Metabolic tests to determine risk for type 1 diabetes in clinical trials.

AIMS: Evaluate the reproducibility and relationship of various metabolic tests conducted as part of the Diabetes Prevention Trial-type 1 diabetes. METHODS: Coefficients of variation, intraclass correlation coefficients, and Pearson correlations between the same metabolic tests performed at different times as well as the different tests were determined. RESULTS: Fasting samples on the same day had a coefficient of variation of < 10 for C-peptide, 11 for insulin, and 2 for glucose. Testing on separate days approximately doubled the variance. Stimulated insulin values had less variance than fasting values and there was only a moderate correlation between fasting and stimulated values on each test. While highly correlated, C-peptide values from mixed meal tolerance tests are significantly lower than that obtained during oral glucose tolerance tests (OGTTs). Neither peak nor area under the curve C-peptide on the oral glucose tolerance test was different between those with abnormal and normal glucose tolerance. Those with abnormal as compared with normal glucose tolerance had lower 30-min C-peptide and a longer time to peak C-peptide. CONCLUSIONS: A large, multi-centre trial, with tests performed over a decade-long period, can provide robust data. C-peptide data from oral glucose tolerance tests and mixed meal tolerance tests differ; therefore, the same stimulation test should be used to evaluate changes in beta cell function over time. Worsening glucose tolerance is associated with lower C-peptide at 30 min and a delay in peak secretion on the oral glucose tolerance test. This Diabetes Prevention Trial-type 1 diabetes data can be used in planning parameters for future studies, including evaluation of new algorithms to determine risk of disease.

Factors affecting improved glycaemic control in youth using insulin pumps.

AIMS: The purpose of this study was to evaluate factors associated with insulin pump therapy resulting in lower HbA(1c) levels in young people with Type 1 diabetes mellitus. METHODS: Insulin pumps were downloaded from 150 youth (81 male), ages 5-20 years. Consecutive insulin pump downloads, 3 months apart, were available for 85 (43 male) of the 150 youth and changes in pump use were correlated with changes (≥0.5%, ≥ 6 mmol/mol) in HbA(1c) levels. RESULTS: Using cross-sectional data, lower HbA(1c) values correlated with use of more frequent daily insulin boluses (r=-0.46, P<0.0001) and more frequent blood glucose checks/day (r=-0.35, P<0.0001). Young people with HbA(1c) levels <7.5% (58 mmol/mol) vs. values of 7.5-9.0% (58-75 mmol/mol) or ≥ 9.0% (75 mmol/mol) tested blood glucose more frequently/day (P<0.0001), bolused more frequently/day (P<0.0001), reported more grams of carbohydrates eaten/day (P<0.05) and had a higher per cent bolus insulin/day (P<0.05) compared with the ≥9.0% of youth. Using longitudinal data, 48 of 85 patients had a change in HbA(1c) level of ≥0.5% (6 mmol/mol) between downloads (24 improved). Increased bolus insulin (OR=1.15, P=0.03) and time of temporary basal rate use (OR=1.017, P=0.01) predicted ≥0.5% (6 mmol/mol) decrease in HbA(1c) in logistic regression. CONCLUSIONS: This study emphasizes the importance of blood glucose testing, of bolus insulin administration and of an increase in the time of temporary basal rate use in relation to improving glycaemic control.

Post-prandial glucose excursions following four methods of bolus insulin administration in subjects with type 1 diabetes.

AIMS: To determine if one method of short-acting insulin bolus administration is superior to other methods in managing a meal high in carbohydrates, calories and fat. METHODS: Nine subjects receiving continuous subcutaneous insulin infusion using insulin lispro (Humalog) agreed to consume the same meal high in carbohydrates, calories and fat on four occasions 1 week apart. They received the same dose of bolus insulin on each of the four occasions randomly assigned and beginning 10 min prior to the meal as either a single bolus, two separate boluses of one-half the same total dose (the second after 90 min), the entire bolus given as a square-wave (over 2 h) or a dual-wave (70% as a bolus and 30% as a square-wave over 2 h). Blood glucose levels were measured at -60 and -30 min and at zero time, and then every half-hour for 6 h using the Hemacue in the out-patient clinic. RESULTS: Changes in blood glucose values from fasting were the lowest after 90 and 120 min (P < 0.01) when the dual wave was administered. When the dual or square-wave methods of insulin administration were used, subjects had significantly lower glucose levels after 4 h in comparison with when the single or double boluses were used (P = 0.04). CONCLUSIONS: We conclude that the dual wave provided the most effective method of insulin administration for this meal. The dual- and square-wave therapies resulted in lower glucose levels 4 h after the meal in comparison with the single and double-bolus treatments.

