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M C Appel

Publications and source records attributed to M C Appel.

At least 37 records · Page 2Linked to original sources
PubMed1989

The inhibitory effect of large doses of methimazole on iodine induced lymphocytic thyroiditis and serum anti-thyroglobulin antibody titers in BB/Wor rats.

The BB/Wor rat spontaneously develops autoimmune insulin dependent diabetes mellitus and lymphocytic thyroiditis (LT). Excess iodine ingestion enhances and low iodine diet decreases the incidence of LT in this rat model but does not affect the incidence of diabetes mellitus. The administration of a low dose of methimazole (MMI; 870 ng/gm bw ip daily) from 30-90 days of age had no significant effect on thyroid function or on the incidence of iodine induced LT and serum anti-thyroglobulin (Tg) antibodies measured by an ELISA assay. A large dose of MMI (0.05% in the drinking water) induced goiter and hypothyroidism. In addition, the incidence of LT was markedly attenuated (76% vs 6%, p less than 0.001) and reduced titers of serum anti-Tg antibodies (0.59 +/- 0.1 OD vs 0.08 +/- 0.01, p less than 0.001) were observed. This inhibitory effect of MMI on the occurrence of iodine induced LT in the BB/Wor rat may be due to the lower antigenicity of the poorly iodinated Tg secondary to MMI therapy and/or to an immunosuppressant effect of MMI itself.

Animals↗
PubMed1988

Differential radiosensitivity among B cell subpopulations.

We have previously shown that low doses of ionizing radiation selectively impair a functionally defined B cell subpopulation. Normal mice, after exposure to 200 rad of ionizing radiation, have normal or near normal splenic plaque-forming cell responses to thymus-independent type 1 Ag, but reduced responses to thymus-independent type 2 Ag. Here, we confirm and extend the original findings by using hapten-specific serum RIA to demonstrate this differential radiosensitivity is systemic. We also examined splenocytes stained with a panel of lymphocyte surface Ag by FACS analysis to determine if these functional changes are accompanied by a physical alteration of the B cell pool of irradiated mice. Single-parameter FACS analyses demonstrate a diminution in both B cell number and the heterogeneity of membrane Ag expression within the surviving B cell pool after irradiation. In contrast, T cells are relatively radioresistant as the relative percentage of T cells in the irradiated splenocyte pool increases, whereas the heterogeneity of membrane Ag expression remains constant. Multiparameter FACS analyses indicate that B cells with the sIgM much greater than sIgD phenotype are more radiosensitive than B cells of the sIgM much less than sIgD phenotype. In addition, immunohistochemical analysis of splenic sections stained with anti-IgM or anti-IgD reveal the enhanced radiosensitivity of marginal zone B cells.

Animals↗
PubMed1988

Both the Lyt-2+ and L3T4+ T cell subsets are required for the transfer of diabetes in nonobese diabetic mice.

The nonobese diabetic mouse is a model of spontaneous type I diabetes mellitus. It is possible to induce diabetes in young, irradiated nonobese diabetic mice by using adoptive transfer of splenocytes or splenic T cells obtained from diabetic donors. This study demonstrates that the induction of diabetes in the adoptive transfer system is dependent on both the L3T4+ and Lyt-2+ subsets of T cells. Neither of these T cell subsets alone mediates the development of severe insulitis or diabetes when adoptively transferred to young, irradiated recipients. In addition, we show that both the L3T4+ and Lyt-2+ subsets must be obtained from diabetic donors in order to transfer diabetes; neither subset can be replaced with cells obtained from young, nondiabetic donors.

Age Factors↗
PubMed1988

Effect of L-thyroxine administration on the incidence of iodine induced and spontaneous lymphocytic thyroiditis in the BB/Wor rat.

Chronic L-thyroxine administration (6 micrograms/100g BW, ip, daily) for 2 or 3 months suppressed serum TSH concentrations and decreased both the incidence of spontaneous lymphocytic thyroiditis (LT) and the serum levels of anti-thyroglobulin (anti-Tg) antibodies in the diabetes prone BB/Wor rat. This suggests that TSH may play a role in the occurrence of LT in this rat model. In contrast to these observations, L-thyroxine administration did not affect the markedly increased incidence of LT or the elevated serum anti-Tg antibodies in iodine supplemented BB/Wor rats, suggesting that TSH stimulation is not necessary for the development of iodine induced LT in this rat model. Other factors, such as the increased antigenicity of highly iodinated Tg, may be more important.

