Yukimasa Hirata

Improvement of Glucose Tolerance in NIDDM by Clofibrate Randomized Double-Blind Study

A randomized double-blind study was performed to examine the effect of clofibrate on glucose tolerance in subjects with non-insulin-dependent diabetes mellitus (NIDDM). Clofibrate (1.5 g/day) or placebo was administered to 70 patients and an oral glucose tolerance test (OGTT) was performed before and 12 wk after treatment. Blood glucose levels were significantly improved in clofibrate-treated groups at all time points during OGTT, whereas there was no change in insulin levels. Improvement of fasting glucose levels required 8 wk of clofibrate treatment. Insulin binding to erythrocytes demonstrated no significant change in the clofibrate-treated subjects.A randomized double-blind study was performed to examine the effect of clofibrate on glucose tolerance in subjects with non-insulin-dependent diabetes mellitus (NIDDM). Clofibrate (1.5 g/day) or placebo was administered to 70 patients and an oral glucose tolerance test (OGTT) was performed before and 12 wk after treatment. Blood glucose levels were significantly improved in clofibrate-treated groups at all time points during OGTT, whereas there was no change in insulin levels. Improvement of fasting glucose levels required 8 wk of clofibrate treatment. Insulin binding to erythrocytes demonstrated no significant change in the clofibrate-treated subjects. These results suggest that clofibrate improves glucose tolerance in NIDDM subjects without a change in insulin receptors and that clofibrate increases insulin sensitivity through an unknown postreceptor mechanism.

Insulin Autoimmune Syndrome Associated With Benign Monoclonal Gammopathy: Evidence for Monoclonal Insulin Autoantibodies

A 64-yr-old man with benign monoclonal gammopathy developed recurrent episodes of severe hypoglycemia but lacked evidence of insulinoma or exogenous insulin administration. The patients plasma was found to contain anti-insulin antibodies and large amounts of extractable insulin (1110 μU/ml), which was identified as human insulin by high-performance liquid chromatography (HPLC). The anti-insulin antibodies consisted solely of IgG and A-light chains. Scatchard analysis of these antibodies revealed an almost straightline relationship, with markedly low affinity and high capacity. An immune complex made of 125l-labeled insulin and the patients antibodies emerged in a molecular-sieve HPLC as almost a single peak, suggesting a homogeneous antibody population. In addition, the patients M protein was separately shownto be the IgG and λ–light-chain type. We suggest that the insulin autoantibodies responsible for the spontaneous hypoglycemia in this patient are monoclonal and of M protein origin.

Human Monoclonal IgG1 Insulin Autoantibody From Insulin Autoimmune Syndrome Directed at Determinant at Asparagine Site on Insulin B-Chain

Purified human insulin autoantibody (IAA) collected from the serum of a man (T.H.) with insulin autoimmune syndrome was characterized. The TH-IAA was found to be of IgG1 (λ-light-chain) subclass. In addition to the single-binding affinity of TH-IAA to human insulin that we have shown in previous studies, the TH-IAA binding to human insulin was completely inhibited by a mouse monoclonal anti-idiotypic antibody against TH-IAA. A competitive inhibition study with various insulins revealed an epitope of human insulin against TH-IAA. These findings suggest that TH-IAA is monoclonal and is directed at a determinant at B-3 (asparagine) on the human insulin B-chain.

Demonstration of Heterogeneity of Autoantibodies to Insulin Receptors in Type B Insulin Resistance by Isoelectric Focusing

With isoelectric focusing, we examined heterogeneity of autoantibodies to insulin receptors in serums of two patients with insulin-resistant diabetes and one patient with hypoglycemia. Immunoglobulins were prepared by ammonium sulfate precipitation and ion-exchange chromatography with DEAE-Sepharose and subjected to isoelectric focusing for separation into 30 fractions. The fractions were tested for their ability to inhibit 125I-labeled insulin binding to human placental membranes, immunoprecipitate solubilized insulin receptor cross-linked with 125I-insulin, and mimic or inhibit the action of insulin in rat adipocytes. The results varied among the three patients. In the first patient, inhibition of 125I-insulin-binding activity (IBA) and insulin-receptor-precipitating activity (IPA) were distributed almost identically, but the distribution of insulinlike bioactivity (ILBA) was somewhat different. In the second patient, some fractions exhibited potent IBA without IPA, and these fractions inhibited the action of insulin in rat adipocytes. In the third patient, all of the isoelectric fractions showed IBA without IPA and were insulin antagonists. These observations indicate that some patients have antibodies with pure insulin-antagonist properties and provide further evidence that autoantibodies to insulin receptors are polyclonal and recognize different antigenic sites on insulin-receptor molecules. The findings also suggest that the ability of antibodies to elicit ILBA is linked to the ability to immunoprecipitate 125I-insulin-cross-linked and solubilized receptors, whereas antibodies that only inhibit insulin binding behave as insulin antagonists.

An insulin-like growth factor II-producing histiocytoma associated with hypoglycemia: Analysis of the peptide, its gene expression, and glucose transporter isoforms☆

An insulin-like growth factor II (IGF-II)-producing histiocytoma was detected in a patient presenting with the classical findings of tumor-related hypoglycemia (low serum insulin and IGF-I concentrations, glucose intolerance, and only modestly increased serum IGF-II levels). Acid-gel filtration of serum extracts showed a single peak of IGF-II immunoreactivity that emerged at the same site as the 125I-labeled human IGF-II standard. High-performance liquid chromatography (HPLC) analysis of the tumor IGF-II demonstrated that it had an identical retention time to that of recombinant human IGF-II. The tumor IGF-II content was extremely high, messenger RNA (mRNA) for IGF-II showed a 100-fold increase in expression compared with normal human liver tissue. Of special interest, a newly identified exon (hE1) was shown to be predominantly expressed in the tumor by Northern blot analysis using leader exon-specific rat IGF-II complementary DNA (cDNA) probes. Although the significance of this finding remains uncertain, this is the first evidence of a new transcription unit in the human IGF-II gene. In addition, immunoblotting showed that the levels of the glucose transporters, GLUT1 and GLUT4, in the tumor were low and undetectable, respectively. This finding makes it unlikely that increased glucose consumption by the tumor accounted for the hypoglycemia in this patient. This case report provides an interesting insight into the pathophysiology of tumor-induced hypoglycemia and new evidence of the abnormal regulation of IGF-II gene expression in human tumors.

Autoimmunity of Insulin‐Dependent Diabetes in Japan

In this paper some findings concerning autoimmunity have been studied in young Japanese patients with diabetes. Patients diagnosed before 30 years old were classified carefully into new categories recommended by WHO in 1980: insulin‐dependent (IDDM), non‐insulin‐dependent (NIDDM) and other types of diabetes. HLA antigen types, islet cell antibodies (ICA) and islet cell surface antibodies (ICSA) were checked in the sera. HLA‐Bw54 and ‐DR4 were found in a significantly high percentage of IDDM patients, especially in those with Insulin‐Dependent Diabetes Mellitus with Special Reference to acute onset of the disease. Positivity of ICA was remarkably high in IDDM Viral Infections patients within one year after the onset, and then decreased very rapidly. ICSA had the same tendency, but the rate of decrease of positivity seemed slower than that of ICA