The impact of the diabetes control and complications trial and humalog insulin on glycohemoglobin levels and severe hypoglycemia in type 1 diabetes.

OBJECTIVE: This study was performed to determine the effects of the Diabetes Control and Complications Trial (DCCT) report in 1993 and the introduction of Lispro (Humalog) insulin in 1996 on glycemic control and on the number of severe hypoglycemic episodes in type 1 diabetic patients of various ages. RESEARCH DESIGN AND METHODS: Diabetes care parameters and HbA1c data from 884 subjects with type 1 diabetes were entered into our database at the time of clinic visits from 1993 through 1998. In addition, a questionnaire was sent to all patients to validate the number of insulin injections per day, the incidence of severe hypoglycemic episodes (as defined by the DCCT), and the use of Humalog insulin. Data were divided into four age-groups: < 5, 5-12, 13-18, and > 18 years of age. RESULTS: Longitudinal HbA1c levels declined significantly after the DCCT report in 1993-1996 (P < 0.001), but the number of severe hypoglycemic events increased (P < 0.001). A second decline in HbA1c levels was observed after the introduction of Humalog insulin in 1996 (P < 0.001). However, severe hypoglycemic episodes did not change (P = 0.26). CONCLUSIONS: Administration of Humalog resulted in an additional reduction in HbA1c levels beyond the reduction in HbA1c values after the DCCT report. In contrast to the increase in severe hypoglycemic events after the DCCT results, the number of severe hypoglycemic episodes did not increase after the introduction of Humalog, despite a further decrease in HbA1c values.

First-phase insulin release during the intravenous glucose tolerance test as a risk factor for type 1 diabetes.

OBJECTIVE: To determine the relationship between first-phase (1 minute + 3 minutes) insulin production during the intravenous glucose tolerance test (IV-GTT) and risk factors for developing type 1 diabetes. STUDY DESIGN: Relatives of persons with type 1 diabetes (n = 59,600) were screened for islet cell antibodies (ICAs). Subjects who had positive screening results underwent IV-GTT (> or =2 times), repeat ICA screening, insulin autoantibody (IAA) screening twice, and an oral glucose tolerance test. RESULTS: Of the 59,600 subjects in the study, 2199 (3.69%) had positive findings on initial ICA test. IV-GTTs were performed in 1622 subjects, with children <8 years having the lowest first-phase insulin release (FPIR) and subjects 8 to 20 years of age having the highest FPIR. The FPIR was lower for subjects with a confirmed positive ICA test result or a positive IAA test result, subjects with higher titers of ICA or IAA, and subjects who had an abnormal (impaired or diabetic) oral glucose tolerance test result. CONCLUSION: FPIR in the IV-GTT correlates strongly with risk factors for development of type 1 diabetes.

Continuous subcutaneous glucose monitoring in children with type 1 diabetes.

PURPOSE: To determine whether the use of continuous subcutaneous glucose monitoring will help in detecting unrecognized nocturnal hypoglycemia and in lowering hemoglobin A1c (HbA1c) levels (without increasing the risk for severe hypoglycemia) in children with type 1 diabetes. METHODS: Eleven children with type 1 diabetes and HbA1c values consistently >8.0% were randomized either to the Continuous Glucose Monitoring System (CGMS) group or to the control group. The CGMS group used 6 3-day sensors within a 30-day period. Both groups self-monitored their blood glucose levels a minimum of 4 times daily. HbA1c levels were measured at the start, at 1-month, and after 3 months of study. RESULTS: The 5 children using the CGMS had 17 asymptomatic episodes (85%) of glucose levels below 60 mg/dL (3.25 mmol/L) and 3 symptomatic episodes (15%) during the night in the study month. The 6 control children had 4 symptomatic nocturnal low episodes during the month. After the 30-day period of wearing the CGMS, the 5 children had a significantly lower mean HbA1c value compared with their initial value (mean +/- standard error of the mean [SEM] decrease =.36% +/-.07%). The mean decrease for the controls was.2% +/-.2%. After 3 months, 4 of the 5 children who used the CGMS continued to have lower HbA1c values in comparison to their initial values (mean +/- SEM decrease = 1.04% +/-.43%). Three of the 6 control participants also had lower HbA1c values at 3 months (mean +/- SEM decrease for the group =.62% +/-.44%). No severe hypoglycemic events occurred in either the CGMS or the control groups. CONCLUSION: In this pilot trial, continuous subcutaneous glucose monitoring was helpful in detecting asymptomatic nocturnal hypoglycemia as well as in lowering HbA1c values without increasing the risk for severe hypoglycemia in children with type 1 diabetes.

