Distribution of elements and water in peripheral nerve of streptozocin-induced diabetic rats

Accumulating evidence suggests that alterations in Na, Ca, K, and other biologically relevant elements play a role in the mechanism of cell injury. The pathogenesis of experimental diabetic neuropathy is unknown but might include changes in the distribution of these elements in morphological compartments. In this study, this possibility was examined via electron-probe X-ray microanalysis to measure both concentrations of elements (millimoles of element per kilogram dry or wet weight) and cell water content (percent water) in frozen, unfixed, unstained sections of peripheral nerve from control and streptozocin-induced diabetic rats. Our results indicate that after 20 wk of experimental diabetes, mitochondria and axoplasm from myelinated axons of proximal sciatic nerve displayed diminished K and Cl content, whereas in tibial nerve, the intraaxonal levels of these elements increased. In distal sciatic nerve, mitochondrial and axoplasmic levels of Ca were increased, whereas other elemental alterations were not observed. These regional changes resulted in a reversal of the decreasing proximodistal concentration gradients for K and Cl, which exist in nondiabetic rat sciatic nerve. Our results cannot be explained on the basis of altered water. Highly distinctive changes in elemental distribution observed might be a critical component of the neurotoxic mechanism underlying diabetic neuropathy.     

Decreased fluidity of polymorphonuclear leukocyte membrane in streptozocin-induced diabetic rats

Using flow cytometry with the excimer-forming lipid technique with pyrenedecanoic acid, we measured membrane fluidity of polymorphonuclear leukocytes (PMNs) from 20 streptozocin (STZ)-induced diabetic rats. Diabetes mellitus was induced in male Sprague-Dawley rats (body wt 243 +/- 11 g) with an injection of 25 mg/kg i.v. STZ. Membrane fluidity of PMNs was significantly lower at 2 wk after the STZ injection when serum glucose reached the plateau (31.1 +/- 5.8 mM), and after 3 wk, membrane fluidity remained unchanged. In 7 STZ-resistant rats for which serum glucose was less than 10 mM at 2 wk after the STZ injection, gradual normalization in membrane fluidity was observed. PMN membrane fluidity at each week correlated inversely with respective serum glucose levels 1 wk previously (r = -0.76) but not with serum lipid levels. Cross-incubation studies ascribed this observation to factors in the diabetic rat serum. Glycosylated protein, which was separated from diabetic rat serum, decreased membrane fluidity of control rat PMNs. Human diabetic subjects have an increased risk for infection, which may be due partly to altered membrane fluidity of their PMNs.     

Lipogenesis from ketone bodies in perfused livers from streptozocin-induced diabetic rats

Production of ketone bodies and their contribution to lipogenesis were measured in isolated livers from normal and streptozocin-induced diabetic (STZ-D) rats perfused with tracer amounts of 3H2O and (R)-3-hydroxy[3-14C]butyrate. Diabetes decreased by 80-95% the total rates of fatty acid and 3-beta-hydroxysterol synthesis in perfused livers and livers of live rats. The activity of cytosolic acetoacetyl-CoA synthetase was slightly (17%) decreased in livers from STZ-D rats. The incorporation of ketone bodies into fatty acids and sterols was markedly inhibited in perfused livers from STZ-D rats despite the stimulation of ketogenesis by diabetes and the presence of oleate. Treatment of the rats with insulin before liver perfusion led to a normalization of the rates of ketogenesis and fatty acid synthesis. The rates of sterol synthesis were only partially normalized by insulin treatment. We conclude that in STZ-D, ketosis does not stimulate hepatic lipogenesis via cytosolic activation of acetoacetate.     

Essential fatty acid diet supplementation. Effects on peripheral nerve and skeletal muscle function and capillarization in streptozocin-induced diabetic rats

