Optimal daily levothyroxine dose in primary hypothyroidism. Its relation to pretreatment thyroid hormone indexes.

Several studies have described the mean optimal replacement daily dose of levothyroxine sodium in subjects with primary hypothyroidism. Furthermore, a cautious approach in replacement therapy of the elderly population is well established. However, the initial dose of levothyroxine has remained variable, especially in young subjects, since the guidelines for the prediction of the final replacement dose are scarce. This study assessed the efficacy of pretreatment thyroid hormone indexes in determination of the final maintenance levothyroxine dose in 156 subjects with primary hypothyroidism. The optimal daily levothyroxine dose as defined by normalization of serum thyroxine and basal thyroid-stimulating hormone levels, as well as thyroid-stimulating hormone response to the intravenous administration of thyrotropin-releasing hormone, varied between 50 micrograms and 200 micrograms and, hence, the subjects were grouped according to the final levothyroxine dose. Significant correlations were noted between the levothyroxine dose for individual groups and pretreatment serum triiodothyronine, thyroxine, and thyroid-stimulating hormone concentrations. However, the serum thyroid-stimulating hormone concentration demonstrated a markedly closer relationship with the levothyroxine dose than did either triiodothyronine or thyroxine for both comparisons. Furthermore, when assessed for all subjects, the correlation between levothyroxine dose and thyroid-stimulating hormone level, alone, remained significant. This study demonstrates that obtaining routine thyroid hormone indexes prior to initiation of replacement levothyroxine therapy may be reliable predictors of the final levothyroxine dose; serum thyroid-stimulating hormone concentration being the best index. Thus, the levothyroxine dose may be reliably predicted depending on a specific range of thyroid-stimulating hormone levels. Therefore, in an individual subject, aiming for the predicted dose rather than the mean dose, a procedure described in the medical literature, may be more helpful in arriving at an optimal levothyroxine dose.

'Subclinical hypothyroidism'. Natural course of the syndrome during a prolonged follow-up study.

OBJECTIVE: To determine the natural course of the syndrome "subclinical hypothyroidism." DESIGN: Prospective study of 30 subjects with "subclinical hypothyroidism," as documented precisely by normal serum thyroxine and triiodothyronine concentrations and high serum thyrotropin levels on three occasions at intervals of 2 to 3 weeks. The subjects were followed up for 4 to 15 years (mean, 8.2 +/- 2.3 years), with repeated determinations of thyroid hormone indices at intervals of 3 to 6 months. SETTING: Endocrinology Clinic at the Veterans Affairs Medical Center. RESULTS: 16 subjects developed definitive primary hypothyroidism within 3 months to 2 years, as reflected by a progressive rise in serum thyrotropin level with a gradual decline in serum thyroxine and triiodothyronine concentrations, with serum thyroxine levels falling to subnormal concentrations. In 14 of these subjects, primary hypothyroidism could be attributed to known etiologic factors, whereas in the remaining two the cause was not apparent. Persistently elevated serum thyrotropin with normal serum thyroxine and triiodothyronine concentrations following a cyclic pattern was observed in 14 subjects during the follow-up period. In 11 of these subjects, there was a history of non-radical surgery or conventional radiation therapy to the neck area, whereas in the remaining three subjects, no apparent cause could be identified. CONCLUSIONS: "Subclinical hypothyroidism" is not always a forerunner of primary hypothyroidism. Two distinct populations evolve: (1) those with true preclinical or subclinical hypothyroidism, which may be predicted by the presence of one of the well-known etiologic factors responsible for onset of primary hypothyroidism, and (2) euthyroidism with reset thyrostat--a permanent state without a definitive progression to hypothyroidism, most probably secondary to a previous subtle insult to the thyroid gland.

Improved metabolic control in insulin-dependent diabetes mellitus with insulin and tolazamide.