Continuous subcutaneous insulin infusion therapy for children and adolescents: an option for routine diabetes care.

OBJECTIVE: The purpose of this study was to determine the feasibility of continuous subcutaneous insulin infusion (CSII) (insulin pump) therapy in routine pediatric diabetes care by comparing the HbA(1c), body mass index (BMI), and hypoglycemic episodes before and after initiation of CSII therapy. RESEARCH DESIGN AND METHODS: Data from 56 patients (7-23 years old) were collected during regularly scheduled visits at a frequency similar to non-CSII patients. RESULTS: The data were analyzed for the entire cohort and 3 subgroups (decreased, stable, or increased HbA(1c)) stratified according to a >/=0.5% change in HbA(1c). The total cohort demonstrated a decrease in HbA(1c) from 8.5% to 8.3%. The decreased cohort (39.4% of the total cohort) demonstrated a significant decrease in HbA(1c) from 8.6% to 7.6%. The mean HbA(1c) of the stable cohort (41.0%) was 8.7%. The increased cohort (19.6%) had an increase in HbA(1c) from 7.8% to 8.8%. Thirty-six patients (64.3%) maintained or achieved a HbA(1c) <8.0% or achieved a HbA(1c) at least 1% lower than their pre-CSII level. Of concern, 6 patients (10.7%) demonstrated a clinically significant increase in HbA(1c) from 8.3% to 9.6%. For the entire cohort, the rate of severe hypoglycemia before and on CSII therapy was 12.3 and 9.5 events per 100 patient-years, respectively. A statistically significant proportion of patients reported a decrease in seizure frequency versus an increase (17.9% vs 1.8%) as well as a decrease in overall hypoglycemic frequency versus an increase (41.1% vs 17.9%). There was not a clinically significant increase in BMI, even in the decreased HbA(1c) cohort. CONCLUSIONS: CSII therapy is an appropriate option for some children in routine pediatric diabetes care. It can effectively decrease the HbA(1c) and reduce hypoglycemic episodes, without producing an abnormal increase in BMI.

Diabetic ketoacidosis with intracerebral complications.

PURPOSE: To describe 11 instances of severe diabetic ketoacidosis (DKA) with secondary intracerebral complications (ICCs), nine of whom were treated early and showed complete recovery. METHODS: Three hundred and eighty-one episodes of DKA were treated at Denver Children's Hospital (DCH) from January 1989 to December 1999. Nine instances of DKA with ICC were prospectively identified during this time period. Two additional occurrences were identified via a medical records search (total incidence, 2.9%). The signs, symptoms and laboratory values which led to their diagnosis and treatment are identified. RESULTS: All nine children who received early treatment with i.v. mannitol showed complete recovery. An additional patient had central nervous system involvement upon arrival at our hospital and showed almost complete recovery. Another patient suffered a cardiorespiratory arrest before transfer to our hospital and died without being treated for cerebral edema. CONCLUSION: Prevention of ICCs by the earlier diagnosis of diabetes and by being aware of possible risk factors for cerebral edema is the eventual goal. Based on our experience, mannitol should be given promptly for the treatment of ICCs indicated by the clinical course even if cerebral edema is not documented by a computed tomography (CT) scan.

Life with continuous subcutaneous insulin infusion (CSII) therapy: child and parental perspectives and predictors of metabolic control.

