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Biomedical subjects

J F Yale

Publications and source records attributed to J F Yale.

At least 37 records · Page 2Linked to original sources
PubMed1991

Diabetes prevention in BB rats by inhibition of endogenous insulin secretion.

Chronic prophylactic exogenous insulin treatment commenced in young diabetes susceptible BB rats has been shown to prevent type I diabetes. This study was undertaken to examine whether this diabetes protection resulted from inhibition of beta-cell insulin secretion by exogenous insulin administration or from either a metabolic (chronic hypoglycemia) or immune effect of this treatment. We compared the effects of prophylactic exogenous insulin treatment with those of an insulin secretion inhibitor, diazoxide, an oral hypoglycemic agent, glyburide, and, water alone as controls in randomly divided BB diabetes-prone littermates treated from age 30 to 150 days. These experiments confirmed that exogenous insulin can prevent type I diabetes in the BB rat. Diazoxide, which inhibits endogenous insulin secretion while causing hyperglycemia (rather than hypoglycemia with insulin), also offered protection from diabetes. In contrast, the oral hypoglycemic agent glyburide, which increased insulin secretion, but decreased plasma glucose during the early part of the experiment, did not affect the incidence of diabetes. The lymphocyte subpopulations were unaffected by these treatments. These data support the hypothesis that decreased beta-cell activity is responsible for the protection against the immune beta-cell destruction.

Analysis of Variance↗
PubMed1991

Effects of SMS 201-995 on the pharmacokinetic profile and cellular immune and toxic effects of cyclosporine in male Wistar rats.

The immunosuppressant cyclosporine and the long-acting somatostatin analog SMS 201-995 (octreotide acetate) may have to be given simultaneously in diseases such as pancreatic transplantation. The aim of the study was to evaluate the effects of SMS 201-995 on the pharmacokinetics of cyclosporine, and to assess whether the addition of SMS 201-995 altered some of the cellular immune and toxic (renal, hepatic, glucose tolerance) effects of cyclosporine. Male Wistar rats were treated with cyclosporine 10 mg/kg/day, SMS 201-995 100 micrograms/kg b.i.d., a combination of the two drugs, or the vehicle alone. The addition of SMS 201-995 delayed the peak plasma levels of cyclosporine without affecting the through levels, and did not alter the effects of cyclosporine on the mononuclear cell subsets. This combination caused significant increases in plasma creatinine and hepatic enzymes, suggesting renal and hepatic toxicity, and severe glucose intolerance. If present in humans, the appearance of severe glucose intolerance with combined administration of SMS 201-995 and cyclosporine for pancreatic transplantation could be misinterpreted as rejection and lead to inappropriate interventions.

Animals↗
PubMed1989

Comparison of daily diets containing 400 kcal (1.67 MJ) of either protein or glucose, and their effects on the response to subsequent total fasting in obese subjects.

Eleven obese subjects (body mass index, 41.3 kg/m2) were examined to determine their metabolic and acid-base responses during two hypoenergetic diets, and the diets' influence on subsequent responses to prolonged total fasting. Subjects were first treated for 2 wk with 400-kcal/d (1.67-MJ/d) diets of either protein (13.2 g nitrogen, 23 mmol potassium) or glucose with 16 mmol potassium chloride and a multivitamin supplement. Mild acidosis developed during the protein diet as well as greater excretions of urinary ammonium and urea N, a greater degree of ketosis, and significantly better N balance (-42.7 vs -80.4 g, p less than 0.05) than during the glucose diet. The subsequent fast was associated with greater negative N balance after protein (-129 vs 83 g), mainly as urea N, but despite similar ketosis there was a greater acidosis after glucose and greater ammonium N excretion and cumulative K losses. These data support the concept of a labile N pool, depleted during a glucose diet and resulting in a decreased loss with the subsequent fast. We suggest a role for K depletion in augmenting fasting ammonium excretion.

Acid-Base Equilibrium↗
PubMed1989

Metabolic responses to intense exercise in lean and obese subjects.

