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Objectives: To determine whether individuals with type 1 diabetes (T1D) who develop any retinopathy at any time prior to five years of diabetes duration have an increased subsequent risk for further progression of retinopathy or onset of proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), diabetes-related retinal photocoagulation or anti-VEGF injections. Additionally, to determine the influence of HbA1c and other risk factors in these individuals. Methods: Diabetic retinopathy (DR) was assessed longitudinally using standardized stereoscopic seven-field fundus photography at time intervals of six months to four years. Early onset DR (EDR) was defined as onset prior to 5 years of T1D duration. Cox models assessed the associations of EDR with subsequent risk of outcomes. Results: In unadjusted models, individuals with EDR (n=484) had an increased subsequent risk of PDR (hazard ratio HR=1.51, 95%CI [1.12,2.02], P=0.006), CSME (HR=1.44, [1.10,1.88], P=0.008) and diabetes-related retinal photocoagulation (HR=1.48, [1.12,1.96], P=0.006) compared to individuals without EDR (n=369). These associations remained significant adjusted for HbA1c, but only the association with PDR remained significant after adjustment for age, duration of T1D, HbA1c, sex, systolic/diastolic blood pressure, pulse, use of ACE inhibitors, albumin excretion rate, and eGFR (HR=1.47, [1.04,2.06], P=0.028). Conclusions: These data suggest that individuals with any sign of retinopathy within the first 5 years of T1D onset may be at higher risk of long-term development of advanced DR, especially PDR. Identification of early onset DR may influence prognosis and help guide therapeutic management to reduce the risk of future visual loss in these individuals.

To determine whether individuals with type 1 diabetes (T1D) who develop any retinopathy at any time prior to 5 years of diabetes duration have an increased subsequent risk for further progression of retinopathy or onset of proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), diabetes-related retinal photocoagulation, or anti-vascular endothelial growth factor injections. Additionally, to determine the influence of HbA1c and other risk factors in these individuals.Diabetic retinopathy (DR) was assessed longitudinally using standardized stereoscopic seven-field fundus photography at time intervals of 6 months to 4 years. Early-onset DR (EDR) was defined as onset prior to 5 years of T1D duration. Cox models assessed the associations of EDR with subsequent risk of outcomes.In unadjusted models, individuals with EDR (n = 484) had an increased subsequent risk of PDR (hazard ratio [HR] 1.51 [95% CI 1.12, 2.02], P = 0.006), CSME (HR 1.44 [1.10, 1.88], P = 0.008), and diabetes-related retinal photocoagulation (HR 1.48 [1.12, 1.96], P = 0.006) compared with individuals without EDR (n = 369). These associations remained significant when adjusted for HbA1c, but only the association with PDR remained significant after adjustment for age, duration of T1D, HbA1c, sex, systolic/diastolic blood pressure, pulse, use of ACE inhibitors, albumin excretion rate, and estimated glomerular filtration rate (HR 1.47 [95% CI 1.04, 2.06], P = 0.028).These data suggest that individuals with any sign of retinopathy within the first 5 years of T1D onset may be at higher risk of long-term development of advanced DR, especially PDR. Identification of early-onset DR may influence prognosis and help guide therapeutic management to reduce the risk of future visual loss in these individuals.

OBJECTIVE This epidemiological analysis of the pooled Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort describes the equivalence of a 1-percentage point increase in HbA1c (such as from 7% to 8%) and years of additional age or duration of type 1 diabetes (T1D) relative to the risk of complications. RESEARCH DESIGN AND METHODS Separate Cox proportional hazards models determined the number of additional years of age and/or duration of T1D that would result in the same increase in risk of microvascular (retinopathy, nephropathy, and neuropathy) and cardiovascular complications and mortality as a 1-percentage point increase in HbA1c. RESULTS The risk of any cardiovascular disease associated with a 1-percentage point increase in HbA1c was equivalent to the risk associated with 4.3 (95% CI 2.7–5.9) additional years of age or 5.6 (95% CI 2.7–6.5) additional years’ duration of T1D. The risk of estimated glomerular filtration rate CONCLUSIONS Our results help evaluate the impact of glycemia on advanced complications in a way that may be more interpretable to health care providers and individuals with T1D.

OBJECTIVE The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy reduced the development and progression of retinopathy in type 1 diabetes (T1D) compared with conventional therapy. The Epidemiology of Diabetes Interventions and Complications (EDIC) study observational follow-up showed persistent benefits. In addition to glycemia, we now examine other potential retinopathy risk factors (modifiable and nonmodifiable) over more than 30 years of follow-up in DCCT/EDIC. RESEARCH DESIGN AND METHODS The retinopathy outcomes were proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), and ocular surgery. The survival (event-free) probability was estimated using the Kaplan-Meier method. Cox proportional hazards models assessed the association between risk factors and subsequent risk of retinopathy. Both forward- and backward-selection approaches determined the multivariable models. RESULTS Rate of ocular events per 1,000 person-years was 12 for PDR, 14.5 for CSME, and 7.6 for ocular surgeries. Approximately 65%, 60%, and 70% of participants remained free of PDR, CSME, and ocular surgery, respectively. The greatest risk factors for PDR in descending order were higher mean HbA1c, longer duration of T1D, elevated albumin excretion rate (AER), and higher mean diastolic blood pressure (DBP). For CSME, risk factors, in descending order, were higher mean HbA1c, longer duration of T1D, and greater age and DBP and, for ocular surgeries, were higher mean HbA1c, older age, and longer duration of T1D. CONCLUSIONS Mean HbA1c was the strongest risk factor for the progression of retinopathy. Although glycemic control is important, elevated AER and DBP were other modifiable risk factors associated with the progression of retinopathy.

