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Relationships between fructosamine and HbA1, and mean blood glucose over the previous 1-8 weeks, determined from self blood glucose monitoring with memory meters, were studied prospectively throughout 16 pregnancies in Type 1 diabetic women. Fructosamine correlated best (Spearman rank) with mean blood glucose over the previous 2 weeks in the first and second trimesters (0.5) and over the previous 1 week in the third trimester (0.39). HbA1 correlated best with mean blood glucose over the previous 8 weeks in the first and second trimesters (0.56), but over the previous 2 weeks in the third trimester (0.524) probably because of increased erythropoiesis in late pregnancy. From Deming regression models, 95% prediction intervals for mean blood glucose for fructosamine and HbA1 values were calculated, showing that fructosamine predicted levels of mean blood glucose more precisely than HbA1. These intervals can be used to estimate an individual pregnant diabetic woman's mean blood glucose from her fructosamine or HbA1 results and to verify self blood glucose monitoring data. In well-controlled diabetic pregnancy, both fructosamine and HbA1 reliably indicated trends in blood glucose but fructosamine estimated blood glucose levels more precisely.

Relationships between maternal glycaemia and neonatal birth weight were studied prospectively in 14 tightly controlled pregnant women with pre-existing type 1 diabetes mellitus. Maternal glycaemia throughout pregnancy was determined from daily self blood glucose (BG) monitoring with memory meters and fortnightly fructosamine (Fr) and glycated haemoglobin (HbA1) measurements. Mean non-fasting BG and mean HbA1 throughout pregnancy correlated strongly (Spearman rank) with birth weight (0.64 and 0.73 respectively), as did mean second trimester non fasting BG (0.54), HbA1 (0.7) and Fr (0.64) and mean third trimester HbA1 (0.65), whereas mean fasting BG showed no significant correlations with birth weight at any age of pregnancy. The disparity between the strong correlation of non fasting BG with birth weight and the poor correlation of fasting BG suggests that postprandial as opposed to basal glycaemia significantly influences foetal growth and neonatal size.

The effects of transfer from animal insulin to semisynthetic human insulin on glycaemic control, insulin dose and anti-insulin antibodies were investigated in a total of 108 patients at four centres in a double-blind controlled study of eight months duration. Six months after transfer from porcine to human insulin there was a mean (+/- SE) increase in pre-breakfast blood glucose of 1.1 +/- 0.6 mmol l-1 (vs a reduction of 1.6 +/- 0.7 mmol l-1 in controls) (p less than 0.01), and a mean increase of pre-lunch blood glucose of 0.9 +/- 0.7 mmol l-1 (vs a reduction of 1.14 +/- 0.7 mmol l-1 in controls) (p less than 0.05). Six months after transfer from bovine to human insulin, there were no significant changes in blood glucose. Glycated haemoglobin showed no significant change six months after transfer from either bovine or porcine to human insulin. Hypoglycaemic symptoms, the total daily insulin dose, and the ratio of short- to intermediate-acting insulin did not change significantly after transfer from either bovine or porcine to human insulin. Transfer from bovine to human insulin resulted in a significant decline in anti-human insulin antibodies (mean (range): 50.5(14.8-125)% of initial levels), vs controls (113(43.4-234)% of initial levels; p = 0.034), and a non-significant decline in anti-bovine insulin antibodies (52.2(25.8-111)% vs 81.7(42.5-128)%; p = 0.082).

A randomized double blind trial of insulin and glibenclamide treatment vs insulin and placebo was carried out in 20 insulin-dependent diabetics. Nine patients were C-peptide secretors and all increased their C-peptide output during a 50 g OGTT at the end of the insulin and glibenclamide treatment period by a mean of 47%. At the same time their mean daily blood glucose fell from 8.4 +/- 1.7 to 7.4 +/- 1.5 mmol/l and their HbA1 from 8.1 +/- 0.5 to 7.5 +/- 0.9% (mean +/- SD). There was no change in any of the measurements of diabetic control in C-peptide non-secretors and no evidence for any extra-pancreatic effects of glibenclamide in this group of patients. Combined insulin and glibenclamide treatment may produce a useful improvement of diabetic control in insulin-dependent diabetics who still secrete some endogenous insulin, although further studies are required.

Insulin antibodies and T-cell lymphocyte cytotoxic reactivity against insulin and its related peptides were studied longitudinally in 3 groups of patients with type I diabetes mellitus (DM). Group 1 patients were those in whom the diagnosis was made within 1 week of the initiation diagnosis. They were subdivided into those receiving MC porcine (A) or MC bovine (B) insulin. Group 2 patients were those with a duration of DM for 2-6 years who were receiving either MC porcine (A) or MC bovine (B) insulins. Group 3 subjects were those who had been on conventional recrystallized insulin and then switched to MC porcine (A) or MC bovine (B) insulins for 2 weeks before the start of the study. The incidence of cytotoxic reactions and insulin antibodies were approximately 40-50% for group 1 (either 1A or 1B) at the initiation of the study. At 3-month follow up all patients in group 1B developed insulin antibodies (p less than 0.02) and a significant increase in the frequency of cytotoxic reactions (p less than 0.01). By contrast there was a decline in the frequency of cytotoxic reactions in group 1A (p less than 0.01 at 1 year) and the increase in insulin antibodies was non-significant. Group 2B had higher frequency in cytotoxic reactions (p less than 0.005) and of insulin antibodies (p less than 0.05) than group 2A. A significant decrease (p less than 0.01) in cytotoxic reactions was observed at 3 months following the switch of patients from conventional bovine insulin preparations to 'A' but not to 'B'. However in both subgroups insulin antibodies persisted for at least 12 months. Cross-reactivity between antibodies to human, porcine and bovine insulins was evident in all groups. The early cellular and humoral immune phenomena were positively correlated in both group 1A and 1B suggesting their common involvement in the pathogenesis of DM.

