Diabetic BB Rats Research Articles

Pancreatic islet function in nondiabetic and diabetic BB rats.

A decreased acute insulin response to glucose in islet cell antibody positive humans predicts diabetes. Because the dominant mechanism leading to decreased in vivo acute insulin response to glucose remains unclear, perifused islets were examined before and after diabetes onset in BB rats to assess the role of glucose sensitivity on insulin secretion in individual islets. Islets from normal WF rats, diabetes-prone rats without inflamed islets, diabetes-prone rats with inflamed islets, and diabetic rats were studied at 2.0, 8.3, and 16.7 mM glucose. Immunoreactive insulin from WF islets at 16.7 mM glucose was 0.15 +/- 0.02 ng.0-7 min-1 x islet-1 for the first phase and 1.00 +/- 0.05 ng.7-20 min-1 x islet-1 for the second phase of biphasic secretion, compared with basal secretion of 0.10 +/- 0.03 ng.20 min-1 x islet-1 at 2 mM glucose. Diabetes-prone noninflamed islets showed a 0.20 +/- 0.03 ng first-phase secretion, a 1.32 +/- 0.13 ng second-phase secretion after 16.7 mM glucose, and 0.093 +/- 0.02 ng.20 min-1 x islet-1 at 2 mM glucose, indicating no intrinsic BB rat strain secretion abnormality. Diabetes-prone inflamed islets had secretions of 0.35 +/- 0.02 ng during the first phase (P < 0.05 vs. WF) and 1.78 +/- 0.29 ng during the second phase (P < 0.05 vs. WF) after 16.7 mM glucose, with 0.24 +/- 0.08 ng.20 min-1 x islet-1 at 2 mM glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Pancreatic islet function in nondiabetic and diabetic BB rats

Pancreatic islet function in nondiabetic and diabetic BB rats

The activation of the arginine-citrulline cycle in macrophages from the spontaneously diabetic BB rat

The activity of the arginine-citrulline cycle was investigated in macrophages from the spontaneous immunologically mediated diabetic BB rat. Peritoneal macrophages were prepared from male diabetes-prone (BBdp), diabetic (BBd) and age-matched non-diabetes-prone (BBn) rats. Cells were incubated at 37 degrees C for 2 h in Krebs-Henseleit bicarbonate buffer containing 0.5 mM L-arginine, 0.1 mM L-[ureido-14C]citrulline and 5 mM D-glucose to measure the activity of the arginine-citrulline cycle. The uptakes of citrulline and arginine by macrophages were measured during a 5 min incubation period with L-[ureido-14C]citrulline and L-[2,3-3H] arginine respectively. The production of NO3- (the major stable oxidation product of NO) increased (P < 0.01) by 112% and 151% in 75-day-old BBdp and 115-day-old BBd macrophages respectively, compared with age-matched BBn cells. The conversion of [14C]citrulline into [14C]arginine increased (P < 0.01) by 704%, 892% and 904% in 50- and 75-day-old BBdp and 115-day-old BBd macrophages respectively, compared with age-matched BBn cells. The enhanced NO synthesis in BBdp and BBd macrophages was associated with a 25-35% increase in the uptake of L-arginine. However, there were no differences in the uptake of citrulline between BBdp or BBd macrophages and age-matched BBn cells. Our results demonstrate for the first time the activation of the arginine-citrulline cycle in macrophages in an autoimmune condition. The inherent increase in the recycling of L-citrulline to L-arginine in BBdp and BBd macrophages may reflect an innate metabolic disorder in these cells. This increased L-arginine synthesis from L-citrulline may play a role in sustaining a sufficient intracellular L-arginine concentration for prolonged generation of NO in BBdp and BBd macrophages. A role for NO in the autoimmune destruction of pancreatic beta-cells in insulin-dependent diabetes mellitus warrants further investigation.