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.

Obesity is believed to be a promoter of type 2 diabetes mellitus (T2DM). Reports indicate that severe obesity in childhood and adolescence increases the risk of T2DM in youth and young adults. T2DM, which is commonly asymptomatic, frequently is not recognized until random blood glucose is measured. Screening blood glucose levels measured in obese individuals are more effective for identifying undiagnosed persons, than screening the general population and therefore introduces a selection bias for discovery. The following commentary will indicate why these observations do not indicate that obesity is the cause of T2DM. Also, it will be shown that the insulin resistance of T2DM occurs primarily in the muscles of lean individuals predisposed to diabetes before they become obese. This insulin resistance is not secondary to, but instead, is the cause of the excessive fat accumulation associated with T2DM. Moreover, this early muscle insulin resistance is the etiology of the hyperlipidemia and excess fat accumulation characteristic of T2DM.

Case series and registry data suggest that diabetic retinopathy requiring treatment is rare in youth with type 1 diabetes (T1D) prior to 18 years of age. We evaluated this question in the standardized clinical trial setting by retrospectively reviewing diabetic retinopathy examinations from participants in the Diabetes Control and Complications Trial (DCCT) who were 13 to

Background: Type 1 diabetes mellitus increases the risk of coronary heart disease. The Pittsburgh IDDM morbidity and mortality study reported greater than 10 fold coronary heart disease mortality compared with US national data [1]. Adults with diabetes have heart disease death rates 2 to 4 times higher than adults without diabetes [2]. Diabetic cardiomyopathy explains much of this survival difference and carnitine deficiency is a cause of cardiomyopathy. Research Design and Methods: Adult subjects (40) with type 1 diabetes mellitus were seen for a routine annual visit having no clinical complaints. Fasting serum samples were collected for annual chemistries and the measurement of carnitine. Results: The mean total (40.8 ± 8.8) [40 - 80 nmol/ml] and free (32.9 ± 7.9) [30 - 60 nmol/ml] carnitine levels for this group included 43% low total and 28% low free carnitine. The mean esterified/free (E/F) carnitine ratio (0.25 ± 0.09) for this group was elevated indicating carnitine insufficiency. Conclusions: Fatty acids are the primary energy source for diabetic heart muscle, and carnitine is essential for intracellular fatty acid transport and ATP production. Therefore, mild carnitine deficiency can compromise fatty acid energy production in a failing heart. Carnitine deficiency in subjects at high risk for cardiovascular failure is a possible unrecognized reason for the 4 fold increased death rate in patients with type 1 diabetes. Supplementation with oral carnitine could reduce that increased risk of heart failure, in patients with type 1 diabetes. Intravenous carnitine may be life saving when managing acute cardiac failure in patients with diabetes mellitus. Normal carnitine levels in patients with type 1 diabetes may provide a biochemical environment that prevents the long recognized idiopathic heart failure that occurs in insulin requiring diabetics as first reported in the 1974 Framingham Study.

Diabetes is a syndrome defined by higher than normal blood glucose levels. Those higher blood glucose levels are associated with the development of physical abnormalities termed complications. Those abnormalities are found in small blood vessels and cause pathology termed retinopathy and nephropathy. Small-vessel abnormalities are part of cardiovascular and peripheral nerve pathology as well. Larger–blood vessel abnormalities are manifest as atherosclerotic plaques that stiffen and reduce blood flow while causing embolic occlusions. This results in ischemic hearts, lungs, and brains, causing life-devastating and -ending events. High glucose levels have been associated with nonvascular damage to the lens of the eye, peripheral nerve, myelin sheath, and nonmyelinated autonomic nerves. These abnormalities cause cataracts, loss of sensation, and proprioception, as well as dysregulation of autonomic function. Autonomic dysfunction compromises normal blood flow, gastric motility, temperature regulation, and sexual function. Preventing these issues has made lowering blood glucose a major goal in the management of diabetes. There has been little concern about the influence of hyperglycemia on the structure or function of the central nervous system (CNS). The major CNS concern related to diabetes is the opposite issue, hypoglycemia. The symptoms of hypoglycemia are very dramatic, involving intoxicated behavior and mentation, seizures, and loss of consciousness. On occasion, hypoglycemia-induced hemiparesis will result in an extensive medical evaluation and rehabilitation. Generally, these abnormalities are transient …

This article discusses the use of microneedles in automated diabetes therapy systems. Advanced bioengineered systems have the potential to close the loop between diagnostic and therapeutic elements of diabetes treatment, thus constituting a “smart” system. Prevalent insulin therapies, and most glucose sensing techniques, involve the transfer of physical entities through the skin. Micromachined needles (microneedles) can achieve this in a noninvasive or minimally invasive manner while contributing various other technological merits. The dynamics of autonomous diabetes therapy systems include highly complex interdependencies between the various physical and biological entities involved, thus warranting multidisciplinary research initiatives. The iterative development of a noninvasive, bioengineered interface such as microneedles necessitates a better understanding of the human skin, its molecular architecture as a polymer film, and its role as a functional biological unit. This review addresses application-specific requirements of a microneedle-based interface system specifically for autonomous diabetes therapy. Key design issues and related parametric interdependencies specific to this application are discussed.

