Yuki Yamashiro

Complements in diabetes mellitus: activation of complement system evidenced by C3d elevation in IDDM

To characterize insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) in terms of the complement system, some components of the system as well as the related substances and indices were studied. CH50, C3, C4 and C3bINA significantly increased in both IDDM and NIDDM compared with non-diabetic healthy controls. ACH50 was also elevated in NIDDM, whereas it was similar in IDDM and controls. Besides, the serum concentration of C3d, a breakdown product of C3, was higher in IDDM than in NIDDM and healthy controls, but that in NIDDM did not differ significantly from the control. B1Hg1 was not different among IDDM, NIDDM and non-diabetic controls. These observations suggested that there is a high level of complements in both types of diabetes mellitus, but the complement activation seems to be much enhanced in IDDM compared with NIDDM.

Vacor inhibits insulin release from islets in vitro

It has been reported that Vacor, a rodenticide containing N-3-pyridylmethyl-N’-p-nitrophenyl urea, causes insulin-dependent diabetes mellitus. The pathomechanism of Vacor-induced diabetes mellitus has not been clarified yet. The effect of Vacor, therefore, was studied in terms of insulin release from isolated rat pancreatic islets. Vacor suppressed glucose-stimulated insulin release, but did not affect the insulin release induced by theophylline or 12-o-tetra-decanoylphorbol 13-acetate. It is suspected that the suppression of insulin release from pancreatic islets by Vacor may contribute to the pathogenesis of Vacor-induced diabetes mellitus and that this suppression might not be related to cAMP and C-kinase.

Complements in non-insulin-dependent diabetes mellitus with complications

A relation of the complement system to the development of complications in non-insulin-dependent diabetes mellitus (NIDDM) was evaluated by measuring some components of the complement system. CH50, C3, C4 and C3bINA were significantly elevated in subjects with NIDDM as compared with healthy non-diabetic controls. However, CH50 and C3 did not differ between diabetics with and without complications. C4 was higher in diabetics with retinopathy as well as with retinopathy and neuropathy than in diabetics without these complications. ACH50, beta 1Hg1 and C3d were similar in subjects with NIDDM and non-diabetics, and not associated with complications of NIDDM. C3d/C3 in NIDDM without complications was lower than in healthy subjects, but did not significantly differ between the types of complications. These results suggest that the high level of complements in NIDDM might be due to enhanced production of complements and the development of diabetic complications would be related to the elevated level of complements.

Lack of expression of antigens for islet cell antibodies in rat fetal pancreas

It is not clear yet when pancreatic islet cells begin to express antigens for islet cell antibodies (ICA). Therefore, we studied whether human ICA-positive sera, crossreacting with adult rat islet cells, react with fetal and neonatal rat islet cells immunohistologically. The ICA did not react with fetal islet cells. On the other hand, neonatal islet cells over 2–3 weeks of age expressed the reactivities almost similar to those of the adult. It was suspected that pancreatic islet cells started to express their antigens to induce ICA gradually after birth.

Heterogeneity of human islet cell antibodies in terms of cross-species reactivity

There has been no consistent view about the cross-species reactivity of islet cell antibodies (ICA), and no report about their target antigens in the pancreatic islet cells of different species. Therefore, we examined the cross-reactivity of human ICA against rodent pancreatic islet cells, and found at least two types of ICA, one having a comparatively strong cross-reactivity and the other lacking it. Furthermore, using human as well as some rodent pancreatic tissues that had been modified chemically, we came to suspect that the target antigens of ICA were sialic acid residues of glycolipids. Therefore, we suggest that there are at least two types of ICA recognizing sialic acid residues of glycolipids, one reacting with antigen(s) commonly present in human and rat islets, and the other with antigen(s) only present in human islets.

Target antigen of islet cell antibody in Japanese insulin-dependent diabetes mellitus.

The target antigens of islet cell antibody (ICA) have not been clarified. We tried to modify the antigen in human pancreatic tissues and characterize the ICA with immunohistochemical methods. Human pancreatic tissues were treated with periodate (A), borohydride (B), neuraminidase (C), methanol (D), chloroform-methanol (E), or protease (F) to modify the antigens, and stained by an immunofluorescent method using ICA-positive sera from five Japanese insulin-dependent diabetes mellitus (IDDM) patients. In all sera the fluorescence of islets disappeared or waned after A, C, D, and E, and did not change after F. The disappearance or loss of fluorescence induced by A was recovered after B. It is, therefore, suggested that one of the antigens of ICA in Japanese IDDM patients is the sialic acid residue of glycolipid.

Lack of favorable effect of immunomodulators on outbred syngeneic rodent islet transplantation

We studied the effect of two immunomodulators, lobenzarit disodium and OK-432, on outbred syngeneic islet transplantation. Six hundred fresh islets taken from two male Wistar rats were transplanted intraportally into other male Wistar rats that had been made diabetic with streptozotocin. Lobenzarit was given to 12 recipients and OK-432 to seven recipients intraperitoneally for 1 month, while nine controls received only intraperitoneal saline. Both drug-treated groups could not maintain lower fasting plasma glucose levels or higher fasting body weights at each time as compared with controls. The islet survival time in lobenzarit-treated (23.5 +/- 8.0 days) and OK-432-treated (25.3 +/- 13.4 days) groups was not longer than that (21.6 +/- 9.4 days) of the control group. All the pancreatic insulin contents of the seven surviving controls, ten surviving lobenzarit and five surviving OK-432 recipients were less than 0.8% of the mean insulin content obtained from 12 normal male rats. The hepatic insulin content of both drug-treated groups was not higher than that of the control group. These results suggest that lobenzarit disodium and OK-432 cannot protect outbred syngeneic islet grafts.

Heterogeneity of islet cell autoantibodies in terms of insulin release from rat islets and insulinoma cells

The clinical significance of cytoplasmic islet cell autoantibodies (ICA) has been studied since their discovery by Bottazzo et al. in 1974. Some ICAs destroy pancreatic B cells in the presence of complement, whereas others take no part in this destruction. This suggests that islet function varies with the amount of ICA produced. In the present investigation we report the heterogeneity of monoclonal islet cell antibodies produced by one of us in terms of insulin release from isolated rat islets as well as from rat insulinoma cells (RINr).

Effect of dimethylthiourea on syngeneic rodent islet transplantation

We studied the effects of a hydroxyl radical scavenger, dimethylthiourea (DMTU), on syngeneic islet grafts. Six hundred fresh islets taken from two Wistar rats were transplanted intraportally into other Wistar rats made diabetic with streptozotocin. DMTU was given to five recipients intraperitoneally for a month while nine controls received only intraperitoneal saline. The DMTU-treated group had significantly lower fasting plasma glucose levels at 1.5, 4.5, 5, 5.5, 6, 7, 9 and 11 weeks and had higher mean fasting body weights between the 2.5th week and their eventual sacrifice. Their islets also survived significantly longer than did those of the controls (73.6 +/- 3.4 vs. 21.6 +/- 9.4 days). This suggests that oxygen free radical production endangers graft survival and that the hydroxyl radical scavenger DMTU protects syngeneic islet grafts.