Screening, prevention and management of osteoporosis and bone loss in adult and pediatric hematopoietic cell transplant recipients.

Long-term survivors of hematopoietic cell transplantation (HCT) are at risk for loss of bone mineral density (BMD) and subsequent osteoporosis. There is a lack of clear guidelines for the screening, prevention and treatment of bone loss after HCT. We reviewed the prevailing literature and provide guidelines developed by our center for the screening and management of this complication. Bone loss occurs predominantly within the first 6-12 months after autologous and allogeneic HCT. Recovery first occurs in the lumbar spine and is followed by a slower recovery of BMD in the femoral neck. BMD may not return to baseline levels in patients with continuing exposure to corticosteroids and calcineurin inhibitors. All HCT recipients should be advised general interventions to reduce fracture risk including adequate intake of calcium and vitamin D. We recommend screening all adult allogeneic and autologous HCT recipients with dual-energy X-ray absorptiometry 1 year after transplantation. Patients at high risk for bone loss (for example, patients receiving ≥ 5 mg of prednisone equivalent daily for > 3 months) can be screened earlier (for example, 3-6 months after HCT). Where indicated, bisphosphonates or other anti-resorptive agents (for example, calcitonin) can be used for prevention or treatment of osteoporosis in adult HCT recipients. Pediatric HCT recipients should be referred to a pediatric endocrinologist for evaluation and treatment of bone loss. There remain several areas of uncertainty that need further research in adult and pediatric HCT recipients, such as the optimal timing and frequency of screening for loss of bone mineral density, relationship of bone loss with risk of fractures, selection of appropriate patients for pharmacologic therapy, and optimal dosing schedule and duration of therapy with anti-resorptive agents.

Hypothyroidism and cognition: preliminary evidence for a specific defect in memory.

The effect(s) of hypothyroidism on adult brain cognitive function are poorly understood. We performed a series of neuropsychological tests in 13 thyroid cancer patients while they continued to take their usual dose of levothyroxine (LT4) and again after discontinuing thyroid hormone. Three euthyroid subjects were also tested twice to assess the effect of repeated testing on performance. The tests assessed memory, mood, and attentional resources and controlled for the practice effects of repeated testing. The mean thyrotropin (TSH) on LT4 was 0.56 +/- 0.76 mU/L and while hypothyroid was 69 +/- 33 mU/L. While hypothyroid, the mean Beck depression score was significantly higher (15.31 +/- 9.41 hypothyroid vs. 7.31 +/- 4.82 on LT4) and the subjects rated themselves worse relative to functional memory, concentration, thinking, alertness, and motivation. Hypothyroidism was associated with a decrease in retrieval from memory (p = 0.0034), and this effect could not be attributed to depression or to practice effects. Thyroid state did not affect immediate recall, verbal learning, inhibitory efficiency, information processing speed, or attention switching. Athyrosis is associated with a decrement in delayed recall of verbal information but not in other objective measures of cognition, suggesting that the memory decrement of hypothyroidism is not caused by a generalized reduction in attentional resources.

Effect of acute high dose dobutamine administration on serum thyrotrophin (TSH).

OBJECTIVE: The interpretation of thyroid function tests in the setting of severe illness is often complicated by concomitant drug administration which may independently produce changes in thyroid hormone concentrations or even secondary hypothyroidism. Although the effects of dopamine on TSH are well established, the effects of dobutamine, another drug commonly used in the setting of severe illness, on TSH are unknown. The aim of the study was to establish the effect(s) of acute high dose dobutamine on serum TSH concentration. DESIGN AND PATIENTS: Thirty subjects undergoing dobutamine stress echocardiogram were compared to twenty controls. Serum TSH was determined between the hours of 0800 and 1000 h at baseline, at maximum dobutamine infusion (20-50 micrograms/kg/min and 15 minutes after stopping dobutamine. MEASUREMENTS: Serum TSH concentration was measured using a third generation chemiluminescent assay. RESULTS: TSH concentration decreased with time in both dobutamine and control subjects and there was an additional statistically significant effect of dobutamine treatment to decrease TSH. TSH concentration remained within the normal range in all subjects who started with normal TSH concentration and remained above normal in the three dobutamine-treated subjects with elevated TSH at baseline. The dobutamine-associated decrease in TSH was still present 15 minutes after discontinuing dobutamine. CONCLUSIONS: These results indicate that acute high dose dobutamine lowers TSH by an unknown mechanism. Additional study with prolonged dobutamine infusion is needed to establish the steady state level and physiological consequences of dobutamine-inhibited TSH.