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

Several mechanistic pathways linking hyperglycemia to diabetes complications, including glycation of proteins and formation of advanced glycation end products (AGEs), have been proposed. We investigated the hypothesis that skin collagen glycation and AGEs predict the risk of progression of microvascular disease. We measured glycation products in the skin collagen of 211 Diabetes Control and Complications Trial (DCCT) volunteers in 1992 who continued to be followed in the Epidemiology of Diabetes Interventions and Complications study for 10 years. We determined whether the earlier measurements of glycated collagen and AGE levels correlated with the risk of progression of retinopathy and nephropathy from the end of the DCCT to 10 years later. In multivariate analyses, the combination of furosine (glycated collagen) and carboxymethyllysine (CML) predicted the progression of retinopathy (χ2 = 59.4, P < 0.0001) and nephropathy (χ2 = 18.2, P = 0.0001), even after adjustment for mean HbA1c (A1C) (χ2 = 32.7, P < 0.0001 for retinopathy) and (χ2 = 12.8, P = 0.0016 for nephropathy). The predictive effect of A1C vanished after adjustment for furosine and CML (χ2 = 0.0002, P = 0.987 for retinopathy and χ2 = 0.0002, P = 0.964 for nephropathy). Furosine explained more of the variation in the 10-year progression of retinopathy and nephropathy than did CML. These results strengthen the role of glycation of proteins and AGE formation in the pathogenesis of retinopathy and nephropathy. Glycation and subsequent AGE formation may explain the risk of these complications associated with prior A1C and provide a rational basis for the phenomenon of “metabolic memory” in the pathogenesis of these diabetes complications.

Repeated ingestion of insulin has been suggested as an immune tolerization therapy to prevent immune-mediated (type 1) diabetes. We performed a placebo-controlled, two-dose, oral insulin tolerance trial in newly diagnosed (< 2 years) diabetic patients who had required insulin replacement for less than 4 weeks and were found to have cytoplasmic islet cell autoantibodies (ICAs). No oral hypoglycemic agents were permitted during the trial. Endogenous insulin reserves were estimated at six-month intervals by plasma C-peptide responses to a mixed meal. Positive ICAs were found in 262 (31%) of the 846 patients screened. Of the 197 who agreed to participate, 187 could be followed for 6 to 36 months. Endogenous insulin retention was dependent upon initial stimulated C-peptide response, age at diabetes onset, and numbers of specific islet cell autoantibodies found. Oral insulin improved plasma C-peptide responses in patients diagnosed at ages greater than 20 years, best seen at the low (1 mg/day) over the high (10 mg/day) insulin dose (P = .003 and P = .01, respectively). In patients diagnosed before age 20 years, the 1 mg dose was ineffective, whereas the 10 mg dose actually accelerated C-peptide loss (P = .003). There were no adverse effects. If confirmed, these findings suggest that diabetic patients over age 20 years with ICA evidence of late-onset immune-mediated diabetes should be considered for oral insulin at 1 mg/day to better retain endogenous insulin secretion.

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 …

Telephone-delivered interventions (TDIs) represent a potentially cost-effective method to increase medical adherence. TDIs for diabetes patients have typically been delivered by nurses or computerized telephone messaging. Psychology undergraduates, however, are less costly than nurses, have a strong background in behavioral science, and provide the personal relationship missing with computerized contact. This paper presents the rationale for and description of a brief, regular, proactive telephone intervention designed to be delivered by psychology undergraduates (i.e., paraprofessionals). “Coaches” administer a 15-min telephone intervention weekly for 3 months and biweekly for 3 additional months. Guided by a semistructured protocol that focuses on behavioral goals, coaches provides support, collaborative problem-solving, and apply basic cognitive-behavioral techniques. Results from a pilot study on type 1 diabetes patients are presented. This preliminary evidence suggests that the program is feasible, acceptable to a large majority of patients, and effective in reducing HbA1c levels.

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.

OBJECTIVE—The Diabetes Control and Complications Trial (DCCT) demonstrated the powerful impact of glycemic control on the progression of diabetic retinopathy. A large number of individuals (2,771) underwent stereoscopic color photography and fluorescein angiography as part of screening for participation in the DCCT. A subgroup of those individuals screened participated in the DCCT and underwent evaluation of their retinal vasculature semiannually for 4–9 years. These data were evaluated to determine how the 2000 American Diabetes Association position statement would apply to the DCCT experience. Specifically, the position statement indicates that the first dilated eye examination should be performed after 3–5 years’ duration of diabetes because vision-threatening retinopathy virtually never develops in patients with type 1 diabetes during that interval. RESEARCH DESIGN AND METHODS—We examined the experience of the DCCT in evaluating retinal photographs in 1,613 patients with type 1 diabetes of RESULTS—Of 1,613 subjects with type 1 diabetes of CONCLUSIONS—Dilated eye examinations and retinal photography should be included in the routine management of type 1 diabetes during the first 5 years to identify the individuals at greatest risk for vision-threatening problems.

