Effect of improved glycemic control on health care costs and utilization.

CONTEXT: Because of the additional costs associated with improving diabetes management, there is interest in whether improved glycemic control leads to reductions in health care costs, and, if so, when such cost savings occur. OBJECTIVE: To determine whether sustained improvements in hemoglobin A(1c) (HbA(1c)) levels among diabetic patients are followed by reductions in health care utilization and costs. DESIGN AND SETTING: Historical cohort study conducted in 1992-1997 in a staff-model health maintenance organization (HMO) in western Washington State. PARTICIPANTS: All diabetic patients aged 18 years or older who were continuously enrolled between January 1992 and March 1996 and had HbA(1c) measured at least once per year in 1992-1994 (n = 4744). Patients whose HbA(1c) decreased 1% or more between 1992 and 1993 and sustained the decline through 1994 were considered to be improved (n = 732). All others were classified as unimproved (n = 4012). MAIN OUTCOME MEASURES: Total health care costs, percentage hospitalized, and number of primary care and specialty visits among the improved vs unimproved cohorts in 1992-1997. RESULTS: Diabetic patients whose HbA(1c) measurements improved were similar demographically to those whose levels did not improve but had higher baseline HbA(1c) measurements (10.0% vs 7.7%; P<.001). Mean total health care costs were $685 to $950 less each year in the improved cohort for 1994 (P =.09), 1995 (P =.003), 1996 (P =.002), and 1997 (P =.01). Cost savings in the improved cohort were statistically significant only among those with the highest baseline HbA(1c) levels (>/=10%) for these years but appeared to be unaffected by presence of complications at baseline. Beginning in the year following improvement (1994), utilization was consistently lower in the improved cohort, reaching statistical significance for primary care visits in 1994 (P =.001), 1995 (P<.001), 1996 (P =.005), and 1997 (P =.004) and for specialty visits in 1997 (P =.02). Differences in hospitalization rates were not statistically significant in any year. CONCLUSION: Our data suggest that a sustained reduction in HbA(1c) level among adult diabetic patients is associated with significant cost savings within 1 to 2 years of improvement.

Patient-level estimates of the cost of complications in diabetes in a managed-care population.

OBJECTIVE: To develop incidence-based estimates of the cost of several diabetes-related complications. DESIGN AND SETTING: This was a retrospective cohort study in a large health maintenance organisation. A total of 8905 patients with type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus and 36,520 age- and gender-matched controls without diabetes were observed from 1992 to 1995. Incidence rates of 6 major diabetes-related complications were computed for both populations. Annual health expenditures in the first and second year following diagnosis were computed for each complication. For comparison, annual costs were derived for individuals without diabetes or the complication of interest. MAIN OUTCOME MEASURES AND RESULTS: Over 3 years of observation, incidence rates for the groups with and without diabetes were as follows: myocardial infarction 9.0 versus 3.2%; stroke 8.7 versus 3.8%; hypertension 26.2 versus 16.9%; end-stage renal disease 5.9 versus 1.4%; foot ulcer 7.9 versus 1.1%; and eye disease 44.3 versus 2.8%. Expressed as a multiple of the average annual cost of care for those without diabetes [$US3400/year (1995 dollars) for those over 65 years of age] and the related complication of interest, excess expenditures for those with diabetes were as follows for the first year following diagnosis: no complications 1.59; myocardial infarction 4.1; stroke 3.5; hypertension 2.56; end-stage renal disease 4.32; foot ulcer 4.0; and eye disease 2.46. For younger cohorts (less prevalent in the sample), incremental costs for each complication were generally greater than in the older group. CONCLUSIONS: The high incidences and costs may support the value of aggressive early intervention for patients with diabetes. These data will be useful for pharmacoeconomic modelling of the cost effectiveness of new and existing therapies for this condition.

Incidence, outcomes, and cost of foot ulcers in patients with diabetes.