The influence of sulfonylurea drugs in enhancing the effect of endogenous insulin is well documented. Furthermore, combination therapy with sulfonylurea and insulin is effective in the treatment of type II diabetes mellitus. Therefore, to assess the efficacy of this type of combination therapy in type I diabetes, we conducted a double-blind clinical trial with tolazamide and insulin in 15 subjects with type I diabetes. The diagnosis of type I diabetes was confirmed by previous episodes of diabetic ketoacidosis and undetectable C-peptide levels in serum samples from blood drawn from patients two hours after breakfast. During the study protocol, placebo or tolazamide was randomly added to insulin and the combination therapy was continued for three months. In the placebo group, levels of fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) did not alter significantly at the end of the study period. However, in the tolazamide group, levels of FPG and HbA1c markedly improved after administration of tolazamide (FPG levels before therapy, 10.8 +/- 0.9 mmol/L [mean +/- SEM]; after therapy, 6.7 +/- 0.4 mmol/L; HbA1c levels before therapy, 10.9% +/- 0.6%; after therapy, 9.6% +/- 0.5%). Therefore, adjuvant therapy with tolazamide and insulin may be beneficial in achieving adequate metabolic control in type I diabetes mellitus.

Serum thyrotropin in primary hypothyroidism. A possible predictor of optimal daily levothyroxine dose in primary hypothyroidism.

BACKGROUND: Pretreatment thyrotropin levels may be a reliable predictor of the optimal daily dose of levothyroxine sodium in patients with primary hypothyroidism. However, the older method of serum thyrotropin determination, with the reference range of less than 1 to 8 mU/L, has given way to a newer, supersensitive thyrotropin assay, with a reference range of 0.5 to 5.0 mU/L. Thus, at present, the previously established relationship between the levothyroxine dose and the pretreatment serum thyrotropin concentration may not be reliable in predicting the optimal daily dose of levothyroxine. METHODS: We reassessed the relationship between the optimal daily levothyroxine dose and the pretreatment serum thyrotropin concentration as determined by the newer assay in 192 consecutive patients with primary hypothyroidism referred to an endocrinology clinic over a period of 4 years. RESULTS: The optimal daily dose of levothyroxine sodium ranged from 25 to 225 micrograms, with most patients (65%) requiring 100 to 150 micrograms/d and a median dose of 125 micrograms. Multiple regression analysis documented a significant curvilinear correlation between the mean pretreatment serum thryrotropin concentration and the optimal daily levothyroxine dose for individual groups divided according to available tablet strengths (r = .994, P < .001). A simple linear regression was also significant (r = .92, P < .001), although with an intercept much higher than the minimum levothyroxine sodium dose of 25 micrograms/d. However, the relationships markedly improved when the linear regressions were determined separately for two further subgroups at the median daily dose of 125 micrograms, providing equations to predict even the smallest optimal daily dose of levothyroxine. CONCLUSION: Pretreatment thyrotropin levels determined by new assays may also provide a useful guideline in determining the optimal daily maintenance dose of levothyroxine in patients with primary hypothyroidism.

Efficacy of insulin and sulfonylurea combination therapy in type II diabetes. A meta-analysis of the randomized placebo-controlled trials.

BACKGROUND: Numerous studies demonstrate the efficacy of the combination therapy of insulin and sulfonylurea in subjects with type II diabetes mellitus. However, two recent meta-analyses of randomized trials during the last decade provided inconsistent conclusions and failed to resolve the controversy. OBJECTIVE: To assess the efficacy of insulin and sulfonylurea combination therapy in type II diabetes mellitus by performing meta-analysis of only the controlled studies selected according to specific strict criteria. METHODS: A computerized literature survey was conducted using the MEDLINE database from January 1980 through March 1992 with the search headings of "sulfonylurea" and "insulin" and "combination therapy in diabetes mellitus. "A manual search was also performed using references from each retrieved report. Case reports, review articles, editorials, and citations reported in non-English-language journals without English translations were excluded. Forty-three citations were obtained. Four strict inclusion criteria were used to select studies: randomized, placebo-controlled trials (oral agent plus insulin vs placebo plus insulin); homogeneous target population (subjects with type II diabetes); intervention using the same sulfonylurea agent in a combination therapy; and uniform outcome measures to evaluate efficacy such as body weight; values for serum glucose, glycohemoglobin, and C peptide; daily insulin dosage; and lipid concentrations. More stringent qualitative subcriteria were then used to eliminate bias in the final unanimous selection by two blinded reviewers. Data were pooled and analyzed using Student's t test and Winer's combined test. RESULTS: Sixteen studies satisfied the inclusion criteria. Metabolic control improved with the combination therapy as reflected by a significant lowering of fasting serum glucose values (P < .01) and glycohemoglobin concentrations (P < .025). Moreover, improved metabolic control was achieved with a significantly smaller daily insulin dose (P < .01) and without a significant change in body weight. Finally, the combination therapy enhanced the endogenous insulin secretion as expressed by an increase in fasting serum C peptide concentration (P < .05). CONCLUSIONS: Combination therapy with insulin and sulfonylurea may be a more appropriate and a suitable option to insulin monotherapy in subjects with non-insulin-dependent diabetes in whom primary or secondary failure to sulfonylurea developed. It may also be a more cost-effective way of long-term management in this group of subjects, especially in the elderly.