Effects of essential fatty acids on nerve conduction, hypoxic resistance, skeletal muscle contractile properties, and capillary density were examined in streptozocin-induced diabetic rats. Nondiabetic and diabetic controls and three diabetic groups treated with 10% supplements of corn oil, evening primrose oil (Efamol), or a mixture of 80% evening primrose oil and 20% fish oil (Efamol Marine) for 2 mo were used. Efamol and Efamol Marine increased plasma gamma-linolenic acid levels, but arachidonic acid was elevated only with Efamol. Diabetes resulted in 15-29% reductions in sciatic motor and sensory saphenous nerve conduction velocity. Efamol prevented conduction deficits more effectively than Efamol Marine, and corn oil had no effect. In vitro measurement of sciatic nerve hypoxic resistance revealed a 49% increase in the time taken for action potential amplitude to decline by 50% with diabetes. Corn oil had no significant effect. With Efamol, hypoxic resistance was within the nondiabetic range. Efamol Marine produced intermediate results. Functional improvements may relate to enhanced vasa nervorum perfusion, because endoneurial capillary density increased by 22% with Efamol, angiogenesis perhaps resulting from eicosanoid production from arachidonic acid. Soleus muscle contractions were prolonged by diabetes. This was partially corrected by treatment, Efamol being most effective. Extensor digitorum longus muscle had reduced tetanic tension with diabetes, and this was prevented by all treatments. Soleus showed a modest increase in capillarization with Efamol, which may have contributed to reduced susceptibility to fatigue. The data suggest involvement of abnormal fatty acid metabolism in the etiology of diabetic neuropathy and myopathy.     

Beneficial effect of Org 2766 in treatment of peripheral neuropathy in streptozocin-induced diabetic rats

An injection of streptozocin (STZ) was used to study diabetes-induced peripheral neuropathy in rats. In such rats the values of motor nerve conduction velocity and sensory nerve conduction velocity were decreased compared with the values obtained in nondiabetic controls from 3 wk after STZ injection onward. In recent years it has been extensively documented that peptides related to ACTH and MSH exert a neurotrophic effect on the nervous system that results in enhanced recovery of function after mechanical nerve damage. This article documents the beneficial effect of the peptide Org 2766, an ACTH-(4-9) analogue, in diabetic peripheral neuropathy. Chronic subcutaneous treatment of diabetic rats with Org 2766 results in a significant enhancement of both motor and sensory nerve conduction velocity compared with saline-treated diabetic rats. Histological analysis of cross sections of the sural nerve showed no difference in the total number of nerve fibers in saline- or peptide-treated diabetic rats. In contrast, a difference in fiber size distribution was demonstrated; i.e., the sural nerves of diabetic rats contained fewer thick myelinated fibers. Treatment with Org 2766 resulted in a normal distribution. Apparently, the peptide Org 2766 has a protective action on nerve fibers and nerve function during STZ-induced diabetes.     

Altered protein phosphorylation in sciatic nerve from rats with streptozocin-induced diabetes

The effect of experimental diabetes on the phosphorylation of proteins in the rat sciatic nerve was studied. Nerves from animals made diabetic with streptozocin were incubated in vitro with [32P]orthophosphate and divided into segments from the proximal to the distal end, and proteins from each segment were then separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The principal labeled species were the major myelin proteins, P0, and the basic proteins. After 6 wk of diabetes, the incorporation of isotope into these proteins rose as a function of distance along the nerve in a proximal to distal direction and was significantly higher at the distal end compared with incorporation into nerves from age-matched controls. The overall level of isotope uptake was similar in nerves from diabetic animals and weight-matched controls. The distribution of 32P among proteins also differed in diabetic nerve compared with both control groups in that P0 and the small basic protein accounted for a greater proportion of total label incorporated along the entire length of nerve. In contrast to intact nerve, there was no significant difference in protein phosphorylation when homogenates from normal and diabetic nerve were incubated with [32P]-gamma-ATP. The results suggest that abnormal protein phosphorylation, particularly of myelin proteins, is a feature of experimental diabetic neuropathy and that the changes are most pronounced in the distal portion of the nerve.     

