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Biomedical subjects

L A Gavin

Publications and source records attributed to L A Gavin.

51 records · Page 3Linked to original sources
PubMed1983

Glucagon does not modulate the alterations in T3 metabolism consequent to dietary manipulation and diabetes.

Low serum T3 levels and hyperglucagonemia are characteristic features of a number of catabolic states such as fasting and uncontrolled diabetes. The present study was performed to elucidate the relationship between this hyperglucagonemia and T3 metabolism. Serum glucagon and T3 and hepatic T4-5'-deiodinase activity (T4 leads to T3) were examined in groups of rats (T4-treated) fed (chow versus carbohydrate), fasted, or diabetic (streptozotocin 100 mg/kg i.p.) for 48-72 h. In the carbohydrate-fed (20% glucose in H2O ad libitum) group the mean serum T3 concentration and mean hepatic T4-5'-deiodinase activity were significantly higher (P less than 0.01) and the mean serum glucagon level significantly lower (P less than 0.05) than the respective means in the chow-fed control group. The mean serum T3 concentration was significantly less (P less than 0.05) in both the fasted (72 h) and diabetic (72 h) groups compared with the control mean, whereas the mean serum glucagon values were similar to the chow-fed group. The mean hepatic T4-5'-deiodinase activity was low in the diabetic group (P less than 0.05) but similar in the fasted group compared with the chow-fed control. A significant inverse correlation (r = -0.9; P less than 0.001) was noted between these alterations in serum T3, hepatic T4-5'-deiodinase activity, and serum glucagon, suggesting that glucagon could be a modulator of T3 metabolism. Hyperglucagonemia was induced in the glucose-fed group with a continuous glucagon infusion for 48 h (0.15 micrograms/kg/min s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

Sequential deiodination of thyroxine to 3,3'-diiodothyronine via 3,5,3'-triiodothyronine and 3,3',5'-triiodothyronine in rat liver homogenate. The effects of fasting versus glucose feeding.

The characteristics of thyroxine (T4) deiodination to 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) and of each of the latter to 3,3'-diiodothyronine (3,3'T2) were examined in rat liver homogenate. Each of the four reactions was enzymatic in nature, demonstrating pH and temperature optima, and tissue and time dependence. All reactions were considerably augmented (greater than 10-fold) by the presence of a thiol agent. At pH 7.2 with 2 muM T4 as substrate, rT3 generation was 3.3 +/- 0.44 (S.E.) and T3 formation was 4.8 +/- 0.57 pmol/min/100 mg of homogenate protein. Fasting for 72 h resulted in a significant inhibition of T4 deiodination, compared to that in the glucose-fed animals, in a 2% homogenate preparation. Enzyme activity for T4 to T3 was reduced by 54% (p less than 0.05) in the homogenate from the fasted rats. Fasting lowered the enzyme activity of T4 to rT3 by 56% (p less than 0.05). Although the monodeiodination of T3 to 3,3'-T2 was also significantly depressed (p less than 0.01) by fasting, rT3 deiodination to 3,3'-T2 was not. The in vitro additon of 5 mM dithioerythritol did not reverse the effect of fasting on any reaction. These results demonstrate that a 72-h fast significantly impairs the sequential deiodination of T4 in liver homogenate. The effect of fasting appears to be mediated mainly through a reduction in enzyme concentration rather than co-factor availability.

Animals↗
PubMed1980

Dietary modification of thyroxine deiodination in rat liver is not mediated by hepatic sulfhydryls.

The enzymatic deiodination of thyroxine (T(4)) is thiol dependent. Fasting (72 h) depresses hepatic T(4) deiodination and lowers the hepatic content of nonprotein sulfhydryls (NP-SH) and reduced glutathione (GSH). It has been proposed that the fasting effect may be mediated through these alterations in hepatic sulfhydryls. To test the importance of tissue (hepatic) thiol content in the modification of T(4) deiodination consequent to dietary manipulation, we examined the sequential deiodination of T(4) to 3,5,3'-triiodothyronine (T(3)) (5'-deiodination) and 3,3',5-triiodothyronine (reverse T(3), rT(3)) (5-deiodination) in liver homogenates without added thiol from groups of rats fed Purina lab chow (P) (a protein-rich diet), glucose alone (G), or glucose plus cysteine (G(c)) for 72 h or fasted (F) for the same period. The initial rate of each reaction was compared to the tissue concentrations of NP-SH and GSH. Dietary manipulation induced significant changes in hepatic deiodination of T(4) to T(3) and rT(3) and sulfhydryl content. There was a marked dissociation between the rate of each reaction and hepatic NP-SH and GSH levels. T(4) deiodination by the alternative pathways was significantly higher (P < 0.01) in G > P > F. In contrast both hepatic NP-SH and GSH concentrations were greater (P < 0.05) in P > F > G. The lack of a relationship between these parameters was further emphasized on analysis of tissue from rats fed G(c). Despite the clearcut (P < 0.01) increase in hepatic NP-SH and GSH consequent to G(c) feeding, there was no alteration in iodothyronine deiodination compared to the group fed glucose alone. These data indicate that the effects of diet on T(4) monodeiodination in liver are not mediated by changes in the tissue level of sulfhydryl compounds but rather involve alterations in the concentrations of the deiodinases.

