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Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Monitoring of glycemic status, as performed by patients and health care providers, is considered a cornerstone of diabetes care. Results of monitoring are used to assess the efficacy of therapy and to make adjustments in diet, exercise, and medications in order to achieve the best possible blood glucose control. The purpose of this review is to summarize current knowledge about the tests used most widely in monitoring the glycemic status of people with diabetes. The review addresses both patient- and physician/laboratory-based testing, and it includes tests of urine glucose and ketones and tests of blood glucose and glycated proteins (hemoglobin and serum proteins). The major emphasis is on the advantages and limitations of each test for routine clinical practice. Use of these tests for diabetes screening and diagnosis will not be addressed in this review. Since this review was first published in 1995, there have been many advances in the field, most notably standardization of glycated hemoglobin testing and new approaches to self-monitoring of blood glucose (SMBG), including minimally invasive continuous glucose monitoring over hours to days at a time. These and other advances are presented in detail in a recent report that was prepared by the National Academy of Clinical Biochemistry (NACB) and published as an American Diabetes Association (ADA) position statement (1). This review will attempt to complement, rather than duplicate, the material in the NACB report. If there was an ideal method of monitoring glycemic status, it might be a small noninvasive device, perhaps similar to a wristwatch that people with diabetes could wear to continuously monitor their blood glucose level. The device would warn of impending hypoglycemia. It also would store blood glucose data and perform a variety of calculations such as hourly, daily, weekly, or monthly blood glucose averages. Unfortunately, such a monitoring device is …

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10-8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10-11) and 8q12 (minimum p value 1.82×10-11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Modern insulin therapy for Type 1 diabetes is part of a comprehensive treatment program designed to achieve and maintain blood glucose levels as close to normal as possible. The insulin regimens most likely to be successful approximate physiologic insulin delivery by combining basal and meal doses. Several options are available, including constant infusion by external pump and multiple daily injection therapy. Modern therapy affords major health benefits through improved blood glucose control, as well as lifestyle benefits associated with increased flexibility and spontaneity.

OBJECTIVE To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy. METHODS Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome. RESULTS After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P < .001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P < .001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. CONCLUSION The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning. TRIAL REGISTRATION (clinicaltrials.gov) Identifiers: NCT00360815 and NCT00360893.

We hypothesized that there would be evidence of functional ovarian hyperandrogenism in girls with premature pubarche (PP) at diagnosis.White girls8 years of age and black girls6 years with PP (n = 15) were studied. Prepubertal girls (n = 13; 5.3-10.9 years) and early pubertal girls (n = 8) served as control subjects. The biochemical marker for functional ovarian hyperandrogenism was the 17-hydroxyprogesterone (17-OHP), androstenedione (AD), and estradiol (E2) response to subcutaneous leuprolide during adrenal suppression with dexamethasone. This was studied in girls with PP and in control subjects.ACTH stimulated 17-hydroxypregnenolone (17-OH Preg), dehydroepiandrosterone (DHEA), and AD levels, and 17-OH Preg:17-OHP and DHEA:AD ratios were significantly higher in girls with PP than in prepubertal control subjects (n = 18) (Por =.003). The ovarian response to leuprolide stimulation was comparable in girls with PP and prepubertal control subjects, but the response in prepubertal study subjects was significantly lower than in pubertal control subjects (P =.016 for Delta17-OHP, P =.001 for DeltaAD, and P =.026 for DeltaE2).Contrary to the hypothesis, PP in girls was not associated with prepubertal evidence of ovarian hyperandrogenism but was associated with functional adrenal hyperandrogenism.