We report here our prospective study of 15,224 non-diabetic, first-degree relatives of probands with immune-mediated (type 1) diabetes (IMD), of which 135 were found to eventually develop diabetes. We determined islet cell, insulin, GAD65, insulinoma-associated antigen-2 and 2beta autoantibodies (ICA, IAA, GAD65A, IA-2A and IA-2betaA), on the first available serum samples. The latter three autoantibodies were however assayed on subsets of the relatives with and without ICA, IAA and/or GAD65A, plus most of the relatives who developed diabetes. Of the relatives who progressed to diabetes, 94% had at least one of these autoantibodies on the first screening, while ICA proved to be the most sensitive single marker (sensitivity 74%). Risk of diabetes was however negligible when ICA was found in the absence of the others (5-year risk=5.3%), but increased dramatically whenever two or more autoantibodies were present (5-year risk=28.2% and 66.2%, respectively). The most predictive combination of markers was ICA plus IA-2A and/or IA-2beta A. Loss of first phase insulin release to IVGTT also occurred only in those ICA-positive relatives who had one or more of the other autoantibodies. The data suggests that significant beta-cell damage is seen only when the underlying autoimmunity has spread to multiple antigenic islet cell determinants. Combinations of the autoantibodies occurred most often in relatives with the highest risk HLA-DR/DQ phenotypes. These data document that only relatives positive for at least two or more of these five autoantibodies are at significant risk of diabetes themselves. Intervention trials for the prevention of type 1 diabetes could be designed based on testing for these autoantibodies alone, without the need for HLA typing and IVGTT testing.

This study was designed to study the pathogenesis of cardiomyopathy in animals with longstanding (6 months) diabetes mellitus. Male Wistar rats were made diabetic by the injection of streptozotocin (35 mg/kg) intraperitoneal at 6 months of age. Myocardial contractility was evaluated at 1 year of age by an echocardiogram. Blood was collected at that time to measure blood glucose and hemoglobin A1c as an indicator of metabolic control. Serum carnitine was also measured on the same sample to evaluate the availability of this substance so essential for fatty acid metabolism in the myocardium. Myocardial anatomy was evaluated by both light and electron microscopy after the animals had diabetes for 6 months. It was found that the left ventricular volume was greater at the end of systole and diastole. There was the suggestion of left ventricular fractional shortening and calculated reduced ejection fraction indicating decreased contractility consistent with cardiomyopathy. The hearts had no evidence of coronary vascular occlusion, and the serum cholesterol was normal. Myocardial ultrastructure revealed abnormal-appearing mitochondria consistent with carnitine deficiency. Serum and myocardial carnitine levels in the animals with diabetes and reduced myocardial function were low. Carnitine levels and metabolism could be important in the pathogenesis of diabetic cardiomyopathy.

Acetyl-L-carnitine (ALC) has been shown to facilitate the repair of transected sciatic nerves. The effect of ALC (50 mg/kg/d) on the diminished nerve conduction velocity (NCV) of rats with streptozotocin (STZ)-induced hyperglycemia of 3 weeks' duration was evaluated. The aldose reductase inhibitor, sorbinil, which is reported to normalize the impaired NCV associated with experimental diabetes, was used as a positive control. Aldose reductase inhibitors are thought to have an effect by decreasing peripheral nerve sorbitol content and increasing nerve myo-inositol. Treatment of STZ-diabetic rats with either ALC or sorbinil resulted in normal NCV. Sorbinil treatment was associated with normalized sciatic nerve sorbitol and myo-inositol; ALC treatment did not reduce the elevated sorbitol levels, but sciatic nerve myo-inositol content was no different from nondiabetic levels. Both ALC and sorbinil treatment of STZ-diabetic rats were associated with a reduction in the elevated malondialdehyde (MDA) content of diabetic sciatic nerve, indicating reduced lipid peroxidation. The beneficial effects of sorbinil and ALC on the altered peripheral nerve function associated with diabetes were similar, but their effects on the polyol pathway (frequently implicated in the pathogenesis of peripheral neuropathy) were different.

Communication and problem-solving skills in families of children with diabetes (n'= 20) and families of healthy children (n = 20) were compared. Families completed paper-pencil measures and engaged in simulated problem-solving situations while being videotaped. In terms of raw behavior frequencies, diabetes families talked less than comparison families and used less of some problem solving skills. When overall verbosity was controlled for, however, fewer differences emerged in terms of problem-solving and communication skills. For diabetes families, significant relationships were found among behavior, adjustment, and illness variables. The importance of understanding the specific influence of diabetes-related stress on family functioning is discussed.

The Diabetes Control and Complications Trial (DCCT), an NIH-sponsored study at 29 institutions in the US. and Canada, began in 1983 to examine the effects of intensive blood glucose management on the complications of type I diabetes. About half of the 1441 patients studied were randomized into a conventional treat­ ment group and half into an intensive management group. About half of each treatment group had diabetes of 1-5 years duration and no retinopathy at random­ ization (primary) and half had diabetes of 1-15 years duration and minimal retinopathy at randomization (secondary). Hemoglobin Ale levels were regularly measured. Information about complications collected systematically included retinal photographs, nerve conduction velocity assessment and evaluation of albu­ minuria and renal function. Differences in mean Hemoglobin Ale level between the intensively-treated group and the group continuing their usual treatment were sustained and substantial. Mean hemoglobin Al c levels were 1 % compared to 3% above the normal range. We measured fibrinogen, haptoglobin, albumin and total protein levels of 1347 patients from April to August of 1991. Mean fibrinogen (measured both by coagulation quantification and clotting time after dilution) and haptoglobin were elevated and albumin level modestly depressed in the overall DCCT group and gender-based differences were also noted. Despite past reports linking diabetes control to plasma protein levels, no trend to normalization was found in the intensively treated group. In fact, mean haptoglobin level was modestly higher in the intensively treated compared to the conventional group. The primary and secondary prevention components had a well-defined difference in total plasma globulin, linked to marginal differences in albumin and total protein level. The globulin was higher in the secondary prevention group, who by study design manifested more microvascular changes. Intensive management of diabetes has no direct favorable effect on the levels of the major blood proteins that influence blood's flow properties.