Animals↗
PubMed1979

The diagnostic dilemma of isolated hyperthyroxinemia in acute illness.

Eighteen patients with a variety of illnesses but no history of thyroid disease were shown to have elevated serum total and free thyroxine (T4) concentrations but low serum total triiodothyronine (T3) levels. Thyroid function tests were requested initially to excluded the possibility of hyperthyroidism in a setting of hypermetabolism. Clinical and laboratory follow-up investigations demonstrated that 15 patients were euthyroid and that hormonal alterations were transient features of the intercurrent illnesses. Three patients did, in fact, have hyperthyroidism. Retrospective analysis of diagnostic data demonstrated that of the initial thyroid function screening tests, serum total T3 concentration, the T3/TF4 ratio, and the indirectly measured free T3 (FT3) index were the most useful parameters in excluding hyperthyroidism. The FT3 index was the most helpful, being normal or low in all the euthyroid and high in each of the hyperthyroid patients.

Acute Disease↗
PubMed1979

Detection of a thyroxine-binding protein physicochemically similar to serum thyroxine-binding globulin in normal human urine.

Urine samples from 10 normal adult males were analyzed for T4-binding globulin (TBG) employing a sensitive and specific RIA for serum TBG. Urine TBG was detected at a concentration of 1.74 +/- 0.87 microgram/100 ml (mean +/- SD). The excretion rate was 13.2 +/- 6.5 microgram/g creatinine. There was no correlation between the daily excretion rate of TBG and the total urinary protein (r = 0.52). Analyses of this T4-binding protein by gel filtration and on both reverse flow paper and gel electrophoresis demonstrated similar characteristics to those of serum TBG and purified TBG. The maximum T4-binding capacity of urine TBG, determined by reverse flow paper electrophoresis and equilibrium dialysis, was similar to that of serum TBG. The association constant for T4 of urinary TBG (0.46 +/- 0.20 X 10(10) M-1), determined by equilibrium dialysis, was significantly less (P less than 0.01) than that of serum TBG at 1.43 +/- 0.23 X 10(10) M-1). The Scatchard analysis of the urinary data demonstrated two T4-binding sites, one of high affinity consistent with TBG and one of low affinity consistent with albumin. It is concluded that the TBG present in urine has the major physical and biochemical features of the intact molecule, but that minor conformational and/or charge alterations occurred during renal excretion. Interpretation of data on thyroid hormones in normal urine should take the presence of TBG into consideration.

Adult↗
PubMed1978

3,3'-Diiodothyronine production, a major pathway of peripheral iodothyronine metabolism in man.