OBJECTIVE—In the context of recent improvements in type 1 diabetes therapy, to describe longitudinal trends in mortality attributable to childhood diabetes and to investigate socioeconomic and health services correlates of mortality. RESEARCH DESIGN AND METHODS—We extracted mortality data for 1968–1998 from National Center for Health Statistics files and covariates from the Bureau of Health Professions Area Resource File. Analytical techniques included linear and Poisson regression and standard descriptive statistics. RESULTS—Childhood (defined as 0–19 years of age) age-adjusted mortality from diabetes declined from 9.5 (1968) to 3.0 (1984) deaths per 10 million but remained relatively constant subsequently. All-cause childhood mortality, however, continued to decline. Older children experienced higher mortality rates, as did those living in counties with higher levels of unemployment. CONCLUSIONS—Despite recent improvements in therapy, diabetes-related mortality among children has not declined for 14 years. This finding may be partially attributable to sociodemographic factors influencing access to care, but the remaining mortality may defy available treatment methods. Reducing childhood diabetes mortality rates below the current apparent plateau may require new prevention and/or treatment strategies.

DIABETES MELLITUS EXACTS AN ENORMOUS TOLL IN the United States by decreasing quality of life and causing death and disability, all at a huge economic cost. Yet simple diagnostic criteria and effective treatment choices that prevent or delay the onset of costly diabetes complications are readily available to health care professionals. It is time for health care professionals and patients with diabetes to take action together to reduce premature morbidity and mortality from diabetes-caused disease. The National Diabetes Education Program is the first joint diabetes initiative of the National Institutes of Health and the Centers for Disease Control and Prevention and involves public and private partnerships to promote early diagnosis and improve the treatment and outcomes for patients with type 1 and type 2 diabetes mellitus. It is estimated that in the United States, type 2 diabetes can be present for up to 9 to 12 years before initial clinical diagnosis. Microvasculardiseaseprogressesduringthis time,causing 15% to 20% of patients to have retinopathy and 5% to 10%tohaveproteinuriaat the timeofdiagnosis. Patientswith type 2 diabetes have high rates of hypertension, dyslipidemia, and obesity, major reasons for their 2to 4-fold higher rates ofcardiovasculardisease. Type2diabetes isoccurring increasingly in younger people. Although every patient can be expected to benefit from any increment in improved glycemic control, blood glucose control is more effective in preventing the initial development of microvascular complications than inpreventing theprogressionofcomplicationsonce theyhave become established. This finding underscores the need for aggressive treatment as soon as type 2 diabetes is diagnosed. Diabetes accounts for almost $100 billion in direct medical costs and indirect expenditures attributable to diabetes each year. Further, while patients with diabetes represented 4.5% of the US population in 1992, they accounted for 15% of total US health care expenditures and 27% of Medicare expenditures. There is a marked correlation between glycemic control of diabetes as measured by glycosylated hemoglobin (HbA1c) testing and the cost of medical care. Medical care charges increase significantly for every 1% increase in HbA1c level above 7%. In 1994, excess expenditures for patients with diabetes in a managed care setting totaled $282.7 million or $3494 per person—2.4 times the cost for control subjects. Nearly 38% of the total excess was spent treating the long-term complications of diabetes, predominantly coronary heart disease and end-stage renal disease. Because of its high and increasing prevalence, type 2 diabetes contributes a significant portion of these costs. There is substantial evidence that the human and economic burden of diabetes can be reduced significantly by early, aggressive therapeutic intervention. The Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that intensive blood glucose control for patients with type 1 and type 2 diabetes significantly reduced the risk for retinopathy, nephropathy, and neuropathy. Lowering blood pressure in a subset of UKPDS patients to a mean of 144/82 mm Hg reduced the risk of strokes, diabetes-related deaths, heart failure, microvascular complications, and vision loss

The National Diabetes Education Program (NDEP) was initiated in 1997 jointly by the National Institutes of Health and the Centers for Disease Control and Prevention to promote early diagnosis and to improve the treatment and outcomes for people with type 1 and type 2 diabetes. This partnership now involves over 200 public, voluntary, and private organizations dedicated to improving the lives of people with diabetes. Because of the Diabetes Control and Complications Trial (DCCT) findings that improved blood glucose control markedly reduces the risk for retinopathy, nephropathy, and neuropathy, the NDEP initially focused on blood glucose control (1,2). This month, the NDEP and its partners are launching an expanded initiative to promote optimal control of lipids and blood pressure, in addition to optimal control of blood glucose. The impact of cardiovascular disease on mortality and morbidity in people with diabetes has been known for years. Approximately two-thirds of people with diabetes die from cardiovascular disease (coronary heart disease, stroke, and other vascular diseases). Recently, data from the National Health and Nutrition Examination Survey showed that over the past 30 years there was a 27% decline in age-adjusted heart disease mortality in women without diabetes, but in women with diabetes, there was a 23% increase (3). In men without diabetes, there was a 36% decline compared with a 13% decline in men with diabetes. …

