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V Trischitta

Publications and source records attributed to V Trischitta.

At least 55 records · Page 3Linked to original sources
PubMed1998

Alterations of bone turnover and bone mass at different skeletal sites due to pure glucocorticoid excess: study in eumenorrheic patients with Cushing's syndrome.

The aim of the present investigation was to study the effect of glucocorticoid excess on bone mass and turnover not influenced by other diseases known to affect skeleton and/or by different gonadal status and sex. We studied several markers of bone turnover and bone mineral density (BMD) by both quantitative computed tomography (at spine and forearm) and dual x-ray absorptiometry (at spine and three femoral sites) in 18 eugonadal female patients affected by Cushing's syndrome (CS) compared to 24 eugonadal healthy female subjects matched for age and body mass index. In CS patients, serum bone Gla protein, a marker of osteoblastic function, was reduced (3.28 +/- 2.3 vs. 6.47 +/- 2.5; P < 0.01), and bone resorption was increased, as indicated by increased urinary hydroxyproline (36.6 +/- 12 vs. 29.0 +/- 9.1, P < 0.05) and urinary deoxypyridinoline (22.1 +/- 8.0 vs. 16.4 +/- 6.3; P < 0.05). BMD was significantly (P < 0.05 or P < 0.01) reduced at all sites, except cortical forearm, in CS patients compared to controls. By comparing z-scores of reduced BMD in CS patients, spinal trabecular BMD was found to be the most severely affected. Furthermore, disease activity, as measured by urinary free cortisol, was significantly correlated with bone Gla protein (r = -0.57; P < 0.02), urinary hydroxyproline (r = 0.57; P < 0.02), urinary deoxypyridinoline (r = 0.48, P < 0.05), and BMD measured at spine and femur. Our results show that compared to matched control subjects, female eumenorrheic CS patients have reduced osteoblastic function, increased bone resorption, and reduced BMD, and that the severity of these abnormalities is statistically related to the severity of disease activity, as indicated by urinary free cortisol. Moreover, our data suggest a site and tissue specificity of the effect of glucocorticoid excess on bone mass.

Absorptiometry, Photon↗
PubMed1998

Elevated PC-1 content in cultured skin fibroblasts correlates with decreased in vivo and in vitro insulin action in nondiabetic subjects: evidence that PC-1 may be an intrinsic factor in impaired insulin receptor signaling.

Membrane glycoprotein PC-1 inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling. PC-1 content is elevated in muscle and adipose tissue from insulin-resistant subjects, and its elevation correlates with in vivo insulin resistance. To determine whether elevated PC-1 content is a primary cause of insulin resistance, we have now measured PC-1 content in cultured skin fibroblasts from nonobese nondiabetic insulin-resistant subjects and found that 1) PC-1 content was significantly higher in these cells when compared with cells from insulin-sensitive subjects (6.7 +/- 0.9 vs. 3.1 +/- 0.6 ng/0.1 mg protein, mean +/- SE, P < 0.01); 2) PC-1 content in fibroblasts was highly correlated with PC-1 content in muscle tissue (r = 0.95, P = 0.01); 3) PC-1 content in fibroblasts negatively correlated with both decreased in vivo insulin sensitivity and decreased in vitro IR autophosphorylation; and 4) in cells from insulin-resistant subjects, insulin stimulation of glycogen synthetase was decreased. These studies indicate, therefore, that the elevation of PC-1 content may be a primary factor in the cause of insulin resistance.

Adult↗
PubMed1998

T426I a new mutation in the thyroid hormone receptor beta gene in a sporadic patient with resistance to thyroid hormone and dysmorphism. Mutations in brief no. 192. Online.

Resistance to thyroid hormone (RTH) is a rare inherited autosomal syndrome caused by mutations in the thyroid hormone receptor beta (TRb) gene. Although RTH is generally a familiar disease, 15% of sporadic cases have been also reported. So far, about 80 different mutations of TRb gene have been identified in patients affected by RTH. All these mutations localize to the binding domain and most of them cluster within two "hot spots" (codons 310-349 and codons 429-460). Here we describe in a patient with RTH, a new mutation in codon 426 (T426I) of the TRb gene leading to a threonine to isoleucine substitution. This is a "de nova" mutation which localizes in the so-called "cold" region, outside the two known "hot spots". The patient had the hallmark of RTH: elevated FT3 and FT4, normal TSH, and clinical features of both hypo and hyperthyroidism. Moreover, several dysmorphisms were present including triangular face appearance, synophris, low set ears, micrognathia with malocclusion, large upper incisors and apparent lack of lower cuspids which have not previously described in RTH patients.