Increased clearance of 1,25(OH)2D3 and tissue-specific responsiveness to 1,25(OH)2D3 in diabetic rats

The kinetics of 1,25-dihydroxyvitamin D3 [1,25(OH)2-D3] and the in vivo response to 1,25(OH)2D3 (7.5, 15, and 30 ng/100 g body wt), infused or injected subcutaneously for 12-14 days, were studied in male spontaneously diabetic and control BB rats. In control rats, increasing doses of 1,25(OH)2D3 produced parallel increases in plasma 1,25(OH)2D3 and calcium, urinary calcium, duodenal CaBP9K, and renal CaBP28K. 1,25-(OH)2D3 at 30 ng/100 g markedly raised plasma osteocalcin and osteoblast/osteoid surfaces in the tibial metaphysis, but inhibited bone mineralization rate. In diabetic rats, plasma 1,25-(OH)2D3 concentrations were decreased, and the rise of plasma 1,25(OH)2D3 during 1,25(OH)2D3 infusion was blunted, but the free 1,25(OH)2D3 index remained normal or above normal. Diabetic rats had an increased metabolic clearance rate of 1,25-(OH)2D3 (0.38 +/- 0.015 vs. 0.24 +/- 0.007 ml.min-1.kg-1), with no further increase in 1,25(OH)2D3-infused diabetic rats; their relative production rate of 1,25(OH)2D3 was unchanged. The responses of plasma and urinary calcium, duodenal CaBP9K, and renal CaBP28K to infused 1,25(OH)2D3 were normal, as was duodenal calcium absorption in 1,25(OH)2D3-injected diabetic rats. However, the virtual absence of osteoblasts/osteoid in trabecular bone was unaltered in diabetic rats infused with 30 ng/100 g 1,25(OH)2D3, with only minimal increase of their low plasma osteocalcin levels. 1,25(OH)2D3 treatment therefore cannot be expected to reverse diabetic osteopenia.

Effect of insulin on the altered thyroid function and adrenergic responsiveness in the diabetic rat

We have previously reported the tail skin temperature response to isoproterenol as being significantly attenuated in male rats 4 weeks after the induction of diabetes with streptozotocin. The current study evaluated the time course of this altered adrenergic responsiveness and the role of thyroid hormone and insulin treatment in the tail skin temperature response. In the first study, the tail skin temperature response to isoproterenol was monitored weekly, for 6 weeks. The tail skin temperature response was similar in control and diabetic animals after 1 week of streptozotocin treatment. However, after 2, 4, 5, and 6 weeks of diabetes the tail skin temperature response was significantly reduced. Total T3, T4, and free T4 concentrations were also significantly reduced in these diabetic animals. In a second study, the effects of graded doses of insulin treatment on thyroid hormone levels was assessed. The reduced thyroid hormone concentrations observed in untreated streptozotocin-diabetic rats were restored towards control levels in animals receiving the lowest dose of insulin (1 U/day), whereas higher doses of insulin were required to more closely restore euglycemia and lower glycated hemoglobin. A subsequent study, utilizing a 1-U/day dose of insulin, resulted in a normalization of the tail skin temperature response to isoproterenol, during 8 weeks of treatment in the treated diabetic rat. In a final study utilizing the spontaneous BB diabetic rat maintained on daily insulin treatment, no differences in the tail skin temperature response or thyroid hormone levels were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased weight gain in BB rats before the clinical onset of insulin-dependent diabetes

Inbred specific pathogen-free diabetes-prone (DP) and diabetes-resistant (DR) BB rats were crossed to produce F 1 and intercrossed to produce F 2 rats. Diabetes segregates in these crosses as a recessive trait on rat chromosome 4. The weight gain of genetically diabetes-prone rats born to F 1 healthy parents was studied to avoid effects of maternal diabetes. The weight gain of the F 2 rats was initially not different from the F 1 parents. The F 2 rats later developing diabetes grew in parallel with their non-affected siblings up until the last 9 days before onset. During these 9 days they showed a decreased weight gain compared to their healthy litter-mates regardless of age. We conclude that decreased weight gain precedes the abrupt clinical onset of diabetes in BB rats and that it may be due to processes associated with the selective loss of β cells.

Sulphatide antigen in islets of Langerhans and in diabetic glomeruli, and anti-sulphatide antibodies in type 1 diabetes mellitus.