Thyroid hormone regulates hyperpolarization-activated cyclic nucleotide-gated channel (HCN2) mRNA in the rat heart.

Thyroid hormone regulation of the cardiac pacemaker gene, the hyperpolarization-activated cyclic nucleotide-gated channel gene (HCN2), was studied in rats by Northern analysis. Thyroid hormone administration to hypothyroid rats resulted in a doubling of the HCN2/beta-actin mRNA ratio. A smaller, not statistically significant, increase in HCN2 mRNA occurred when euthyroid animals were made hyperthyroid. A single large dose of L-triiodothyronine given to hypothyroid rats caused a 4.7-fold increase in myocardial HCN2 mRNA expression level and only a 2.3-fold increase in the beta-actin mRNA level. Although the rat HCN2 promoter has not been cloned, we identified a consensus thyroid hormone response element in the promoter sequence of the human HCN2 gene. Therefore, the increase in rat HCN2 mRNA is likely due to L-triiodothyronine stimulation of HCN2 gene transcription. The results suggest that the regulation of heart rate by thyroid hormone may be explained, at least in part, by the positive effect of this hormone on HCN2 gene expression.

The effect of thyroid hormone on size of fat depots accounts for most of the changes in leptin mRNA and serum levels in the rat.

The physiological consequences and mechanism(s) for thyroid hormone-induced alterations in serum leptin are not known. To address this, leptin expression in rats was evaluated in relationship to food intake, fat mass, and body temperature in rats with pharmacologically altered thyroid status. Total body weight, food intake, and temperature were decreased in hypothyroid rats. Fat weight was decreased in both chronically hypothyroid and hyperthyroid rats (n = 6/group). Serum leptin was linearly correlated with fat weight, epididymal and retroperitoneal fat leptin mRNA concentration, but not total body weight. Serum leptin was decreased in the chronically hyperthyroid rats. When fat weight was used as a covariant, serum leptin was not different between the three groups. Epididymal fat leptin mRNA was higher in euthyroid (n = 7) than in hypothyroid and hyperthyroid rats. Retroperitoneal fat leptin mRNA was not affected by thyroid status. A positive linear relationship between food intake and free triiodothyronine (FT3) index was observed, but not between food intake and serum leptin alone. In a time course study, serum leptin, epididymal fat leptin mRNA content, and fat weight did not change within 24 hours of high-dose triiodothyronine (T3) (n = 6/group), but both temperature and epididymal fat S14 mRNA content rapidly increased. These findings demonstrate that thyroid state influences circulating leptin levels, but primarily does so indirectly through the regulation of fat mass. Leptin does not influence core body temperature across thyroidal state. Finally, thyroid state is more important to regulate food intake, through an as yet undefined mechanism, than are thyroid state-associated changes in serum leptin.

Malignant ophthalmopathy presenting one week after radioiodine treatment of hyperthyroidism.

A 46-year-old woman presented with malignant ophthalmopathy 1 week after a therapeutic dose of radioiodine for treatment of hyperthyroidism. The patient was a smoker and had clinical evidence of mild thyroid-associated ophthalmopathy (TAO) prior to treatment with radioiodine. Anti-thyrotropin (TSH) receptor antibodies and antiflavoprotein antibodies were not detected at the time of presentation with malignant ophthalmopathy. The patient responded rapidly to anti-inflammatory treatment with intravenous methylprednisolone and orbital radiation.

Up-regulation of type 2 iodothyronine deiodinase mRNA in reactive astrocytes following traumatic brain injury in the rat.

Type 2 5'-deiodinase (5'-D2), which converts thyroxine to the more active thyroid hormone 3,5,3'-triiodothyronine (T3), is believed to be an important source of intracellular T3 in the brain. The activity of this enzyme is increased in hypothyroidism and decreased in hyperthyroidism, and as such, it serves an important role to protect the brain from wide fluctuations in T3 during changes in thyroidal state. Although it has been hypothesized that T3 may facilitate neuronal regeneration after CNS injury, the 5'-D2 response to brain injury is unknown. To assess the 5'-D2 mRNA response to injury, we performed in situ hybridization following traumatic brain injury. In unlesioned animals, 5'-D2 mRNA was undetectable. At 3 days posttrauma, 5'-D2 mRNA was detected in ipsilateral cortex near the contusion. A significant further increase of 5'-D2 mRNA was noted 7 days posttrauma in both hippocampus and cortex. Similar response was also observed on the contralateral side. Colocalization of 5'-D2 mRNA with glial fibrillary acidic protein indicates that reactive astrocytes were the major cellular source for the trauma-induced 5'-D2 expression. These data demonstrate, for the first time, a trauma-induced, astrocytic up-regulation of 5'-D2 mRNA, suggesting a potential role for T3 action in adult brain's response to injury and recovery.

