Sulfated beef insulin treatment elicits CD8+ T cells that may abrogate immunologic insulin resistance in type I diabetes.

The in vitro responses of T cells from 13 insulin-nonresistant and 1 immunologically insulin-resistant (IIR) type I diabetes patients to sulfated beef insulin (SBI) were analyzed. Insulin A-loop specific CD4+ T cells from these patients did not respond to SBI. After 1 yr of treatment with SBI the IIR patient's T cell and antibody responses to beef, pork, and human insulin progressed from very high to nondetectable levels. This occurred in parallel to the appearance of her insulin-specific CD8+ T cells, which inhibited the response of her A-loop-specific CD4+ T cells to insulin. A transient increase in her CD8+ anti-insulin antibody activity coincided with a relative lack of her CD8+ T cell activity. CD8+ T cells that regulate T cell responsiveness to insulin are probably present but difficult to detect in most type I diabetes patients. These T cells were identified in only 2 of 13 insulin-nonresistant patients who presented with lipoatrophy and insulin allergy, respectively, and who possessed high-titered, anti-insulin antibodies. Our data demonstrate that CD8+ T cells play an important role in controlling peripheral tolerance to insulin and may abrogate IIR in a diabetic patient treated with SBI.

Clinically unrecognized ventricular dysfunction in young diabetic patients.

Left ventricular function at rest and during supine bicycle exercise was assessed by gated radionuclide angiography in 20 diabetic patients and 18 normal control subjects without clinical evidence of heart disease. The diabetic patients were aged 21 to 44 years and all except one used insulin. No subject developed chest pain or electrocardiographic changes during exercise. Both groups had a similar rest and exercise heart rate and blood pressure, and both achieved similar work loads. The control group had an ejection fraction at rest of 65.4 +/- 6.2% (mean +/- SD) and only 1 of 18 showed a decrease with exercise; peak exercise ejection fraction averaged 77.1 +/- 7.8%. The diabetic group had a mean ejection fraction at rest of 63.7 +/- 6.5%, similar to that of the control group, but 7 of 20 showed a decrease during exercise; the exercise ejection fraction averaged 67.7 +/- 9.7%, significantly lower than that of the control group (p less than 0.01). The diabetic patients varied widely in ejection fraction response to exercise, ranging from an increase of 25% to a decrease of 21%. This response did not correlate with age, sex, duration of diabetes, smoking, retinopathy, exercise heart rate, blood pressure or rate-pressure product, work load attained or ejection fraction at rest. These data suggest that approximately one-third of patients with diabetes have subclinical left ventricular dysfunction without correlation to risk factors for atherosclerosis or other diabetic complications. Whether this is due to unrecognized coronary artery disease or primary myocardial disease remains unknown.

The Toronto Tri-Hospital Gestational Diabetes Project. A preliminary review.