Clinical coincidence between diabetes and neurological disorders, and sharing of antigen determinants between islets of Langerhans and neural tissue, has been suggested. Sulphatide is a neural epitope which can be visualized with a monoclonal antibody Sulph I. Different tissues were examined by immunohistological methods. Sulphatide and anti-sulphatide antibodies were determined by thin-layer chromatographic techniques. IgG was isolated using protein A columns. A specific staining by Sulph I was found of rat islets, assigned to the secretory granules of both alpha and beta cells. No labelling of the exocrine tissue or other body tissues was seen, except for nerve and kidney structures. The latter showed staining of the distal tubules and, in addition, but only in the diabetic kidney, of glomeruli located in the subendothelial area in the capillary loops and the mesangial space. Sera from 38% of 40 spontaneously diabetic BB rats displayed anti-sulphatide antibodies, mainly IgG, whereas all 30 control Lewis rats were negative. Most recently we have demonstrated anti-sulphatide antibodies in 88% of 57 patients with newly diagnosed Type 1 diabetes (titres of > 1:400); all 135 healthy control persons were negative. The sulphatide antibody reactivity was present in the IgG fractions of the patients' sera. Thus, sulphatide is demonstrated in islets of Langerhans and in kidney related to the diabetic lesion, and, furthermore, anti-sulphatide antibodies exist in Type 1 diabetes mellitus.

Abnormal Activity in Diabetic Rat Saphenous Nerve

This study was conducted to test whether abnormal spontaneous activity similar to that found after peripheral nerve trauma develops in diabetic nerve, and whether duration and/or severity of hyperglycemia affected ongoing activity. We maintained 32 diabetic BB Wistar rats on a euglycemic or hyperglycemic control regimen for 3-15 mo; 22 nondiabetic BB rats served as controls. All animals underwent acute saphenous nerve recordings. Whole nerve conduction velocities in 3- to 6-mo-old euglycemic diabetic rats were not different from controls, but 3- to 6-mo-old hyperglycemic diabetic conduction velocities were slower than in controls (P < 0.001) or euglycemic diabetic rats (P < 0.05). Compared with controls, 9- to 12-mo-old diabetic nerve conduction velocities were slower under both euglycemic (P < 0.029) and hyperglycemic (P < 0.04) regimens, but treatment groups did not differ. Combined 3- to 6-mo-old diabetic rats exhibited less resting sympathetic activity than controls under both euglycemic (P < 0.022) and hyperglycemic (P < 0.001) regimens. Sympathetic activity in 9- to 12-mo-old diabetic rats did not differ from controls. However, less sympathetic activity was found in older controls than in younger ones (P < 0.028). 1) saphenous nerve conduction velocity was slower in diabetic BB rats than in controls; 2) good glycemic control maintained normal conduction velocity in young adults, but the effect diminished with age; 3) resting sympathetic activity levels in young adult BB rats were lower than controls; and 4) sympathetic activity in old BB rats was diminished whether diabetes was present or not.

Sympathetic autonomic neuropathy in the heart of the spontaneous diabetic BB rat

There is evidence that autonomic nerves are disturbed in spontaneous diabetic BB rats indicating a peripheral diabetic autonomic neuropathy. For histofluorescent visualization of catecholamine containing nerve fibres in myocardium the method of De La Torre was applied. For electron microscopy, tissue specimens of ventricular and atrial myocardium were prepared. In myocardium of BB rats diabetic for 28 weeks morphometric quantification of catecholamine histofluorescence revealed a loss of fluorescent nerve fibres and varicosities of 57% from 1.18 +/- 0.17 to 0.51 +/- 0.18 per cent of the total field area (p < 0.009). Ultrastructurally, morphometric quantification of the density of axon profiles containing synaptic vesicles in transverse sectioned atrial myocardium showed a decrease of 42% (p < 0.021) in the diabetic group. In the diabetic nerves, axoplasmic lysis and a reduction in the Schwann cell envelope were prominent. Morphologic changes of nerves in ventricles were comparable to the findings in atrial tissue. It is concluded that a diabetic autonomic neuropathy of intramural sympathetic nervous tissue occurs in myocardium of spontaneous diabetic BB rats despite insulin substitution.

Normalization of Decreased Plasma Concentrations of Growth Hormone-Binding Protein by Insulin Treatment in Spontaneously Diabetic BB Rats

Normalization of Decreased Plasma Concentrations of Growth Hormone-Binding Protein by Insulin Treatment in Spontaneously Diabetic BB Rats

Enhanced glucose metabolism and respiratory burst in peritoneal macrophages from spontaneously diabetic BB rats.

