S. Srikanta

Pre-Type I Diabetes: Linear Loss of Beta Cell Response to Intravenous Glucose

Twenty-one intravenous (i.v.) glucose tolerance tests were performed on nine subjects before the onset of overt type I diabetes mellitus. Islet cell antibodies (6 of 9 subjects) and elevated levels of la-positive T-lymphocytes (3 of 3 subjects studied) were detected during the prediabetic period. Elevations of fasting blood glucose and peak glucose during oral glucose tolerance tests were not observed until the year before onset of clinically overt diabetes. During the prediabetic period, there was a progressive loss of early-phase insulin release to i. v. glucose (rate of decline, 20–40 μU/ml insulin release/yr; correlation coefficient, 0.9).

Acquired Defect in Interleukin-2 Production in Patients with Type I Diabetes Mellitus

Deficient production of interleukin-2 has been reported in Type I diabetes, but its cause has not been elucidated. We therefore measured interleukin-2 production in 27 patients with Type I diabetes, 20 patients with Type II diabetes (6 requiring insulin), 5 monozygotic twin pairs discordant for Type I diabetes, and 10 nondiabetic persons with islet-cell antibodies. Interleukin-2 production was decreased in patients with Type I diabetes as compared with controls (35.8 +/- 2.5 vs. 61.6 +/- 4.6 percent, P less than 0.001). Interleukin-2 production did not differ between patients with Type II diabetes and controls, regardless of whether the patients used insulin. Twins with Type I diabetes had decreased interleukin-2 production as compared with normal controls (33.2 +/- 5.4 vs. 61.6 +/- 4.6 percent, P less than 0.001) and with their nondiabetic twins (33.2 +/- 5.4 vs. 54.5 +/- 3.4 percent, P less than 0.005). Interleukin-2 production in nondiabetic twins and in nondiabetic persons with islet-cell antibodies was normal. There was no correlation between glycosylated hemoglobin levels and interleukin-2 production in any diabetic group. We conclude that patients with Type I diabetes have an acquired defect in interleukin-2 production, whereas patients with Type II diabetes do not, and that this defect is not correlated with an ongoing autoimmune process, with hyperglycemia, or with insulin administration or oral hypoglycemic therapy. Thus, the defect appears to be related to marked beta-cell destruction, although not to the metabolic consequences thereof or the responsible autoimmune process.

“Cytoplasmic” Islet Cell Antibodies: Evidence That the Target Antigen Is a Sialoglycoconjugate

We have biochemically treated (periodate, borohydride, neuraminidase, organic solvents) frozen sections of human pancreas and studied the reactivity of islet-cellantibody-positive human sera and monoclonal antibodies. The autoantigen of pancreatic sections has the properties ofsialic acid containing glycolipid.

Differential Sensitivity to β-Cell Secretagogues in “Early,” Type I Diabetes Mellitus

The insulin secretory response to various β-cell secretagogues was studied in four children (ages 11,11, 12, and 10 yr) in “early” stages or remission of type I diabetes mellitus. One child was an anti-islet antibody positive monozygotic twin of a type I diabetic subject, two children had impaired glucose tolerance and elevated levels of la-positive T-cells, and the fourth was in remission (off insulin) of type I diabetes 6 mo after immunotherapy. The peak first-phase (0–10 min) insulin increment after intravenous (i.v.) glucose was negligible in each patient, whereas the peak responses to i.v. glucagon, tolbutamide, arginine, and oral glucose ranged between 10% and 43% of median responses in normal control subjects. The rank order of response to a variety of secretagogues was remarkably similar in all four subjects: i.v. arginine > i.v. glucagon > oral glucose > i.v. tolbutamide > i.v. glucose. These studies indicate that a “functional” β-cell defect, namely a complete loss of response to i.v. glucose and a partial loss to other secretagogues, exists in type I diabetic patients before complete β-cell destruction. This alteration in β-cell responsiveness probably underlies our prior observation of slowly progressive loss of i.v.-glucose-induced insulin release in islet cell antibody-positive siblings of type I diabetic subjects.

Assay for Islet Cell Antibodies: Protein A—Monoclonal Antibody Method

Assays for islet cell antibodies (ICA) are finding increasing application in clinical diabetology. We have developed a new islet cell antibody assay system (ICA-pA), whose salient features include: (1) utilization of fluorescein-conjugated staphylococcal protein A as a standard second-step reagent, the advantages of this approach being improved “signal” (islet)/“noise” (acini) ratio due to reduction of interfering background acinar pancreatic staining, and facilitation of assay standardization provided by the use of a chemically pure conjugated protein A reagent; (2) monoclonal antibody counterstaining with rhodamine-conjugated BISL-32 for the rapid identification of islets in pancreatic sections; and (3) quantitation of circulating serum ICA by microimmunofluorometric techniques.

Pre-Type 1 (insulin-dependent) diabetes: common endocrinological course despite immunological and immunogenetic heterogeneity

SummaryIn an ongoing prospective study 32 individuals have been evaluated for insulin secretory dynamics, islet cell antibodies and HLA antigens, during the preclinical phase of Type 1 diabetes mellitus. Twenty-four out of the 32 subjects were islet cell antibody-positive. To date, 14 subjects (10 islet cell antibody-positive, four islet cell antibody-negative) have progressed to develop overt diabetes. Several patterns of HLA-DR expression were noted (DR3/DR4, DR3/DR3, DR3/x, DR3/DR1, DR4/x, DR4/DR7, DR5/DR7, DR1/DR7 and DR1/DR2). Irrespective of differences in islet cell antibody status or HLA-DR alleles, pre-diabetic individuals exhibited a similar slow course of progressive β-cell dys-function.

Progressive Autoimmune Beta Cell Insufficiency: Occurrence in the Absence of High-Risk HLA Alleles DR3, DR4

In a prospective screening program for type I diabetes mellitus, we identified a unique family in which several members (mother and three siblings) expressed an unusual set of HLA-DR alleles (DR2+, DR3/4−) and were in different phases of immunologically mediated islet beta cell dysfunction. Immunologic and/or clinical manifestations of type I diabetes were absent in all siblings not sharing both HLA haplotypes in common with the proband. This article illustrates: the clinical utility of prospective family screening for predictive markers, such as islet cell antibodies, progressive autoimmune beta cell destruction can occur in the absence of the “high-risk” alleles HLA-DR3 and DR4, and HLA identity with the proband, rather than specific HLA alleles, i.e., presence of DR3, DR4 and absence of DR2, is an essential factor.