Sustained elevations of plasma glucose and insulin concentrations follow intense (80% maximum oxygen uptake) exercise performed in the postabsorptive state. To provide insights into possible mechanisms and influence of obesity, 8 lean and 12 obese subjects [106 +/- 11% (SD) and 193 +/- 31% of reference table weight, respectively] eating previously isocaloric diets were exercised to exhaustion (7 +/- 3 min) on a cycle ergometer, then followed for 60 min of recovery. The obese subjects at rest had slightly increased plasma glucose and insulin and elevated blood glycerol concentrations. Both lean and obese subjects had little or no changes in plasma glucose or insulin during exercise, but the increases during the recovery period were greater and/or sustained longer in the obese. Such results raise the possibility of transient hepatic insulin resistance after exercise and are possibly relevant to restoration of depleted muscle glycogen. Both groups had a marked fall in plasma FFA during exercise; the reduction was sustained in the lean but not in the obese subjects. Blood glycerol increased during the recovery period to higher values in the obese than in the lean subjects. Plasma norepinephrine increased about 4-fold in both groups, returning promptly to preexercise values. In contrast, the exercise-induced increment in plasma epinephrine [values at exhaustion, 933 +/- 548 vs. 1970 +/- 787 pmol/L; P less than 0.005] was markedly attenuated in the obese subjects. Thus, the obese subjects had exercise-induced changes in glucose and inulin metabolism consistent with greater postexercise insulin resistance, despite an impaired plasma epinephrine response to intense exercise.

Adult↗
PubMed1989

The conservative treatment of adult flexible flatfoot.

The purpose of this article is to attend to the nonsurgical treatment of adult symptomatic flexible flatfoot and its sequelae. Other articles in this issue thoroughly discuss the etiology, radiographic changes, and nonconservative treatment of the congenital and acquired flatfoot presented in children and adults.

Adult↗
PubMed1988

Metabolic time course and immunologic concomitants of adoptive transfer of type I diabetes in the BB rat.

The metabolic and cellular immune changes during adoptive transfer of type I diabetes mellitus in the BB rat were examined. Concanavalin A (Sigma Chemical Co, St Louis) stimulation of acutely diabetic BB rat splenocytes increased the Ia-positive cells, but no other lymphocyte subset. Each spleen cell preparation was divided into two and injected into two separate recipients. Thirty-day-old diabetes-prone BB rats received these splenocytes intravenously (62 +/- 5 x 10(6) cells, n = 30) or buffer alone (controls, n = 14). Seventy-seven percent of the cell-injected rats became diabetic before 60 days of age, 15 +/- 1 days after injection. They were glucose intolerant two to three days before onset, with normal fasting glucose. All controls maintained normal glucose tolerance. The morphology revealed intense insulitis in all the rats that became diabetic, and its absence in all the controls. Eighty-three percent of the spleen cell preparations produced the same outcome in both recipients. The cell-injected rats had an increase in lymphocyte counts eight days after injection compared with the controls. The most affected subsets were the pan T cells (OX19+) and helper T cells (W3/25+). While the rats that ultimately became diabetic had a decrease of their lymphocyte subsets to control levels between eight and 14 days, the injected rats that maintained normal glucose tolerance maintained elevated T cells. We conclude that (1) adoptive transfer of diabetes occurs in the presence of an increase of the helper T (W3/25+) lymphocytes after spleen cell injections; (2) glucose intolerance precedes by two to three days fasting hyperglycemia; and (3) while the lymphocyte counts are increased in all recipients of splenocyte preparations, these counts decrease rapidly only in the rats that develop diabetes, possibly by entrapment of lymphocytes in the insulitis.

Animals↗
PubMed1988

Immunological responses to chronic heat exposure and food restriction in rats.

Immunological variables were studied in rats chronically exposed to high environmental temperature (35 degrees C). Responses were compared with those of rats at 25 degrees C both fed ad libitum and pair fed to the decreased intake found in heat-exposed rats. Heat-exposed rats showed slower delayed-type hypersensitivity responses to keyhole limpet hemocyanin. They showed lower counts of peripheral blood total T cells (OX19+) as well as helper T cells (W3/25+) and smaller numbers of splenic T cells. The thymus was decreased in size. Increased levels of serum IgG antitetanus toxoid antibodies were found in heat-exposed rats. [3H]-thymidine incorporation into Concanavalin A (ConA)-stimulated splenic lymphocytes was decreased in pair-fed rats but not significantly altered in heat-exposed rats compared with controls. Heat exposure alters some aspects of both cellular and humoral immune function in a manner different from that induced by comparable food restriction without heat exposure.

Animals↗
PubMed1988

Pharmacokinetic profile of cyclosporine A and G and their effects on cellular immunity and glucose tolerance in male and female Wistar rats.

