Exploratory Multisite MR Spectroscopic Imaging Shows White Matter Neuroaxonal Loss Associated with Complications of Type 1 Diabetes in Children.

BACKGROUND AND PURPOSE: Type 1 diabetes affects over 200,000 children in the United States and is associated with an increased risk of cognitive dysfunction. Prior single-site, single-voxel MRS case reports and studies have identified associations between reduced NAA/Cr, a marker of neuroaxonal loss, and type 1 diabetes. However, NAA/Cr differences among children with various disease complications or across different brain tissues remain unclear. To better understand this phenomenon and the role of MRS in characterizing it, we conducted a multisite pilot study. MATERIALS AND METHODS: In 25 children, 6-14 years of age, with type 1 diabetes across 3 sites, we acquired T1WI and axial 2D MRSI along with phantom studies to calibrate scanner effects. We quantified tissue-weighted NAA/Cr in WM and deep GM and modeled them against study covariates. RESULTS: We found that MRSI differentiated WM and deep GM by NAA/Cr on the individual level. On the population level, we found significant negative associations of WM NAA/Cr with chronic hyperglycemia quantified by hemoglobin A1c (P < .005) and a history of diabetic ketoacidosis at disease onset (P < .05). We found a statistical interaction (P < .05) between A1c and ketoacidosis, suggesting that neuroaxonal loss from ketoacidosis may outweigh that from poor glucose control. These associations were not present in deep GM. CONCLUSIONS: Our pilot study suggests that MRSI differentiates GM and WM by NAA/Cr in this population, disease complications may lead to neuroaxonal loss in WM in children, and deeper investigation is warranted to further untangle how diabetic ketoacidosis and chronic hyperglycemia affect brain health and cognition in type 1 diabetes.

Predictors of early renal function decline in adults with Type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes and the Pittsburgh Epidemiology of Diabetes Complications studies.

AIM: Diabetic kidney disease is one of the leading complications of Type 1 diabetes, but its prediction remains a challenge. We examined predictors of rapid decline in estimated GFR (eGFR) in two Type 1 diabetes cohorts: the Coronary Artery Calcification in Type 1 Diabetes (CACTI) and the Pittsburgh Epidemiology of Diabetes Complications (EDC). METHODS: A select subset of participants (CACTI: n = 210 and EDC: n = 98) diagnosed before 17 years of age with Type 1 diabetes duration ≥ 7 years, and follow-up data on eGFR by CKD-EPI creatinine for up to 8 years were included in the analyses. Early renal function decline was defined as annual decline in eGFR ≥ 3 ml/min/1.73 m2 , and normal age-related decline as eGFR ≤ 1 ml/min/1.73 m2 . Parallel logistic regression models were constructed in the two cohorts. RESULTS: Early renal function decline incidence was 36% in CACTI and 41% in EDC. In both cohorts, greater baseline eGFR (CACTI: OR 3.12, 95% CI 1.97-5.05; EDC: OR 1.92, 95% CI 1.17-3.15 per 10 ml/min/1.73 m2 ) and log albumin-to-creatinine (ACR) (CACTI: OR 3.24, 95% CI 1.80-5.83; EDC: OR 1.87, 95% CI 1.18-2.96 per 1 unit) predicted greater odds of early renal function decline in fully adjusted models. Conversely, ACE inhibition predicted lower odds of early renal function decline in women in CACTI, but similar relationships were not observed in women in EDC. CONCLUSIONS: A substantial proportion of people with Type 1 diabetes in the EDC and CACTI cohorts experienced early renal function decline over time. ACE inhibition appeared to be protective only in women in CACTI where the prevalence of its use was twofold higher compared with the EDC.

Discriminatory value of alanine aminotransferase for diabetes prediction: the Insulin Resistance Atherosclerosis Study.