Glycosylation of proteins. Lack of influence of aging.

In elderly nondiabetic individuals, increased glycosylation of hemoglobin has been reported. Most elderly subjects suffer from chronic disorders and consume one or more medications. Thus, it is conceivable that the increased glycosylation of hemoglobin may be secondary to factors other than old age. Furthermore, the data are sparse regarding the effect of aging on glycosylation of other proteins. In this study, glycosylated hemoglobin (GHb), glycosylated protein (GP), glycosylated albumin (GA), and fasting plasma glucose (FPG) concentrations were determined in 93 healthy nondiabetic subjects after an overnight fast. Strict criteria were observed to define the healthy status of these subjects to eliminate the influence of all other factors known to facilitate glycosylation of hemoglobin. No significant correlations were noted between age and FPG, GHb, GP, or GA (P greater than .05 for all correlations). Furthermore, no significant differences were observed between groups according to age for any of the parameters studied. Therefore, this study demonstrates that aging may not influence glycosylation of proteins in healthy subjects, and the previously observed increase in GHb concentrations in elderly populations may be related to associated factors rather than old age.

Adjuvant therapy with tolazamide and insulin improves metabolic control in type I diabetes mellitus.

Sulfonylurea agents have been well documented to be effective in type II diabetes mellitus by increasing insulin secretion as well as by enhancing cellular binding of endogenous insulin. We have examined in 20 type I diabetic subjects the efficacy of tolazamide, a common sulfonylurea agent, as adjuvant therapy in combination with an appropriate diet and insulin. This regimen decreased the insulin dose while continuing to maintain adequate metabolic control, as reflected by fasting plasma glucose (FPG) less than 150 mg/dl and HbA1 levels less than 9%, and reduced number of hypoglycemic episodes to almost nil in a group of subjects with adequate metabolic control before institution of combination therapy. In subjects in whom metabolic control was inadequate (FPG greater than 150 mg/dl and HbA1 greater than 9%) with insulin alone, the adjuvant therapy with tolazamide improved or normalized hyperglycemia and HbA1. In 13 subjects in whom adequate metabolic control was achieved with combination therapy, metabolic control worsened on withdrawal of tolazamide while continuing insulin in the same dosage and adequate metabolic control promptly returned on reinstitution of combination therapy with insulin and tolazamide. In the remaining seven subjects, metabolic control remained adequate with combination therapy during the 4-10-mo follow-up period. This study therefore demonstrates that combination therapy with sulfonylurea agent and insulin may be beneficial in management of type I diabetes. Furthermore, this regimen may be helpful in prevention of extreme plasma glucose excursions observed in brittle diabetic individuals. A larger, long-term clinical trial with this regimen in type I diabetic subjects must be undertaken to establish this preliminary finding.

The effect of recurrent practice at home on the acceptability of capillary blood glucose readings. Accuracy of self blood glucose testing.

