The worsening from NGT to IGT in Japanese subjects may be associated with a decrease in early-phase insulin secretion in nonobese as well as in obese subjects. Hyperinsulinemia in IGT is not common. We suggest that impaired early-phase insulin secretion may be the initial abnormality in the development of glucose intolerance in Japanese people. Insulin resistance may be a consequence of hyperglycemia and/or obesity.

We and others have previously demonstrated that the human insulin receptor messenger RNA (mRNA) is alternatively spliced such that the 36-nucleotide sequence encoded by exon 11 of the receptor gene is included (Ex11+) or excluded (Ex11-). Although both Ex11- and Ex11+ insulin receptors which differ in the presence or absence of 12 amino acids in the carboxy-terminal alpha-subunit have been demonstrated to function as insulin receptors when independently overexpressed and studied, the possibility that subtle functional differences between the two isoforms exist has received limited attention. Given that the relative abundance of the two mRNA transcripts is highly regulated in a tissue-specific manner, differences in the functional properties of the two receptor variants might contribute to tissue-specific differences in insulin receptor function and insulin action that are known to exist. To address this hypothesis, we transfected cDNAs encoding the two receptor isoforms into Chinese hamster ovary (CHO) cells and prepared several stable CHO cell lines expressing high numbers of Ex11- or Ex11+ receptors. Several functional properties of the expressed insulin receptors were compared in parallel with the following results: 1) steady state binding of insulin to cells expressing the Ex11- isoform exhibited higher (approximately 2-fold) affinity; 2) using two different methods, a significant difference in receptor-mediated insulin internalization was noted such that the Ex11- isoform displayed a higher (approximately 25% increase in the rate constant, Ke) rate of internalization; 3) partially purified Ex11- and Ex11+ receptors displayed similar maximal and insulin dose-response characteristics for receptor autophosphorylation and kinase activity toward an exogenous substrate (poly Glu-Tyr, 4:1); 4) the ability of expressed Ex11- and Ex11+ receptors to couple to a metabolic (glucose incorporation into glycogen) and mitogenic (thymidine incorporation into DNA) action of insulin was not discernibly different. Thus, when expressed in CHO cells, the two alternatively spliced isoforms of the insulin receptor have subtle differences in insulin binding affinity and the kinetics of ligand-stimulated internalization that would be expected to influence the pattern of insulin receptor expression and signaling in vivo in a tissue-specific manner.

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Autoantibodies to glutamic acid decarboxylase (GAD), previously reported to be the 64,000-M(r) (64K) islet cell protein, were measured by a radioimmunoassay using purified pig brain GAD in 29 insulin-dependent diabetes mellitus (IDDM) patients with autoimmune thyroid disease (AITD) and in 29 sex- and disease duration-matched IDDM patients without AITD. Islet cell antibodies (ICAs) and 64K antibodies were also determined. In IDDM patients with short-duration diabetes (< 1 year), the prevalence and levels of GAD antibodies were 100% (8 of 8) and 609 +/- 166 U (means +/- SE), respectively, in IDDM patients with AITD and 81.8% (9 of 11) and 90 +/- 51 U, respectively, in patients without AITD. In patients with long-standing IDDM (3-22 years), the prevalence and levels of GAD antibodies were 76.2% (16 of 21) and 193 +/- 66 U, respectively, in patients with AITD and 50.0% (9 of 18) and 36 +/- 14 U, respectively, in patients without AITD. For up to 6 years after the onset of IDDM, the levels of GAD antibodies in IDDM patients with AITD were significantly higher than in IDDM patients without AITD. A close and significant correlation was found between GAD antibodies and ICA or 64K antibodies in IDDM patients with AITD. Our results demonstrate that high levels of GAD antibodies were present in IDDM patients with AITD. The observed differences in GAD immunoreactivity between IDDM patients with and without AITD might help evaluate the role of GAD antibodies in IDDM.

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The goal of the Fourth International Workshop for Standardization of ICA Measurements was to determine the specificity of ICA assays and their ability to distinguish between control sera (n = 57) and sera from IDDM-related individuals--representing relatives of IDDM patients (n = 21), healthy individuals who later developed IDDM (n = 8), or newly diagnosed IDDM patients (n = 23). Results from 28 laboratories were analyzed. The mean specificity (percentage of control sera reported as negative) among 27 laboratories was 91%, including 6 laboratories with 100% specificity. Nevertheless, 78% of laboratories found at least one control sample > 0 JDF U. Among samples from first-degree relatives, the mean concordance was 86%, including three sera found negative (0 JDF U) by all laboratories. Among individuals who later developed diabetes, the mean concordance was 93%, with two sera found positive by 100% of laboratories. In sera from newly diagnosed IDDM patients, the mean concordance was 82%. Three sera were found positive and one serum negative by all laboratories. The JDF U of the sera considered to be positive were significantly greater than each laboratory's average for the controls. In conclusion, the results from laboratories participating in the Fourth International ICA Workshop demonstrated excellent specificity, good concordance, and an ability to separate control sera from defined, IDDM-related subjects.

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