Identification of domains of c-Jun mediating androgen receptor transactivation.

The proto-oncoprotein c-Jun, when complexed with c-Fos, forms the climeric complex identified as AP-1 which regulates transcription directly by binding to AP-1-responsive genes. We have previously reported an indirect mechanism by which c-Jun is able to regulate transcription by stimulating androgen receptor transactivation in the absence of c-Fos or any apparent DNA binding. A series of c-Jun mutants were tested in order to characterize the domains of c-Jun responsible for this effect. The studies reported here indicate that a functional bZIP region and a portion of the N-terminal activation functions is necessary for c-Jun stimulation of androgen receptor transactivation. Testing c-Jun/v-Jun chimeras, we show that v-Jun is unable to stimulate androgen receptor transactivation and the effect is dependent on the c-Jun activation functions. c-Jun exhibits a bell-shaped activity on androgen receptor-mediated transactivation which appears to be distinct from c-Jun's transactivation ability. A c-Jun mutant deficient in transactivation is able to stimulate androgen receptor activity. These results indicate that c-Jun's transactivation ability can be separated from c-Jun's ability to stimulate the androgen receptor transactivation.

Concentrations of leptin in the serum of pregnant, lactating, and cycling rats and of leptin messenger ribonucleic acid in rat placental tissue.

Leptin concentrations were measured in the serum of cycling, pregnant, and lactating Sprague-Dawley rats. Serum leptin concentrations did not vary significantly during the estrous cycle. In contrast, as gestation advanced, serum leptin concentrations increased significantly, p < 0.0001. Following delivery, leptin concentrations declined and remained stable during lactation. Leptin messenger ribonucleic acid (mRNA) was identified in the visceral adipose tissue and placenta of rats sacrificed on days 14 and 21 of pregnancy. The relative abundance of placental leptin mRNA increased approximately 4 to 5 fold from day 14 to 21 of gestation. The pattern of elevated leptin concentrations in the serum of late pregnant rats is similar to that reported in pregnant women, therefore the rat may be a useful model for the study of leptin during pregnancy. The increase in leptin in the serum of late pregnant rats, as well as an increase in placental mRNA, raises the possibility that leptin may serve a physiological role for the late parturient rat and/or its young.

Thyroid hormones inhibit type 2 iodothyronine deiodinase in the rat cerebral cortex by both pre- and posttranslational mechanisms.

The type 2 5'-deiodinase (D2) appears to play an important role in maintaining the intracerebral T3 content relatively constant during changes in thyroidal state. Previous studies have demonstrated that the regulation of this enzyme by thyroid hormone and its analogs occurs at a posttranslational level. The availability of the rat D2 complementary DNA now allows an assessment of whether pretranslational regulation of this enzyme also occurs in the cerebral cortex. In rats rendered hypothyroid by the addition of methimazole to the drinking water, D2 messenger RNA (mRNA) is increased 70% (P = 0.03). Treatment with L-T3 (50 microg/100 g BW) for 4 days results in an 80% decrease in D2 mRNA compared with that in euthyroid controls (P < 0.001). Administration of lower doses of L-T3 (0.25-3 microg/100 g BW x day) is associated with a dose-dependent decrease in cortical D2 mRNA, but little or no change in D2 activity. The decrease in D2 mRNA in response to T3 treatment can be demonstrated within 4 h. Treatment of hypothyroid rats for 2 weeks with graded doses of L-T4 (0.1-1.5 microg/100 g BW x day) results in a significant decrease in cortical D2 activity, but not mRNA. The association between D2 activity and D2 mRNA in euthyroid, hypothyroid, and hormone-treated rats across a full range of thyroidal states suggests that L-T4 treatment is associated with greater changes in cortical D2 activity (via posttranslational effects) than mRNA, whereas L-T3 treatment has a greater effect on decreasing D2 mRNA (i.e. pretranslational effects). In conclusion, these studies demonstrate both pre- and posttranslational regulation of cortical D2 expression. The relative contribution of each mechanism depends on the ambient thyroid hormone concentration.