OBJECTIVE: The purpose of this study was twofold (i): to evaluate metabolic control in patients receiving CSII therapy in a routine pediatric diabetes clinic by describing reasons for initiating therapy and daily management issues, including needle fear; and (ii) to assess the change in parental involvement and anxiety once their child initiated CSII therapy. RESEARCH DESIGN AND METHODS: The study included 52 subjects (aged 7.6-23.6 yr) from a general pediatric diabetes clinic. Management issues were defined as diet, exercise, home blood glucose monitoring (HBGM) frequency, and self/staff assessment of needle fear. Characteristics were analyzed both according to a 0.5% change in HbA1c status (decreased vs. stable vs. increased) compared with pre-CSII therapy, and final HbA1c achieved (< or = 8.1 vs. > 8.1%). RESULTS: The primary recommendation source for CSII use was most often the physician/diabetes team (48.1%), followed by a combination of the former with a personal referral source (32.7%). The most common reason (71.2%) for CSII initiation was a combination of wanting to achieve better metabolic control, dislike of insulin injections, and/or increased flexibility in daily living. Over one-quarter (26.9%) of subjects were identified as being needle-fearful, and this characteristic was predictive of final metabolic control (3/25 subjects 8.1%, p = 0.03). On CSII therapy, dietary carbohydrate consistency was highly variable, and most subjects (65.3%) exclusively used an insulin to carbohydrate ratio for insulin bolus dosage calculation. The most common adjustment strategy (63.5%) for exercise was a combination of decreasing the insulin basal rate, disconnecting the pump, and/or eating extra carbohydrates. For the total cohort, the frequency of HBGM significantly increased on CSII therapy (4.31-4.85 tests/day, p = 0.02). Females did not have a significant change in HBGM frequency, while the youngest subjects had the highest HBGM frequency. Parental involvement and anxiety primarily stayed the same or decreased, regardless of the child's age (< or = 18 vs. > 18 yr) or metabolic control. CONCLUSIONS: Analyses of the various characteristics identified only needle fearfulness as being predictive of poor metabolic control. Interestingly, poor control with CSII therapy did not result in a significant increase in parental involvement and/or anxiety.

Impact of insulin lispro on HbA1c values in insulin pump users.

AIM: To compare the therapeutic efficacy of the short-acting insulin analogue insulin lispro (Humalog) with that of buffered regular human insulin (Velosulin) in patients on insulin pump therapy. PATIENTS AND METHODS: Sixty-two (45 women and 17 men) young patients with type 1 diabetes using insulin pump therapy were compared while using buffered regular human insulin for a mean +/- s.e.m. of 20.1+/-1.2 months or insulin lispro for a mean +/- s.e.m. of 19.7+/-0.5 months. The initial mean +/- s.e.m. age and duration of diabetes were 29.1+/-0.9 and 17.7+/-0.9 years, respectively. The mean HbA1c values, basal insulin dosages, premeal insulin dosages and number of low blood sugars were recorded during treatment with both insulins. RESULTS: Mean +/- s.e.m. HbA1c values were significantly lower (p < 0.001; paired Wilcoxon t-test) during insulin lispro treatment (7.4+/-0.1%) as compared to treatment with buffered regular human insulin (7.9+/-0.1%). Total units of insulin (mean +/- s.e.m.)/kg/day was significantly (p = 0.03) lower (0.61+/-0.02) during the insulin lispro treatment period as compared to the buffered regular human insulin treated period (0.65+/-0.03). Total mean +/- s.e.m. (U/kg/day) of basal insulin administered per day was higher when patients received insulin lispro treatment (0.44+/-0.02 vs. 0.42+/-0.01 for buffered regular human insulin treated period; p = 0.002). The premeal insulin boluses (mean +/- s.e.m.) for the two treatment groups were significantly different with less insulin required for the insulin lispro treatment period for all three meals (p < 0.001, t-test). The number of mild/moderate and severe hypoglycaemic episodes were similar in the two groups. CONCLUSION: We conclude that use of insulin lispro in pump therapy significantly lowers HbA1c values in comparison to therapy with buffered regular human insulin insulin without increasing hypoglycaemic episodes.

Effect of Bacillus Calmette-Guerin vaccination on new-onset type 1 diabetes. A randomized clinical study.

