Hun Ki Min

Effect of SMS 201–995 in Rapidly Progressive Diabetic Retinopathy

merit, making the cold urticaria mechanism unlikely. W.S. also has features that are inconsistent with the two cases of adrenergic urticaria reported by Shelley and Shelley (3). His hives are never surrounded by halos (W.S. is Black but not so dark as to obscure halos). His lesions invariably resolve within minutes of ingestion of sugar, instead of lasting for more than an hour, as occurred in the truck driver reported by Shelley and Shelley. [I have received a letter from a nurse who described hypoglycemic hives in her granddaughter who has insulin-dependent diabetes mellitus. Her hives do not resolve until several hours after taking sugar. I have no information as to whether she has associated flares or halos. In addition, she sometimes gets hives when her insulin is peaking, even without hypoglycemia, suggesting that her hives might be partly due to insulin allergy.] In addition, W.S. does not develop an erythematous flare in association with his hives and does not develop hives with fever, exercise, or environmental heat, which would be typical of patients with cholinergic urticaria (4). Thus, W.S. develops hives only in association with hypoglycemia, and they do not seem to have the characteristics of cold, cholinergic, or adrenergic urticaria, unless adrenergic urticaria can have varied presentations. One aspect of the report by Shelley and Shelley (3) puzzled me. Figueiredo et al. describe (^-receptors as activating adenylate cyclase, increasing cAMP, and preventing mast cell degranulation, whereas a-receptors do the opposite, a concept that is certainly consistent with what is known about asthma. By this logic, we expect (B-receptor blockade to predispose to hives by resulting in unopposed a-receptor stimulation of mast cell degranulation. However, Shelley and Shelley report that treatment with the global (3-receptor blocker propranolol prevented adrenergic hives, whereas treatment with a semiselective (^-receptor blocker did not. It is interesting that one patient described by Shelley and Shelley (3) also had vitiligo. We previously reported that vitiligo patients have lower plasma catecholamines than control patients (5). It is possible that chronically lower catecholamines in such patients upregulate their receptors such that the effect of a brisk increase in plasma catecholamines, e.g., hives, is enhanced. The opposite effect, downregulation of adrenergic receptors with pheochromocytoma together with hypovolemia, accounts for the postural hypotension encountered in that setting. In summary, W.S.s hypoglycemic hives appear to be a unique entity distinct from cold, cholinergic, or adrenergic urticaria, unless the latter has a more variable presentation than has been reported previously.

Effects of several simple sugars on serum glucose and serum fructose levels in normal and diabetic subjects

Fructose has a reaction constant 7.5 times as high as that of glucose in its nonenzymatic reaction with protein in vitro. The effects of glucose, sucrose and fructose ingestion on serum fructose and glucose levels were studied to evaluate the overall biohazard, i.e., the probability of their altering proteins while circulating in the blood. Normal and diabetic subjects were given either 75 g glucose, 75 g fructose, 75 g sucrose, or 112.5 g fructose after fasting, and their serum levels of sugars were measured at 0, 1, 2 and 3 h. In normal subjects, fructose ingestion produced significantly lower serum glucose levels and significantly higher serum fructose levels than did glucose ingestion, while sucrose produced intermediate results. The glycemic effect was found to be lowest for fructose and highest for glucose. The calculated overall biohazard was, however, highest for fructose and lowest for glucose in normal subjects. Furthermore, the serum fructosemic index was directly proportional to the amount of fructose ingested. In diabetic subjects, blood fructose clearance was significantly more delayed than in the controls when the same amount of fructose was ingested. These results suggest that an evaluation of the effects of simple in the diabetic diet requires a closer examination of the overall biological effects of the sugars.

Initial role of macrophage in the development of anti-β-cell cellular autoimmunity in multiple low-dose streptozotocin-induced diabetes in mice

Multiple injections of low doses of streptozotocin to susceptible strains of mice produce an experimental autoimmune diabetes mellitus. To investigate the possible initial role of macrophages in the development of insulitis, we studied the effect of macrophage-toxic silica administration on the development of in vitro cellular cytotoxic immune response against pancreatic beta-cells. Multiple streptozotocin-treated mice developed hyperglycemia at day 12 and their splenocytes showed cytotoxicity against cultured rat insulinoma cells. Mice given silica and streptozotocin together remained normoglycemic and their splenocytes showed no cytotoxicity. In contrast, in vitro depletion of macrophages from the splenocytes of mice given multiple streptozotocin alone did not abolish the cytotoxicity. These results show that macrophages themselves contribute little to the cellular cytotoxicity, but are necessary for the development of cytotoxic cells. From these results we suggest that there are at least two different steps in the development of insulitis; the presentation of beta-cell autoantigen by macrophages to helper-T cells, followed by the development of beta-cell-specific cytotoxic cells.

