J. Egeberg

Antipancreatic Cellular Hypersensitivity in Diabetes Mellitus

The occurrence of organ-specific, cellular hypersensitivity against pancreatic components was examined in twenty-two diabetics by means of the leucocyte migration test. An extract was prepared from pooled porcine pancreatic glands, in which atrophy of the exocrine tissue had been induced by ligation of the pancreatic duct. A specifically altered in vitro reactivity to the pancreatic preparation, consistent with a state of organ-specific, cellular hypersensitivity, was demonstrated in the diabetic group as compared to a control group. Intracutaneous injection of the same preparation in six diabetics with a positive in vitro reaction induced a typical delayed type reaction in four.

Nicotinamide Prevents Interleukin-1 Effects on Accumulated Insulin Release and Nitric Oxide Production in Rat Islets of Langerhans

Nicotinamide (NA) prevents macrophage- and interleukin-1 (IL-1)-mediated β-cell damage in vitro as well as diabetes development in animal models of insulin-dependent diabetes mellitus (IDDM). IL-1 β-mediated inhibition of insulin release and damage to β-cells are associated with intracellular production of nitric oxide (NO) radicals. Therefore, we studied whether NA prevented IL-1 β-induced islet NO production, measured as nitrite release from isolated rat islets, and, if so, whether this action was associated with prevention of IL-1 β-mediated inhibition of insulin release. NA dose- and time-dependently inhibited and delayed IL-1 β-induced islet NO production. Light microscopy detected that 25 mM of NA protected against IL-1 β-induced islet damage. Five to 50 mM of NA dose-dependently reduced inhibition of accumulated islet insulin release induced by 150 pg/ml of IL-1 β. NA was not able to reverse the reduced ability of IL-1 β-treated islets to respond to an acute glucose challenge. NO or nitrite did not interact directly with NA, because NA did not reduce sodium nitroprusside-generated nitrite. No-synthase inhibition with L-arginine depletion abolished NO production but only partially reduced IL-1 β-induced inhibition of accumulated insulin release. Complete inhibition of IL-1 β effects could not be obtained by adding L-arginine analogues to L-arginine-depleted medium, indicating that an NO-independent action of IL-1 β on islet insulin release may exist. These results suggest a novel mechanism for NA-mediated protection of IL-1–induced P-cell damage via an inhibitory effect of NA on the formation of NO.

HLA, Autoimmunity and Insulin-Dependent Diabetes Mellitus

The etiology and pathogenesis of juvenile diabetes mellitus (JDM), i. e., in sulin-dependent diabetes in nonobese individuals, are still poorly understood.

ANTI‐PANCREATIC, CELLULAR HYPERSENSITIVITY IN DIABETES MELLITUS. ANTIGENIC ACTIVITY OF FETAL CALF PANCREAS AND CORRELATION WITH CLINICAL TYPE OF DIABETES

Lymphocytic infiltration in and around the islets of Langerhans is a characteristic feature of juvenile diabetes mellitus of short duration (5, 6). The significance of this phenomenon still remains to be elucidated, but the observation is from the theoretic point easy to associate with the finding of anti-pancreatic, cellular hypersensltivity in diabetes mellitus (8), and both features suggest that celi-mediated immunity may play a role during the initial pathogenic phase of juvenile diabetes. In our preliminary work the anti-pancreatic, cellular hypersensitivity was demonstrated in patients with diabetes mellitus by means of the leucocyte migration test (LMT) (2) with a preparation of duct-ligated, porcine pancreas as antigen. The number of patients with diabetes examined, however, was small. The purpose of the present study has been: I) By means of the L M T to asses the occurrence of antipancreatic, cellular hypersensitivity in diabetes, using a pancreatic antigen prepared from another species.

Basement membrane thickness, insulin antibodies and HLA-antigens in long standing insulin dependent diabetics with and without severe retinopathy

SummaryThe study was designed to show whether there was any relation between muscle capillary basement membrane thickness, HLA-antigens, antiinsulin antibodies and proliferative retinopathy. Electron microscopic measurements of muscle capillary basement membrane thickness were performed on muscle biopsies from 15 insulin-dependent diabetics with severe proliferative retinopathy, 24 insulindependent diabetics with minimal retinopathy and 18 age-and sex matched non-diabetics. All the patients had had diabetes for 20 years or more. None had biochemical or clinical evidence of diabetic nephropathy. Basement membrane thickness was measured according to the methods of Siperstein and Williamson. Muscle capillary basement membrane thickening occurred in 32 of 39 diabetics, using the Siperstein method, but patients with proliferative retinopathy did not exhibit thicker basement membranes than patients with no or minimal changes in the retina. There were apparrent differences in HLA-antigens between diabetics with and without proliferative retinopathy, but they did not reach statistical significance. There was no correlation between muscle capillary basement membrane thickness and the quantity of insulin antibodies. The results indicate that factors other than basement membrane thickening and genetic factors in the HLA-region, are responsible for the development of proliferative retinopathy.