Glucose metabolism and respiratory burst were studied in vitro in resident peritoneal macrophages from non-diabetes-prone BB, spontaneously diabetic BB, diabetes-prone BB, and STZ-induced diabetic BBn rats, in the presence or absence of phorbol myristate acetate plus ionomycin. Glycolysis and pentose phosphate pathway activity were increased in BBd compared with BBn cells. PMA plus IONO did not influence glycolysis in BBn macrophages and slightly decreased it in BBd macrophages. In contrast, PMA plus IONO increased the pentose phosphate pathway activity in BBn and BBd macrophages with a much greater increase in BBd cells. The release of O2- was greater in BBd than BBn cells; PMA plus IONO also induced a much greater release of O2- in BBd cells. H2O2 release was undetectable in unstimulated BBn cells, and stimulation by PMA plus IONO caused a small incremental release. In contrast, the release of H2O2 was measurable in unstimulated cells and further increased by 50% in BBd cells with PMA-plus-IONO stimulation. The release of O2- and H2O2 was increased in macrophages from 75-day-old BBdp rats but not in 50-day-old BBdp rats, compared with age-matched BBn rats. No differences were observed in either glucose metabolism or release of O2- and H2O2 between BBn and STZ-BBn cells in the absence or presence of PMA plus IONO. These data suggest that enhanced oxidative metabolism in BBd macrophages is unlikely to be attributable to diabetes per se.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes mellitus induced inhibition of glucosaminyl N-deacetylase: effect of short-term blood glucose control in diabetic rats.

Inhibition of glucosaminyl N-deacetylase activity, a key enzyme in heparan sulphate sulphation, may be involved in the development of late diabetic vascular complications. We examined the effect of short- and long-term metabolic control on N-deacetylase activity in streptozotocin diabetic H and U rats. Spontaneously diabetic BB rats were included in parts of the study. Over a 3-week period blood glucose was maintained at predetermined levels (6-10 mmol/l or 10-20 mmol/l) by insulin treatment and then during the final 2 days rapidly reversed in half of each group. In the U rats, the hepatic N-deacetylase activity significantly decreased by 10-15% following short- and long-term poor metabolic control and the inhibition was entirely reversed by short-term good control. In the H rats a similar, not significant, effect was seen. BB rats in long-term poor control showed a 10% reduction in hepatic N-deacetylase activity (p = 0.003). Glomerular N-deacetylase activity was reduced in U rats after long-term poor control (p = 0.004) but not in H and BB rats. There was an overall correlation between urinary albumin excretion and glomerular N-deacetylase activity (r = -0.60, p < 0.0001). We conclude that diabetes-induced inhibition of hepatic N-deacetylase is not restricted to the streptozotocin diabetic model, and that short-term blood glucose control is of major importance. Genetic factors and tissue specificity influence the vulnerability of the enzyme. Finally, the study suggests an association between N-deacetylase activity and urinary albumin excretion.

Enhanced glucose metabolism and respiratory burst in peritoneal macrophages from spontaneously diabetic BB rats

Enhanced glucose metabolism and respiratory burst in peritoneal macrophages from spontaneously diabetic BB rats

CD8+ T-cells are required for adoptive transfer of the BB rat diabetic syndrome.

LGLs with NK activity account for the majority of BB rat PBLs expressing CD8, and it has been suggested that these LGL/NK cells are involved in the pathogenesis of the BB rat diabetic syndrome. By using a recently developed mouse MoAb, 3.2.3, specific for rat LGL, we demonstrate that BB and WF rat LGLs are phenotypically and functionally similar. To directly assess the role of LGLs in the development of diabetes in vivo, an adoptive transfer of T-cells to young LGL/NK cell-depleted diabetes-prone BB rats was performed. CD4+8- and CD4-8+ T-cells (> 98.5% pure), isolated from diabetic BB rats, were activated in vitro and injected into 30-day-old diabetes-prone BB rats. Recipients were either chronically injected with 3.2.3 (n = 15) or received an isotype-matched irrelevant MoAB (n = 14). Secondary lymphoid organs of 3.2.3-treated recipients contained < 0.1% 3.2.3+ lymphocytes, and this depletion was associated with a major decrease in the NK activity of their splenocytes. Despite this, the incidence of diabetes in 3.2.3-treated animals (40%) was not significantly different from that observed in control recipients (57%). Thus, the BB rat diabetic syndrome can be adoptively transferred in the absence of LGL/NK cells, suggesting that BB rat CD8+ T-cells are involved in the diabetogenic process. To assess the pathogenic role of CD8+ T-cells, we compared the incidence of diabetes in three groups of diabetes-prone BB recipients after injection of T-cells isolated from diabetic donors.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of diabetes and induction of non-specific suppressor cell activity in the BB rat by an immunomodulatory azaspirane, SK&F 106610.