OBJECTIVE: To judge how reliably patients perform capillary blood glucose testing over time with recurrent practice at home and to assess if a clinic glucose meter is an acceptable alternative to the clinical laboratory for monitoring patient performance. RESEARCH DESIGN AND METHODS: We compared capillary blood glucose readings obtained by patients with their own equipment and the venous blood glucose determinations by the clinical laboratory at three biweekly visits during the initial phase in 40 subjects attending the diabetes clinic at the Veterans' Affairs Medical Center in Phoenix, Arizona. We also compared patient-generated readings using their own equipment and the readings obtained by the clinic glucose meter and strips at five weekly visits during the second phase in 11 subjects who continued further participation. Error grid analysis was used for both comparisons. Capillary blood glucose readings obtained with clinic glucose meter and strips on one hand were correlated with venous blood glucose levels determined by the clinical laboratory. RESULTS: During the initial phase, 30 subjects consistently obtained clinically acceptable comparisons (zone A on the error grid, i.e., within 20% of the laboratory value) or improved over time, 9 subjects showed deterioration, and 1 subject failed to obtain zone A results on any of the visits. Three subjects who had consistently obtained zone A results during the initial phase maintained their performance, whereas eight subjects who had failed to achieve zone A values by the end of the initial phase gradually improved and ultimately achieved zone A values by the end of the study. A highly significant correlation was noted between clinic meter readings and laboratory values (r = 0.93, P < 0.00001). CONCLUSIONS: Clinically acceptable user proficiency in capillary blood glucose testing can be maintained in most subjects, with recurrent intensive education during follow-up clinic visits. Therefore, we recommend that these comparisons be performed and patient's technique be observed at each visit to monitor their performance. The clinic glucose meter is a suitable alternative to a clinical laboratory for user proficiency checks.

Impaired pituitary thyrotroph function in uncontrolled type II diabetes mellitus: normalization on recovery.

Altered thyroid hormone metabolism with decreased serum T3 and increased rT3 concentrations in patients with uncontrolled diabetes mellitus has been well documented. However, data regarding TSH secretion are sparse, especially the influence of glycemic control. Therefore, we examined serum T4, free T4, T3, rT3, T3 resin uptake, and TSH as well as the TSH response to TRH administration [expressed as TSH increment (delta TSH) and area under the curve (theta TSH)] in 29 newly discovered type II diabetic patients (DM) before treatment and in 12 normal subjects. The study was repeated in the DM patients after attainment of euglycemia and normalization of glycosylated hemoglobin (HbA1C) following therapy with diet and tolazamide for 8-12 weeks. Serum T4, free T4, and T3 resin uptake were not significantly different in DM compared to those in normal subjects. Serum T3 was low and rT3 was high in DM before treatment, and both normalized on achieving the euglycemic state. Basal TSH in uncontrolled DM was not significantly different from that in normal subjects and remained unchanged during treatment. However, delta TSH and theta TSH were significantly reduced (P less than 0.01) in uncontrolled DM. Both fasting plasma glucose (FBS) and HbA1C levels correlated inversely with delta TSH as well as theta TSH (FBS vs. delta TSH, r = -0.42; FBS vs. theta TSH, r = -0.38; HbA1C vs. delta TSH, r = -0.40; HbA1C vs. theta TSH, r = -0.42; P less than 0.05 for all correlations). Finally, TSH responses returned to normal on attainment of euglycemia and normal HbA1C concentrations. These studies indicate that regulation of TSH secretion is altered in DM during the decompensated state and normalizes when euglycemia is achieved.

Impaired pancreatic alpha-cell response in hyperthyroidism.

Recently, we observed that in hyperthyroid patients, plasma glucagon was not adequately suppressed by an oral glucose load, suggesting altered pancreatic alpha-cell sensitivity. To further assess pancreatic alpha-cell function in hyperthyroidism, plasma glucose, glucagon, and insulin resonses to a protein meal were determined in normal subjects and hyperthyroid patients. Fasting plasma glucose was normal in hyperthyroid patients. A protein meal produced an increase in plasma glucose levels in hyperthyroid patients, whereas in normal subjects protein feeding was followed by a decline in blood glucose levels. Basal glucagon was markedly elevated in three of nine hyperthyroid patients, whereas in the remaining six, fasting plasma glucagon was unaltered. In both groups, protein feeding induced a glucagon rise; however, the increment was significantly smaller in hyperthyroid patients. In hyperthyroidism, fasting plasma insulin was raised and the insulin response to a protein meal was exaggerated. Furthermore, the insulin elevations were sustained and did not return to the basal level by 180 min as observed in normal subjects. We conclude that 1) the plasma glucagon response to a protein meal is blunted in hyperthyroidism, a finding which confirms our recent observation of decreased sensitivity of the pancreatic alpha-cell in hyperthyroidism; 2) fasting hyperinsulinemia with simultaneous euglycemia is consistent with the presence of insulin resistance in hyperthyroidism; and 3) the sustained and exaggerated plasma insulin rise after ingestion of a protein meal suggests hypersensitivity of the pancreatic beta-cell in hyperthyroidism.