Role of blocking TSH receptor antibodies on the development of hypothyroidism and thyroid atrophy in primary myxedema.

We studied blocking type TSH receptor antibodies in 28 patients with primary myxedema and 21 patients with goitrous Hashimoto’s thyroiditis by measuring the ability of their IgG to inhibit TSH binding to its receptor, and to inhibit TSH-stimulated cAMP increases and 3H-thymidine incorporation in a rat thyroid cell line, FRTL-5. The incidences of TSH binding inhibitor immunoglobulin (TBII), thyroid stimulation blocking antibody (TSBAb) and thyroid growth blocking antibody (TGBAb) in patients with primary myxedema were 53.6%, 75% and 65.2%, respectively. However, in goitrous Hashimoto’s thyroiditis, these were 14.3%, 0% and 17.7%, respectively. These antibodies inhibited the receptor binding of 125I-bTSH dose-dependently, and also inhibited dose-dependently not only TSH-stimulated but also Graves’ IgG-stimulated cAMP increase and 3H-thymidine incorporation. TBII activities of patients with primary myxedema were significantly correlated with both their TSBAb (r=0.665; p<0.01) and TGBAb (r=0.618; p<0.01) activities. Thirteen patients whose TBII activities were more than 50% had both strong TSBAb (75.1–100%) and TGBAb (57.4–100%) activities. Transient neonatal hypothyroidism was found in an infant born to a mother having potent TBII activities. Serum of the baby also had potent TBII activities and the baby’s IgG inhibited TSH-stimulated cAMP increase and 3H-thymidine incorporation. These data suggest that a significant proportion of patients with primary myxedema have potent blocking type TSH receptor antibodies. These might play a role in primary myxedema causing hypothyroidism and thyroid atrophy through inhibition of TSH-stimulated cAMP generation.

Glucose, insulin and C-peptide kinetics during intravenous glucose tolerance test in chronic liver disease

To elucidate the mechanism of glucose intolerance in chronic liver disease (CLD), the kinetics of plasma glucose, insulin and C-peptide were studied after intravenous glucose loading in patients with CLD. Fasting plasma insulin levels were higher in patients with CLD than in normal subjects. This hyperinsulinemia was attributed primarily to an increased pancreatic secretion of insulin. Patients with CLD were divided into two groups, one with normal fasting plasma glucose (FBS less than 100 mg/dl (Group I) and the other with higher FBS (Group II). In Group I, the glucose disappearance rate was normal and a brisk acute insulin response (AIR) to glucose was noted. The glucose disappearance rate in Group II was lower than that in normal subjects, and AIR to glucose was blunted. It is suggested that normal glucose tolerance in Group I patients could be interpreted as a state of compensation by hypersecretion of insulin. On the other hand, the glucose intolerance in Group II patients could be due to inadequate insulin secretion to overcome insulin resistance of CLD.

Immunogenetic Aspects of Adult Onset IDDM in Korea

Insulin-dependent diabetes mellitus (IDDM) is a clinical diabetes of severe insulin deficiency, resulting from a slowly progressing autoimmune destruction process of pancreatic beta cell. Noninsulin-dependent diabetes mellitus (NIDDM) is a less severe form of diabetes of unknown etiology, although insulin resistance is suspected as the prime abnormality. This distinction is sometimes difficult as there is no clear transition point to apply.1 Certain HLA class II molecules, particularly DR3 or DR4, have been known to be associated with IDDM susceptibility.2 With the recent advances of molecular biology, the presence of DNA sequences coding for non-aspartic acid in the 57th position of the DQ beta chain and arginine in the 52nd position of the DQ alpha chain are known to be highly associated with IDDM in Caucasians.3,4 The associations of HLA alleles with IDDM, but not with NIDDM, was taken as an evidence that IDDM and NIDDM are two distinctively different diseases. Recently, however, several investigators suggest that HLA might also play a role in NIDDM.5–8

Changes in the Properties of the Thyrotropin Receptor Antibody in Patients with Graves` Disease after Radioiodine Treatment