Immunomodulatory azaspirane compounds have immunosuppressive activity in animal models of autoimmune disease such as adjuvant-induced arthritis and experimental autoimmune encephalomyelitis. The mechanism of action of azaspiranes appears to be the induction of antigen non-specific (natural) suppressor cell activity. In this study, we tested the azaspirane, SK&F 106610 in an animal model of autoimmune (type 1) diabetes, the BB rat. Oral administration of SK&F 106610 (15 mg/kg/day) to diabetes-prone BB rats, from age 30 days, significantly decreased diabetes incidence at 100 days from 80% (24 of 30 control rats) to 32% (10 of 31 drug-treated rats, P < 0.001). Protection from diabetes by SK&F 106610 was accompanied by decreased lymphocytic infiltration of the pancreatic islets (insulitis). No changes occurred in splenic T cell, B cell or macrophage subsets, or in proliferative responses to the mitogens lipopolysaccharide and concanavalin A (Con-A). Cell mixing experiments in vitro, however, revealed increased antigen non-specific suppressor activity (suppression of splenic lymphoproliferative response to Con-A) in spleens of SK&F 106610-treated rats. The suppressor cell activity was enriched in a low density fraction of splenic cells relatively depleted of T cells, B cells, macrophages and natural killer cells. These results indicate that the azaspirane compound, SK&F 106610 can prevent insulitis and autoimmune diabetes in BB rats and that these actions may be related to the activation of non-specific (natural) suppressor cells.

Synergy between tetrandrine and FK 506 in prevention of diabetes in BB rats

Delayed administration of tetrandrine, a novel broad-spectrum anti-inflammatory agent, to BB rats at a dosage schedule of 20 mg kg −1 day −1 from 79 days of age reduced the cumulative incidence of diabetes from 73.1 to 41.7% (p<0.01). Brief treatment with the potent immunosuppressive agent FK506 at a dosage schedule of 0.5 mg kg −1 day −1 from 79 days of age for 5 days had no significant effect on the cumulative incidence of diabetes (66.7%, p > 0.1). However, the combination of tetrandrine and FK506 in the afore-mentioned dosage schedules reduced the incidence of diabetes to only 3.6% (p <0.001). These results suggest that the strong synergy between tetrandrine and FK506 may offer a safe and effective therapeutic strategy for the treatment of patients with recent onset or imminent IDDM.

Protection from BB rat diabetes by the platelet-activating factor inhibitor BN50730.

The platelet-activating factor inhibitor BN50730, a hetrazepine, was injected intraperitoneally daily from 30 days of age into diabetes-prone BB rats. While 96% (22/23) Tween 80 injected control rats developed diabetes, 0.05 mg/kg BN50730 decreased the frequency to 72% (17/24; n.s.) and 0.5 mg/kg to 56% (14/25; p < 0.01). Mean onset age in controls was 81 +/- 9 days (mean +/- SD), but BN50730 delayed onset to 87 +/- 15 days in the low and 93 +/- 12. days (p < 0.01) in high dose rats. The relative degree of insulitis was reduced in both low (p < 0.01) and high (p < 0.05) dose treated groups. Serum insulin in young prediabetic controls decreased from 84 +/- 34 microU/ml to 38 +/- 20 in the 22 rats developing diabetes (p < 0.001). Serum insulin in BN50730-protected compared to unprotected rats was 114 +/- 49 and 32 +/- 22 (p < 0.001) in the low, and 91 +/- 46 and 21 +/- 15 (p < 0.001) microU/ml in the high dose group, respectively. Increased serum insulin correlated with preserved islet beta cells and decreased insulitis. Treatment did not affect thyroiditis. Thus, platelet-activating factor may be involved in insulitis pathogenesis and platelet-activating factor inhibitors may decrease autoimmune beta cell destruction.

Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation.