螺内酯对糖尿病大鼠肾小球保护作用的机制探讨

目的 观察螺内酯对糖尿病大鼠肾小球的保护作用并探讨其机制。 方法 将SD大鼠随机分为健康对照组、病理组、螺内酯治疗组。治疗30 d后处死，观察肾小球病理形态变化；RT-PCR法观察肾脏皮质纤溶酶原激活剂抑制物1(PAI-1) 和转化生长因子β1(TGF-β1)mRNA的变化； Western印迹法观察肾脏皮质PAI-1的表达；免疫组化方法观察肾脏皮质TGF-β1、纤连蛋白(FN)变化及检测肾皮质丙二醛(MDA) 含量、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px) 、总抗氧化能力(T-AOC)活性。 结果 与病理组比，螺内酯治疗后可下调肾皮质TGF-β1、PAI-1 mRNA与蛋白表达（P均< 0.05）；降低肾皮质MDA水平[（0.95±0.20）比（1.23±0.31） nmol/mg，P < 0.05]；增强SOD、GSH-Px、T-AOC活性[分别为（550.19±20.06）比（509.53±33.25） U/mg，（21.67±2.70）比（18.91±2.30） U/mg，（1.15±0.21）比（0.86±0.26） U/mg，P均< 0.05]；减少FN在肾小球的沉积(P < 0.01)；改善肾小球的病理状况。 结论 螺内酯可能通过下调糖尿病大鼠肾皮质TGF-β1、PAI-1表达，降低肾皮质氧化应激水平，起到保护糖尿病大鼠肾脏，延缓肾小球硬化的作用。     

Alterations in retrograde axonal transport in streptozocin-induced diabetic rats

Retrograde axonal transport in the sciatic nerve of rats with streptozocin-induced diabetes was studied by the [3H]N-succinimidyl propionate [( 3H]NSP) method. The accumulation of retrogradely transported labeled proteins in the dorsal root ganglia and the ventral horn of spinal cord 1 day after [3H]NSP injection was not statistically significantly different from controls in rats diabetic for 1 or 14 days at the time of [3H]NSP injection. However, accumulation of labeled proteins in the dorsal root ganglia 7 days after [3H]NSP injection was reduced by 35% and transport to the ventral horn of spinal cord 7 days after [3H]NSP injection was reduced by 70% at the same time points. Partial control of the diabetes with insulin resulted in a partial reversal of these deficits. The early occurrence of defects in retrograde transport suggests that such defects may play a role in the pathogenesis of the neuropathy.     

Autoregulation of renal blood flow in streptozocin-induced diabetic rats

Autoregulation of renal blood flow (RBF) was studied in male Wistar rats. We studied 11 control rats, 11 rats with severe streptozocin (STZ)-induced hyperglycemia (diabetic group), and 10 moderately hyperglycemic rats made diabetic by injection of STZ but given 2-8 U s.c. insulin daily (insulin-treated group). RBF was measured by an electromagnetic flowmeter during stepwise reduction of renal perfusion pressure 4-8 wk after injection of STZ (older group). RBF autoregulation of the diabetic group was impaired compared with the control group. In the insulin-treated group, autoregulatory capability was less attenuated than in the diabetic group. The average autoregulatory index (ARI) of the diabetic group (0.61 +/- 0.05) was greater than that of the control (0.24 +/- 0.02, P less than .01) and the insulin-treated (0.33 +/- 0.07, P less than .05) groups. To study the relationship between autoregulation and the duration of diabetes, an autoregulatory study was also made in a group of 22 rats (11 diabetic and 11 control) that were tested 2-3 wk after injection of STZ (younger group). The ARI in the younger diabetic group was smaller than that in the older diabetic group (P less than .05). The results suggest that in uncontrolled diabetes RBF fluctuates with blood pressure change, and protection against hypertensive injury of glomerular capillaries may be diminished. Autoregulatory disability develops with time, and insulin treatment diminishes impairment of autoregulation. These findings may also explain the adverse consequences of hypertension on the progression of diabetic nephropathy in poorly controlled diabetes.     

Deficiency of cardiac beta-adrenergic receptor in streptozocin-induced diabetic rats

The number of beta-adrenergic receptors in cardiac myocytes isolated from rats made diabetic with streptozocin (STZ) for 10 wk was measured by use of a hydrophilic nonselective antagonist [3H]CGP 12177 and was found to decrease to 59% of the number in control rats (P less than .05), without any change in affinity. Similarly, using [125I]iodocyanopindolol as a ligand, we found a decrease in the beta-adrenergic-receptor number on cardiac plasma membrane isolated from the diabetic rats [29% decrease (P less than .05) at 1 wk, 50% (P less than .01) at 3 wk, and 49% (P less than .01) at 10 wk compared with control rats]. However, the serum triiodothyronine level that had been known to modulate the beta-adrenergic-receptor-adenylate cyclase system was decreased in the 1-wk-diabetic rats but not in the 10-wk-diabetic rats compared with each control group. Furthermore, there was no difference in urinary catecholamine excretion between diabetic and control groups. In the 10-wk-diabetic rats, the response of adenylate cyclase to isoproterenol was significantly defective (56% decrease compared with control rats; P less than .05), although both the basal and the forskolin-stimulated maximum adenylate cyclase activities and a half-maximum concentration of isoproterenol for the stimulation of adenylate cyclase were similar in control and diabetic rats. On the other hand, both cholera toxin-dependent and islet-activating protein-dependent [32P]NAD incorporations into cardiac plasma membrane were markedly increased in the diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Subcutaneous transplantation of islets into streptozocin-induced diabetic rats