OBJECTIVE: To determine the incidence of foot ulcers in a large cohort of patients with diabetes, the risk of developing serious complications after diagnosis, and the attributable cost of care compared with that in patients without foot ulcers. RESEARCH DESIGN AND METHODS: Retrospective cohort study of patients with diabetes in a large staff-model health maintenance organization from 1993 to 1995. Patients with diabetes were identified by algorithm using administrative, laboratory, and pharmacy records. The data were used to calculate incidence of foot ulcers, risk of osteomyelitis, amputation, and death after diagnosis of foot ulcer, and attributable costs in foot ulcer patients compared with patients without foot ulcers. RESULTS: Among 8,905 patients identified with type 1 or type 2 diabetes, 514 developed a foot ulcer over 3 years of observation (cumulative incidence 5.8%). On or after the time of diagnosis, 77 (15%) patients developed osteomyelitis and 80 (15.6%) required amputation. Survival at 3 years was 72% for the foot ulcer patients versus 87% for a group of age- and sex-matched diabetic patients without foot ulcers (P < 0.001). The attributable cost for a 40- to 65-year-old male with a new foot ulcer was $27,987 for the 2 years after diagnosis. CONCLUSIONS: The incidence of foot ulcers in this cohort of patients with diabetes was nearly 2.0% per year. For those who developed ulcers, morbidity, mortality, and excess care costs were substantial compared with those for patients without foot ulcers. The results appear to support the value of foot-ulcer prevention programs for patients with diabetes.

A population-based approach to diabetes management in a primary care setting: early results and lessons learned.

OBJECTIVE: To determine the effect of a multifaceted program of support on the ability of primary care teams to deliver population-based diabetes care. DESIGN: Ongoing evaluation of a population-based intervention. SETTING/PARTICIPANTS: Group Health Cooperative of Puget Sound, a staff model HMO in which more than 200 primary care providers treat approximately 15,000 diabetic patients. INTERVENTION: A program of support to improve the ability of primary care teams to deliver population-based diabetes care was implemented. The elements of the program are based on an integrated model of well-validated components of delivery of effective care to chronically ill populations. These elements have been introduced since the beginning of 1995, and some aspects of the program were pilot-tested in a few practice sites before being implemented throughout the organization. The program elements include 1) a continually updated on-line registry of diabetic patients; 2) evidence-based guidelines on retinal screening, foot care, screening for microalbuminuria, and glycemic management; 3) improved support for patient self-management; 4) practice redesign to encourage group visits for diabetic patients in the primary care setting; and 5) decentralized expertise through a diabetes expert care team (a diabetologist and a nurse certified diabetes educator) seeing patients jointly with primary care teams. MAIN OUTCOME MEASURES: Patient and provider satisfaction through existing system-wide measurement processes; process measures, health outcomes, and costs are tracked continuously. RESULTS: Patient and provider satisfaction have improved steadily. Interest in and use of the electronic Diabetes Registry have grown considerably. Rates of retinal eye screening, documented foot examinations, and testing for microalbuminuria and hemoglobin A1c have increased substantially. CONCLUSIONS: Providing support to primary care teams in several key areas has made a population-based approach to diabetes care a practical reality in the setting of a staff model HMO. It may be an important mechanism for improving standards of care for many diabetic patients.

Ultrastructural allelic variation in HLA-DQB1 promoter elements.

Sequence variation among HLA class II promoter elements may contribute to functional differences in transcriptional regulation of different class II alleles. In addition to influencing the binding sites for nuclear transcription factors, promoter polymorphism may also alter intrinsic structural properties of the DNA strands, such as conformation and curvature, which influence the formation of stable transcription complexes. We used SSCP analysis of PCR-amplified promoter regions from the DQB1 locus to evaluate conformational polymorphism within DQ alleles. Distinct electrophoretic migration patterns of the SSCP products were detected for six DQB1 alleles; analysis of the DQB1*0302 promoter, known to be associated with type 1 diabetes, showed no SSCP differences between IDDM patients and normal controls. Using computer modeling based on a "nearest-neighbor" energy of predicted curvature theory, we examined the effect of allelic promoter region sequence polymorphism on the predicted curvature of double-stranded DNA, and found distinct allelic differences in predicted DNA curvature, both in transcriptional consensus binding sites and in regions located between binding sites. These data are consistent with a model in which intrinsic sequence variation in the promoter region results in ultrastructural differences which may influence DNA bending and interactions with multimeric DNA-protein transcription complexes.