OBJECTIVE: We undertook this study to test whether Bacillus Calmette-Guerin (BCG) vaccine preserves beta-cell function and increases the remission rate in children with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: This was a randomized double-blind placebo-controlled trial offered to children referred to the Barbara Davis Center for Childhood Diabetes or the Baystate Medical Center with a diagnosis of new-onset type 1 diabetes. There were 94 children aged 5-18 years who received either BCG or saline intradermally within 4 months of onset of symptoms and who were then evaluated at 3-month intervals for 2 years. The primary end point was remission, defined as insulin independence for 4 weeks. Secondary end points were C-peptide levels (fasting and in response to a mixed meal challenge), insulin dose, and HbA1c. RESULTS: Of the patients, 47 were randomized to each arm; 7 in the placebo group and 9 in the BCG group did not complete 1 year of the study and are not included in the analysis. One patient from each group achieved remission. Fasting and stimulated C-peptide levels did not differ by treatment arm but declined in both groups and were lower initially and during the entire 2-year period in younger children. Insulin requirements and HbA1c levels did not differ in the two groups. CONCLUSIONS: Vaccination with BCG at the time of onset of type 1 diabetes does not increase the remission rate or preserve beta-cell function.

Correlation of fingerstick blood glucose measurements with GlucoWatch biographer glucose results in young subjects with type 1 diabetes.

OBJECTIVE: The purpose of this study was to compare measurements of glucose obtained via iontophoretic extraction with the GlucoWatch automatic glucose biographer (Cygnus, Inc., Redwood City, CA) with capillary blood glucose values that were determined 1) in a controlled outpatient clinic setting and 2) in a home setting. RESEARCH DESIGN AND METHODS: There were 76 GlucoWatch biographers used on 28 different young adults (21 women and 7 men) with type 1 diabetes (age 30.9 +/- 6.9 years and duration of diabetes 18.4 +/- 8.1 years [mean +/- SD]) in a controlled outpatient clinic setting. Some subjects participated on multiple days. Subjects wore two GlucoWatch biographers, each on the forearm (ventral aspect). Comparisons were made to HemoCue blood glucose analyzer (Aktiebolgat Leo, Helsingborg, Sweden) capillary blood glucose measurements. In addition, GlucoWatch biographers (one each day for 3 consecutive days) were used by 12 subjects (8 women, 4 men) in a home setting. Comparisons were made to capillary blood glucose values determined using the One Touch Profile meter (Johnson & Johnson, New Brunswick, NJ). RESULTS: GlucoWatch biographer glucose values correlated well with capillary blood glucose values determined using the HemoCue analyzer in the clinic setting (r = 0.90, 1,554 paired data points) and using the One Touch Profile meter in the home setting (r = 0.85, 204 paired data points). When 36 subjects wore two biographers simultaneously, the correlation between the two biographers was r = 0.94. The error grid analysis demonstrated that > 96% of biographer glucose values determined in the clinic or home setting were in the clinically acceptable A and B regions. CONCLUSIONS: This study confirms the accuracy and precision of glucose values as determined using the GlucoWatch biographer in clinic and home settings.

Long-term efficacy of humalog in subjects with Type 1 diabetes mellitus.

AIMS: To evaluate the long-term effectiveness of Humalog insulin in lowering post meal glucose excursions. METHODS: Twenty young subjects with Type 1 diabetes mellitus (DM) who had received insulin-lispro (Humalog) for a least 1 year (mean +/- SD 1.8+/-1.6 years) were studied on two occasions, 3-14 days apart. They consumed a similar breakfast consisting of 450-600 kCal having fasted overnight. The same amount of human soluble Humulin Regular or Humalog insulin was given 10 min before the meal in a randomized, double-blind fashion. RESULTS: Postprandial glucose excursions at 30, 60, and 120 min were significantly lower (P<0.001, ANCOVA) when subjects received Humalog as compared to human soluble insulin. Serum-free insulin levels were significantly higher (P<0.001, ANOVA) at 30 and 60 min when subjects received Humalog as compared with human soluble insulin. Humalog antibody levels after up to 5.4 years of receiving Humalog insulin were not elevated beyond the values at 1 year. CONCLUSIONS: We conclude that Humalog insulin is effective in lowering postprandial glucose excursions even after up to 5.4 years of treatment.

Use of insulin lispro in the outpatient management of ketonuria.