Craniofacial Abnormalities↗
PubMed1998

Membrane glycoprotein PC-1 and insulin resistance.

Peripheral resistance to insulin is a major component of non-insulin dependent diabetes mellitus. Defects in insulin receptor tyrosine kinase activity have been demonstrated in several tissues from insulin resistant subjects, but mutations in the insulin receptor gene occur in only a small fraction of cases. Therefore, other molecules that are capable of modulating the function of the insulin receptor are likely candidates in the search for the cellular mechanisms of insulin resistance. We have isolated an inhibitor of insulin receptor tyrosine kinase activity from cultured fibroblasts of an insulin resistant NIDDM patient and identified it as membrane glycoprotein PC-1. Subsequently we have demonstrated that expression of PC-1 is elevated in fibroblasts from other insulin resistant subjects, both with and without NIDDM. Studies in muscle, the primary site for insulin-mediated glucose disposal, have shown that the levels of PC-1 in this tissue are inversely correlated to insulin action both in vivo and in vitro. Transfection of PC-1 into cultured cells has confirmed that overexpression of PC-1 can produce impairments in insulin receptor tyrosine kinase activity and the subsequent cellular responses to insulin. Preliminary data suggests a direct interaction between PC-1 and the insulin receptor. However, the mechanisms whereby PC-1 inhibits insulin receptor signaling remain to be determined.

Animals↗
PubMed1997

Increased adipose tissue PC-1 protein content, but not tumour necrosis factor-alpha gene expression, is associated with a reduction of both whole body insulin sensitivity and insulin receptor tyrosine-kinase activity.

In the present study we measured PC-1 content, tumour necrosis factor (TNF)-alpha gene expression, and insulin stimulation of insulin receptor tyrosine-kinase activity in adipose tissue from non-obese, non-diabetic subjects. These parameters were correlated with in vivo insulin action as measured by the intravenous insulin tolerance test (Kitt values). PC-1 content was negatively correlated with Kitt values (r = -0.5, p = 0.04) and positively with plasma insulin levels both fasting (r = 0.58, p = 0.009) and after 120 min during oral glucose tolerance test (OGTT) (r = 0.67, p = 0.002). Moreover, adipose tissue PC-1 content was higher in relatively insulin-resistant subjects (Kitt values lower than 6) than in relatively insulin-sensitive subjects (Kitt values higher than 6) (525 +/- 49 ng/mg protein vs 336 +/- 45, respectively, p = 0.012). Adipose tissue insulin receptor tyrosine-kinase activity in response to insulin was significantly lower at all insulin concentrations tested (p = 0.017, by two-way analysis of variance test) in insulin-resistant than in insulin-sensitive subjects (Kitt values lower or higher than 6, respectively). In contrast to PC-1, no significant correlation was observed between adipose tissue TNF-alpha mRNA content and Kitt values, and plasma insulin levels, both fasting and at after 120 min during OGTT. Also, no difference was observed in TNF-alpha mRNA content between subjects with Kitt values higher or lower than 6. These studies in adipose tissue, together with our previous studies in skeletal muscle raise the possibility that PC-1, by regulating insulin receptor function, may play a role in the degree of insulin sensitivity in non-obese, non-diabetic subjects.

Adipose Tissue↗
PubMed1996

PC-1 content in skeletal muscle of non-obese, non-diabetic subjects: relationship to insulin receptor tyrosine kinase and whole body insulin sensitivity.