Patient-reported experience with Velosulin human insulin in continuous subcutaneous insulin infusion.

A multicenter, retrospective survey of 339 patients with insulin-dependent diabetes mellitus was done to evaluate patient experience with Velosulin Human insulin, a regular insulin in a phosphate buffer, used in continuous subcutaneous insulin infusion. Patients had used this insulin exclusively for 3 months preceding the survey. Responses were elicited through interviews conducted by physicians or nurses. Patients were queried as to the occurrence of specific complications associated with pump therapy that occurred while using Velosulin Human insulin, including hypoglycemia, diabetic ketoacidosis, unexplained hyperglycemia, tubing obstruction, and infection or abscess at the infusion site. Most patients reported that they did not experience any of these complications during the preceding 3 months. The most frequently cited complication was hyperglycemia unexplained by dosage, exercise, or dietary changes, reported by 110 (32%) patients. The second most frequently reported complication was tubing obstruction, reported by 99 (29%) patients. The reported frequencies of the other complications were: severe hypoglycemia, 45 (13%) patients; diabetic ketoacidosis, 28 (8%) patients; and infection or abscess at the infusion site, 26 (8%) patients. The low morbidity reported by the patients in this survey probably was due in large part to careful patient selection, a high level of motivation on the part of the patients, and experience and education on the part of the health care team, as well as to the use of buffered regular human insulin.

Retrograde versus antegrade cannulation in the intravenous glucose tolerance test.

To investigate whether drawing blood from a retrogradely cannulated hand vein rather than an antegradely cannulated arm vein improves reproducibility in the intravenous tolerance test (IVGTT) we compared these two methods directly by drawing blood from the two sites on the same arm simultaneously. We found no difference in intrasubject coefficients of variation for the measurement of insulin response to glucose (21.5% vs. 22.5%) or insulin sensitivity (22.8 vs. 24.7%) for these two methods. However, the values for insulin response to glucose were significantly increased when blood was drawn from the hand site (410.1 vs. 328.7 pM, P < 0.05). In addition, the failure rate for studies using the retrogradely cannulated hand vein was significantly increased (5% of arm veins vs. 20% of hand veins cannulated, P < 0.05) particularly in female subjects. In conclusion, drawing blood samples from a retrogradely cannulated hand vein appears to have no effect on the reproducibility of the intravenous glucose tolerance test. The acute insulin response to glucose obtained from samples drawn in this manner is, however, significantly increased and this should be borne in mind when comparing results from centers using these different methods.

The contribution of insulin-dependent and insulin-independent glucose uptake to intravenous glucose tolerance in healthy human subjects.

Glucose disposal occurs by both insulin-independent and insulin-dependent mechanisms, the latter being determined by the interaction of insulin sensitivity and insulin secretion. To determine the role of insulin-independent and insulin-dependent factors in glucose tolerance, we performed intravenous glucose tolerance tests on 93 young healthy subjects (55 male, 38 female; 18-44 years of age; body mass index, 19.5-52.2 kg/m2). From these tests, we determined glucose tolerance as the glucose disappearance constant (Kg), calculated beta-cell function as the incremental insulin response to glucose for 19 min after an intravenous glucose bolus (IIR0-19), and derived an insulin sensitivity index (SI) and glucose effectiveness at basal insulin (SG) using the minimal model of glucose kinetics. To eliminate the effect of basal insulin on SG and estimate insulin-independent glucose uptake, we calculated glucose effectiveness at zero insulin (GEZI = SG - [SI x basal insulin]). Insulin-dependent glucose uptake was estimated as SI x IIR0-19, because the relationship between SI and beta-cell function has been shown to be hyperbolic. Using linear regression to determine the influence of these factors on glucose tolerance, we found that GEZI was significantly related to Kg (r = 0.70; P < 0.0001), suggesting a major contribution of insulin-independent glucose uptake to glucose disappearance. As expected, SI x IIR0-19 also correlated well with Kg (r = 0.74; P < 0.0001), confirming the importance of insulin-dependent glucose uptake to glucose tolerance. Although IIR0-19 alone correlated with Kg (r = 0.35; P = 0.0005), SI did not (r = 0.18; P > 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)

High genetic risk for IDDM in the Pacific Northwest. First report from the Washington State Diabetes Prediction Study.