We investigated the effect of a single dose of 131I upon thyrotropin receptor antibodies (TRAb) in 21 patients with Graves’ disease. The thyrotropin receptor antibodies were assessed by parallel measurements of thyrotropin binding inhibitor immunoglobulin (TBII), thyroid stimulating antibody (TSAb) and thyroid stimulation blocking antibody (TSBAb) in serum by radoreceptor assay, stimulation of adenlate cyclase and inhibition of TSH-stimulated adenylate cyclase activation in FRTL-5 cells, respectively. Prior to radioiodine treatment, TBII was detected in all 21 patients and TSAb in 19 patients. After radioiodine treatment, TBII activities did not change during the 12-months observation period, but in eight patients TSAb activities gradually decreased and were undetectable at the end of the 12-month observation period. Persistence of TSAb was not associated with the clinical outcome. Eight patients developed hypothyroidism within one year after radioiodine treatment. Three of the hypothyroid patients developed TSBAb, and the appearance of TSBAb coincided with the development of hypothyroidism. These results suggest that TSBAb might develop after radioiodine treatment in a minority of patients with Graves’ disease and that the appearance of TSBAb, in addition to radiation-induced thyroid destruction, might be involved in the development of hypothyroidism following radioiodine treatment.

RFLP analysis of HLA-DR beta and -DQ beta genes in the Korean patients with insulin-dependent diabetes mellitus.

Human genomic DNA samples from 19 Korean patients and 31 controls of known serological DR antigen specificity were studied for insulin-dependent diabetes mellitus (IDDM)-associated variation in HLA-DRβ and - DQβ restriction fragment length polymorphisms (RFLPs). Genotyping allowed for accurate assignment of HLA-DR types. For HLA-DRw6, a 12kb/DRβ/Taq I fragment was decreased in Korean IDDM (p<0.05). However, we could not find an increased frequency of a 12kb/DQβ/Bam HI fragment or decreased frequency of a 3.7kb/DQβ/Bam HI fragment in Korean IDDM. These results suggest a possible protective role of the HLA-DRw6 specificity in IDDM, irrespective of ethnic background, the absence of a specific DQβ RFLP pattern associated with IDDM in Koreans, and the difference of the Korean population in the genetic of IDDM, compared to the Caucasoid population.

Characteristics of Anti-TSH antibody and Its Relationship with TSH Receptor Antibody*

Using the TSH binding inhibition IgG (TBII) assay three patients with Graves’ disease were discovered to have serum TSH-binding immunoglobulins of high affinity. These IgGs bound 61%, 33% and 60% of radiolabeled TSH, respectively, higher than the maximal specific binding (25%) in the TBII assay. Such binding was detected even in the absence of TSH receptor with only small differences in the precipitable radioactivity (61 %, 28%, and 61 %, respectively) compared with non-specific binding (11.3%). The 125I-bTSH binding of IgGs was competitively inhibited by the addition of bTSH. The 7s fraction was found to be a major binding component by gel filtration chromatography. Myxedema sera with high TSH levels did not affect the reaction. Moreover IgG binding to bTSH was not inhibited by the addition of serial dilutions of TBII positive pooled Graves’ IgG (0.1–10mg/ml) from a different untreated patient. The titers of these TSH binding antibodies were not changed during the treatment of Graves’ disease. Following guinea pig fat cell membrane receptor purification, the IgG of one patient with Graves’ disease revealed TBII activity of 46.3%. However, no binding of 125I-bTSH in the absence of the TSH receptor was evident. These studies suggest that 1) anti-TSH antibodies and TSH receptor antibodies are present independent of one another in the sera of some patients with Graves’ disease, and 2) TSH receptor antibodies do not affect the binding of anti-TSH antibodies to TSH.

HLA-DR Antigen Expression on the Thyrocytes of Graves’ Disease Patients

To confirm the expression of HLA-DR antigen on the thyrocytes of Graves’ disease patients and study the relation between the degree of DR antigen expression and clinical or laboratory indices, double immunofluorescence and immunoenzymatic staining were performed on frozen thyroid sections. DR antigen was expressed on the thyrocytes of 8 of 11 patients with Graves’ disease (73%) but not found on the thyrocytes from 6 normal controls. The degree of DR antigen expression had no apparent correlation with the age, duration of the disease, activity of TBII, titers of antimicrosomal and antithyroglobulin antibody. There was no apparent spatial or quantitative relation between lymphoid follicle formation and the DR antigen expression on the thyroid follicles. But DR antigen tended to be expressed on the thyroid tissue with interstitial, lymphocyte infiltration. In conclusion, DR antigen was expressed on the thyrocytes of Graves’ disease patients but the clinical and immunological significance remains to be clarified.