Using time-dependent methods, the temporal relationships between the detection of insulin and islet cell autoantibodies and the onset of insulin dependent diabetes (IDDM) were analyzed in a prospective study of 4694 nondiabetic relatives of 1929 patients with IDDM who had been followed for a median of 4 yr. Insulin autoantibodies were detected in 1.5% of relatives at their initial test whereas an additional 1.0% subsequently became positive for these antibodies during follow-up. Islet cell autoantibodies were detected in 2.6% of the relatives at the time of their first test and an additional 0.9% were observed to develop them during the follow-up period. The risk of developing IDDM was significantly higher (P = 0.0001) among those who were found to have one of these antibodies, but was highest among those under the age of 20 yr at inception of this study who tested positive for both. Among older relatives, the detection of insulin autoantibodies among those who were islet cell antibody positive did not convey an additional risk of IDDM. In a subset of relatives, the presence of either antibody was associated with a higher frequency (P0.001) of diabetes associated human leukocyte antigen-DR 3/4 heterozygotes. Islet cell autoantibodies were highly associated with elevated fasting and 60-min glucose concentrations (P = 0.0001) as well as decreased early phase (1 and 3 min) insulin response to an iv glucose tolerance test (P = 0.0001). Insulin antibodies were significantly associated with decreased early phase insulin response to iv glucose (P = 0.0003). These data confirm independent risks associated with each antibody and suggest that their temporal relationship may be an important reflection of the pathogenic process underlying IDDM observations which facilitate its predictability.

Prediabetes, the interval preceding the clinical recognition of diabetes mellitus, is believed to consist of several months or years of beta-cell destruction associated with no clinically recognized signs other than possible increased growth velocity. This increased growth rate may be the result of increased insulin, increased growth hormone, or both. As insulin-dependent diabetes approaches clinical recognition, insulin deficiency becomes manifest as slowing of growth velocity and more obvious weight loss. If a prepubertal child has insulin-dependent diabetes mellitus, sexual maturation is frequently delayed and physical growth is adversely affected. Insulin is an anabolic hormone that regulates metabolic pathways involved in the production of protein, glycogen, and fat. The normal release of growth hormone and the hepatic production of insulin-like growth factor I is modulated by the action of insulin. The absence of physiologic insulin response leads to dysfunctional quantities of growth hormone, insulin-like growth factor I, and sex hormones, resulting in growth impairment and delayed sexual maturation. Delayed sexual maturation may cause concern because it has a major impact on growth and maturation of children. However, there is evidence that sex hormones have a stimulating effect on the tissue damage associated with chronic hyperglycemia. The loss of physiologic insulin release significantly affects physical growth, sexual maturation, and the chronic complications associated with insulin-dependent diabetes mellitus.

Intact lenses from New Zealand white rabbits were incubated in tissue culture media containing either 5 mM glucose or 5 mM glucose plus 30 mM galactose. The standard media did not contain taurine. Lenses were also cultured in a third medium containing 30 mM galactose plus 0.2 mM taurine. The frequency of cataract formation was evaluated as a function of the culture media. One lens (1/10), in media containing 5 mM glucose, developed a lenticular opacification during a 72-h incubation. Lenses (12/15) incubated in 30 mM galactose, without taurine, developed cataracts; fewer lenses (2/13) exposed to 30 mM galactose plus 0.2 mM taurine developed cataracts (p < 0.005). Galactose cataracts have been associated with lens edema attributed to the osmotic stress of tissue polyol (galactitol) accumulation. The water content of the noncataractous and cataractous lenses in this experiment did not differ. Lens edema, therefore, was not thought to be important in cataract pathogenesis. Taurine, an organic osmolyte was lower (5.1 +/- 1.5 mumol/g protein) in cataractous lenses than in control lenses (10.0 +/- 1.0 mumol/g protein). Malondialdehyde, an indicator of lipid peroxidation, was higher (36.6 +/- 5.0 mumol/g protein) in lens-containing opacifications than in noncataractous lenses (10.1 +/- 1.9 mumol/gm protein) (p < 0.01). The levels of malondialdehyde suggest that lipid peroxidation was increased in the process of sugar cataractogenesis. The malondialdehyde content of all the lenses correlated inversely (r = -0.53, p < 0.01) with the coincident lens taurine levels. Taurine appears to protect the lens against the development of sugar cataracts; its inverse relationship with lens malondialdehyde suggests this is an antioxidant effect.