A combination of immune, genetic, and metabolic markers potentially implicated in the development of insulin-dependent diabetes mellitus (IDDM) was studied in the general population. We screened 3,992 healthy schoolchildren, 12-18 years of age with no family history of IDDM, for islet cell antibodies (ICAs). Of the children, 69 (1.7%) were found to be ICA positive (ICA+), of whom 7 (0.17%) also were positive for insulin autoantibodies (IAAs). ICA+ children (group 1) were human leukocyte antigen (HLA) typed at the DQ locus along with 123 matched (group 2) and 235 random (group 3) control subjects (from the original cohort of 3,992). Of the ICA+ children, 28 underwent beta-cell function (beta-CF) studies. High-risk DQ types were surprisingly prevalent in all groups with 35.8% of random control subjects carrying DQB1*0302 and 8.9% carrying the highest risk HLA type for IDDM, DQB1*0302/*0201. Those individuals with higher ICA titer (> 19 Juvenile Diabetes Foundation units [JDF U]) had a significantly higher prevalence of DQB1*0302 than those with lower titer ICA or normal control subjects. Six of 7 individual positive for both ICA and IAA and typed at the DQ locus were DQB1*0302/*0201 heterozygotes or DQB1*0302 or DQB1*0201 homozygotes, representing three of the highest risk genotypes for IDDM. No correlation was observed between ICA titer or DQ type and beta-CF except that all those with beta-CF below the 5th percentile carried either DQB1*0302 or DQB1*0201. Prospective follow-up is underway to determine if any combination of DQ type and immune markers predicts decline in beta-CF and the development of IDDM.

Insulin (auto)antibodies from human IDDM cross-react with retroviral antigen p73.

In NOD mice, endogenous retroviruses including intracisternal type A particles (IAP) are expressed in the pancreatic beta cells. Furthermore, in these mice, insulin autoantibodies (IAA) cross-react with retroviral protein p73 (the IAP gag gene product), suggesting molecular mimicry between insulin and p73. We therefore investigated whether IAA and insulin antibodies (IA) associated with human IDDM cross-reacted with p73. Fifty IAA positive sera from 30 newly diagnosed IDDM before insulin therapy and 20 non-diabetic first degree relatives of IDDM and 27 IA positive sera from insulin treated IDDM, initially defined as IAA or IA positive by radioimmunoassay, were evaluated. Binding to insulin and to p73 of these sera were analysed by ELISA. Approximately 65% of sera which bound insulin by ELISA also bound p73. Only one sample negative for insulin binding was positive for p73 binding. Preabsorption with either insulin or p73 inhibited binding to both insulin and p73. However, preabsorption with mouse hemoglobin had no effect on their binding. Repeat measurement of binding to insulin and p73 in 10 non-diabetic first degree relatives of IDDM over an average of 16.6 months showed that each individual's reactivity to insulin and to p73 was relatively stable over time. Furthermore, in different individuals, binding to p73 and to insulin was closely correlated over time. In addition, 75 healthy teenagers (IAA negative by RIA) were used as normal controls in this study. p73 binding was found in only two (2.7%) of the 75 subjects. These results indicate that approximately 65% of ELISA (+) IAA and IA subjects have antibodies which recognize both insulin and p73, suggesting that IAA and IA from some subjects recognize an epitope shared between human insulin and the murine gag gene product. This raises the possibility that for some subjects who are IAA positive, the immunizing antigen may be antigenically similar to p73, rather than insulin, and that endogenous retroviruses may be involved in human IDDM.

Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function.

To determine the relationship between insulin sensitivity and beta-cell function, we quantified the insulin sensitivity index using the minimal model in 93 relatively young, apparently healthy human subjects of varying degrees of obesity (55 male, 38 female; 18-44 yr of age; body mass index 19.5-52.2 kg/m2) and with fasting glucose levels < 6.4 mM. SI was compared with measures of body adiposity and beta-cell function. Although lean individuals showed a wide range of SI, body mass index and SI were related in a curvilinear manner (P < 0.0001) so that on average, an increase in body mass index was associated generally with a lower value for SI. The relationship between the SI and the beta-cell measures was more clearly curvilinear and reciprocal for fasting insulin (P < 0.0001), first-phase insulin response (AIRglucose; P < 0.0001), glucose potentiation slope (n = 56; P < 0.005), and beta-cell secretory capacity (AIRmax; n = 43; P < 0.0001). The curvilinear relationship between SI and the beta-cell measures could not be distinguished from a hyperbola, i.e., SI x beta-cell function = constant. This hyperbolic relationship described the data significantly better than a linear function (P < 0.05). The nature of this relationship is consistent with a regulated feedback loop control system such that for any difference in SI, a proportionate reciprocal difference occurs in insulin levels and responses in subjects with similar carbohydrate tolerance. We conclude that in human subjects with normal glucose tolerance and varying degrees of obesity, beta-cell function varies quantitatively with differences in insulin sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of bolus and infusion protocols for determining acute insulin response to intravenous glucose in normal humans. The ICARUS Group. Islet Cell Antibody Register User's Study.

OBJECTIVE: To help standardize methodology for intravenous glucose tolerance testing in preclinical IDDM by comparing a 30-s bolus and a 3-min infusion of glucose. RESEARCH DESIGN AND METHODS: We tested 20 healthy nondiabetic adults at four centers (in Seattle, Boston, Melbourne, and London). Each subject had four intravenous glucose tolerance tests (two bolus and two infusion). The acute insulin response to glucose was calculated as the mean of the 1' + 3', the mean of 1' to 10', or as the integrated area from 0 to 10'. Glucose and insulin profiles and intrasubject coefficient of variation were compared. RESULTS: With the infusion protocol, the 1' insulin was significantly higher, resulting in a higher acute insulin response to glucose when calculated as 1' + 3' (525 +/- 66 vs. 376 +/- 35 pM, P < 0.004). When calculated over 10 min, however, the acute insulin response to glucose was not different between protocols. In addition, the intrasubject coefficient of variation was significantly better when calculated over 10 min in both protocols, but no significant differences were noted between the bolus and infusion (infusion: AIRg [area from 0 to 10'] 10.4 +/- 2.1% vs. AIRg [1' + 3'] 14.9 +/- 2.8%, P < 0.007; bolus: AIRg [area from 0 to 10'] 14.6 +/- 2.8% vs. AIRg [1' + 3'] 19.8 +/- 3.5%, P < 0.007). Comparison of the insulin assays between the four centers showed close correlation and gave indistinguishable results in terms of within-subject coefficient of variation. Glucose profiles were similar in both protocols. Although the glucose values were lower with the bolus protocol from 4' to 40', the rate of fall from 10 to 30' (and thus the rate of glucose disposal) was indistinguishable between the two. CONCLUSIONS: These data suggest that neither protocol gives significant advantage over the other. However, to allow comparison of the acute insulin response to glucose between different protocols used in centers around the world, the ICARUS 3-min infusion protocol is recommended, with acute insulin response to glucose calculated over 10 min after the end of glucose administration; this reduces the within-subject coefficient of variation and provides similar acute insulin response to glucose with both protocols.

Prospective evaluation of beta-cell function in insulin autoantibody-positive relatives of insulin-dependent diabetic patients.