AIMS: To examine the incremental usefulness of adding alanine aminotransferase to established risk factors for predicting future diabetes. METHODS: The study population of the Insulin Resistance Atherosclerosis Study included 724 people aged 40-69 years. We excluded people who had excessive alcohol intake or were treated with lipid-lowering agents. Incident diabetes was assessed after a mean follow-up period of 5.2 years. RESULTS: Alanine aminotransferase had a non-linear relationship with incident diabetes (Wald chi-squared test, P < 0.001; P for linearity = 0.005) independent of demographic variables, family history of diabetes, BMI and fasting glucose; therefore, we used Youden's J statistic to dichotomize alanine aminotransferase [threshold ≥ 0.43 µkat/L ( ≥ 26 IU/l)]. Dichotomized alanine aminotransferase increased the area under the receiver-operating characteristic curve (0.805 vs. 0.823; P = 0.007) of a model that included demographic variables, family history of diabetes, BMI and fasting glucose as independent variables. The net reclassification improvement was 9.6% (95% CI 1.8-17.4; P = 0.016), and the integrated discrimination improvement was 0.031 (95% CI 0.011-0.050; P = 0.002). Dichotomized alanine aminotransferase reclassified a net of 9.6% of individuals more appropriately. CONCLUSIONS: Alanine aminotransferase may be useful for classifying individuals who are at risk of future diabetes after accounting for the effect of other risk factors, including family history, adiposity and plasma glucose.

The association of alanine aminotransferase within the normal and mildly elevated range with lipoproteins and apolipoproteins: the Insulin Resistance Atherosclerosis Study.

AIMS/HYPOTHESIS: Markers of liver injury, such as alanine aminotransferase (ALT), have been associated with atherogenic lipoprotein changes. We examined the extent to which this association was explained by insulin resistance, adiposity, glucose tolerance and chronic inflammation. METHODS: In this analysis we included 824 non-diabetic participants (age 40-69 years) in the Insulin Resistance Atherosclerosis Study. No participants reported excessive alcohol intake or treatment with lipid-lowering medications. Lipoproteins and apolipoproteins were measured by conventional methods and lipoprotein heterogeneity by nuclear magnetic resonance (NMR) spectroscopy. RESULTS: ALT had a positive relationship with triacylglycerols, LDL-to-HDL-cholesterol ratio and apolipoprotein B (ApoB) after adjusting for demographic variables (p < 0.001 for all three relationships). ALT was also associated with the following NMR lipoproteins: positively with large VLDL (p < 0.001), intermediate-density lipoprotein (IDL) (p < 0.001) and small LDL subclass particles (p < 0.001), and VLDL particle size (p < 0.001); and negatively with large LDL subclass particles (p < 0.05) and LDL (p < 0.001) and HDL particle sizes (p < 0.01). ALT remained associated with IDL and small LDL subclass particles and ApoB after adjusting for glucose tolerance, adiposity, directly measured insulin sensitivity and C-reactive protein. CONCLUSIONS/INTERPRETATION: ALT is associated with a wide range of atherogenic lipoprotein changes, which are partially explained by insulin resistance, adiposity, glucose tolerance and chronic inflammation. Because of the significant variability in the relationship between ALT and liver fat, further studies are needed to assess the extent of the lipoprotein changes using a direct measure of liver fat.

Components of metabolic syndrome and 5-year change in insulin clearance - the Insulin Resistance Atherosclerosis Study.

AIMS: Cross-sectional evidence indicates that abdominal adiposity, hypertension, dyslipidaemia and glycaemia are associated with reduced metabolic clearance rate of insulin (MCRI). Little is known about the progression of MCRI and whether components of metabolic syndrome are associated with the change in MCRI. In this study, we examined the association between components of metabolic syndrome and the 5-year change of MCRI. METHODS: At baseline and 5-year follow-up, we measured fasting plasma triglycerides (TG), high-density lipoprotein (HDL) cholesterol, blood pressure (BP), waist circumference (WC) and fasting blood glucose (FBG) in 784 non-diabetic participants in the Insulin Resistance Atherosclerosis Study. MCRI, insulin sensitivity (SI ) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests. RESULTS: We observed a 29% decline of MCRI at follow-up. TG, systolic BP and WC at baseline were inversely associated with a decline of MCRI regression models adjusted for age, sex, ethnicity, smoking, alcohol consumption, energy expenditure, family history of diabetes, BMI, SI and AIR [ß = -0.057 (95% confidence interval, CI: -0.11, -0.0084) for TG, ß = -0.0019 (95% CI: -0.0035, -0.00023) for systolic BP and ß = -0.0084 (95% CI: -0.013, -0.0039) for WC; all p < 0.05]. Higher HDL cholesterol at baseline was associated with an increase in MCRI [multivariable-adjusted ß = 0.0029 (95% CI: 0.0010, 0.0048), p = 0.002]. FBG at baseline was not associated with MCRI at follow-up [multivariable-adjusted ß = 0.0014 (95% CI: -0.0026, 0.0029)]. CONCLUSIONS: MCRI declined progressively over 5 years in a non-diabetic cohort. Components of metabolic syndrome at baseline were associated with a significant change in MCRI.