This study examined the effects of the widely used immunosuppressor cyclosporine A and of one of its derivatives, cyclosporine G, on glucose tolerance, cellular immunity, and renal and hepatic function, in relation to their pharmacokinetic profile in Wistar rats. After 3 weeks of daily cyclosporine A doses of 10 mg/kg body weight plasma cyclosporine levels were higher in male than in female rats. This was associated in male rats with marked decrease in lymphocyte subsets, affecting particularly the OX19+ T cells, with glucose intolerance, and an increase in plasma creatinine. The female rats had none of these effects. After 3 weeks of daily cyclosporine G doses of 10 mg/kg body weight, plasma cyclosporine levels were higher in male than female animals, and higher than with cyclosporine A in both sexes. Similar cellular immune effects and glucose intolerance were seen in male rats, but of a lesser magnitude than with cyclosporine A. No increase in creatinine was seen, but rats of both sexes treated with cyclosporine G had elevated plasma bilirubin. We conclude that (1) both cyclosporine A and G can cause glucose intolerance, (2) the cyclosporine plasma levels are higher in male than in female rats and with cyclosporine G than with cyclosporine A, for the same oral dose, (3) the absence of glucose intolerance, nephrotoxicity, and cellular immune changes in female rats treated with cyclosporine A is related to their lower cyclosporine levels, and (4) cyclosporine G is less nephrotoxic than cyclosporine A, but more hepatotoxic.

Animals↗
PubMed1988

Diabetes prevention in BB rats by frequent blood withdrawal started at a young age.

The BB rat diabetic syndrome has been prevented by various immunosuppressive and reconstitution measures. We observed an effect of multiple blood samplings on diabetes incidence and examined its immunological correlates. Individual litters were divided into two groups; one was sampled and the other was sham sampled as the control group. Sixty-four diabetes-prone and 59 non-diabetes-prone rats were studied. The sampled rats had blood removed at 15 (28% of total blood volume), 30 (30%), 50 (21%), 75 (16%), and 120 days of age. The sham-sampled control rats had blood removed only at 120 days of age. The incidence of diabetes in the sampled group was markedly lower than that of their sham-sampled littermates (22 vs. 78%). This result was associated with a correction of their OX19+ (pan-T-lymphocytes) and W3/25+ (helper/inducer) T-lymphocyte-number defects. An increase in lymphocyte subsets was also seen in the non-diabetes-prone BB rats, significant for all but the OX19+ cells. Islet pathology and pancreatic insulin content were consistent with metabolic outcomes. The effect of blood withdrawal thus has implications for understanding the pathogenesis of both the diabetes syndrome and the lymphopenia of the BB rat. Furthermore, it suggests that a stimulation of lymphopoiesis by blood withdrawal (analogous to that of erythropoiesis) may be a hitherto unrecognized physiological response in normal animals.

Aging↗
PubMed1988

Major histocompatibility complex gene product expression on pancreatic beta cells in acutely diabetic BB rats.

Type I diabetes mellitus was induced in young, diabetes-prone BB rats by the passive transfer of concanavalin A-activated T lymphocytes from the spleens of acutely diabetic BB rats. The pancreas of the recipients was examined 1-2 days after the onset of glycosuria by immunocytochemistry by means of monoclonal antibodies for determining whether 1) Class I and/or II major histocompatibility gene complex (MHC) products were expressed on beta cells and 2) the mononuclear cell infiltrates were represented by T cells. Marked expression of Class I MHC gene products was evident on beta cells. In contrast, Class II MHC gene products were not identified on normal-appearing beta cells. Dendritic cells dispersed throughout the acinar and interstitial pancreas were markedly increased in number. The mononuclear cell infiltrate contained few cells (1-15%) recognized by a pan-T cell marker. Although it is possible that this passive transfer model might differ considerably from the spontaneously occurring diabetic state in the rat, this study suggests that 1) Class I, rather than Class II, MHC gene expression may be pivotal to beta-cell injury in diabetic rats, and 2) non-T cells may constitute an effector cell population central to beta-cell necrosis in Type I diabetes mellitus.

Animals↗
PubMed1987

Urine C-peptide as index of integrated insulin secretion in hypocaloric states in obese human subjects.

To determine the effects of different hypocaloric diets on insulin secretion, 24-h urine C-peptide was measured in 11 obese subjects on a weight-maintaining baseline diet, and the results were compared with values obtained during 14-day periods of diets containing 400 kcal/day of only protein (n = 6) or glucose (n = 5), followed by 14 days of fasting and 14 days of refeeding on 800-1000 kcal/day. A significant positive correlation between total caloric intake and urine C-peptide excretion was found once the C-peptide excretion reached steady state after several days on each diet. Multiple regression analysis showed no contribution of body weight to urine C-peptide during the different diets. In contrast, a significant correlation was found between body weight and urine C-peptide in the fasting state. A marked and identical decrease of approximately 75% in urine C-peptide occurred over the first 5-7 days of the two 400-kcal diets, followed by a further decrease during fasting to 5% of baseline values. Refeeding was associated with a progressive increase. Plasma insulin and C-peptide followed the same trends as found for urine C-peptide, although the magnitude of change was much smaller. C-peptide clearance was not assessed because of the variation in plasma levels on eating meals. However, the same responses were found when C-peptide excretion was factored for creatinine excretion. Thus, the major determinant of urine C-peptide excretion appears to be food intake, and adaptations take 5-7 days to reach steady state.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Insulin binding and glucose transport in adipocytes in neonatal streptozocin-injected rat model of diabetes mellitus.