In the present study, we have measured protein kinase C (PKC) specific activities and total diacylglycerol (DAG) level in the aorta and heart of rats, which showed that after 2 weeks of streptozotocin (STZ)-induced diabetes, membranous PKC specific activity and total DAG content were increased significantly by 88% and 40% in the aorta and by 21% and 72% in the heart, respectively. Hyperglycemia was identified as being a causal factor since elevated glucose levels increased DAG levels in cultured aortic endothelial and smooth muscle cells. Analysis by immunoblotting revealed that only alpha and beta II PKC isoenzymes are detected in these two tissues and vascular cells among those studied. In STZ-induced diabetic rats, beta II isoenzyme is preferentially increased in both aorta and heart, whereas PKC alpha did not change significantly. The increases in membranous PKC specific activity and DAG level are observed in both spontaneous diabetes-prone diabetic BB rats as well as in STZ-induced diabetic BB and Sprague-Dawley rats, which persisted for up to 5 weeks. After 2 weeks of diabetes without treatment, the normalization of blood glucose levels for up to 3 weeks with islet cell transplants in STZ-induced diabetic BB rats reversed the biochemical changes only in the heart, but not in the aorta. These results suggest that PKC activity and DAG level may be persistently activated in the macrovascular tissues from diabetic animals and indicate a possible role for these biochemical parameters in the development of diabetic chronic vascular complications.

Insulin response of cultured islets from diabetic and nondiabetic BB rats

This study examines the insulin response of pancreatic islets isolated from diabetic BB rats (BBD), nondiabetic BB rats (BBN), and Wistar rats to in vitro stimulation. After a 48-hour culture period, insulin release in response to glucose (17.8 mmol/L) either alone, with glucose-dependent insulinotropic polypeptide (GIP) ± somatostatin (SS), or with Arg ± SS was measured. A static incubation system was used. Insulin secretion from islets cultured in 4.4 mmol/L glucose (basal) did not differ between BBN and BBD rats (0.50% ± 0.08%, 0.67% ± 0.25% of total islet cell content [TCC], respectively). High glucose concentrations (17.8 mmol/L) stimulated a modest increase in insulin release from BBD and BBN islets (1.8% ± 0.48% and 2.1% ± 0.19% TCC, respectively). The addition of GIP (1 nmol/L) enhanced glucose-stimulated insulin secretion from BBN rat islets (2.9% ± 0.42% TCC), but had no effect on BBD islets (2.04% ± 0.57% TCC). Somatostatin (1 μmol/L) completely reversed the glucose- and/or GIP-stimulated insulin secretion from both BBN and BBD rat islets to basal levels (0.42% ± 0.043%, 0.42% ± 0.09% TCC, respectively). Arg (1 mmol/L) enhanced glucose-stimulated insulin secretion in both groups, although the greatest response was elicited from BBD rat islets (8.4-fold v 3.2-fold). Experiments comparing BB rats with Wistar rats demonstrated significant differences in the glucose-stimulated (17.8 mmol/L) insulin response of the islets. Islets taken from BBN and BBD were less responsive to glucose than those from Wistar rats. However, islets from BBD rats were hyperresponsive to Arg when compared with islets from Wistar rats. These data indicate that there are significant differences in insulin secretion between Wistar and BB rats.

Delayed onset and decreased incidence of diabetes in BB rats fed free radical scavengers

We tested the hypothesis that free radicals play a role in the selective destruction of pancreatic beta-cells in BB Wor rats. Diabetes-prone BB rats of both sexes and 40 days of age were divided into three groups. The control group was fed ad libitum Purina rat chow powder, while the experimental group was fed ad libitum the rat chow powder blended with a mixture of four known free radical scavengers: allopurinol, mercaptopropionylglycine, dimethylthiourea and Vitamin E. A third group was pair-fed 10 g chow powder/rat/day, since in earlier experiments we observed that rats on the experimental diet consumed only about 10 g/rat/day. All rats were studied up to age 120 days. Body weight and food intake were measured daily. Urine was tested for glucose beginning at age 60 days. When glucosuria appeared, blood glucose and urinary ketones were measured. Body weight gain in the experimental and pair-fed groups was similar, but lower than the control group. Life table analysis of the data showed a decreased and a delayed onset of diabetes in the rats fed free radical scavengers. Thus, the results of this study demonstrated that calorie restriction and the related impaired growth did not affect the incidence of diabetes in the BB rat. In addition, the results suggested a role for free radicals in the spontaneous destruction of pancreatic beta-cells in the BB rat.