Animals↗
PubMed1987

Genetic control of diabetes and insulitis in the nonobese diabetic (NOD) mouse.

Genetic analysis of the development of diabetes and insulitis has been performed in the nonobese diabetic (NOD) mouse strain, a model of insulin-dependent (type I) diabetes mellitus. (NOD X C57BL/10)F1, F2, and (F1 X NOD) first-, second-, and third-backcross generations were studied. The data obtained were consistent with the hypothesis that diabetes is controlled by at least three functionally recessive diabetogenic genes, or gene complexes, one of which is linked to the MHC of the NOD. In contrast, pancreatic inflammation leading to insulitis was found to be controlled by a single incompletely dominant gene. One of the two diabetogenic loci that is not linked to the MHC appears to be essential for the development of severe insulitis. This diabetogenic gene may be identical to the gene that controls the initiation of the autoimmune response that progresses to insulitis. Although this gene appears to be functionally recessive in its control of diabetes, it is incompletely dominant in its control of insulitis. The MHC-linked diabetogenic gene, although not required for the development of insulitis, apparently influences the progression of the autoimmune response since NOD MHC homozygotes in the backcross generations displayed the highest incidence and most severe cases of insulitis. Interestingly, we have found two MHC heterozygous backcross females that have become diabetic, suggesting that either the MHC-linked diabetogenic gene is not strictly recessive or that a recombination event has occurred between the diabetogenic gene and the K or I-A regions of the MHC. The third diabetogenic locus appears to influence the progression of severe insulitis to overt diabetes. In animals homozygous at this locus, diabetes may result from a decreased ability to develop a protective suppressor response to the autoimmune process.

Animals↗
PubMed1987

Iodine-induced thyroiditis and hypothyroidism in the hemithyroidectomized BB/W rat.

We have recently reported that iodine administration (0.05% iodine in drinking water) to weanling, diabetes mellitus- and lymphocytic thyroiditis (LT)-prone Biobreeding Worcester (BB/W) rats strikingly increases the incidence of LT without occurrence of iodine-induced hypothyroidism, which frequently results when excess iodine is administered to euthyroid patients with Hashimoto's thyroiditis. Since hypothyroidism did not occur in the iodine-treated BB/W rats, hemithyroidectomy was carried out in 30-day-old BB/W rats to increase thyroid mass and functional reserve. Iodine administration for 60 days markedly increased antithyroglobulin antibodies (0.40 +/- 0.08 vs. 0.15 +/- 0.06 OD; P less than 0.02), the incidence of LT (68% vs. 13%; P less than 0.001), and thyroid weight of the residual lobe (10.5 +/- 0.7 vs. 6.3 +/- 0.3 mg/100 g BW; P less than 0.001) and induced hypothyroidism (T4, 2.5 +/- 0.2 vs. 3.0 micrograms/dL; P less than 0.05; T3, 25.1 +/- 1.9 vs. 37.5 ng/dL; P less than 0.001; TSH, 252 +/- 49 vs. 61 +/- 14 microU/mL; P less than 0.02). Hypothyroidism in the iodine-treated rats occurred primarily in those with LT. Similar studies were carried out in the non-diabetes mellitus-, non-LT-prone, genetically equivalent BB/W rats (W-line), the parent strain Wistar-Furth rats, and Sprague-Dawley rats. Iodine administration did not induce LT or antithyroglobulin antibodies in these three strains and did not affect thyroid function in Wistar-Furth and Sprague-Dawley rats. However, in the W-line rats, iodine excess did induce thyroid enlargement in the residual lobe (8.4 +/- 0.2 vs. 6.4 +/- 0.2 mg/100 g BW; P less than 0.001), a decrease in serum T3 (71.5 +/- 2.9 vs. 86.0 +/- 2.5 ng/dL; P less than 0.001), and an increase in serum TSH (344 +/- 65 vs. 69 +/- 6.0 microU/mL; P less than 0.001). It is evident, therefore, that hemithyroidectomy in BB/W rats sufficiently reduces functioning thyroid tissue, resulting in iodine-induced LT and hypothyroidism, similar to iodine-induced hypothyroidism in euthyroid patients with Hashimoto's thyroiditis. It is unclear, however, why iodine administration also induced hypothyroidism in hemithyroidectomized, genetically similar, W-line rats in the absence of LT. This observation suggests that iodine-induced hypothyroidism in rats may be genetically determined.