Onset of type I diabetes mellitus, hypothyroidism, and hypogonadism on withdrawal of glucocorticoid therapy and remission on its resumption in a patient with rheumatoid arthritis.

A 57-year-old white man manifested adrenal insufficiency, insulin-dependent diabetes mellitus reflected by diabetic ketosis, primary hypothyroidism, and primary hypogonadism on rapid withdrawal of glucocorticoid therapy of several years' duration for rheumatoid arthritis. Resumption and continuation of glucocorticoid therapy for six months resulted in remission of type I diabetes mellitus and hypogonadism, and a euthyroid state was achieved by replacement therapy with L-thyroxine.

Acute psychosis in a patient receiving trimethoprim-sulfamethoxazole intravenously.

A 55-year-old man became acutely psychotic and had a pseudoseizure after receiving six doses of intravenously administered trimethoprim-sulfamethoxazole. These symptoms resolved within 24 hours after discontinuation of the medication; this finding suggests a causal effect of the drug administration.

Thyroid hormone indices in adult healthy subjects: no influence of aging.

Controversy exists regarding the influence of aging on thyroid hormone metabolism. Several investigators report lowering of T3 and/or a rise in reverse T3 (rT3) in elderly subjects. Others suggest that these thyroid hormone alterations were secondary to associated disorders rather than old age, and questioned the "healthy" status of the subjects studied in the earlier reports. Therefore, to assess the possible effect of aging we studied T3 resin uptake, T4, free T4, T3, and rT3 concentrations in 152 euthyroid healthy adult subjects. These subjects were selected carefully and were therefore devoid of any illness, acute or chronic, and were not treated with any medications at the time of study. No significant alterations were noted in any of the thyroid hormone concentrations in subjects divided into groups according to age. Nor was there a significant difference in these parameters between men and women of any individual age group or for all ages combined. Therefore, old age per se may not influence thyroid hormone metabolism and hence may not induce changes in serum thyroid hormone concentrations. The changes in thyroid hormones noted previously in elderly subjects may be a reflection of concurrent disorders and not old age.

Low triiodothyronine and raised reverse triiodothyronine levels in patients over fifty years of age who have type II diabetes mellitus: influence of metabolic control, not age.

Several studies have demonstrated that the uncontrolled diabetic state in both type I as well as type II diabetes mellitus is characterized by altered thyroid hormone metabolism, which results in the lowering of serum triiodothyronine (T3) levels and a reciprocal elevation of T3 (rT3) levels. Because the majority of type II diabetics are over 50 years of age and because numerous previous reports have implicated aging as a cause of low T3 and high rT3 levels, we studied 220 type II diabetics from 40-85 years of age to assess the influence of aging and metabolic control on thyroid hormone levels. Serum thyroxine (T4) free T4, T3 resin uptake, and thyroid-stimulating hormone (TSH) measurements in diabetic patients were not significantly altered compared with 37 young normal control subjects, irrespective of age or the grade of metabolic control. Serum T3 levels declined and rT3 levels rose in the diabetic patients with worsening of the metabolic control. However, with comparable metabolic control, the levels were not significantly different from the younger patients. Therefore, low T3 and high rT3 levels observed in patients of any age who have type II diabetes mellitus may be exclusively caused by deranged metabolic control of their disease.

Hepatic regulation of pancreatic alpha-cell function.