In this study, we assessed maternal-fetal outcomes in untreated patients with increasing carbohydrate intolerance not meeting the current criteria for the diagnosis of gestational diabetes mellitus (GDM), examined the relationship between birth weight and mode of delivery among women with untreated borderline GDM, treated overt GDM, and normoglycemia, and established more efficient screening strategies for detection of GDM. This was a prospective analytic cohort study in which nondiabetic women aged > or = 24 years were eligible for enrollment. A 50-g glucose challenge test (GCT) and a 100-g oral glucose tolerance test (OGTT) were administered at 26 and 28 weeks gestational age, respectively. Risk factors for unfavorable maternal-fetal outcomes were recorded. Time since the last meal prior to the screening test was recorded, as well. Caregivers and patients were blinded to glucose values except when test results met the National Diabetes Data Group criteria for GDM. Maternal and fetal outcomes, including the mode of the delivery, were recorded in the postpartum period. Of 4,274 patients screened, 3,836 (90%) continued to the diagnostic oral glucose tolerance test. GDM was seen in 145 women. Increasing carbohydrate intolerance in women without overt gestational diabetes was associated with a significantly increased incidence of cesarean section, preeclampsia, macrosomia, and need for phototherapy, as well as an increased length of maternal and neonatal hospital stay. Multivariate analysis showed that increasing carbohydrate intolerance remained an independent predictor for various unfavorable outcomes, but the strength of the associations was diminished. Compared with normoglycemic control subjects, the untreated borderline GDM group had increased rates of macrosomia (28.7 vs. 13.7%, P < 0.001) and cesarean delivery (29.6 vs. 20.2%, P = 0.03). Usual care of known GDM patients normalized birth weights, but the cesarean delivery rate was about 33%, whether macrosomia was present or absent. An increased risk of cesarean delivery among treated patients compared with normoglycemic control subjects persisted after adjustment for multiple maternal risk factors. As for the screening tests, time since the last meal had a marked effect on mean plasma glucose. Receiver operating characteristic curve analysis allowed the selection of the most efficient cut points for the GCT based on the time since the last meal. These cut points were 8.2, 7.9, and 8.3 mmol/l (1 mmol/l = 18.015 mg/dl) for elapsed postprandial time of < 2, 2-3, and > 3 h, respectively. With this change from the current threshold of 7.8 mmol/l, the number of patients with a positive screening test dropped from 18.5 to 13.7%. There was an increase in positive predictive value from 14.4 to 18.7%. The overall rate of patient misclassification fell from 18.0 to 13.1%. In conclusion, increasing maternal carbohydrate intolerance in pregnant women without GDM is associated with a graded increase in adverse maternal and fetal outcomes. Infant macrosomia is an important factor in high cesarean delivery rates for women with untreated borderline GDM. Although detection and treatment of GDM normalizes birth weights, rates of cesarean delivery remain inexplicably high. Recognition of GDM may lead to a lower threshold for surgical delivery. The efficiency of screening for GDM can be enhanced by adjusting the current GCT threshold of 7.8 mmol/l to new values related to time since the last meal before screening. Further analyses are underway to elucidate whether maternal risk factors can be used to achieve additional efficiency gains in screening.

Glycemic responses to foods: possible differences between insulin-dependent and noninsulin-dependent diabetics.

The effect on the blood glucose response of varying the amount (25 or 50 g) and type (bread or beans) of carbohydrate (CH2O) in test meals and of adding fat and protein was examined in a group of insulin dependent and noninsulin dependent diabetic volunteers. With noninsulin-dependent diabetics, the blood glucose area after a half bread portion was 48% that of the full bread meal (p less than 0.001). White pea beans (50 g CH2O) gave a blood glucose response of 41 +/- 5% (p less than 0.001) that of bread (50 g CH2O). A combined meal of bread (25 g CH2O) and beans (25 g CH2O) gave a blood glucose response of 60 +/- 8% of the full bread meal (p less than 0.005) and similar to that expected. Addition to bread of butter and skim milk cheese either singly or in combination had little effect on the glycemic response although a reduced rise was seen after addition of fat and protein as peanut butter. Insulin-dependent diabetics tended to respond similarly to noninsulin-dependent diabetics but their greater variability indicates that other factors in addition to the nature of the food may also be major determinants of their glycemic responses to foods.

Maternal and neonatal outcomes in pregestational and gestational diabetes mellitus, and the influence of maternal obesity and weight gain: the DEPOSIT study. Diabetes Endocrine Pregnancy Outcome Study in Toronto.