Pancreatic islet transplantation into type 1 diabetic patients is currently being performed by intraportal infusion. This method, albeit reproducible, has some disadvantages including potential development of portal hypertension, hemorrhage, and an inability to retrieve or detect the transplanted tissue. Other transplant sites have been examined in animal models including the omentum, peritoneal cavity, and the spleen. A transplant site that has not been successful in supporting functional islet tissue transplantation in humans is the subcutaneous space due primarily to the lack of a well-defined vascular bed. This site has many favorable characteristics such as ease of access for transplantation and potential for removal of the transplanted tissue with a minimally invasive surgical procedure. This report addresses the evaluation of a subcutaneously placed device for the support of rat syngeneic islet transplantation in a streptozocin-induced diabetic model. The data generated support the use of this device for islet engraftment. In addition, beta cell function in this device compared favorably with the function of islets transplanted to the renal subcapsular space as well as islets within the native pancreas.     

Increased liver glucose-transporter protein and mRNA in streptozocin-induced diabetic rats

The effect of insulin-deficient diabetic states on the rat liver glucose-transporter (L-transporter isoform) protein and mRNA levels were studied. Rats were injected with 65 mg/kg streptozocin to induce diabetes and were maintained for 10 days and then treated with or without insulin for the next 5 days. The L-transporter isoform with apparent Mr of 55,000 was observed to be increased approximately twofold in the membranes from liver homogenates of diabetic rats compared with control rats when assessed by Western blot analysis with an anti-peptide antibody directed against rat L-transporter isoform. Insulin treatment of diabetic rats decreased the amount of L-transporter isoform protein toward levels observed in nondiabetic rats. Northern blot analysis demonstrated similar alterations in the rat L-transporter isoform mRNA that paralleled the changes observed in the L-transporter isoform protein. The increased levels of the L-transporter isoform protein and mRNA in diabetic rats are in marked contrast to the effects of insulin deficiency in rat adipocytes, which specifically decrease the amount of the adipocyte glucose-transporter isoform protein and mRNA. These results suggest that glucose-transporter isoforms in rat liver and adipocytes are regulated by different mechanisms and that an increased synthesis of the L-transporter isoform may contribute to the increased glucose output that occurs from the liver during insulin deficiency.     

Insulinlike effects of sodium selenate in streptozocin-induced diabetic rats.

Treatment of streptozocin (STZ)-induced diabetic rats with sodium selenate (10-15 mumol.kg-1.day-1) for 7 wk resulted in a decrease in plasma glucose, food intake, and water intake to control or near control levels. Plasma insulin was reduced in control rats given sodium selenate to the level found in the diabetic and treated diabetic group. Treatment did not affect control rats with regard to the other measurements cited. Sodium selenate enhanced weight gain in responding diabetic rats to that seen in controls; sodium selenate's actions thus resembled those of insulin. Thus selenate, like vanadium, appears to have insulinlike effects when administered in vivo.     

Effect of niceritrol on streptozocin-induced diabetic neuropathy in rats.

Niceritrol, a drug with peripheral tissue vasodilatory and serum lipid-lowering activity, was administered for 2 mo to rats with streptozocin-induced diabetes. Physiological and biochemical studies were subsequently conducted on rat nerve tissue. A markedly lower value of approximately 47% in sciatic nerve blood flow (SNBF) was detected in an untreated diabetic (DC) group than in a nondiabetic control group (CC). A significant delay in caudal motor nerve conduction velocity (MNCV) and significantly higher glucose, sorbitol, and fructose values were observed in the sciatic nerve and serum lipids. In contrast, a niceritrol-treated diabetic (DN) group had significantly higher SNBF, MNCV, and sciatic nerve myo-inositol values and lower serum triglyceride levels than group DC. No differences between these two groups were noted in glucose, sorbitol, and fructose levels in the sciatic nerve, or in cholesterol and glucose in serum. These findings suggest that niceritrol has a clear inhibitory effect on the development of delayed MNCV in the diabetic rat, which may be due to reduced nerve blood flow and/or decreased nerve myo-inositol levels.     