The direct feedback regulation between the endocrine gland and its target organ is an expected biological relationship. However, such a phenomenon is far from being well established in the case of the endocrine pancreas and its major target organ, the liver, especially since plasma glucose has been established as the prime regulator. In this perspective, I have reexamined the feedback regulation between plasma glucose and glucagon secretion by the pancreatic alpha cell. Surprisingly, available data in the literature appear to document a frequent breakdown of this well-established interdependence between plasma glucose and pancreatic alpha cells, as reflected by a sustained elevation of plasma glucagon levels in several physiologic and pathologic states with concurrent euglycemia or hyperglycemia. Moreover, normal or low glucagon concentrations in the presence of fasting hypoglycemia in patients with insulinoma or non-islet cell tumors secreting insulin-like peptides and in patients with hepatic glycogen storage disorders may enhance our hypothesis that plasma glucose level may not be the major regulator of glucagon secretion. Extensive data in the literature show that hyperglucagonemic states are characterized by a unique metabolic environment, namely hepatic glycogen depletion. Similarly, hepatic glycogen stores are abundant in the presence of normal or low glucagon concentrations. These findings imply a distinct relationship between hepatic glycogen content and plasma glucagon level.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-kinetics of pancreatic alpha- and beta-cell responses to a protein meal in normal subjects.

A protein meal is well known to induce a prompt secretion of insulin and glucagon. However, the data regarding the dose-response relationship between the protein meal and the insulin and glucagon responses are sparse. This study assessed the effects of ingestion of protein meals of varying amounts on plasma glucose [S], insulin [I], and glucagon [G] concentrations in eight normal subjects. Protein meals were administered after an overnight fast in a randomized sequence at intervals of 10 days in four different quantities: 250 mg/kg body weight (BW) (A), 500 mg/kg BW (B), 1 g/kg BW (C), and 2 g/kg BW (D). Mean S levels were not significantly altered following A, B, or C, although significant decreases in S responses were noted after C and D as reflected by absolute changes (delta) and/or the cumulative responses (CR) and the areas under the curve (sigma). Mean I increased promptly to peak concentration by 30 minutes, although in individual subjects the peak was achieved either at 30 or 60 minutes following all protein meals. The increase was progressively greater and the return was delayed with increasing quantities resulting in progressive elevations in delta I and percent increase from basal concentration (%), as well as CRI and sigma I. G increased following all protein meals as well. The mean peak G concentrations were achieved by 90 minutes, although in individual subjects the peak G was reached at 90 or 120 minutes, a significant delay in comparison to the peak I levels. G returned to base line only following ingestion of A during the study period.(ABSTRACT TRUNCATED AT 250 WORDS)

Is hepatic glycogen content a regulator of glucagon secretion?

The role of plasma glucose as a major regulator of glucagon secretion is well established. However, this feedback regulation appears to break down in several states in which a closer relationship is apparently evident between plasma glucagon and hepatic glycogen content. Therefore, we assessed plasma glucagon as well as glucose response (delta glucose) to intravenous (IV) bolus administration of 1 mg glucagon after an overnight fast (a reliable and accurate estimate of the magnitude of hepatic glycogen content) in a population of normal subjects and subjects with hepatic cirrhosis and hyperthyroidism, both of which are disorders characterized by hepatic glycogen depletion. Plasma glucose concentrations were not significantly different in either group. However, plasma glucagon and insulin concentrations were significantly increased and delta glucose significantly decreased in both cirrhotic patients and hyperthyroid patients as compared with normal subjects. Furthermore, a significant relationship (r = -.55, P less than .0001) was noted between delta glucose and plasma glucagon, but not plasma insulin. Therefore, we believe that pancreatic alpha-cell function may be dependent on hepatic glycogen content. Moreover, the primary action of glucagon may be to induce gluconeogenesis in the absence of hepatic glycogen stores due to declining insulin concentrations or insulin resistance.

Pancreatic alpha-cell function in idiopathic reactive hypoglycemia.

