Necropsy evidence of central cholinergic deficits in senile dementia.

After the death of a 12-year old girl with newly discovered insulin-dependent diabetes mellitus, we used monoclonal antibodies in an effort to identify the cells invading the pancreas. The majority of infiltrating lymphocytes were of the T cytotoxic/suppressor phenotype, but other T-cell subpopulations were present. Some of the T cells were "activated" (positive for HLA-DR antigen, and the interleukin-2 receptor). Immunocytes bearing IgG were scattered in the gland, and complement-fixing IgG antibodies were deposited in some islets. Increased expression of Class I (HLA-A, B, and C) molecules was observed in the affected islet cells, and in damaged islets showing scant lymphocytic infiltration, some beta cells (still producing insulin), but not glucagon or somatostatin cells, were HLA-DR positive. The capillary endothelium was markedly dilated and strongly HLA-DR positive. These findings may contribute to an understanding of the sequence of events leading to the destruction of beta cells in classic Type I diabetes mellitus.

In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis.

Insulin-dependent diabetic (IDD) patients have a high prevalence of circulating autoantibodies against islet of Langerhans cells at the time of diagnosis1–4. Inflammatory cells within the islets5, leukocyte migration inhibition in response to pancreatic antigens6 and an association with certain HLA-D/DR histocompatibility antigens7,8, have also been observed. It seems that the autoantibodies may be pathogenically relevant as they react primarily with β-cells9, but the specific target antigen(s) have yet to be identified. In the present study we determined whether sera from insulin-dependent diabetic children are able to immunoprecipitate proteins from detergent lysates of human islet cells. We report that sera from 8 out of 10 newly diagnosed diabetic children consistently immunoprecipitate a protein having a molecular weight (M r) of  64,000 (64K). An additional protein (38K) was precipitated from islet cells obtained from a HLA-DR3-positive donor. Neither of the proteins was precipitated by non-diabetic sera nor detected in immunoprecipitates from human lymphocyte lysates. It is suggested that the 64K and/or 38K protein components may represent cell-specific target antigens in insulin-dependent diabetes.

Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins

Evidence for a long prediabetic period in type i (insulin-dependent) diabetes mellitus

Insulin-dependent diabetes mellitus (IDDM), also known as juvenile diabetes, results from destruction of the insulin-producing beta cells in the pancreas [1]. Both viruses and autoimmunity have been suggested as possible causes. The evidence for viruses comes largely from experiments in animals, but several studies in humans point to viruses as an occasional trigger of this disease.

https://www.nejm.org/doi/pdf/10.1056/NEJM197905243002102?listPDF=true

Virus-Induced Diabetes Mellitus

Islet-cell antibodies in diabetes mellitus.

Islet-cell antibodies in juvenile diabetes mellitus of recent onset

In a random series of 139 insulin-dependent diabetics aged 30 or under at the onset of disease islet-cell antibody (ICA) was detected in 33 cases (24%). In 27 patients who had had diabetes for less than one year 16 (59%) had ICA. Only one out of 51 patients with maturity onset diabetes who were not dependent on insulin were positive for ICA. Four out of 19 patients with late onset insulin-dependent diabetes had ICA. There was no association between the presence of ICA and any particular HLA phenotype. Within families containing two or more HLA haploidentical siblings with juvenile onset diabetes ICA was a variable finding both in its occurrence and in its relation to the duration of disease. A possible mode of action for the HLA-linked gene may be to permit a rapid immunological destructive process, possibly associated with viral infection.

https://www.bmj.com/content/bmj/1/6025/1565.full.pdf

HLA-linked genes and islet-cell antibodies in diabetes mellitus.

Sera from 54 pairs of identical twins, 29 discordant and 25 concordant for insulin-dependent diabetes, and 11 pairs of concordant non-insulin dependent identical twins were examined for pancreatic islet-cell antibodies (ICAs). ICAs were found in 10 of the 29 diabetic discordant and eight of the 50 concordant twins (difference not significant P greater than 0-05). Six out of nine twins tested within one year of onset of diabetes were positive, whereas nine out of 29 tested after one to 10 years and three out of 41 tested after 10 years were positive. Only one of the 22 non-insulin-dependent twins had ICAs. Repeat ICA testing in five pair of insulin-dependent twins and in the siblings of one pair showed that ICAs may be present in people with normal glucose tolerance9 may precede clinical diabetes by several years; and may decline in titre or disappear with increasing duration of disease. Thyroid or gastric autoantibodies, or both, were found in 36 out of 108 insulin-dependent twins and three out of 22 non-insulin dependent twins (difference not significant P less than 0-05). Only four twins had both ICAs and thyrogastric antibodies. There were no significant associations between autoantibodies and HLA histocompatibility types. As ICAs are more common in the diabetic than the non-diabetic twins of the discordant pairs they must be associated with juvenile onset diabetes. ICAs may appear some years before the onset of diabetes, but their prevalence declines with increasing duration of diabetes. The factors determining the production of ICA differ from those for thyroid and gastric autoantibodies.

Geoffrey Walker

Papers

Islet-cell antibodies in diabetes mellitus.

Islet-cell antibodies in juvenile diabetes mellitus of recent onset

HLA-linked genes and islet-cell antibodies in diabetes mellitus.

Islet-cell, thyroid, and gastric autoantibodies in diabetic identical twins.

Salicylate interference with plasma-paracetamol method