Decreased collagen production in diabetic rats

Many of the chronic complications of diabetes mellitus involve defects in the connective tissue such as poor wound healing, diminished bone formation, and decreased linear growth. Because collagen is the major protein component of these connective tissues, we examined collagen production in diabetic rats as a probe of this generalized defect in connective tissue metabolism. Doses of streptozocin ranging from 35 to 300 mg/kg were used to induce diabetes of graded metabolic severity in rats. Parietal bone or articular cartilage was removed and incubated at 37 degrees C with 5 microCi L-[5-3H]proline for 2 h, and collagen and noncollagen protein production were quantitated after separation with purified bacterial collagenase. Within 2 wk after induction of diabetes, collagen production was significantly reduced in bone and cartilage from diabetic rats to 52% (P less than .01) and 51% (P less than .01) of control (buffer-injected) levels, respectively. In contrast, noncollagen protein production in bone and cartilage from diabetic animals was no different from in tissue from control rats. The correlation between collagen relative to total protein production (relative rate) and the degree of hyperglycemia was highly significant for both bone (r = -.77, P less than .001) and cartilage (r = -.87, P less than .001). Other factors found to correlate with altered collagen production were the duration of diabetes and the amount of weight loss. Thus, diabetes is associated with a marked decrease in collagen production, which was seen early after induction of diabetes and was specific when compared with noncollagen protein production. Cumulative effects of these marked changes in collagen production may contribute to the chronic connective tissue complications in diabetes.     

Decreased inner cell mass proportion in blastocysts from diabetic rats

Late morulae and blastocysts were recovered from streptozocin-induced diabetic pregnant rats and individually examined for numbers of inner cell mass (ICM) cells and trophectoderm (TE) cells. Compared with embryos collected from control rats, exposure to maternal diabetes significantly decreased mean ICM cell number of blastocysts recovered on day 5 of gestation, but the TE population of these embryos remained unaffected. The mean ICM proportion was therefore significantly lower than that of control embryos. These differences were not observed between the two groups of morulae collected on day 5, suggesting that the distinctive susceptibility of the ICM was expressed after blastocyst formation. On day 6, a significant inhibitory effect of diabetes was observed on the growth of both ICM and TE cells, but because the reduction was more severe in the ICM than in the TE, the mean ICM proportion of these blastocysts was again significantly lower than in control embryos. A linear quadratic relationship was obtained between the numbers of ICM cells of individual blastocysts and their respective numbers of TE cells in each of the two experimental groups. However, the slope of the curve was slower in the diabetic group than the control group. The disturbed ICM cell growth in the blastocysts from diabetic rats was found to be associated with a significantly increased incidence of cell death predominantly located in the ICM. Because it is known that excessive reduction of the ICM is incompatible with normal embryogenesis after implantation, our results suggest that the differential sensitivity of ICM and TE cells in preimplantation blastocysts may contribute to the pattern of postimplantation defects described in diabetic pregnancies.     

Regional brain glucose metabolism and blood flow in streptozocin-induced diabetic rats

Brain regional glucose metabolism and regional blood flow were measured from autoradiographs by the uptake of [3H]-2-deoxy-D-glucose and [14C]iodoantipyrine in streptozocin-induced diabetic (STZ-D) rats. After 2 days of diabetes, glucose metabolism in the neocortex, basal ganglia, and white matter increased by 34, 37, and 8%, respectively, whereas blood flow was unchanged. After 4 mo, glucose metabolism in the same three regions was decreased by 32, 43, and 60%. This reduction was paralleled by a statistically nonsignificant reduction in blood flow in neocortex and basal ganglia. It is suggested that the decrease of brain glucose metabolism in STZ-D reflects increased ketone body oxidation and reduction of electrochemical work.     