We prospectively studied pregnancy outcome in 428 women with gestational diabetes mellitus (DM) and 196 women with pregestational DM, with particular reference to the influence of maternal obesity and excessive weight gain. These were consecutive singleton pregnancies delivered in our institution over 5 years. After controlling for multiple risk factors, including maternal BMI and pregnancy weight gain, women with pregestational DM were at increased risk (compared to those with gestational DM) for Caesarean delivery (OR 3.6, 95%CI 2.3-5.6), shoulder dystocia or cephalopelvic disproportion (OR 2.2, 95%CI 1.3-3.6), and gestational hypertension or toxaemia (OR 3.0, 95%CI 1.7-5.4). The offspring of these women were also at increased risk for admission to the neonatal intensive care unit (OR 4.0, 95%CI 2.3-6.8), large-for-gestational-age birthweight (OR 3.5, 95%CI 2.2-5.6), and preterm birth before 37 weeks (OR 3.8, 95%CI 2.5-5.9). Maternal obesity, and, to a lesser degree, excessive weight gain, were also independent risk factors for all these adverse maternal and neonatal outcomes, regardless of the type of DM, except for shoulder dystocia/cephalopelvic disproportion.

Anorexia nervosa and bulimia in female adolescents with insulin dependent diabetes mellitus: a systematic study.

An unselected sample of 46 female adolescents with insulin-dependent diabetes mellitus (IDDM) for more than one year were assessed systematically for the presence of anorexia nervosa and bulimia. These disorders and their partial syndromes were found in 19.5% of this population. Anorexia nervosa and bulimia diagnosed on the basis of DSM-III criteria were each found in 6.5% of the population representing approximately a 6-fold and 2-fold increase respectively in the expected prevalence for similar nondiabetic individuals. Bulimic symptoms were associated with poor metabolic control as reflected in blood levels of glycosylated hemoglobin (HbAl). These findings have important implications both for the pathogenesis of anorexia nervosa and bulimia and for the management of some cases of IDDM with unstable metabolic control.

Pregnancy and diabetes.

Pregnancy in the diabetic is no longer the universal tragedy for mother and child that it once was but avoidable fetal loss wil continue to occur unless gestational diabetes is detected, and unless meticulous control and monitoring of the insulin dependent diabetic is maintained. As Kinch has so succinctly stated "careful composite chemical control oa cooperative patient" is pivotal.

The oral hypoglycemics: boon or bane?

Following the UGDP study on oral hypoglycemic agents, and the Biometric Society's subsequent re-evaluation of the data, this form of therapy has been the subject of both attack and defence worldwide. This article reviews the basic findings of the UGDP study and comments on the data, following with suggestions for treatment of adult onset diabetes in the light of these findings.

Weight in diabetes.

Diabetes is being increasingly detected among the overweight. The author discusses the links between diabetes and obesity, and outlines methods by which satisfactory weight reduction may be achieved.

Eating disorders in female adolescents with insulin dependent diabetes mellitus.

Recent case reports have suggested an association between anorexia nervosa and/or bulimia with insulin-dependent diabetes mellitus (IDDM). Fifty-eight females aged fifteen to twenty-two with IDDM for more than one year were assessed for the presence of eating disorders. Patients were screened for eating and weight pathology using the Eating Disorder Inventory (EDI) and Eating Attitudes Test-26 (EAT-26). Glycosylated hemoglobin (HbA1) was measured to assess metabolic control. Subjects who scored above the cut-off points associated with eating and weight pathology were interviewed. Clinically significant eating and weight pathology was found in 20.7 percent of the population. Of these subjects, anorexia nervosa was found in 6.9 percent and the syndrome of bulimia, based on DSM-III criteria, was found in 6.9 percent. In patients with bulimia, there was a strong inverse correlation between bulimic symptoms and metabolic control. These findings suggest that anorexia nervosa may be more common in female adolescents with IDDM than in nondiabetic populations and that bulimic symptoms may be a risk factor for poor metabolic control.

T cell autoreactivity to insulin in diabetic and related non-diabetic individuals.