The association of inflammatory and fibrinolytic proteins with 5 year change in insulin clearance: the Insulin Resistance Atherosclerosis Study (IRAS).

AIMS/HYPOTHESIS: Insulin clearance may decline as an early mechanism compensating for deteriorating insulin sensitivity. However, no previous studies have investigated the association between subclinical inflammation or impaired fibrinolysis and insulin clearance. We examined the association between plasminogen activator inhibitor (PAI)-1, C-reactive protein (CRP), TNF-α, leptin and fibrinogen and the progression of metabolic clearance rate of insulin (MCRI) over time. METHODS: We studied 784 non-diabetic white, Hispanic and African-American individuals in the Insulin Resistance Atherosclerosis Study (IRAS). Insulin sensitivity, acute insulin response and MCRI were determined from frequently sampled intravenous glucose tolerance tests at baseline and at 5-year follow-up. Inflammatory and fibrinolytic proteins were measured in fasting plasma at baseline. RESULTS: MCRI had declined significantly by 29% at the 5-year follow-up. We observed a significant association between higher plasma PAI-1 levels and the decline in MCRI in multivariable-adjusted regression models (ß = -0.045 [95% CI -0.081, -0.0091]). Higher plasma CRP and leptin levels were associated with a decline in MCRI in unadjusted models, but these associations were non-significant after adjusting for BMI and waist circumference (ß = -0.016 [95% CI -0.041, 0.0083] for CRP; ß = -0.044 [95% CI -0.10, 0.011] for leptin). A higher plasma TNF-α concentration was associated with a decline in MCRI in unadjusted (ß = -0.071 [95% CI -0.14, -0.00087]) but not in multivariable-adjusted (ß = -0.056 [95% CI -0.13, 0.017]) models. Plasma fibrinogen level was not associated with the change in MCRI. CONCLUSIONS/INTERPRETATION: We identified that higher plasma PAI-1 (but not CRP, TNF-α, leptin or fibrinogen) levels independently predicted the progressive decline of insulin clearance in the multiethnic cohort of the IRAS.

Analysis of FTO gene variants with obesity and glucose homeostasis measures in the multiethnic Insulin Resistance Atherosclerosis Study cohort.

OBJECTIVE: Previous studies have replicated the association of variants within FTO (fat mass- and obesity-associated) intron 1 with obesity and adiposity quantitative traits in populations of European ancestry. Non-European populations, however, have not been so intensively studied. The goal of this investigation was to examine the association of FTO single-nucleotide polymorphisms (SNPs), prominent in the literature in a multiethnic sample of non-Hispanic White American (n=458), Hispanic American (n=373) and African American (n=288) subjects from the Insulin Resistance Atherosclerosis Study (IRAS). This cohort provides the unique ability to evaluate how variation within FTO influences measures of adiposity and glucose homeostasis in three different ethnicities, which were ascertained and examined using a common protocol. DESIGN: A total of 26 FTO SNPs were genotyped, including those consistently associated in the literature (rs9939609, rs8050136, rs1121980, rs1421085, rs17817449 and rs3751812), and tested for association with adiposity and glucose homeostasis traits. RESULTS: For the adiposity phenotypes, these and other SNPs were associated with body mass index (BMI) in both non-Hispanic Whites (P-values ranging from 0.015 to 0.048) and Hispanic Americans (P-values ranging from 7.1 × 10(-6) to 0.027). In Hispanic Americans, four other SNPs (rs8047395, rs10852521, rs8057044 and rs8044769) still showed evidence of association after multiple comparisons adjustment (P-values ranging from 5.0 × 10(-5) to 5.2 × 10(-4)). The historically associated BMI SNPs were not associated in the African Americans, but rs1108102 was associated with BMI (P-value of 5.4 × 10(-4)) after accounting for multiple comparisons. For glucose homeostasis traits, associations were seen with acute insulin response in non-Hispanic Whites and African Americans. However, all associations with glucose homeostasis measures were no longer significant after adjusting for multiple comparisons. CONCLUSION: These results replicate the association of FTO intron 1 variants with BMI in non-Hispanic Whites and Hispanic Americans but show little evidence of association in African Americans, suggesting that the effect of FTO variants on adiposity phenotypes shows genetic heterogeneity dependent on ethnicity.

