A total of 656 patients with type 1 diabetes and 764 control subjects aged 20–55 years were examined. CAC was assessed by electron-beam computed tomography. Insulin resistance was computed with linear regression based on an equation previously validated in clamp studies on type 1 diabetic adults. Insulin resistance was associated with CAC (OR 1.6 in type 1 diabetes and 1.4 in control subjects, P < 0.001), independent of coronary artery disease risk factors. There was a male excess of CAC in control subjects (OR 2.7, adjusted for age, smoking, and LDL and HDL cholesterol levels) and in type 1 diabetic patients (OR 2.2, adjusted for the same factors and diabetes duration). After adjusting for insulin resistance, the CAC male excess in diabetic patients decreased from OR 2.2 (P < 0.001) to 1.8 (P = 0.04). After adjustment for waist-to-hip ratio, waist circumference, or visceral fat, the gender difference in CAC was not significant in diabetic subjects. In conclusion, gender differences in insulin resistance-associated fat distribution may explain why type 1 diabetes increases coronary calcification in women relatively more than in men.

OBJECTIVE—Coronary artery disease (CAD) occurs earlier in life and is more often fatal in people with type 1 diabetes. This excess risk seems to be higher than in those with type 2 diabetes and is poorly explained by conventional risk factors. The role of glycemic control is controversial and has not been previously addressed in a prospective manner using a reliable marker for subclinical CAD, such as coronary artery calcification (CAC), measured by electron beam computed tomography (EBCT). RESEARCH DESIGN AND METHODS—We measured CAC twice during an interval of 2.7 years in 109 men and women with type 1 diabetes (aged 22–50 years). Progression of CAC was found in 21 patients, based on change in the square root-transformed volume score. RESULTS—In multiple logistic regression, CAC progression was associated with baseline hyperglycemia (odds ratio [OR] 7.11, 95% CI 1.38–36.6, P = 0.02), adjusted for the presence of CAC at baseline (P = 0.01), duration of diabetes (P = 0.02), sex (P = 0.09), and age (P = 0.27). There was also a significant interactive effect of higher insulin dose and higher BMI (P = 0.03). CONCLUSIONS—In conclusion, in this young cohort with type 1 diabetes, suboptimal glycemic control (HbA1c >7.5%) was a strong risk factor for progression of CAC. Insulin resistance may also play a role.

Background Type 1 diabetes (TID) is characterized by a loss of pancreatic islet beta cell function resulting in loss of insulin production. Genetic and environmental factors may trigger immune responses targeting beta cells thus generating islet antibodies (IA). Immune response pathways involve a cascade of events, initiated by cytokines and chemokines, producing inflammation which can result in tissue damage. Methods A nested case-control study was performed to identify temporal changes in cytokine levels in 75 DAISY subjects: 25 diagnosed T1D, 25 persistent IA, and 25 controls. Serum samples were selected at four time points: (T1) earliest, (T2) just prior to IA, (T3) just after IA, and (T4) prior to T1D diagnosis or most recent. Cytokines (IFN-α2a, IL-6, IL-17, IL-1β, IP-10, MCP-1, IFN-γ, IL-1α, and IL-1ra) were measured using the Meso Scale Discovery system Human Custom Cytokine 9-Plex assay. Results Multivariate mixed models adjusting for HLA risk, first-degree relative status, age, and gender, showed MCP-1 and IFN-үto be significantly higher at T3 in T1D compared to IA subjects. At T4, IP-10 was significantly higher in IA subjects than controls. Conclusions This repeated measures nested case-control study identified increased inflammatory markers in IA children who developed T1D compared to IA children who had not progressed to clinical disease. It also showed increased inflammation in both T1D and IA children when compared to controls. Results suggest inflammation may be related to both the development of IA and progression to T1D.

Despite improvements in glucose, lipids and blood pressure control, vascular complications remain the most important cause of morbidity and mortality in patients with type 1 diabetes. For that reason, there is a need to identify additional risk factors to utilize in clinical practice or translate to novel therapies to prevent vascular complications. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes that has been linked with the development and progression of both micro- and macrovascular complications. Adolescents and adults with type 1 diabetes have reduced insulin sensitivity, even when compared to their non-diabetic counterparts of similar adiposity, serum triglycerides, high-density lipoprotein cholesterol, level of habitual physical activity, and in adolescents, pubertal stage. Reduced insulin sensitivity is thought to contribute both to the initiation and progression of macro- and microvascular complications in type 1 diabetes. There are currently clinical trials underway examining the benefits of improving insulin sensitivity with regards to vascular complications in type 1 diabetes. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes, is implicated in the pathogenesis of vascular complications and is potentially an important therapeutic target to prevent vascular complications. In this review, we will focus on the pathophysiologic contribution of insulin sensitivity to vascular complications and summarize related ongoing clinical trials.