Evaluation and treatment of persistent thyroglobulinemia in patients with well-differentiated thyroid cancer.

Whereas in the past a negative diagnostic 131I whole body scan (WBS) was interpreted as the lack of significant residual or recurrent thyroid cancer, today the patient with negative WBS and measurable serum thyroglobulin (Tg) presents a diagnostic and therapeutic dilemma. Previous studies have shown a high rate of visualization of uptake and a decrease in Tg after one or more therapeutic doses of 131I. In order to further assess the significance of this finding, retrospective analysis of patients with persistent thyroglobulinemia and negative WBS was performed for evidence of surgically amenable disease. Seven out of seventeen patients had neck ultrasound and/or computerized tomography (neck +/- chest) showing the presence of pathologically confirmed malignant masses ranging from 1 to 4 cm in size. Their serum Tg while on L-thyroxine ranged between 2.4 and 1173 pmol/l. Removal of the identified masses resulted in a greater than 75% reduction in serum Tg in four out of five patients in the group. One patient achieved a serum Tg of < 1.5 pmol/l while hypothyroid. Empiric 131I treatment of eleven patients with persistent thyroglobulinemia resulted in demonstrated uptake on post-therapy scan in seven. Further study is needed to compare the efficacy, safety and cost of a diagnostic approach to radiologically identify and surgically resect identified disease versus empiric therapeutic 131I treatment and high-dose WBS in this group of patients. Patients with negative WBS and persistent thyroglobulinemia, even to levels < 4.5 pmol/l, may have significant foci of thyroid cancer in surgically accessible areas. This suggests the need for a redefinition or clarification of the term 'recurrence' in thyroid cancer.

Fifty years of experience with propylthiouracil-associated hepatotoxicity: what have we learned?

The aim of this study was to determine the optimal management of patients with propylthiouracil (PTU) hepatotoxicity. A MEDLINE search for English language cases of PTU hepatotoxicity between 1966 and April 1996 was performed, and additional cases were cross-referenced. Twenty-seven cases were selected based on the availability of information on patient management after the onset of hepatotoxicity. Eighty-five percent of the selected cases met this criterion. A detailed summary of the management of two cases of PTU hepatotoxicity at our institutions is also provided. Although most patients recovered once PTU was stopped, seven patients died. Patients with PTU hepatotoxicity who survived were more likely to have received 131I during the course of their illness than those who died (P < 0.03, by Fisher's exact test). In our two patients, hyperbilirubinemia was linearly associated with progressively decreasing T4 levels (r = 0.91; P < 0.001) despite the presence of clinical thyrotoxicosis in one of the patients. These findings demonstrate the need for appropriate clinical evaluation and treatment of thyroid disease during the course of hepatotoxicity. Additionally, we report the first pediatric patient with PTU hepatotoxicity to undergo liver transplantation. The emerging role of liver transplantation in these patients is discussed.

Thyroid carcinoma found at parathyroidectomy: association with primary, secondary, and tertiary hyperparathyroidism.

BACKGROUND: Frequent reports of an association between primary hyperparathyroidism (HPT) and well differentiated thyroid carcinoma, compared with the few reports of associated secondary HPT and thyroid carcinoma, may have implications for different etiologic relationships between the conditions. METHODS: A retrospective review was performed of patients who underwent surgery for HPT between 1975 and 1996 in a single institution. The prevalence of well differentiated thyroid carcinoma diagnosed at the time of parathyroidectomy (PTX) was compared for patients with primary, secondary, or tertiary HPT. RESULTS: There were 845 operations for HPT in 824 patients. Twenty-two patients were found to have thyroid carcinoma at the time of PTX. Thyroid carcinoma was found in 2.6% of the patients with primary and 3.2% of the patients with either secondary or tertiary HPT (P = 0.550). Twenty-one of the patients had papillary carcinoma and 1 had a follicular carcinoma. Eighteen of the carcinomas were < 1 cm in size. A prior history of head and neck irradiation was associated with the diagnosis of thyroid carcinoma at the time of PTX (P < 0.001). Neither renal failure, organ transplantation, female gender, lymphocytic infiltration, nor follicular adenoma of the adjacent thyroid were significant in the association between HPT and thyroid carcinoma. CONCLUSIONS: These data suggest that the association between thyroid carcinoma and HPT is coincidental and possibly related to the closer surveillance of the thyroid gland due to PTX and often concomitant removal of thyroid tissue. Patients with HPT and a history of head and neck irradiation are at increased risk of thyroid carcinoma.