Universal versus targeted screening of infants for sickle cell disease: a cost-effectiveness analysis.

OBJECTIVE: To compare the health outcomes, costs, and incremental cost-effectiveness of universal neonatal screening for sickle cell disease (SCD) with screening targeted to African Americans. STUDY DESIGN: A cost-effectiveness analysis was done by using a Markov simulation model that considered the costs and outcomes associated with the prevention and treatment of sepsis in those with sickle cell anemia and sickle beta(0)-thalassemia. Three strategies were compared: (1) no screening, (2) targeted screening of African Americans, and (3) universal screening for SCD. RESULTS: In the base case analysis, targeted screening of African Americans compared with no screening cost $6709 per additional year of life saved, and universal screening compared with targeted screening cost $30,760 per additional year of life saved. In a sensitivity analysis, the cost per additional year of life saved with universal screening compared with targeted screening was positively correlated with the delivery rate of targeted screening and was inversely related to the proportion of African Americans in the population. CONCLUSIONS: Targeted screening of African American newborns for SCD compared with no screening is always cost-effective. Universal screening compared with targeted screening always identifies more infants with disease, prevents more deaths, and is cost-effective given certain delivery rates for targeted screening and proportions of African Americans in the population.

DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison's disease.

Of 957 patients with type 1 diabetes without known Addison's disease 1.6% (n = 15) were positive for 21-hydroxylase autoantibodies. Among DQ8/DQ2 heterozygous patients, the percentage expressing 21-hydroxylase autoantibodies was 5% (10 of 208) vs. less than 0.5% of patients with neither DQ8 nor DQ2. Three of the diabetic patients found to have 21-hydroxylase autoantibodies on screening were subsequently diagnosed with Addison's disease. Overall, the genotype DQ8/DQ2, consisting of DRB1*0404/DQ8 with DRB1*0301/DQ2, was present in 14 of 21 patients with Addison's disease (8 of 12 with diabetes and 6 of 9 without diabetes or antiislet autoantibodies) vs. 0.7% of the general population (109 of 15,547; P < 10(-6)) and 11% of patients with DM without Addison's disease (62 of 578; P < 10(-6)). Among patients with diabetes with DQ8, Addison's disease was strongly associated with the specific DRB1 subtype, DRB1*0404 (8 of 9 patients from 8 families, in contrast to only 109 of 408 DQ8 DM patients with diabetes without Addison's disease having DRB1*0404; P < 0.001). Among 21-hydroxylase autoantibody-positive DQ8 patients, 80% with DRB1*0404 (12 of 15) had Addison's disease, in contrast to 1 of 10 autoantibody-positive patients with DRB1*0401 or DRB1*0402 (P < 0.001). We conclude that patients with DRB1*0404 and 21-hydroxylase autoantibodies are at high risk for Addison's disease. Patients with DRB1*0401 and DRB1*0402 have more limited progression to Addison's disease despite the presence of 21-hydroxylase autoantibodies.

Definition of multiple ICA512/phogrin autoantibody epitopes and detection of intramolecular epitope spreading in relatives of patients with type 1 diabetes.