OBJECTIVE: To compare the effectiveness of the use of insulin lispro with the use of regular insulin in managing children with diabetes in outpatient settings. DESIGN: In this prospective study, telephone records of 75 children treated for ketonuria were analyzed. Outcome was based on the number of successful home treatment episodes (hospitalization not required), the amount of insulin the patients needed, and the time to resolution of ketonuria. RESULTS: Doses of supplemental insulin used to treat patients with both moderate and large urine ketone values were similar (P>.05) in the insulin lispro and regular insulin groups. Likewise, the time to resolution of moderate or large ketonuria was not statistically different (P>.05) between the 2 groups. No hospitalizations were required for any of the patients for whom management via telephone was attempted. CONCLUSION: These data indicate that insulin lispro is an effective option for the outpatient management of ketonuria.

Dual-parameter model for prediction of type I diabetes mellitus.

The recent cloning and recombinant expression of novel islet autoantigens [glutamic acid decarboxylase (GAD) 65 and islet-cell autoantibody 512 (ICA512)] has made possible the determination of whether the quantitative expression of autoantibodies to these molecules is correlated with age of diabetes onset and rate of progression to diabetes, similar to insulin autoantibodies (IAAs). We measured autoantibodies reacting with GAD65 (GAD65AA), ICA512 (ICA512AA), and insulin in patients who recently had received a diagnosis of diabetes and in first-degree relatives prospectively identified and then followed because of the expression of high titers of ICA. Levels of IAAs (but not GAD65AA or ICA512AA) correlated inversely with age at diagnosis of diabetes and directly with time to diabetes onset among the ICA-positive relatives. In multiple linear regression models, the level of IAAs remained a significant predictor of the time to diabetes after allowing for first-phase insulin secretion. The unique and dramatic association of IAAs with progression to diabetes suggests that IAAs contribute directly to disease pathogenesis or that levels of IAAs are influenced uniquely by the process, leading--at different rates in different prediabetic individuals--to type I diabetes. In addition, the linear regression model described (involving two variables, first-phase insulin secretion and levels of IAAs) aids in the prediction of time to diabetes among ICA-positive relatives.

Slicing the pie. Correlating HbA--values with average blood glucose values in a pie chart form.

OBJECTIVE: The purpose of this study was to define the correlation between HbA1c values and the percentage of home blood glucose (HBG) measurements within given ranges in a pie chart in three age-groups of subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: HbA1c values were compared with HBG measurements in subjects who did at least three blood glucose tests per day over 30 days in three age groups: 5-11, 12-16, and 17-35 years. The blood glucose values were arbitrarily divided into three groups, defined as the percentage of HBG measurements within, above, and below target range. Each range was then compared with the corresponding HbA1c value. Longitudinal data were also collected for 279 of the subjects after a mean of 139 days. RESULTS: A strong correlation (P = 0.001) was found between HbA1c values and the average blood glucose, and also with the percentage of HBG measurements within, above, and below target range in each of the three age-groups (P < 0.001). Analyses of longitudinal data showed a strong correlation of the changes in HbA1c values to the changes in blood glucose values. CONCLUSIONS: These data showed that a pie-shaped graph of the HBG data can be useful as a clinical parameter in helping patients and families attain desired HbA1c values.

Effectiveness of postprandial Humalog in toddlers with diabetes.

OBJECTIVE: The purpose of this study was to determine whether postprandial administration of the new rapid-acting insulin analog Humalog could effectively reduce glucose excursions in children <5 years old. DESIGN: Human Regular insulin given before a meal was compared with the same dose of Humalog after a meal of equal carbohydrate content in five toddlers with insulin-dependent (type 1) diabetes mellitus. In addition, the use of Humalog before a meal was compared with Humalog given after a meal of equal carbohydrate content in five other toddlers. The dose of long-acting insulin was not changed during the study period. Blood glucose levels were determined at fasting and at 1, 2, and 4 hours postprandially. RESULTS: The 2-hour glucose excursions were significantly lower when postprandial Humalog administration was compared with preprandial Human Regular insulin administration. In contrast, glucose excursions were similar when Humalog was taken before or after the meal. CONCLUSION: These data show that it is efficacious to give Humalog insulin postprandially in toddlers with type 1 diabetes, allowing increased safety for the young child. The insulin dose can be both matched to the actual food intake and timed to give families increased flexibility and control at mealtime.

24-hour ambulatory blood pressure and renal disease in young subjects with type I diabetes.