Animals↗
PubMed1987

Effect of iodine intake and methimazole on lymphocytic thyroiditis in the BB/W rat.

Spontaneous LT and elevated serum anti-Tg occur in the diabetes prone BB/W rat, but thyroid function is essentially normal in the rats with LT. Prolonged low dose MMI decreases the incidence of LT in BB/W rats. The administration of excess iodine beginning at 30 days of age markedly accelerates the occurrence of LT and anti-Tg at 90 days of age. Low iodine intake decreases the incidence of LT. Excess iodine intake did not induce LT in W-line, Wistar-Furth, and Sprague-Dawley rats. This suggests that iodine induced LT occurs only in genetically susceptible rats. Despite the increased incidence of LT during iodine administration, thyroid function remains essentially normal. This is in contrast to the frequent induction of hypothyroidism following iodine administration to euthyroid patients with Hashimoto's thyroiditis. In order to decrease thyroid reserve, rats were hemi-TX at 30 days of age. The administration of iodine markedly increased the incidence of LT and serum anti-Tg, increased the weight of the remaining lobe, and induced hypothyroidism as determined by significantly lower serum T4 and T3 concentrations and elevated serum TSH concentrations. Excess iodine administration to hemi-TX W-line rats (genetically equivalent, non-diabetes, non-LT prone BB/W rats) did not induce LT but did induce hypothyroidism, suggesting that BB/W and W-line rats are susceptible to iodine induced hypothyroidism, perhaps unrelated to the induction of LT. Excess iodine did not induce LT or affect thyroid function in hemi-TX Wistar-Furth and Sprague-Dawley rats.

Animals↗
PubMed1986

Differential regulation of glucokinase activity in pancreatic islets and liver of the rat.

The differential tissue-specific regulation of glucokinase activity in liver and pancreatic islet cells was investigated in the insulinoma-bearing rat. A transplantable insulinoma caused hyperinsulinemia and hypoglycemia in the host by 2-3 months after implantation. Suppression of the pancreatic B-cells by the high insulin and/or low glucose manifested itself by a decrease of insulin in islet tissue. Removal of the tumor initiated transient insulin deficiency and hyperglycemia with extremes of these changes at 24 h after tumor resection. These conditions markedly affected glucose phosphorylation in the islet cells: glucokinase activity was reduced 71% in islet samples from insulinoma-bearing rats, and the enzyme fully recovered within 24 h after tumor resection. Hexokinase activity, by contrast, was not affected by these manipulations. To evaluate the relative contributions of hypoglycemia and hyperinsulinemia in islet glucokinase adaptation, glucose was intravenously infused to insulinoma-bearing rats; glycemia in excess of 150 mg/100 ml combined with excessive hyperinsulinemia resulted in a partial recovery of islet glucokinase activity, first apparent after 9 h of glucose infusion and with doubling of the activity after 24 h after glucose loading. In contrast, liver glucokinase was increased nearly 4-fold at the time of extreme hypoglycemia and hyperinsulinemia and rapidly fell to control rates following tumor removal. Intravenous infusion of glucose for 24 h into the tumor-bearing rat (i.e. hyperglycemia combined with excessive plasma insulin) had no influence on liver glucokinase activity. Liver hexokinase was not influenced by any of these experimental manipulations. The data indicate that the activities of pancreatic islet and liver glucokinase are regulated in a differential manner. Insulin is apparently the primary determinant of liver glucokinase and glucose seems to control islet glucokinase. Biochemical mechanisms for differential organ-specific regulation of glucokinase activity seem to have evolved such that this enzyme may play a dual role in glucose homeostasis, namely to serve as insulin-dependent glucose sensor in the B-cells and as insulin-sensitive determinant of hepatic glucose use.