Objective To describe patient selection, treatment administration, response evaluation, and side effect management associated with sapropterin therapy in infants and children aged Study design Six case reports are presented from 4 US metabolic clinics treating phenylketonuria with sapropterin in patients aged 7 months to 4 years. Outcomes included blood phenylalanine (Phe) levels before and during treatment. For 3 of 6 cases, diet records were used to monitor changes in dietary Phe. Results Severity of phenylketonuria ranged from mild to severe (classic). Treatment with sapropterin was safe and generally well tolerated. Blood Phe levels were reduced, or maximum dietary Phe tolerance was increased in patients with blood Phe that was well controlled by diet. Conclusions Given the increasing evidence that maintaining blood Phe levels below 360 μmol/L is important for the normal development of neurocognitive and behavioral function, sapropterin can be combined with a Phe-restricted diet to control blood Phe levels in young patients responsive to sapropterin therapy.

Two methods are commonly used to measure sorbitol in mammalian tissues. The first uses sorbitol dehydrogenase for a coupled enzymatic reaction; unfortunately, other polyols are also substrates for this enzyme. The second uses gas-liquid chromatography (GLC) for separation of polyols and mass quantitation of sorbitol. A comparison of these two methods for the measurement of sorbitol in duplicate samples of lens, nerve, and erythrocytes indicates that GLC of polyol acetates consistently finds less sorbitol than measured by sorbitol dehydrogenase. Erythritol, threitol, ribitol, arabitol, and galactitol are polyols found in variable quantities in these tissues, which have a variable influence on the activity of sorbitol dehydrogenase and therefore alter sorbitol quantitation with this enzyme. Moreover, there is an unidentified substance(s) that reacts with sorbitol dehydrogenase which seems to increase in association with hyperglycemia in the lens and nerve, but not in erythrocytes. The quantity of this unknown substance(s) seems to be reduced by the aldose reductase inhibitor sorbinil in erythrocytes and to a lesser extent sciatic nerve and lens. Since enzymatic sorbitol quantitation in the lens, nerve, and erythrocytes is influenced by many known and unknown factors other than sorbitol, we recommend that GLC of polyol acetates be used to measure sorbitol in biologic tissues.

An adolescent female with type B insulin resistance and hyperandrogenemia is described. Evidence presented suggests that hyperinsulinemia leads to an increase in serum total and free testosterone. Support for this hypothesis is noted during an in vivo experiment in which large doses of regular insulin (305 U/kg-day) were infused iv, and multiple serum total testosterone measurements obtained. After 35 days of iv insulin therapy, the serum total testosterone values rose from 4.9 nmol/L (142 ng/dL) to 22.8 nmol/L (660 ng/dL), and the ovarian volume increased 2-fold. Basal (9.8 nmol/L; 282 ng/dL) and stimulated (16.8 nmol/L; 481 ng/dL) androstenedione measurements were elevated, and the dehydroepiandrosterone/androstenedione ratio was low, suggesting increased 3 beta-hydroxysteroid dehydrogenase activity. After resolution of the insulin-resistant state and the concomitant hyperinsulinemia, the serum total testosterone values returned to normal. This case illustrates that long term hyperinsulinemia leads to elevation of serum total testosterone.

Background/Objective: We previously reported that chronic hyperglycemia, but not hypoglycemia, was associated with the reduction of neuronal size in the rat brain. We hypothesized that hyperglycemia-induced changes in neuronal structure would have negative consequences, such as impaired learning and memory. We therefore assessed the effects of hyperglycemia and hypoglycemia on neuronal dendritic structure and cognitive functioning in young rats. Design/Methods: Experimental manipulations were conducted on male Wistar rats for 8 wk, beginning at 4 wk of age. At the completion of the treatments, all rats were trained in the radial-arm water maze, a spatial (hippocampus-dependent) learning and memory task. Three groups of rats were tested: an untreated control group, a streptozotocin-induced diabetic (STZ-D) group, and an intermittent hypoglycemic group. Following behavioral training, the brains of all animals were examined with histologic and biochemical measurements. Results: Peripheral hyperglycemia was associated with significant increases in brain sorbitol (7.5 ± 1.6 vs. 5.84 ± 1.0 μM/mg) and inositol (9.6 ± 1.4 vs. 7.1 ± 1.1 μM/mg) and reduced taurine (0.65 ± 0.1 vs. 1.3 ± 0.1 mg/mg). Histologic evaluation revealed neurons with reduced dendritic branching and spine density in STZ-D rats but not in control or hypoglycemic animals. In addition, the STZ-D group exhibited impaired performance on the water maze memory test. Conclusions: Hyperglycemia, but not hypoglycemia, was associated with adverse effects on the brain polyol pathway activity, neuronal structural changes, and impaired long-term spatial memory. This finding suggests that the hyperglycemic component of diabetes mellitus has a greater adverse effect on brain functioning than does intermittent hypoglycemia.

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.

Brief, cost-effective interventions to promote diabetes self-management are needed. This study evaluated the effects of a brief, regular, proactive, telephone "coaching" intervention delivered by paraprofessionals on diabetes adherence, glycemic control, diabetes-related medical symptoms, and depressive symptoms. Therapeutic mechanisms underlying the intervention's effect on the primary outcomes were also examined. Adults diagnosed with type 2 diabetes (N = 62) were randomly assigned to receive the "coaching" intervention and treatment as usual, or only treatment as usual. The intervention increased frequency of exercise and feet inspection, improved diet, reduced diabetes medical symptoms, and lowered depressive symptoms. Self-efficacy, reinforcement, and awareness of self-care goals mediated the treatment effect on depression, exercise, and feet inspection, respectively. A brief telephone intervention delivered by paraprofessionals had positive effects on type 2 diabetes patients.