Using a cellular cytotoxicity assay, we have investigated the antigenicity of pharmaceutical insulins and of highly purified insulin constituents (unformulated monocomponent (MC) insulin, insulin B-component and C-peptide) in control, insulin naive, subjects and in three groups of type I diabetic patients. These were: Group 1, newly diagnosed patients receiving either porcine or bovine MC insulins for less than one week; Group 2, established patients receiving porcine or bovine MC insulin for 2-6 years; Group 3, established patients receiving conventional bovine insulin for 2-6 years, and tested within two weeks of switching to either porcine or bovine MC insulins. In control subjects, there was a higher incidence of cytotoxic reactions with beef (72%) than with porcine (33%) pharmaceutical preparations (p less than 0.01) but there was a similar incidence of reactions with the purified beef and pork constituents. All patients, except those Group 3 patients receiving bovine MC insulins, had a significantly increased incidence of aggregate reactions to the spectrum of antigens. In porcine treated patients, there was an increase in the incidence of reactions to pharmaceutical preparations in Group 1 (p less than 0.05) and Group 3 (p less than 0.001), but this was absent from each of the bovine treated groups. All patient groups showed significant increases in the incidence of reactions against insulin constituents of their therapeutic analog. In Groups 1 and 2, but not 3, there was significant analog cross reactivity. We deduce that the reactivity seen in control subjects is principally directed against unidentified formulation constituents of bovine pharmaceutical preparations. Patients on both acute and chronic therapy with insulin show T-cell sensitization to MC insulin and its components. Chronic therapy with conventional bovine insulin induces tolerogenesis, but this is reversed on exposure to a fresh insulin analog.

T- and K-cell cytotoxic activity has been measured in groups of type I diabetic patients and comparable groups of healthy control subjects. The mean cytotoxic indices for T-cell activity were 0.72 for 13 type I diabetics and -2.38 for a control group. These values are not significantly different. K-cell cytotoxic activity was measured using both chicken red blood cells and Chang liver cells coated with appropriate xenogenic antibodies. Using the chicken red blood cell system the percentage specific chromium release was 55.3 for 17 type I diabetics and 50.0 for a control group. These values are not significantly different. Using the chicken red blood cell system the percentage specific chromium release was 55.3 for 17 type I diabetics and 50.0 for a control group. These values are not significantly different. Using the Chang liver cell system the percentage specific chromium release was 13.9 for 37 type I diabetics and 9.7 for a control group. This difference is statistically significant (p less than 0.05).

Ninety-six juvenile onset type diabetics showed an increase in the frequency of HLA B8 and B15 and a decrease in frequency of HLA B7 antigens. Sixty-four maturity onset diabetics showed no disturbance in the frequency of these antigens. Fifty-four of the juvenile onset type diabetics, with an average duration of disease of 3.2 years were tested for the presence of islet cell antibodies (ICAs). Thirty-two per cent were positive, the incidence decreasing from 70% in those patients tested within 1 year of diagnosis to zero in those patients tested within 1 year of diagnosis to zero in those patients tested more than 5 years after diagnosis. No correlation was found between the incidence of ICAs and either cell-mediated immune reactions or HLA type. B15 positive patients were associated with cell-mediated immune reactions to pancreatic antigens and with the presence of other tissue autoantibodies. HLA phenotypes were not associated with environmental data. Diabetic siblings had identical HLA A-B haplotypes more often than could be expected to occur by chance.

CD1 mice infected with Coxsackie B4 virus showed an early polymorph infiltration of the pancreas, which later changed to a mononuclear exudate. A state of glucose tolerance developed concurrently and both events coincided with the inhibition of migration of spleen cells in the presence of the virus. The relevance of these findings to human juvenile-onset diabetes mellitus is discussed.

Ninety-six juvenile onset type diabetics showed an increase in the frequency of HLA B8 and B15 and a decrease in frequency of HLA B7 antigens. Sixty-four maturity onset diabetics showed no disturbance in the frequency of these antigens. Fifty-four of the juvenile onset type diabetics, with an average duration of disease of 3.2 years were tested for the presence of islet cell antibodies (ICAs). Thirty-two percent were positive, the frequency decreasing from 70% in those patients tested within one year of diagnosis to 0.5% in those patients tested more than 5 years after diagnosis. No correlation was found between HLA type and the frequency of ICAs, but there was an increase in other autoantibodies in B15 positive patients. Preliminary absorption studies suggest a cross reactivity of ICAs and Coxsackie B4 virus.

Some of the routine methods of measuring glycosylated haemoglobin depend on its difference in charge from haemoglobin A and do not distinguish between glycosylated haemoglobin and fetal haemoglobin. Two insulin dependent diabetics showed persistent discrepancies between their capillary blood glucose values and their glycosylated haemoglobin values measured by agar gel electrophoresis: the blood values were normal but the glycosylated haemoglobin values were raised. In one patient increases in insulin dose in response to the glycosylated haemoglobin results repeatedly produced hypoglycaemia. Both patients were found to have higher than normal concentrations of fetal haemoglobin; and when measured by the thiobarbituric acid reaction their glycosylated haemoglobin levels were almost normal. This problem may be avoided by using a method that distinguishes between fetal and glycosylated haemoglobin or by testing glycosylation of hair or serum albumin if discrepancies arise. This is particularly important during pregnancy, when some women have an increase in fetal haemoglobin.