The related tyrosine phosphatase-like proteins, islet cell antigen 512 (ICA512) and phosphatase homologue in granules of insulinoma (phogrin), are major targets of autoantibodies in patients with type 1 diabetes. In the current study, we have examined the overlapping specificities and antigenic epitopes of autoantibodies to ICA512 and phogrin and determined whether intramolecular epitope spreading occurs during the development of diabetic autoimmunity. ICA512 autoantibodies and phogrin autoantibodies were detected in 65-70% (n = 110) of patients with new-onset type 1 diabetes and 60-65% (n = 42) of prediabetic relatives of patients with type 1 diabetes. Of the sera, 10% reacted with ICA512 but not phogrin, whereas only 1% of sera reacted with phogrin but not ICA512. The binding of phogrin autoantibodies in 88 dual (ICA512 and phogrin) autoantibody-positive sera could be completely blocked by excess recombinant ICA512, whereas the blocking of ICA512 autoantibodies with recombinant phogrin was only partial (mean inhibition of 58.9 +/- 3.7%, mean +/- SE). Binding and competition analysis using multiple chimeric ICA512/phogrin constructs demonstrated that a major unique epitope for ICA512 autoantibodies is localized to amino acids 762-887. A conformational epitope associated with the carboxy-terminal 31 amino acids of ICA512 was recognized by one-third of sera, and a minor epitope is located on amino acids 601-762 of ICA512. The major epitopes for phogrin-selective autoantibodies were localized to amino acids 640-922 of phogrin. Sequential serum samples were analyzed in 22 relatives who expressed ICA512/phogrin autoantibodies. Intramolecular epitope spreading was found for 5 of 13 relatives who have progressed to type 1 diabetes. Among nine relatives who have remained nondiabetic, three demonstrated a decrease in the number of epitopes recognized. These studies highlight the complexity of autoantibody recognition of ICA512/phogrin and are consistent with the hypothesis that ICA512/phogrin may be recognized as a consequence of beta-cell destruction.

Intensity and amount of physical activity in relation to insulin sensitivity: the Insulin Resistance Atherosclerosis Study.

CONTEXT: Exercise training is associated with improved insulin sensitivity (SI), but the potential impact of habitual, nonvigorous activity is uncertain. OBJECTIVE: To determine whether habitual, nonvigorous physical activity, as well as vigorous and overall activity, is associated with better SI. DESIGN: A multicultural epidemiologic study. SETTING: The Insulin Resistance Atherosclerosis Study, conducted in Oakland, Calif; Los Angeles, Calif; the San Luis Valley, Colo; and San Antonio, Tex. PARTICIPANTS: A total of 1467 men and women of African American, Hispanic, and non-Hispanic white ethnicity, aged 40 to 69 years, with glucose tolerance ranging from normal to mild non-insulin-dependent diabetes mellitus. MAIN OUTCOME MEASURE: Insulin sensitivity as measured by an intravenous glucose tolerance test. RESULTS: The mean SI for individuals who participated in vigorous activity 5 or more times per week was 1.59 min(-1) x microU(-1) x mL(-1) x 10(-4) (95% confidence interval [CI], 1.39-1.79) compared with 0.90 (95% CI, 0.83-0.97) for those who rarely or never participated in vigorous activity, after adjusting for potential confounders (P<.001). When habitual physical activity (estimated energy expenditure [EEE]) was assessed by 1-year recall of activities, the correlation coefficient between SI and total EEE was 0.14 (P<.001). After adjustment for confounders, vigorous and nonvigorous levels of EEE (metabolic equivalent levels > or = 6.0 and <6.0, respectively) were each positively and independently associated with SI (P< or =.01 for each). The association was attenuated after adjustment for the potential mediators, body mass index (a measure of weight in kilograms divided by the square of the height in meters), and waist-to-hip ratio. Results were similar for subgroups of sex, ethnicity, and diabetes. CONCLUSIONS: Increased participation in nonvigorous as well as overall and vigorous physical activity was associated with significantly higher SI. These findings lend further support to current public health recommendations for increased moderate-intensity physical activity on most days.