Twenty-four hour ambulatory blood pressure (ABP) was evaluated in 150 teenage and young adults with insulin-dependent diabetes mellitus (IDDM) to define high-risk subjects who are likely to develop early diabetic nephropathy. Their age range was 16-28 years with diabetes of 3.5-25.8 years duration. All subjects had office blood pressure (BP) measured, wore an ABP monitor for 24 h, and collected two or more timed urine samples for albumin excretion rates (AERs). Eighty-six subjects had no elevation of AER (< 7.6 micrograms/min), 29 subjects had borderline elevations (7.6-20 micrograms/min), 24 subjects had microalbuminuria (20.1-200 micrograms/min), and 11 had macroalbuminuria (> 200 micrograms/min). Age, gender, duration of diabetes, and single office BP readings were similar in the four groups (p > 0.05, logistic regression). All 24-h ABP parameters were significantly higher in subjects with diabetes having AER values greater than 7.6 micrograms/min when compared with healthy age- and gender-matched nondiabetic controls (p < 0.05, Dunnett's t test). The percent of nighttime systolic and diastolic ABP readings above the 90th percentile of normal for age, gender, and race and the percent of readings in the hypertensive range (> 140/90) were significantly related with AERs (p < 0.01; logistic regression). A higher percentage of ABP values above the 90th percentile for age, gender, and ethnic group or of ABP readings above hypertensive levels (> or = 140/90) are associated with diabetic renal disease.

Altered immune response to insulin in newly diagnosed compared to insulin-treated diabetic patients and healthy control subjects.

Insulin-dependent diabetes mellitus (IDDM) is the result of a T-cell mediated autoimmune beta-cell destruction, which is accompanied by autoantibodies. We analysed the cellular and humoral immune response to insulin and insulin peptides in patients with recent-onset IDDM, IDDM patients treated with insulin, non-diabetic first degree relatives and unrelated control subjects. There were no differences in T-cell reactivity to whole insulin or insulin peptides in general between age-matched groups of IDDM patients, relatives or healthy control subjects. In contrast to investigations in NOD mice, no immunodominant or disease-specific insulin peptide could be identified. Surprisingly, a positive correlation of T-cell responses to insulin with age was noticed (p < 0.005). This resulted in an inverse relation of insulin autoantibodies (IAA) and insulin reactive T-cells (p < 0.001) together with the well-described negative correlation of IAA with age. Interestingly, insulin-treated patients differed from age-matched recent-onset IDDM patients: first, simultaneous immune recognition of insulin with T-cells and IAA was only seen in patients treated for 6 months with insulin; second, insulin-treated patients rarely responded to whole insulin; third, they displayed less determinant spreading, and finally, recognition of multiple insulin peptides was not accompanied by crossreactivity to whole insulin. These distinct observations in insulin-treated IDDM patients, together with the inverse correlation between humoral and cellular responses to insulin, may result from activation or modulation of different T-cell subsets, and may be of relevance to insulin therapy trials, in which selective activation of non-destructive T-cell subsets may be a key to successful intervention.

24-h ambulatory blood pressure monitoring in healthy young adult Anglo, Hispanic, and African-American subjects.

The purpose of this study was to compare office and 24-h ambulatory blood pressure (ABP) values for adolescent and young adult males and females of Anglo, Hispanic, and African-American descent. One hundred and eighteen healthy subjects (62 females, 56 males) participated, with an ethnic distribution of 50 Anglo, 32 Hispanic, and 36 African-American subjects. All subjects came to the clinic for height, weight, sitting blood pressure (BP), and to begin 24-h ABP monitoring using the SpaceLabs model 90207 automatic noninvasive monitor. The monitor recorded readings every 0.5 h from 06:00 to 22:00 and every hour at night from 22:00 to 06:00. Office systolic and diastolic BP values were higher for all males compared to all females. Mean 24-h, nighttime, and daytime systolic ABP values were also significantly higher for males compared to females. The 24-h mean and daytime systolic ABP values were significantly different by ethnic groups. The African-American subjects always had the highest readings. Mean 24-h diastolic ABP was also significantly different by ethnic groups, with the African-American subjects being higher than the Anglos or the Hispanics. Diastolic ABP (24-h mean, daytime, and nighttime) values (for all subjects combined) increased gradually and varied significantly with age. This study provides preliminary normative data about ABP in an understudied population (ie, teenagers and young adults of different ethnic backgrounds). It also shows that higher blood pressures are present among males and among subjects of African-American descent in the teenage and young adult population.