Adenoma, Islet Cell↗
PubMed1986

Differential effects of 1,25-dihydroxyvitamin D3 on cytosolic calcium in two human cell lines (HL-60 and U-937).

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) has been shown to induce maturational changes in the human promyelocytic leukemia cell line HL-60 and in the human monocytic cell line U-937. Changes in cytosolic calcium have been reported to regulate cellular processes. We used the fluorescent dye Quin 2 to examine the effects of vitamin D metabolites on cytosolic calcium levels in HL-60 and U-937 cells. 1,25-(OH)2D3 (20 nM) increases cytosolic calcium by 24% over a 5-min period in HL-60 but not in U-937 cells. 1,25-(OH)2D3 (0.2 nM and 4 nM) has no effect on cytosolic calcium levels in either cell type. 24,25-(OH)2D3 (20 nM) has no effect on cytosolic calcium in HL-60 cells. Nifedipine (1 mM) has no effect on cytosolic calcium levels over 30 min and likewise does not block the 1,25-(OH)2D3-induced increase in cytosolic calcium in HL-60 cells. However, chelation of extracellular calcium with EGTA (10 mM) blocks the 1,25-(OH)2D3-induced increment in cytosolic calcium, but does not block the 1,25-(OH)2D3-induced maturational changes in HL-60 cells. The data suggest that 1,25-(OH)2D3 but not 24,25-(OH)2D3 increases cytosolic calcium in HL-60 cells within 5 min and the increment is due to increased influx of calcium. 1,25-(OH)2D3 modifies membrane permeability to calcium independent of calcium channels sensitive to nifedipine. Finally, 1,25-(OH)2D3-induced maturational changes in HL-60 cells can take place without an increase in cytosolic calcium.

Aminoquinolines↗
PubMed1986

Spleen cell transfusion in the Bio-Breeding/Worcester rat. Prevention of diabetes, major histocompatibility complex restriction, and long-term persistence of transfused cells.

We report that transfusions of RT1u Wistar-Furth (WF) spleen cells prevented spontaneous diabetes in the RT1u BB/W rat while RT1b Buffalo rat spleen cells did not. In addition, donor origin WF T lymphocytes were detected in nondiabetic-susceptible BB/W recipients 5 mo after transfusion. Survival of donor-origin lymphocytes may provide the cellular mechanism by which major histocompatibility complex-compatible WF spleen cell transfusions prevent BB rat diabetes.

Animals↗
PubMed1986

The effect of iodide ingestion on the development of spontaneous lymphocytic thyroiditis in the diabetes-prone BB/W rat.

It has been suggested that the incidence of Hashimoto's thyroiditis is increased in the presence of high iodide intake. The diabetes-prone BB/W rat develops spontaneous histological autoimmune lymphocytic thyroiditis (LT) without functional hypothyroidism between 60 and 120 days of age. Studies were carried out to determine whether iodine administration to BB/W rats would affect the incidence and severity of LT and induce hypothyroidism. Iodide (0.05% in water) or tap water (C) was administered ad libitum to 42 10-month-old BB/W rats and 71 30-day-old BB/W rats for 8 weeks. For control purposes, 0.05% iodide or tap water (C) was also administered ad libitum to 42 30-day-old nondiabetic and non-LT-prone BB/W genetically equivalent rats (W-line) for 12 weeks and 41 21-day-old Wistar rats for 7 weeks. In a separate experiment, weanling BB/W rats were fed a low iodine diet, a control iodine-sufficient (C) diet, or Purina chow (P) and tap water ad libitum for 8 weeks. In each experiment, blood was obtained at the time of death for the measurement of serum T4, T3, TSH, and antithyroglobulin antibody (anti-Tg Ab), and the thyroids were removed for histological evaluation (0 = no LT; 1-4 = LT). Iodide administration (0.05%) induced a significant increase in the incidence of LT in 30-day-old BB/W rats (I, 77%; C, 30%, P less than .001). Thyroid weight and serum T4, T3, and anti-Tg Ab concentrations were not affected by iodide administration. However, the presence of LT was associated with a significant increase in thyroid weight and anti-Tg Ab concentrations. BB/W rats subjected to a low iodine diet exhibited a significantly decreased incidence of LT (low I, 8.6%; C, 47.3%; P less than 0.01), but no statistically significant difference in anti-Tg Ab levels. Increased iodide intake did not significantly affect the incidence of LT in adult BB/W rats and did not induce LT or affect thyroid function in W-line or Wistar rats. These data show that iodine intake significantly affects the incidence of spontaneous LT in young, genetically predisposed rats.