Idiopathic reactive hypoglycemia (IRH) is a well-documented but overdiagnosed syndrome. The presence of transient hypoglycemia and enhanced insulin secretion and/or increased insulin sensitivity before the onset of IRH is well documented. However, the data regarding glucagon secretion are sparse. Therefore, this study assessed glucagon and insulin responses to (1) oral ingestion of 100 g glucose oral glucose tolerance test (OGTT) and (2) a 100-g protein meal after an overnight fast in a randomized sequence at intervals of 7 to 10 days in five subjects with previously well-documented IRH and six normal subjects. Basal plasma glucose and insulin levels were not significantly different in both groups. However, basal glucagon was significantly higher (P < .025) in IRH subjects (347 +/- 83 ng/L) compared with normals (135 +/- 20 ng/L). In IRH subjects during the OGTT, hypoglycemia (2.7 +/- 0.11 mmol/L) occurred at 150 +/- 16 minutes and was preceded by a markedly higher (P < .01) peak glucose concentration (11.7 +/- 0.6 mmol/L) at 36 +/- 6 minutes in comparison to normals (8.8 +/- 0.4 mmol/L), indicating the presence of impaired glucose tolerance in these subjects. Similarly, the plasma insulin increase was significantly higher (P < .01) but delayed in IRH subjects compared with normals. In contrast, glucagon suppression was not significantly different in both groups, although glucagon failed to increase following hypoglycemia in IRH. During a protein meal, plasma glucose declined in both groups, with a significantly (P < .05) greater decrease in IRH subjects (-0.8 +/- 0.2 mmol/L) compared with normals (0.5 +/- 0.1 mmol/L). However, the glucagon increase was significantly (P < .01) blunted in IRH subjects (61% +/- 15%) in comparison to normals (152% +/- 39%). Thus, basal hyperglucagonemia with normal glucose concentration may suggest the presence of a hyposensitivity of the glucagon receptor in IRH. Moreover, the lack of appropriate suppression during the OGTT despite marked hyperglycemia, the lack of an increase at the onset of hypoglycemia, and the inhibited response to a protein meal in IRH subjects compared with normals denote altered glucagon secretion in IRH. Therefore, it is likely that glucagon receptor downregulation and impaired glucagon sensitivity and secretion may contribute to postprandial hypoglycemia in IRH.

Osteomalacia associated with prostatic cancer and osteoblastic metastases.

A patient with carcinoma of the prostate, extensive bony metastases, and osteomalacia is reported. The diagnosis of osteomalacia was suspected because of generalized weakness and bone pains, hypocalcemia, hypophosphatemia, and raised alkaline phosphatase. It was documented by low 1,25-dihydroxyvitamin D level. Furthermore, it was confirmed by improvement in patient's symptomatology and normalization of serum calcium and phosphorus after treatment with 1,25-dihydroxyvitamin D3 (Rocaltrol).

Thyroid hormone indices during illness in six hypothyroid subjects rendered euthyroid with levothyroxine therapy.

PURPOSE: We wanted to evaluate changes in the natural course of serum thyroxine (T4), tri-iodothyronine (T3), reverse tri-iodothyronine (rT3), and thyroid stimulating hormone (TSH) concentrations during hospitalization for an acute illness, in subjects rendered euthyroid with Levothyroxine (LT4) replacement therapy. METHODS: Six male subjects ranging in age 30 - 65 years with a history of primary hypothyroidism were included. They were euthyroid prior to hospitalization. LT4 continued to be administered orally in the same pre-admission daily dose. Serum, T4, T3, rT3, and TSH concentrations were determined on day of admission to the intensive care unit (ICU) for an acute illness. These were repeated during the first week on alternate days and again during a follow-up visit 1 week after discharge. Student's t-test, analysis of variance, and linear regression were used to analyze the data. RESULTS: Serum T4, T3 declined to a nadir and serum rT3 rose to its peak by day 3 of hospitalization before returning to pre admission euthyroid levels. Serum TSH declined initially but rose to supernormal levels on day 7 before normalization. Significant correlations were noted between TSH on one hand and T3/T4 (r = 0.76, p < 0.001) and rT3/T4 (r= - 0.64, p < 0.001) ratios. CONCLUSIONS: Alterations ensuing during a short stay in the hospital due to an acute illness in subjects with primary hypothyroidism rendered euthyroid with appropriate replacement therapy with Levothyroxine (LT4) are almost identical to those in normal subjects. These changes are probably secondary to altered thyroid hormone metabolism. The altered levels of thyroid hormones and TSH noted in these subjects are transient and therefore providers should refrain from initiating frequent changes in daily LT4 replacement dose during the acute illness in these subjects.