During the preclinical period of insulin-dependent diabetes mellitus (IDDM), progression to clinical IDDM is characterized by declining beta-cell function. Although the presence of insulin autoantibodies (IAA) improves the ability of islet cell antibodies (ICA) to predict subsequent clinical IDDM, few studies have examined the risk of developing IDDM in subjects positive for IAA but negative for both ICA and antibodies to glutamic acid decarboxylase (64kA). To investigate this question, detailed beta-cell function tests (acute insulin response to glucose [AIRgluc] and slope of glucose potentiation) were performed on eight IAA-positive first-degree relatives of insulin-dependent diabetics. All eight subjects were negative for ICA, and seven were tested for 64kA and were negative. Five subjects were studied prospectively for 22.4 +/- 9.4 months, while three subjects had only initial studies. Initial beta-cell function tests were normal in each subject. AIRgluc was 122.2% +/- 19.0% of the expected normal response, while slope was 168.6% +/- 20.6% of expected normal response. beta-cell function remained normal and remarkably stable in the five subjects followed prospectively. AIRgluc did not significantly change from an initial value of 147.9% +/- 23.1% of expected to 153.2% +/- 22.4% (NS). The slope of glucose potentiation varied little from 165.5% +/- 39.4% initially to 159.5% +/- 27.3% (NS) at the most recent determination. We conclude that among nondiabetic first-degree relatives of IDDM subjects, the presence of IAA in the absence of ICA and 64kA is not usually associated with and therefore does not reliably predict beta-cell dysfunction or progressive deterioration in beta-cell function.

Standardization of IVGTT to predict IDDM.

OBJECTIVE: To review current practice in centers that use the IVGTT for prediction of IDDM. To establish consensus protocol for performance of the test. RESEARCH DESIGN AND METHODS: Postal questionnaires were delivered to 12 centers. RESULTS: Eleven centers used a glucose dose of 0.5 g/kg and 1 used 0.3 g/kg; the dosage in adults was limited to a maximum of 25-50 g in some centers but others applied no upper limit. The glucose concentration of the infusate varied between 20 and 66%. Eight centers injected glucose manually, two used a syringe pump, and two used gravity infusion. The period of infusion ranged from 30 +/- 10 s to 4 +/- 2 min, and time zero was taken as the start (1 center), middle (1 center), or end (10 centers) of the infusion. The potential range in timing of the +1-min sample varied between 1 and 7 min from the start of the infusion. Quality-assurance standards for the insulin assays used were not always appropriate for the fasting and low stimulated range of insulin levels. CONCLUSIONS: The first-phase insulin response to the IVGTT is widely measured as an index of risk of progression to IDDM. We established that methodology varies widely. Because of this, a new standard protocol for use in prediction of IDDM was agreed by an ICARUS working group and is described herein.

Increased specificity and sensitivity of insulin antibody measurements in autoimmune thyroid disease and type I diabetes.

Insulin autoantibodies (IAA), a marker for insulin-dependent diabetes mellitus (IDDM), have been reported in other diseases such as thyroid disease and after treatment with sulfhydryl containing medications. Reported prevalences of IAA in non-diabetics vary widely, probably due in part to methodological differences between laboratories. In addition, certain sera may have a high non-specific binding to insulin. We compared a radioimmunoassay (RIA) for IAA which included non-specific binding with an RIA that incorporated a competitive displacement with cold insulin to remove non-specific binding. Using the RIA which measured specific plus non-specific binding, IAA positivity was found in 22/92 (23.9%) of sera from thyroid disease patients, 16/124 (12.9%) of random masked sera from a hospital laboratory, 27/335 (8.1%) of first degree relatives of IDDM patients, 63/178 (35.4%) of subjects with newly diagnosed IDDM, and 0/92 (0%) of normal controls. Insulin antibodies (IA) were found in 80/99 (80.8%) of insulin-treated diabetic subjects. In contrast, using the displacement assay which allowed measurement of specific binding, the frequency of IAA positivity was lower for subjects with thyroid disease (7/92 (7.6%)), random hospital sera (12/124 (9.8%)), and for first degree relatives of IDDM patients (8/335 (2.4%)), while higher for subjects with newly diagnosed IDDM (71/178 (39.9%)). Subjects with insulin-treated diabetes (78/99 (78.8%)) and normal subjects (1/92 (1.1%)) showed little change. Strikingly, three of the eight (37.5%) relatives of IDDM patients that were positive in the RIA measuring specific binding were detected only because cold displacement was utilized. We conclude: (1) subjects with thyroid disease and first degree relatives of IDDM patients frequently have high non-specific binding for IAA in an RIA not employing a cold displacement step, (2) in some newly diagnosed IDDM patients and first degree relatives of IDDM patients, IAA may be missed by an assay not optimized to measure specific binding, and (3) displacement with cold insulin increases both the specificity and sensitivity of RIAs measuring insulin autoantibodies.