Used 24-hr recall interviews to assess adherence in a sample of seventy-eight 6- to 19-year-olds with insulin-dependent diabetes mellitus over a 3-month period. Thirteen adherence measures were quantified and grouped into six adherence factors (Injection, Exercise, Diet Type, Testing/Eating Frequency, Calories Consumed, and Concentrated Sweets). Prevailing glucose levels over a 2- to 3-month interval were indexed by glycosylated hemoglobin A1c (HA1c) and glycosylated serum protein (GSP) assays. Fasting triglycerides (TRIG) and total cholesterol (CHOL) assays were used to estimate lipid metabolism. Adolescents were generally less adherent than their young counterparts. Using hierarchical multiple-regression techniques, HA1c and GSP were not reliably predicted by most of the adherence factors; only Calories Consumed showed any predictive power. No significant regression equations emerged for CHOL. In contrast, TRIG was significantly associated with five of the six adherence factors; in all cases, adherence interacted with the patients' metabolic status (as defined by HA1c) at study entry, suggesting that adherence had different effects for youngsters in good versus poor diabetes control.

Rats with streptozotocin-induced diabetes (STZ-D) have reduced serum carnitine levels and bradycardia. Heart rates (HRs) of 24nondiabetic rats (NRs) and 24 STZ-D rats were compared. L-carnitine (C) was added to the drinking water of rats (12 STZ-D+C) to raise their serum carnitine level. The intrinsic HR for each animal was determined after parasympathetic and sympathetic blockade. The HRs of STZ-D rats (278+/-15 beats per minute) were less than those of NRs (348+/-8 beats per minute) (P

Background Streptozotocin-induced diabetes (STZ-D) in rats has been associated with carnitine deficiency, bradycardia and left ventricular enlargement. Aim The purpose of this study was to determine whether oral carnitine supplementation would normalize carnitine levels and cardiac function in STZ-D rats. Methods Wistar rats (48) were made hyperglycemic by STZ at 26 weeks of age. Same age normal Wistar rats (24) were used for comparison. Echocardiograms were performed at baseline 2, 6, 10, and 18 weeks after STZ administration in all animals. HbA1c, serum carnitine and free fatty acids (FFA) were measured at the same times. Since STZ-D rats become carnitine deficient, 15 STZ-D rats received supplemental oral carnitine for 16 weeks. Results The heart rates for the STZ-D rats (290 ± 19 bpm) were less than control rats (324 ± 20 bpm) (p < 0.05). After 4 weeks of oral carnitine supplementation, the serum carnitine and heart rates of the STZ-D rats returned to normal. Dobutamine stress increased the heart rates of all study animals, but the increase in STZ-D rats (141 ± 8 bpm) was greater than controls (79 ± 8 bpm) (p < 0.05). The heart rates of STZ-D rats given oral carnitine, however, were no different than controls (94 ± 9 bpm). The left ventricular mass/body weight ratio (LVM/BW) in the diabetic animals (2.7 ± 0.5) was greater than control animals (2.2 ± 0.3) (p < 0.05) after 18 weeks of diabetes. In contrast, the LVM/BW (2.3 ± .2) of the STZ-D animals receiving supplemental carnitine was the same as the control animals at 18 weeks. Conclusion Thus, supplemental oral carnitine in STZ-D rats normalized serum carnitine, heart rate regulation and left ventricular size. These findings suggest a metabolic mechanism for the cardiac dysfunction noted in this diabetic animal model.

Children with diabetes onset before 5 years of age have reduced neurocognitive function. This problem has been attributed to hypoglycemia, a complication of insulin therapy. The eye, kidney, and nerve complications of diabetes (hyperglycemia) have been reduced by intensified insulin therapy which is associated with a 3-fold increase in severe hypoglycemia and therefore is not recommended for children less than 13 years of age. Since hyperglycemia is much more common than intermittent hypoglycemia during early childhood diabetes, it is important to determine if hyperglycemia affects brain growth and development. Rats were exposed to 4 weeks of either continuous hyperglycemia (diabetes) or intermittent (3 h, 3 times/week) hypoglycemia from 4 to 8 weeks of age. The brains of these animals were compared to those of similarly aged normal control animals. The cell number was increased, and the cell size reduced in the cortex of diabetic animals as assessed by DNA/wet weight of brain and protein/DNA content. Reduced amounts of protein, fatty acids, and cholesterol/microgram DNA also indicate smaller cells with reduced myelin content in the cortex of the diabetic animals. Histologic evaluation of these brains confirmed the biochemical findings. These observations require further confirmation and evaluation but indicate that continuous hyperglycemia may be more damaging than intermittent hypoglycemia to the developing brain. This is an important consideration for the management of diabetes mellitus in young children.

Telephone-delivered interventions (TDIs) represent a potentially cost-effective method to increase medical adherence. TDIs for diabetes patients have typically been delivered by nurses or computerized telephone messaging. Psychology undergraduates, however, are less costly than nurses, have a strong background in behavioral science, and provide the personal relationship missing with computerized contact. This paper presents the rationale for and description of a brief, regular, proactive telephone intervention designed to be delivered by psychology undergraduates (i.e., paraprofessionals). "Coaches" administer a 15-min telephone intervention weekly for 3 months and biweekly for 3 additional months. Guided by a semistructured protocol that focuses on behavioral goals, coaches provides support, collaborative problem-solving, and apply basic cognitive-behavioral techniques. Results from a pilot study on type 1 diabetes patients are presented. This preliminary evidence suggests that the program is feasible, acceptable to a large majority of patients, and effective in reducing HbA1c levels.