Animals↗
PubMed1984

Effects of vasoactive intestinal peptide on canine prostatic contraction and secretion.

Vasoactive intestinal peptide (VIP)-like immunoreactivity was found in intrinsic autonomic ganglion cells and nerve fibers located at the surface and within the canine prostate. In anesthetized dogs, porcine VIP (100-3,000 ng/kg iv) decreased arterial pressure and increased heart rate but did not result in the release of fluid from the prostate, indicating that VIP neither contracted glandular smooth muscle to expel fluid nor provoked secretion. Intravenous infusions of VIP at 10, 50, 100, and/or 200 ng X kg-1 X min-1 produced dose-related decreases in arterial pressure, increases in heart rate, and potentiation of the secretory response to the intravenous administration of pilocarpine and to electrical stimulation of the hypogastric nerves at 2 but not at 20 Hz. VIP at 1 microgram/ml neither contracted isolated strips of prostate nor modified their contraction by norepinephrine. It is unlikely that VIP mediates hypogastric nerve-induced prostatic contraction or secretion in the dog, but VIP may serve as a neuromodulator of nerve-induced secretion.

Animals↗
PubMed1983

Diabetes-induced alterations in liver protein synthesis. Changes in the relative abundance of mRNAs for albumin and other plasma proteins.

Mechanisms responsible for diabetes-induced alterations in liver protein synthesis were investigated in vivo and in perfused liver using Bio-Breeding Worcester (BB/W) control rats, spontaneously diabetic BB/W rats maintained on insulin therapy, and diabetic BB/W rats withdrawn from insulin therapy for 48 h. Withdrawal of insulin therapy in the diabetic rats resulted in marked alterations in a number of parameters related to liver protein synthesis compared to BB/W control or insulin-maintained diabetic rats. Alterations seen in vivo following withdrawal of insulin included changes in the relative concentrations of several plasma proteins, a 40% reduction in total liver RNA relative to DNA, a 5-fold reduction in albumin synthesis relative to the synthesis of total liver proteins, a 5-fold reduction in albumin mRNA relative to total RNA, reductions in the relative abundance of mRNAs for at least four plasma proteins other than albumin, and a relative increase in mRNA for at least one plasma protein. Alterations observed in perfused liver included reductions in total liver protein synthesis (60% of control), albumin production (24% of control), and total secretory protein production (44% of control). All parameters studied were essentially unchanged from BB/W control values when the diabetic rats were maintained on insulin therapy. The results indicate that insulin deficiency leads to marked reductions in liver protein synthesis, particularly the synthesis of albumin and other plasma proteins. The mechanisms responsible for these alterations include changes in the relative abundance of specific mRNAs and a decrease in total cellular RNA.

Animals↗
PubMed1982

Spontaneous autoimmune diabetes mellitus in the BB rat.

The BioBreeding Rat is a recently discovered model of spontaneous diabetes mellitus. Studies to date have revealed the following characteristics of the syndrome: genetic predisposition, equal frequency and severity among males and females, absence of obesity, life sustaining requirement for insulin therapy, lymphocytic insulitis with destruction of pancreatic beta-cells, lymphocytic thyroiditis and the presence of autoantibodies to smooth muscle, thyroid colloid and other cellular antigens. Animals raised in a germ-free environment evidence diabetes with equal frequency and severity. Support for a cell-mediated autoimmune pathogenesis of the diabetic syndrome is derived from the following experiments: administration of antiserum to rat lymphocytes prevents diabetes in susceptible animals and normalizes plasma glucose levels in 36% of diabetic rats; neonatal thymectomy almost completely prevents the occurrence of diabetes. Although the BB rat may not be an appropriate model for studying the vascular complications of diabetes, peripheral nerve functional and ultrastructural defects have been reported and renal glomerular immuneglobulin deposits have been observed in long-term diabetic animals.