T cell autoreactivity to insulin in type I diabetic and related non-diabetic individuals was analyzed. Peripheral T lymphocytes from both insulin-treated diabetic and untreated non-diabetic members of four families were found to proliferate in vitro in response to human insulin. T cell autoreactivity to insulin therefore does not appear to be diagnostic of the onset of type I diabetes. Highest T cell responses to human insulin were usually detected in insulin-dependent type I diabetes patients treated with a mixture of beef and pork insulin than with self insulin, the greater the dose of animal insulin the higher the T cell response. The T cell repertoires for self insulin appear to be similar in diabetics and non-diabetics based on their patterns of T cell reactivity to beef insulin, port insulin, human insulin, and various peptide of human insulin. The autoreactive T cells analyzed recognize two conformational epitopes of human insulin formed by interactions between A chain and B chain residues. One epitope is associated with the A chain loop and is present in the A1-A14/B1-B16 peptide, and the other epitope consists mainly of B chain residues located in the A16-A21/B10-B25 peptide. These two epitopes are present in amphipathic alpha-helical regions of insulin. HLA-DR (DR3, DR4, and DR5) and HLA-DQ (DQw2/DQw3) Ag can restrict these T cell responses to human insulin epitopes. The ability to detect insulin-specific autoreactive T cells in healthy non-diabetic individuals supports the hypothesis that autoreactive lymphocytes do not necessarily elicit autoimmune disease if present in an environment in which their activity is immunoregulated.

Impact of time since last meal on the gestational glucose challenge test. The Toronto Tri-Hospital Gestational Diabetes Project.

OBJECTIVE: The purpose of the study was to evaluate the impact of time since the last meal on the glucose challenge test and to find cut points that are most likely to predict the outcome of the oral glucose tolerance test in patients screened for gestational diabetes. STUDY DESIGN: This prospective analytic cohort study was carried out at the University of Toronto Perinatal Complex. A 50 gm glucose load was given at 26 weeks' gestation and the time since previous meal ingestion was recorded. At 28 weeks' gestation a 100 gm oral glucose tolerance test was administered. A total of 4274 eligible patients were screened. RESULTS: Time since the last meal had a marked effect on mean plasma glucose. Receiver-operator characteristic curve analysis with National Diabetes Data Group criteria to interpret the oral glucose tolerance allowed the selection of the most efficient cut points for the glucose challenge test on the basis of time since the last meal. These cut points were 8.2, 7.9, and 8.3 mmol/L for elapsed postprandial times of < 2, 2 to 3, and > 3 hours, respectively. With this change from the current threshold of 7.8 mmol/L the number of patients with a positive screening test dropped from 18.5% to 13.7%. There was an increase in positive predictive value from 14.4% to 18.7%. The rate of patient misclassification fell from 18.0% to 13.1%. CONCLUSION: We suggest that screening strategies for detection of gestational diabetes be reconsidered, to account for the impact of variable postprandial status on the test results.

Impact of increasing carbohydrate intolerance on maternal-fetal outcomes in 3637 women without gestational diabetes. The Toronto Tri-Hospital Gestational Diabetes Project.

OBJECTIVE: Our purpose was to assess maternal-fetal outcomes in patients with increasing carbohydrate intolerance not meeting the current criteria for the diagnosis of gestational diabetes. STUDY DESIGN: We conducted a prospective analytic cohort study in which nondiabetic women aged > or = 24 years, receiving prenatal care in three Toronto teaching hospitals, were eligible for enrollment. A glucose challenge test and an oral glucose tolerance test were administered at 26 and 28 weeks' gestation, respectively; risk factors for unfavorable maternal-fetal outcomes were recorded. Caregivers and patients were blinded to glucose values except when test results met the current criteria for gestational diabetes. RESULTS: Of 4274 patients screened, 3836 (90%) continued to the diagnostic oral glucose tolerance test. The study cohort was formed by the 3637 (95%) patients without gestational diabetes, carrying singleton fetuses. Increasing carbohydrate intolerance in women without overt gestational diabetes was associated with a significantly increased incidence of cesarean sections, preeclampsia, macrosomia, and need for phototherapy, as well as an increased length of maternal and neonatal hospital stay. Multivariate analysis showed that increasing carbohydrate intolerance is an independent predictor for various unfavorable outcomes. CONCLUSION: Increasing maternal carbohydrate intolerance in pregnant women without gestational diabetes is associated with a graded increase in adverse maternal-fetal outcomes.