The dietary adherence of a sample of 97 patients with insulin-dependent diabetes mellitus has been quantitatively described. Now, in an effort to understand the poor dietary aherence found, diet-related knowledge and skill and their relationship to dietary adherence among 90 diabetic children have been studied. Diet-related competencies assessed were the ability to: (1) recall the personal diet plan, (2) correctly fill one's plate from a buffet, with the diet plan in hand, and (3) choose an appropriate meal from a restaurant menu. Adherence to the diet was assessed by unobtrusive observations at meals. Error rates on the three tests of knowledge and skill were .21, .28, and .51, respectively. The mean error rate at mealtime was .35, only slightly higher than the error rate for filling a plate when the children knew they were being tested. In a multiple regression analysis, age (r = .37) and sex (R = .48) were associated with adherence to the diet plan. Ability to choose correctly from a menu, duration of diabetes, and ability to correctly fill a plate from a buffet also entered the regression equation (R = .54). The data suggest that many children did not possess the knowledge and skill required for good dietary adherence, regardless of motivation. Health educators may underestimate the complexity of the behaviors expected of chronically ill patients.

Patient adherence is one determinant of the success of medical therapy, but little is known about the extent to which health professionals routinely assess adherence. This study evaluated the extent of patient adherence assessment by senior medical students in an outpatient diabetes clinic. The number of adherence questions students asked was low in all areas of the patients’ diabetes regimen. The number of questions asked did not relate to patients’ clinical status or their self‐reported regimen adherence. Findings suggest a need for systematic attention to adherence issues in physician education.

Research on the education of diabetic patients in diet management suffers from lack of an adequate method for describing patients' dietary behavior. In this report, a method is proposed for the quantitative assessment of dietary adherence in patients with IDDM. The method relies on comparisons between individualized diet plans and actual consumption as reflected by 24-h diet recalls. Data are presented that suggest this method has reliability and validity. In a sample of 97 patients with IDDM, nearly two-thirds adhered to the number and timing of planned feedings, while only about 10% of patients adhered to planned exchanges, 90% of the time. The average patient added or deleted one exchange for every four exchanges in the diet plan.

In March 1976, 128 persons in Camas, Washington, had laboratory-confirmed giardiasis. A questionnaire survey of 498 Camas residents revealed that 3.8% had clinical giardiasis, while none of 318 residents in a control town were ill. No associations between illness and sex, pet ownership, travel, time spent in wilderness areas, public gatherings, or food preference were found. Giardia cysts were recovered from raw water entering the city water treatment system via two streams and also from two storage reservoirs containing chlorinated and filtered stream water. Failure to remove Giardia cysts was attributed to the water plants' inadequate flocculation, coagulation, and sedimentation combined with deterioration of the filter media. Investigation of the watershed revealed no signs of human fecal contamination. Animal trapping in the watershed area yielded three beavers (Castor canadensis) infected with Giardia that were infective for specific pathogen-free beagle pups.

Practicing pediatricians were surveyed to assess their need for diabetes education programs. Pediatricians generally have fewer than five diabetic patients, frequently see them less than once every four months, prescribe single daily insulin injections, and do not include dietetic services in their treatment program. Among the pediatricians surveyed, practices correlated weakly with therapeutic goals for metabolic control, and goals correlated weakly with belief that hyperglycemia causes microvascular complications of diabetes. Belief in the importance of hyperglycemia did not correlate with actual care practices reported. The data support the idea that presentation of the latest advances in scientific rationale is an inadequate basis for physicians' continuing education.