Animals↗
PubMed1982

Autoantibodies in the BB/W rat.

The BioBreeding/Worcester (BB/W) rat is a model of spontaneous autoimmune diabetes mellitus and lymphocytic thyroiditis. Additional features supporting an immunologic pathogenesis of the BB/W syndrome include the protective action of antilymphocyte serum, neonatal bone marrow transfusions, and neonatal thymectomy. To evaluate other manifestations of immune dysregulation, the BB/W colony was surveyed for the presence of autoantibodies to a variety of tissue and cell constituents. Anti-smooth muscle and anti-thyroid colloid antibodies were present with great frequency in diabetic animals as well as in normoglycemic offspring of diabetic parents. Anti-parietal cell antibodies were less frequent and islet cell cytoplasmic and adrenal antibodies were not detected. These data suggest that the underlying defect in the BB/W rat is more likely to be an abnormal immune regulatory system than antigenically altered target tissues ("altered self") under attack by a normal immune surveillance system.

Animals↗
PubMed1981

Hepatic carbohydrate metabolism in the spontaneously diabetic Bio-Breeding Worcester rat.

The effects of diabetes on hepatic carbohydrate metabolism were investigated in spontaneously diabetic Bio-Breeding Worcester (BB/W) rats. The juvenile-onset-type syndrome displayed by these animals is characterized by beta-cell destruction with subsequent ketosis-prone insulinopenia. Livers from diabetic animals demonstrated increased adenosine 3',5'-cyclic monophosphate levels but subnormal total protein and glycogen content. Isolated perfused livers of diabetic BB/W rats demonstrated an increased rate of glucose production from [14C]lactate and an impaired rate of glycogen synthesis. These data were consonant with hepatic enzyme studies demonstrating markedly increased activities of component gluconeogenic (glucose-6-phosphatase, fructose-1,6-diphosphatase, phosphoenolpyruvate carboxykinase) and glycogenolytic (glycogen phosphorylase) enzymes with decreased activities of glycolytic (hexokinase, pyruvate kinase) and glycogenic (glycogen synthase) enzymes. These findings agree with previous studies using alloxan- and streptozotocin-induced diabetic animals and suggest that accelerated hepatic gluconeogenesis and impaired glucose utilization are pathognomonic of all insulin-deficient diabetic syndromes.

Animals↗
PubMed1980

Serially transplantable chemically induced rat islet cell tumor.

A serially transplantable, chemically induced pancreatic islet cell tumor was developed in Lewis rats. The original tumor was induced by the administration of streptozotocin and nicotinamide. It was subsequently maintained by ip or sc transplantation of tissue fragments into recipient animals. Tumors generally grew to 0.5--2.0 cm in diameter within 3--4 months of transplantation. They were well encapsulated, without gross evidence of metastasis. Peroxidase immunocytochemical staining revealed a predominance of insulin-positive cells. Somatostatin-positive cells were also present and varied widely in numbers between different tumors. In addition, small numbers of glucagon-positive cells were observed in all of the tumors. On electron microscopy, cells containing secretory granules, indistinguishable from nonneoplastic beta-cells, were most abundant. Other granulated cells were also observed, but the granule morphology was not identical to that of any of the other classically described islet cell types. Tumor extracts contained an average of 3260 micrograms insulin, 22.6 micrograms somatostatin, and 0.84 micrograms glucagon per g wet wt of tissue. Tumors caused marked, progressive hypoglycemia in recipients, with plasma glucose levels frequently falling below 30 mg/dl before death. Furthermore, the recipients' islets were markedly reduced in size due to a decreased beta-cell volume.

Adenoma, Islet Cell↗