The neonatal streptozocin (STZ)-injected rat (NSIR) model of diabetes mellitus resembles human non-insulin-dependent diabetes mellitus (NIDDM) with respect to abnormalities in insulin secretory responses. The suggestion that insulin deficiency leads to insulin resistance, a prominent feature of human NIDDM, led us to examine insulin binding and glucose transport in the NSIR during the development of hyperglycemia. Male Wistar rats were injected at 2 days of age with STZ (90 mg/kg i.p.) or vehicle alone. Mild insulin deficiency, reflected by minimally decreased fed plasma insulin concentrations, was apparent at 4 wk (mean +/- SE, control vs. NSIR, 2.32 +/- 0.19 vs. 1.75 +/- 0.21 ng/ml) and at 8 wk. Pancreatic insulin content was dramatically reduced in NSIR to 12 and 5% of control values at 4 and 8 wk, respectively (P less than .001). Fed plasma glucose concentrations increased in the NSIR between 4 and 5 wk and were significantly elevated at 8 wk (251 +/- 25 vs. 527 +/- 52 mg/dl, P less than .001). 125l-labeled insulin binding showed a progressive increase as a function of adipocyte volume in control and NSIR. Epididymal fat pad weights and adipocyte volumes were significantly decreased in the NSIR. Thus, insulin binding did not differ when expressed per cell number but was increased in NSIR when corrected for cell size (percent specific binding X 10(2), 8.49 +/- 0.96 vs. 11.56 +/- 1.08/microliter cell vol; P less than .05, all ages combined).(ABSTRACT TRUNCATED AT 250 WORDS)

3-O-Methylglucose↗
PubMed1987

Immunological and metabolic concomitants of cyclosporin prevention of diabetes in BB rats.

The metabolic and immunological effects of cyclosporin given to prevent diabetes in BB rats were examined. Diabetes-prone (BBdp) and normal (BBn) BB rats received either oral cyclosporin (10 mg X kg-1 X day-1 or its vehicle from age 30-150 days. Six of 21 (29%) vehicle-treated rats became glycosuric, with hyperglycemia, weight loss, and unremitting insulin requirements, and showed destruction of islet beta-cells. Five of 24 (21%) cyclosporin-treated rats became glycosuric, but none demonstrated weight loss, all required insulin only intermittently after onset, and all showed persistence of islet beta-cells. Cyclosporin induced hypoinsulinemic glucose intolerance in BBn rats. Cyclosporin inhibited the normal rise with age of peripheral blood lymphocyte cell numbers, identified with monoclonal antibodies. OX19+ (pan-T) and W3/25+ helper T-lymphocytes were affected, and there was an increase in the large W3/13+ OX19- population characteristic of BBdp rats; in addition, this subset appeared in BBn rats. Cyclosporin also caused the appearance and/or increase in both BBdp and BBn rats of W3/25+ OX19- and OX8+ OX19- subsets. Suppressor/cytotoxic (OX8+) T-lymphocytes and Ia+ cells were less affected. The incidence of hyperglycemia and glycosuria was therefore unaltered by cyclosporin, although the diabetic syndrome was milder. BBn rats receiving cyclosporin showed glucose intolerance, suggesting that in BBdp rats, the net effects of immunosuppression on beta-cell destruction may have been counterbalanced by the direct effect on the same cells. The attenuation of diabetes in BBdp rats occurred through further immunosuppression rather than by correction of its preexisting immunodeficiency.

Animals↗
PubMed1987

Response to cyclosporine administration at onset of diabetes in BB rats.

The metabolic and immunological effects of cyclosporine A given at onset of spontaneous Type I diabetes in BB rats were examined, as an analogy to the current use of this agent in newly-diagnosed human diabetics. Diabetes-prone (BBdp) rats were monitored until appearance of hyperglycemia, at which time treatment with both cyclosporine (10 mg/kg/day) and insulin was immediately started. Cyclosporine induced no remission in any rats and did not affect their daily insulin requirements. After 9 weeks of cyclosporine treatment, islet morphology showed the typical "end-stage" picture in all rats, with essentially total beta cell loss. Pancreatic insulin contents were less than 1% of normal levels. During the 9 weeks of cyclosporine treatment, there was a decrease in numbers of peripheral blood Ia-positive lymphocytes, an increase in OX8+ lymphocytes (suppressor/cytotoxic and natural killer cells) but no change in the other subsets. There was a significant increase in plasma creatinine. We conclude that this dose of cyclosporine started at onset of diabetes in BB rats is unable to arrest and/or reverse the beta cell destructive process.

Animals↗