Effect of insulin resistance and hyperglycemia on proinsulin release in a primate model of diabetes mellitus.

An elevated plasma proinsulin (PI) to immunoreactive insulin (IRI) ratio occurs in relatives of patients with insulin-dependent diabetes mellitus and in subjects with non-insulin-dependent diabetes mellitus. To determine whether this alteration is the result of B-cell dysfunction and/or insulin resistance, we infused nicotinic acid for 3 weeks to produce insulin resistance in five adolescent male baboons before and after the administration of streptozocin (200 mg/kg). We measured basal PI and IRI levels and the acute incremental PI (APIR) and IRI (AIRIR) responses to iv arginine. The quantity of IRI comprised of PI was calculated in the basal state (PI/IRI) and following arginine injection (APIR/AIRIR). Streptozocin administration did not change the fasting plasma glucose (FPG) compared to that in the normal animals (4.7 +/- 0.3 vs. 4.3 +/- 0.2 mM) but raised the PI/IRI (16.4 +/- 3.4 vs. 5.9 +/- 1.7%) and APIR/AIRIR (7.1 +/- 1.0 vs. 2.8 +/- 1.0%) due to a concurrent reduction in IRI and increase in PI concentrations. The induction of experimental insulin resistance with nicotinic acid in the normal animals had no effect on the FPG (4.4 +/- 0.2 mM) but in the streptozocin treated animals, fasting hyperglycemia (8.3 +/- 1.7 mM) developed. Neither the basal PI/IRI (10.2 +/- 2.2%) or the APIR/AIRIR (2.3 +/- 0.6%) increased in the insulin-resistant streptozocin animals thus being no different to that of normal control animals before or during experimental insulin resistance. We conclude that disproportionate proinsulinemia is a manifestation of B-cell damage from streptozocin which is not exacerbated by insulin resistance or hyperglycemia.

Risk for developing type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies.

First-degree relatives of Type 1 (insulin-dependent) diabetic patients are at increased risk for developing clinical diabetes. The presence of islet cell or insulin autoantibodies further identifies relatives at greater risk, but not all immunologic-marker-positive relatives progress to disease. Beta-cell dysfunction, however, seems to be more prevalent than clinical Type 1 diabetes, since stable subclinical pancreatic Beta-cell dysfunction may occur. Antibodies against a Mr 64,000 (64K) islet Beta-cell protein, identified as glutamic acid decarboxylase, have been reported both at and several years prior to the clinical onset of Type 1 diabetes. We measured 64K antibodies in first-degree relatives with varying degrees of Beta-cell dysfunction and risk for subsequent Type 1 diabetes to determine whether 64K antibodies improve the predictive power of islet cell antibodies and/or insulin autoantibodies. In the Seattle Family Study first-degree relatives of Type 1 diabetic patients are followed prospectively using detailed Beta-cell function tests, insulin sensitivity, quantitative evaluation of islet cell antibodies and fluid phase assay insulin autoantibodies. 64K antibodies were measured using dog islets. Relatives were selected, based on Beta-cell function to represent individuals at high (n = 6) and low (n = 30) risk for subsequent Type 1 diabetes. The 30 low-risk individuals followed-up for 78 months, had stable Beta-cell function, and six (20%) were negative for all autoantibodies, ten (33%) were positive for insulin autoantibodies, 16 (53%) were islet cell antibody positive while six (20%) were positive for 64K antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)