Dietary fat and insulin sensitivity in a triethnic population: the role of obesity. The Insulin Resistance Atherosclerosis Study (IRAS)

From the Insulin Resistance Atherosclerosis Study (IRAS), 1173 men and women of African-American, non-Hispanic white, and Hispanic ethnicity with no history of diabetes were included in an evaluation of the cross-sectional relation of habitual dietary fat intake with insulin sensitivity (SI) as assessed by minimal-model analysis of a 12-sample, insulin-modified frequently sampled intravenous-glucose-tolerance test. Dietary intake was measured by a food-frequency interview modified to enhance sensitivity to food choices within the three ethnic groups. Percentage of energy from total fat was associated with rank of SI (SI(rank); r = -0.06, P = 0.03), with log fasting insulin (r = 0.10, P < 0.001), and with BMI (r = 0.10, P < 0.001). Multiple-linear-regression models included SI(rank) as the dependent variable, dietary fat (g/d) as the primary independent variable adjusted sequentially for total energy, other covariates, body mass index, and waist-hip circumference ratio (WHR). For all subjects combined, total fat intake was inversely related to SI(rank), but this association was not significant (P = 0.14) and was attenuated by adjustment for body mass index and WHR (P = 0.44). The association of total fat (g/d) with SI(rank) differed significantly (P < 0.01) for obese compared with nonobese individuals. Higher fat intake was associated with lower SI(rank) among obese (beta = -1.40, P = 0.03) but not among nonobese persons (beta = 0.16, P = 0.80). Among the obese (body mass index < or = 63), adjustment for body mass index largely accounted for the observed association of dietary fat with SI(rank). These findings were generally consistent for monounsaturated, polyunsaturated, and saturated fats. Among individuals already at increased risk for non-insulin-dependent diabetes mellitus because of obesity, high intake of dietary fat may worsen insulin sensitivity. This effect may be mediated by the relation of dietary fat to obesity.

The design of trials for prevention of IDDM.

Several large clinical trials for the prevention of IDDM in islet cell antibody positive first-degree relatives are planned or underway. The design of these trials rests in part on assumptions about the natural history of autoimmunity during the prediabetic period and on the likely effectiveness of the intervention being tested. At this time, most of the factors that influence the required sample size can only be roughly estimated.

Early exposure to cow's milk and solid foods in infancy, genetic predisposition, and risk of IDDM.

Using a case-control study design, we examined the hypothesis that early exposure to cow's milk and solid foods increased the risk of IDDM. An infant diet history was collected from 164 IDDM subjects from the Colorado IDDM Registry with a mean birth year of 1973, and 145 nondiabetic population control subjects who were frequency matched to diabetic subjects on age, sex, and ethnicity. Early exposure was defined as exposure occurring before 3 mo of age. After controlling for ethnicity, birth order, and family income, more diabetic subjects were exposed early to cow's milk (OR 4.5, 95% CI 0.9-21.4) and solid foods (OR 2.5, CI 1.4-4.3) than control subjects. To examine this association while accounting for the genetic susceptibility to IDDM, we defined individuals as high and low risk by an HLA-DQB1 molecular marker. Early exposure to cow's milk was not associated with elevated risk for IDDM in low-risk individuals. Relative to unexposed low-risk individuals, early exposure to cow's milk was strongly associated in individuals with a high risK marker (OR 11.3, CI 1.2-102.0). Similar findings were observed for early exposure to solid foods. These data indicate that early exposure to cow's milk and solid foods may be associated with increased risk of IDDM. The inclusion of HLA-encoded risk in the analyses demonstrates the combined effect of genetic and environmental factors.

Incidence of insulin-dependent diabetes mellitus in Colorado.

We examined the incidence of insulin-dependent diabetes mellitus in children 0-17 years of age in Colorado from 1978 to 1988. Cases were ascertained from a statewide registry based on physician surveillance. A total of 1,376 children were diagnosed during this interval in a population averaging 860,000 children. The degree of ascertainment was estimated to be 93.3%. The age-adjusted incidence rate of insulin-dependent diabetes mellitus was 14.8/100,000 person-years. The rate was lower in individuals of Spanish origin (Hispanics) (8.7/100,000 person-years) compared with non-Hispanic individuals (15.5/100,000 person-years) (incidence rate ratio = 0.6, 95% confidence interval = 0.4-0.8). Incidence rates were higher in winter and lower in summer for children 5-17 years old. Children diagnosed before the age of 5 years showed no significant seasonal pattern, although peak incidences were observed in autumn and spring. No temporal trend in diabetes incidence was observed overall or by ethnic group. The increasing insulin-dependent diabetes incidence reported by registries in Europe during this time period was not observed in Colorado.