A.N. Gorsuch

EVIDENCE FOR A LONG PREDIABETIC PERIOD IN TYPE I (INSULIN-DEPENDENT) DIABETES MELLITUS

In a prospective investigation of the prediabetic period before onset of type 1 (insulin-dependent) diabetes, HLA genotypes were determined in 582 healthy parents and siblings of 160 affected children. Islet cell antibody was sought by both the conventional (ICA-IgG) and the complement fixation (CF-ICA) techniques during regular prospective observation over a mean period of 2.0 years. 4 siblings and 2 parents became diabetic; the interval before detection of any biochemical abnormality exceeded a year in 4 of these (range 3-30 months), and in all cases ICA-IgG was positive from the outset, CF-ICA being positive in 5. These observations suggest that the initiation of pathogenesis may precede the abrupt clinical onset of diabetes by several years, even in children. This has important implications, both for research and for possible future prophylaxis.

COMPLEMENT-FIXING ISLET-CELL ANTIBODIES IN TYPE-I DIABETES: POSSIBLE MONITORS OF ACTIVE BETA-CELL DAMAGE

Evidence is presented for the existence of a separate species of islet-cell antibodies which fix complement. Investigations in type I diabetics, non-diabetic polyendocrine patients, and unaffected first-degree relatives of type I diabetic probands show that the complement-fixing islet-cell antibodies are more closely related to the onset of clinical disease than the conventional islet-cell antibody, and they tend to disappear more rapidly. The complement-fixing antibodies may reflect damage of pancreatic beta cells more selectively and may be preferable to the conventional antibody as a serological marker for studying the natural history of type I diabetes.

Can Future Type I Diabetes Be Predicted? A Study in Families of Affected Children

This article examines the risk of type I (insulin-dependent) diabetes in siblings of affected children, in relation to HLA genotypes. The 288 available siblings of 160 diabetic probands were grouped according to the number of HLA haplotypes in common with their probands. HLA-identical siblings (both haplotypes in common) have an approximately 100 times greater risk of developing the disease than that in the general population, and this risk is significantly higher than that in haplo-identical siblings (one haplotype in common) P = 0.008). Thus, in Northern European populations, some 30% of HLA-identical siblings are expected to be diabetic by the age of 30 yr. The risk in nonidentical siblings (neither haplotype in common) is not significantly increased. These findings carry implications for genetic counseling and research.

A new look at HLA genetics with particular reference to type-1 diabetes.

HLA genotypes were ascertained in 150 families with a diabetic child from the same geographical area. There was preferential zygotic assortment of the paternal HLA A1-B8 haplotype (63--65% compared with the expected 50%) in 69 diabetic families and 33 control families (pooled from elsewhere) who were informative for this haplotype. In diabetic families, the offspring also had an increased incidence of the maternal HLA A2-B15-Cw3 haplotype. Irrespective of which parent contributed the HLA A1-B8 haplotype, there was a significantly increased incidence of male children (63%) who inherited this particular haplotype. This probably explains the known excess of male diabetic children.

EVIDENCE FOR RAISED K-CELL LEVELS IN TYPE-I DIABETES

The proportion of blood mononuclear cells forming low-affinity rosettes with sheep erythrocytes (K cells) was abnormally high in 13 (57%) of 23 children with classical type-1 diabetes at diagnosis but normal in children who had had diabetes for more than a year. A raised proportion of K cells was also found in 5 out of 10 unaffected siblings with islet-cell antibodies and at least one HLA haplotype in common with the diabetic proband; and in 10 (45%) of 22 subjects with type-1 diabetes and co-existent autoimmune thyroid disease irrespective of the duration of diabetes or the presence of islet-cell antibodies. These findings may be new evidence for lymphocyte-mediated beta-cell destruction and support the idea of immunogenetic heterogeneity within type-1 diabetes.

Type 1 diabetes and the HLA-D locus

SummaryHLA-D specificities have been investigated in 58 classical Type 1 diabetics and 43 healthy subjects. Both groups were selected according to the HLA-B locus antigens which are known to have a significant positive or negative association with the disease. The results indicate that (1) the primary association of the disease is with HLA-DW3, (2) the increased frequency of DW4 in diabetics with rare exception is co-existent with the presence of DW3, (3) the low frequency of DW2 is secondary to the increase in DW3 and/or DW4, and is not consistent with a primary ‘protective’ role. It is suggested that these data support the hypothesis of interaction between HLA-linked genes operating by separate mechanisms to confer the susceptibility to young onset Type 1 diabetes (Type 1 A).

Increased killer cell activity in insulin dependent (Type 1) diabetes mellitus

SummaryAntibody dependent cell mediated cytotoxicity in relation to the levels of circulating killer cells was investigated in 16 newly diagnosed classical insulin dependent (Type 1) diabetics, 11 islet cell antibody positive non diabetic children with at least one HLA haplotype in common with their diabetic sibling, and in 15 normal controls. Antibody dependent cell mediated cytotoxicity was evaluated using, as target, 51Cr labelled human 0+ erythrocytes sensitised with an anti-CD antiserum. Killer cells were measured by the low affinity E-rosetting cell technique. Increased killer cell levels (>normal mean + 2SD) were accompanied by a significant enhancement in antibody dependent cell mediated cytotoxicity both in newly diagnosed diabetics (p < 0.05) and in unaffected siblings (p < 0.01). These preliminary results indicate that raised antibody dependent cell mediated cytotoxicity is a feature of insulin dependent diabetes at diagnosis and suggest that active B cell damage might be occurring some time before the onset of clinical symptoms.

The Bf system in diabetes-gene interaction or linkage disequilibrium?

SummaryHLA and Bf genotypes have been determined in 75 Type 1 (insulin-dependent) diabetic probands ascertained from two family studies. The Bf associations were similar in those families with two affected children compared with those families with one affected child. The strong association of B18 with the rare allele BfF1 was confirmed but, with rare exception, the gene encoding for BfF1 only occurred on chromosomes coding for both B18 and CW5. These findings are similar to the strong allelic association between these specificities found more frequently in Southern Europe and Spain, but no HLA-A locus association was found in the present study. All HLA-B 8 positive subjects and 15 out of 16 BW62 positive probands possessed BfS. In contrast to other reports, we could not find any evidence to support the idea that BfF1 is associated with a younger age of onset of diabetes. It is concluded that there is no specific susceptibility gene for Type 1 diabetes linked to the Bf locus and that the Bf associations can be explained purely on the basis of the known allelic association, or linkage disequilibrium, within the HLA system.