Isolation of a liver-specific promoter for human growth hormone receptor gene.

The biological actions of growth hormone (GH) are mediated through the growth hormone receptor (GHR). The GHR gene is expressed in a tissue specific manner and multiple variants (V1 to V8) of GHR mRNA have been detected in human tissues. To understand the regulation of GHR gene expression, a human genomic clone containing the 5'-untranslated region (5'UTR) of the V1, V4, V7 and V8 exons of the GHR was isolated. The 2 kilobase (kb) 5' upstream sequence of the V1 specific UTR has promoter activity in transient transfection assays of the human hepatoma cell line, HepG2. The exclusive expression of the V1 variant in adult liver, and the lack of expression of the other variants in this tissue, suggests that the V1 5'UTR represents the liver specific 5' noncoding exon for the human GHR gene. The data are consistent with the first isolation of a liver specific promoter for human GHR.

c-Jun can mediate androgen receptor-induced transactivation.

The proto-oncoprotein c-Jun forms as a heterodimer with c-Fos, the transcription factor AP-1. AP-1 regulates transcription through transactivation, a process requiring DNA binding. Here we report an indirect mechanism by which c-Jun can regulate transcription via the androgen receptor. In this process, c-Jun is able to support androgen receptor-mediated transactivation in the absence of an interaction with c-Fos or any apparent DNA binding. This positive effect of c-Jun was dose-dependent. Both exogenously added and endogenously induced c-Jun are able to act on the androgen receptor. Transactivation by the androgen receptor can undergo self-squelching, and this was relieved by transfected c-Jun. Using a time-course experiment, we provide evidence that the c-Jun effect is primary. c-Fos is able to block human androgen receptor activity in both the absence and presence of transfected c-Jun. Using a modified form of the yeast two-hybrid system, we show in Cos cells that c-Jun can interact with the DNA binding domain/hinge region (CD regions) of the androgen receptor. Therefore, we propose that c-Jun functions as a mediator for androgen receptor-induced transactivation.

Association between dementia and elevated TSH: a community-based study.

We report on 194 individuals (96 men and 98 women), aged 65 and over, who had dementia assessments and basal TSH measurements as part of an ongoing epidemiological study of dementing disorders in a larger population. Dementia was diagnosed according to DSM-III-R and measured by the Clinical Dementia Rating scale; CDR scores of 0, 0.5, and > or = 1, represent individuals with no dementia (n = 122), possible dementia (n = 29), and definite dementia (n = 43), respectively. The odds ratio for the association of elevated TSH with definite dementia (CDR > or = 1) was 3.8 (95% confidence interval = 1.6, 9.1) and with possible and/or definite dementia (CDR > or = 0.5) was 3.8 (95% confidence interval = 1.6, 9.2), after adjusting for the effects of age, gender, and level of education. This is the first community-based study to report an association between TSH elevation and dementia. Our findings are consistent with recent evidence that subclinical hypothyroidism is associated with cognitive impairment, and that thyroidal state may influence cerebral metabolism.

Insulin increases the processing efficiency of messenger ribonucleic acid-S14 nuclear precursor.

Feeding a lipogenic diet increases transcription and enhances processing of the rat hepatic messenger RNA (mRNA)-S14 gene. To determine the separate roles of insulin and increased glucose in these processes, we used the streptozotocin-induced diabetic rat model. Diabetes caused a reduction in mature mRNA-S14 in chow- and lipogenic diet-fed animals (P < 0.006 and P < 0.001, respectively). Insulin restored these levels to normal. Despite the known effects of insulin and carbohydrate on the transcription of this gene, we were unable to demonstrate significant changes in the nuclear proteins that bind to carbohydrate response regions. Yet, insulin restored the content of the mRNA by increasing the ratio of mature to precursor mRNA-S14. Insulin significantly increased this ratio (P < 0.0001) independent of diet and diabetes, further supporting the action of insulin on increasing processing from precursor to mature mRNA. The mechanism of the enhanced processing was studied by ribonuclease mapping and primer extension analysis. Ribonuclease mapping showed that lipogenic diet feeding increases the efficiency of processing at a step before formation of the branched form of the precursor mRNA. Taken together, our data demonstrate for the first time that insulin significantly enhances the efficiency of processing of a pre-mRNA.