Evidence for impaired coupling of receptors to Gi protein in adipocytes from streptozocin-induced diabetic rats

Adenosine and prostaglandins of the E series inhibit lipolysis in adipocytes by binding to cell surface receptors. This inhibition is mediated via Gi. It has been reported that Gi is almost absent in livers from diabetic rats. Therefore, we have evaluated the sensitivity of adipocytes from diabetic rats to the adenosine analogue N6-phenylisopropyl adenosine (PIA) and to prostaglandin E1 (PGE1). Diabetes was induced with streptozocin (65 mg/kg i.v.), and after 7 days, adipocytes were isolated. Lipolysis (measured in the presence of adenosine deaminase) was inhibited by PIA and PGE1 in both control and diabetic cells. However, the dose-response curves were markedly shifted to the right in the cells from diabetic rats. The IC50 for PIA was 0.30 +/- 0.02 nM in controls and 0.83 +/- 0.08 in diabetic rats (P less than 0.001), and the IC50 for PGE1 was 3.16 +/- 0.18 nM in controls and 5.26 +/- 0.57 nM in diabetic rats (P less than 0.02). These findings indicate decreased sensitivity to both adenosine and PGE1. Adipocyte membranes were isolated from control and diabetic rats. Adenosine receptors (measured by binding of 125I-labeled hydroxy-PIA) were not altered in cells from diabetic rats. However, the ability of Gpp(NH)p (a nonhydrolyzable GTP analogue) to inhibit adenosine-receptor binding was markedly decreased in membranes from diabetic rats, suggesting a change at the level of Gi. The alpha-subunits of Gi1, Gi2, Gi3, and Gs were quantitated on Western blots with a series of recently characterized anti-peptide antisera. This revealed that the amounts of each of these G proteins were normal in membranes from the diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased neuropeptide Y concentrations in specific hypothalamic regions of streptozocin-induced diabetic rats

Untreated streptozocin-induced diabetic (STZ-D) rats have previously been shown to have significantly increased hypothalamic concentrations of neuropeptide Y (NPY), a regulatory peptide that powerfully stimulates eating and drinking and inhibits secretion of several pituitary hormones when injected centrally. Tissue NPY concentrations have been measured by radioimmunoassay in selected hypothalamic regions microdissected from fresh, unfixed brain slices to localize diabetes-associated NPY changes precisely within the hypothalamus. Significant (35-200%) increases in NPY concentrations (P less than .01 vs. matched nondiabetic controls) were found in specific hypothalamic regions between 3 and 14 wk after induction of STZ-D. These regions included the paraventricular and ventromedial nuclei and lateral hypothalamic area, major appetite-regulating areas that are sensitive to the hyperphagic and polydipsic actions of NPY. Increased NPYergic activity in these areas may, at least partly, drive the increased eating and drinking characteristic of STZ-D. NPY concentrations were also increased in the arcuate nucleus and medial preoptic area. Because both of these regions are important in modulating pituitary hormone secretion, local NPY increases may be involved in the impaired secretion of luteinizing hormone, thyroid-stimulating hormone, growth hormone, and prolactin known to occur in STZ-D. Our finding of NPY increases in specific hypothalamic nuclei associated with functional changes found in STZ-D suggests that this peptide may have a role in the altered metabolic and neuroendocrine regulation of the syndrome.     

Persistent grossly elevated plasma immunoglobulin A levels in untreated streptozocin-induced diabetic rats

Experimental diabetes mellitus was induced in adult male and female rats by injecting streptozocin (STZ; 60 mg/kg i.p.) in preparation for a screening survey of changes in the pattern of undenatured plasma proteins, as revealed by two-dimensional (2-D) gel electrophoresis followed by silver staining. As early as 8-12 days later, the 2-D gels revealed three high-molecular-weight plasma protein spots, which persisted for 150 days in the blood of untreated diabetic rats. Such spots were not seen in plasma of normal control rats. Evidence is presented for the presumptive characterization of these proteins as oligomers of immunoglobulin A (IgA). Specific measurement of total IgA content of diabetic plasma samples by single-radial immunodiffusion, after reduction with dithiothreitol and alkylation with iodoacetamide, reveals that IgA content increases linearly from control values of 11.1 +/- 4.6 to 358 +/- 249 mg/dl (means +/- SE) 21 days after STZ and persists at these high levels for as long as 150 days. Diabetic rats injected daily with insulin showed IgA levels only two to four times higher than normal. Neither experiments designed to quantitate the rates of clearance (catabolism plus excretion) of 125I-labeled secretory IgA from the circulation of normal and diabetic rats nor measurement of total IgA in the bile from diabetic and normal bile fistula rats supports the view that slowed clearance from the circulation or impaired biliary excretion in the diabetic rat causes observed gross hyperimmunoglobulinemia A.