3,3'-Diiodothyronine (3,3'-T(2)) has been detected in human serum and in thyroglobulin. However, no quantitative assessment of its clearance rate (CR), production rate (PR), or of the importance of extrathyroidal sources of 3,3'-T(2) relative to direct thyroidal secretion is yet available. This study examines these parameters in seven euthyroid subjects, and in eight athyreotic subjects (H) eumetabolic due to thyroxine therapy (HT(4)) (n = 5) or triiodothyronine replacement (HT(3)) (n = 3). A highly specific radioimmunoassay for the measurement of 3,3'-T(2) in whole serum was developed. Serum 3,3'-T(2) concentrations were (mean +/- SD) 6.0+/-1.0 ng/100 ml in 13 normal subjects, 9.0+/-4.6 ng/100 ml in 25 hyperthyroid patients, and 2.7+/-1.1 ng/100 ml in 17 hypothyroid patients. The values in each of the latter two groups were significantly different from normal. 3,3'-T(2) was detected regularly in normal concentrations in 11 hypothyroid patients eumetabolic by treatment with synthetic T(4), in 10 eumetabolic patients suffering from nonthyroidal systemic illness, and in 2 subjects with elevated serum T(4)-binding globulin. The 3,3'-T(2) CR was assessed from data acquired from the (125)I-3,3'-T(2) constant infusion technique. The 3,3'-T(2) PR was calculated from CR and serum concentration of 3,3'-T(2) determined by radio-immunoassay. In the HT(4) subjects the 3,3'-T(2) CR averaged 840+/-377 liters/day and 3,3'-T(2) PR 33.9+/-12.5 mug/day. These results were not significantly different from those in the control group: 3,3'-T(2) CR 628+/-218 liters/day and 3,3'-T(2) PR 39.8+/-19.8 mug/day (all corrected to 70 kg body wt). In addition to 3,3'-T(2) PR, T(3), and reverse triiodothyronine (rT(3)) PR were determined in three of the HT(4) subjects. In each case studied, the 3,3'-T(2) PR was close to the combined triiodothyronine (T(3) + rT(3)) PR. The mean molar ratio of T(2) PR/(T(3) + rT(3)) PR was 1.08+/-0.10. The results obtained in the HT(4) subjects indicate that the production of 3,3'-T(2) is a major route of T(4) metabolism. The combined studies of 3,3'-T(2), T(3) and rT(3) PR in the HT(4) subjects indicate that both T(3) and rT(3) are major precursors of 3,3'-T(2). In the HT(3) subjects, the conversion of T(3) to 3,3'-T(2), determined as the molar ratio of 3,3'-T(2) PR to T(3) PR, ranged from 0.36 to 0.92, providing further evidence that T(3) is a precursor of 3,3'-T(2). From the close agreement between the mean values for 3,3'-T(2) PR in the euthyroid and HT(4) group it is concluded that most, if not all of the 3,3'-T(2) produced in normal humans is derived by extrathyroidal conversion from T(3) and rT(3).

Humans↗
PubMedDate not supplied

Troglitazone add-on therapy to a combination of sulfonylureas plus metformin achieved and sustained effective diabetes control.

OBJECTIVE: To elucidate the effect of triple combination oral agent therapy on type 2 diabetes. METHODS: We performed a prospective longitudinal study on 40 patients with type 2 diabetes who had failed to achieve a glycosylated hemoglobin (HbA1c) of < or = 8.0% despite optimal therapy with a combination of sulfonylureas plus metformin. Troglitazone was added and then titrated, with the intent to achieve at least a 1% reduction in HbA1c within 3 months. Responders were reassessed at 6 and 12 months. Nonresponders were reassessed at 6 months; in the absence of a significant HbA1c response, participation in the study was discontinued. RESULTS: Of the 40 study subjects, 25 were responders, 10 were nonresponders, and 5 were withdrawn from the study before completion of 3 months of therapy because of side effects. The 25 responders had a mean baseline HbA1c of 9.9%, which decreased significantly to 7.8% after 3 months of troglitazone therapy and to 7.4% at 6 months and at 12 months. In addition, the fasting blood glucose (FBG) in the responders decreased significantly from 168 mg/dL at baseline to 118 mg/dL at 6 months, which was sustained at 121 mg/dL at 12 months. In the responder group, a mean HbA1c < or = 8% was achieved in 68% at 6 months and sustained in 65% after 1 year. Furthermore, 40% of responders achieved a mean HbA1c < or = 7.0% at 6 months, and 39% sustained this degree of control at 12 months. The 10 nonresponders showed no significant change in HbA1c or FBG during the 6 months of troglitazone therapy. No difference existed in the mean baseline FBG, HbA1c, or C peptide level between the two groups. Responders, however, had a significantly lower mean body mass index (BMI) (31 kg/m2) than did nonresponders (37 kg/m2). Although responders were older than nonresponders (mean age, 65 years versus 55 years), no significant difference was noted in duration of diabetes (11.6 years versus 8.7 years). Multivariate analysis showed that male gender and BMI were the strongest predictors of a response to troglitazone add-on therapy to the prior combination of sulfonylureas plus metformin. CONCLUSION: This study showed that oral therapy with troglitazone added to sulfonylureas plus metformin achieved and sustained a significant improvement in control of diabetes in 71% of patients who had failed to achieve HbA1c < or = 8% with dual oral agent therapy. The positive response was evident within 3 months, reached maximum by 6 months, and was sustained to 12 months of therapy. Therefore, patients who fail to achieve HbA1c < or = 8% with sulfonylureas plus metformin should have at least 3 months of troglitazone add-on therapy before advancing to traditional insulin treatment.

Administration, Oral↗