Reverse T3 does not reliably differentiate hypothyroid sick syndrome from euthyroid sick syndrome.

To assess the efficacy of reverse T3 in differentiating between the hypothyroid and euthyroid state in the setting of illness, all reverse T3 determinations obtained over a 4-year period in a University teaching hospital were analyzed in the context of concurrent thyroid function tests, bilirubin, albumin, creatinine, subsequent treatment, and follow-up. Based on T4 (or free T4 index) and TSH, the thyroidal state of the patient and the appropriateness of the reverse T3 determination were assigned. A total of 262 reverse T3 determinations were made in 246 patients. There is an inverse linear relationship between the log TSH and the reverse T3. Patients with hypothyroidism plus illness may have a normal reverse T3 and patients with euthyroidism may have a low reverse T3. Reverse T3 is linearly related to bilirubin up to a bilirubin of approximately 171 microM (10 mg/dL). Sixty percent of the reverse T3 determinations were obtained for seemingly inappropriate indications. In association with a low free T4 index/T4, an unmeasurable reverse T3 did not lead to institution of thyroid hormone treatment in over 52% of cases. Although reverse T3 may be elevated in the setting of nonthyroidal illness, it is not reliable in distinguishing between the hypothyroid sick patient and the euthyroid sick patient. This is probably because of drug and disease effects on thyroid hormone metabolism as well as the presence of sufficient T4 substrate for conversion to reverse T3 in many hypothyroid sick patients.

Plasma glucose and insulin responses to bananas of varying ripeness in persons with noninsulin-dependent diabetes mellitus.

With progressive ripeness there is a decrease in starch and an increase in free sugar content of bananas. The starch also is considered to be poorly digestible. Therefore, we decided to study plasma glucose, serum insulin, C-peptide, and plasma glucagon responses to bananas with increasing degrees of ripeness. Seven male subjects with untreated noninsulin-dependent diabetes mellitus ingested 50 g carbohydrate as bananas of stage 4 (more yellow than green), 5 (yellow with green tip), 6 (all yellow), and 7 (yellow flecked with brown) ripeness. They also received 50 glucose on two occasions for comparative purposes. On a separate occasion water only was given as a control. The area responses were quantified by determining incremental areas using the water control as baseline. The mean glucose area following the 50 g glucose meals was 15.1 +/- 1.9 mM.h. After the ingestion of bananas of 4, 5, 6 and 7 ripeness the glucose area response was 42, 41, 51 and 48% of that after glucose ingestion, respectively. The insulin area response following glucose meals was 888 pM.h. Responses to 4, 5, 6 and 7 bananas were 85, 70, 61, 85%, respectively, of that following glucose ingestion. C-peptide data were similar to the insulin data. The glucagon area response was negative after glucose ingestion but was positive following banana ingestion. In summary, the glucose, insulin, C-peptide, and glucagon area responses varied little with ripeness of the bananas.

Metabolic response to cottage cheese or egg white protein, with or without glucose, in type II diabetic subjects.

Test meals with 25 g protein in the form of cottage cheese or egg white were given with or without 50 g glucose to male subjects with mild to moderately severe, untreated, type II diabetes. Water was given as a control meal. The glucose, insulin, C-peptide, alpha amino nitrogen (AAN), glucagon, plasma urea nitrogen (PUN), nonesterified fatty acid (NEFA), and triglyceride area responses were determined using the water meal as a baseline. The glucose area responses following ingestion of cottage cheese or egg white were very small compared with those of the glucose meal, and were not significantly different from one another. The serum insulin area response was 3.6-fold greater following ingestion of cottage cheese compared with egg white (309 v 86 pmol/L.h). The simultaneous ingestion of glucose with cottage cheese or egg white protein decreased the glucose area response to glucose by 11% and 20%, respectively. When either protein was ingested with glucose, the insulin area response was greater than the sum of the individual responses, indicating a synergistic effect (glucose alone, 732 pmol/L.h; glucose with cottage cheese, 1,637 pmol/L.h; glucose with egg white, 1,213 pmol/L.h). The C-peptide area response was similar to the insulin area response. The AAN area response was approximately twofold greater following ingestion of cottage cheese compared with egg white. Following ingestion of glucose, it was negative. When protein was ingested with glucose, the AAN area responses were additive. The glucagon area response was similar following ingestion of cottage cheese or egg white protein. Following glucose ingestion, the glucagon area response was negative.(ABSTRACT TRUNCATED AT 250 WORDS)