This study compared glycemic control achieved with insulin lispro or buffered regular human insulin in patients with Type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) using an external insulin pump. In this 24-week multicenter, randomized, two-way crossover, open-label trial, 58 patients on CSII with adequate glycemic control received either insulin lispro or buffered regular human insulin for 12 weeks, followed by the alternate treatment for another 12 weeks. Efficacy and safety measures included hemoglobin A(1c) (HbA(1c)) at baseline and endpoint, home blood glucose monitoring, hypoglycemia, and frequency of pump catheter occlusion. Patients consumed a standard test meal on three occasions, with determinations of fasting, 1- and 2-h postprandial glucose values. Insulin lispro use was associated with a significantly lower HbA(1c) than was buffered regular human insulin (7.41+/-0.97 vs. 7.65+/-0.85 mmol/l; P=.004). Fasting serum glucose values before the test meal were similar between the two therapies. The 1-h (11.16+/-4.29 vs. 13.20+/-4.68 mmol/l; P=.012) and 2-h (9.64+/-4.10 vs. 12.53+/-4.64 mmol/l; P=.001) postprandial glucose concentrations were significantly lower during treatment with insulin lispro. No differences between treatments were observed in basal or bolus insulin doses, weight gain, or the incidence and rate of hypoglycemia, hyperglycemia, or pump occlusions. When used in external pumps, insulin lispro provides better glycemic control than buffered regular human insulin with a similar adverse event profile.

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are two of the most serious acute complications of diabetes. These hyperglycemic emergencies continue to be important causes of morbidity and mortality among patients with diabetes in spite of major advances in the understanding of their pathogenesis and more uniform agreement about their diagnosis and treatment. The annual incidence rate for DKA estimated from population-based studies ranges from 4.6 to 8 episodes per 1,000 patients with diabetes (1,2), and in more recent epidemiological studies in the U.S., it was estimated that hospitalizations for DKA during the past two decades are increasing (3). Currently, DKA appears in 4-9% of all hospital discharge summaries among patients with diabetes (4,5). The incidence of HHS is difficult to determine because of the lack of population-based studies and the multiple combined illnesses often found in these patients. In general, it is estimated that the rate of hospital admissions due to HHS is lower than the rate due to DKA and accounts for

Insulin dependent diabetes mellitus (Type 1 diabetes) can adversely affect the growth of children. Type 1 diabetes is characterized by total insulin deficiency. Insulin is an anabolic hormone that regulates the metabolic pathways that increase the synthesis of proteins, glycogen, and fat. Insulin activates a transporter system that moves glucose into muscle cells for the production of energy and into adipocytes for both the production and storage of energy. Clinical observations indicate that insulin deficiency is associated with growth failure and that hyperinsulinemia is accompanied by weight gain and accelerated linear growth (1). Insulin promotes growth by increasing the intracellular availability of substrate (glucose) for energy production, and also exerts an indirect effect by increasing insulin-like growth factor (IGF-1), which is the primary agent that stimulates linear bone growth (2). Because Type 1 diabetes is associated with abnormal insulin production and release, it is not surprising that growth irregularities have been associated with Type 1 diabetes in growing children. Type 1 diabetes is an endocrine problem precipitated by the total absence of insulin, which contributes to the associated hormonal abnormalities seen in Table 16.1.

Nerve conduction velocity (NCV) increased with age in nondiabetic male Wistar rats for the first 26 weeks of life. The NCV of animals made hyperglycemic at age 6 weeks by administration of streptozotocin (STZ) also increases, but at a slower rate. Animals with 4 weeks of hyperglycemia and reduced NCV treated with an aldose reductase inhibitor (sorbinil) or a short-chain acyl-carnitine (acetyl- l -carnitine [ALC]) daily for 16 weeks showed an improvement in NCV. Morphometric studies of tibial nerves collected from animals after 20 weeks of hyperglycemia (age 26 weeks) showed a consistent reduction in the width of the myelin sheath and little change in axon area. The number of large myelinated fibers (>6.5 μm) found in nerves collected from hyperglycemic animals was less than the number found in nondiabetic animals. Treatment of hyperglycemic rats with either sorbinil or ALC was associated with increased NCV, myelin width, and large myelinated fibers. The apparent metabolic effect of these agents was similar for fatty acid metabolism, but different for polyol pathway activity. We conclude that in animals hyperglycemic long enough to slow NCV, sorbinil and/or ALC treatment reduces the functional, structural, and biochemical changes associated with hyperglycemia that occur in the myelin sheath.

The international community of diabetologists is rapidly becoming involved in intervention trials aimed at preventing insulin-dependent diabetes in high risk relatives. Whereas age and relationship to a proband with insulin-dependent diabetes mellitus interacting with detected islet cell autoantibodies (ICA) are risk factors, their independent contribution to that risk remains unclear. In a prospective study of 6851 nondiabetic relatives of 2742 probands conducted between 1979-1993, we found age, but not relationship, to be a dramatic risk variable in ICA-positive persons as estimated by the Cox regression model. The 5-yr risk of insulin-dependent diabetes mellitus was 66% for those found to have ICA detectable before age 10 yr, falling progressively to less than 16% for ICA-positive relatives over age 40 yr. In ICA-negative relatives, age and relationship are independent prognostic variables.