Iodine-concentrating cells in the endostyle of Ammocoetes

SummaryThe iodine-concentrating cells in the endostyle were examined in four larvae of petromyzon planeri. The visceral cells (types 2c, 3, and 4) were provided with cilia and contained granules with a characteristic content of concentric lamellae. Type 3 was particularly rich in ergastoplasm. The parietal cells (type 5) were short with a polymorphous content indicating a resorptive rather than a synthetic function. Based on the ultrastructure of the cells it has not been possible to decide which group forms the follicular epithelium in the petromyzone after metamorphosis, but it is most likely type 3 with its protein-synthetizing apparatus.

Irradiation Protects Against Pancreatic Islet Degeneration and Hyperglycaemia Following Streptozotocin Treatment of Mice

SummaryFive daily injections of streptozotocin (40 mg/kg) produce islet inflammation, necrosis of pancreatic B cells and hyperglycaemia in the mouse. Anti-pancreatic autoimmunity has been suggested as part of the cause of these events. We have studied the possible effect of total-body irradiation in long-term studies (246 days) and report here that insulitis, islet necrosis and insulin depletion are reduced after irradiation. In parallel the level of hyperglycaemia is reduced. It is concluded that immunological mechanisms are to some extent responsible for the development of streptozotocin-induced diabetes.

Repetitive Exposure of Pancreatic Islets to Interleukin-1β. An In Vitro Model of Pre-diabetes?

The slowly progressing loss of glucose tolerance over years before clinical onset of Type 1 (insulin-dependent) diabetes mellitus may be due to repetitive immunological attacks on the pancreatic beta-cell mass. Accordingly, we studied the effects of repetitive exposure of isolated rat pancreatic islets to the beta-cytotoxic immune-mediator interleukin-1 beta. Islets were exposed thrice to 60 U/ml of recombinant interleukin-1 beta for 24 hr. The islets were allowed to recover for 6 d between the interleukin-1 beta exposure periods. After each of the three interleukin-1 beta exposure periods, islet capacity to release insulin was decreased to 12, 6 and 3% of control, respectively, and islet insulin content decreased to 75, 56 and 21%, respectively. After the two recovery culture periods, the capacity for insulin release reversed to 75 and 30% of control, respectively. An increase in islet insulin content was only seen after the first recovery culture. During repetitive as well as long-term (6 d) interleukin-1 beta exposure of islets, medium accumulation of glucagon was either increased or unaffected. In analogy, beta-cells exposed to interleukin-1 beta for 6 d showed ultrastructural signs of degeneration and cytolysis, whereas alpha-cells were intact. In conclusion, interleukin-1 beta injury to beta-cells was partially reversible, but successive episodes of islet interleukin-1 beta exposure were increasingly detrimental; alpha-cell function and structure did not show susceptibility to damage by interleukin-1 beta. These findings may contribute to our understanding of islet cell behaviour before and during onset of Type 1 diabetes.

The influence of the major histocompatibility complex (H-2) on experimental diabetes in mice

SummaryMice with different histocompatibility loci on an identical background genome (congenic resistant lines of mice) were used to study the possible influence of the histocompatibility complex on experimental diabetes. The major histocompatibility complex (H-2) was not found to influence the diabetogenic effect of encephalomyocarditis (EMC) virus. In contrast the glucose intolerance following heterologous and homologous immunization with pancreatic antigens appeared H-2 influenced. Antibodies against cell surface components on viable B-cells were present in serum from mice with glucose intolerance induced by homologous immunization. The results suggest that the susceptibility to experimental autoimmune diabetes in mice is influenced by the H-2 complex.

THE CLINICAL SIGNIFICANCE OF INSULIN ANTIBODIES

Mild transient local reactions have been reported to appear with frequencies from 5 to 50 per cent (6, 10, 18, 20). On the other hand, severe generalized, even anaphylactic reactions have been rare. Frequencies from 0.2 to 1.0 per cent have been observed (3, 10). Kniker (12) and Dolovitch et al. (8) have shown IgA and especially IgE to be responsible in most cases. Jorpes (l l) , Yalow &z Berson (20), Deckert (4) and Federlin et al. (9) found, that contaminating impurities in the insulin preparations were responsible for the reactions. During treatment with recrystallized or highly purified insulin preparations allergic reactions have been curiosities.