Insulin sensitivity varies widely in non-obese, non-diabetic subjects, and we have previously reported that in vivo insulin action correlates with in vitro insulin stimulated insulin receptor tyrosine-kinase activity in skeletal muscle. Plasma membrane glyco-protein PC-1 content is elevated in fibroblasts of insulin-resistant subjects, and expression of PC-1 cDNA in cultured cells reduces both insulin receptor tyrosine-kinase activity and the biological actions of insulin. In the present study we investigated non-obese, non-diabetic subjects and found a significant negative correlation between muscle PC-1 content and both in vivo insulin action as measured by the intravenous insulin tolerance test (r = -0.51, p = 0.035) and the sensitivity (ED50) of in vitro insulin stimulation of insulin receptor tyrosine-kinase activity (r = 0.66, p = 0.027). These studies indicate, therefore, that increased muscle PC-1 content is associated with reduced insulin action both in vivo and in vitro. Moreover, they suggest a possible role for PC-1 in regulating insulin receptor function in human skeletal muscle.

Blood Glucose↗
PubMed1995

Peptide-based radioimmunoassay for the two isoforms of the human insulin receptor.

The insulin receptor exists in two isoforms differing by the absence (HIR-A) or presence (HIR-B) of 12 amino acids in the COOH-terminus of the alpha-subunit as a consequence of alternative splicing of exon 11. In this study, we developed a radioimmunoassay for the two isoforms employing antibodies raised against two peptides, one (Pep-12) corresponding to residues encoded by exon 11, and the other (Pep-13) corresponding to a COOH-terminal domain of the alpha-subunit which is common to both HIR-A and HIR-B isoforms. These peptides were iodinated and used as both ligands and standards. The assay is specific, highly reproducible, and sensitive with a detection limit of 10 fmol of receptor. One mole of purified insulin receptor, measured by Scatchard analysis, is read as one mole of receptor in the radioimmunoassay with either Pep-12 or Pep-13 as standards. The radioimmunoassay is applicable to the measurement of total content and relative abundance of the two isoforms in extracts from various tissues. We applied the radioimmunoassay to measure the relative abundance of the two isoforms in fat and muscle from normal, obese non-diabetic and non-insulin-dependent diabetic (NIDDM) subjects. Results demonstrate that expression of the low-affinity HIR-B form is significantly increased in obese and NIDDM subjects compared with control subjects. In addition, the increased expression of the HIR-B isoform was significantly correlated with both body mass index (r = 0.52; p = 0.006) and fasting glucose levels (r = 0.59; p = 0.001).

3T3 Cells↗
PubMed1995

Insulin receptor tyrosine-kinase activity is altered in both muscle and adipose tissue from non-obese normoglycaemic insulin-resistant subjects.

We performed i.v. insulin tolerance test in 30 non-obese (BMI < 30 male and < 28 female) non-diabetic (by oral glucose tolerance test) subjects and subdivided them into three groups of 10 subjects each, according to their insulin sensitivity (K(itt) values). Then we compared the tyrosine-kinase activity of immunopurified insulin receptors (using 32P-ATP and poly-glu-tyr (4:1) from both muscle and adipose tissue in 7 of the most insulin-sensitive and 7 of the most insulin-resistant subjects. No difference was observed between the two groups in the basal (no insulin) receptor tyrosine-kinase activity from both tissues. In contrast, tyrosine-kinase activity response to insulin was significantly higher (p < 0.05 by 2-way ANOVA test) in receptors from both tissues of insulin-sensitive subjects. In addition, a decreased tyrosine-kinase sensitivity to insulin was observed in muscle, but not adipose, tissue of insulin-resistant subjects (insulin ED50 being 0.87 +/- 0.05 nmol/l vs 2.03 +/- 0.07, p < 0.05 in insulin-sensitive and -resistant subjects). Insulin ED50 of muscle receptor tyrosine-kinase significantly (p = 0.001) correlated to both K(itt) values (r = -0.79) and plasma insulin values at 120 min during OGTT (r = + 0.80). Insulin receptor content, as assessed by radioimmunoassay, was similar in both muscle (7.9 +/- 1.3 and 9.2 +/- 1.9 ng/mg protein) and adipose tissue (8.2 +/- 1.3 and 7.5 +/- 1.4) of insulin-sensitive and -resistant subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1995

Cervical dumbbell ganglioneuroma in an eighteen month old child. A case report.

Dumbbell neurogenic tumors are unusual in children. The authors report an extremely rare case of cervical intraspinal ganglioneuroma with a contiguous paravertebral component in an eighteen month old female patient. Both the intraspinal and the extraspinal parts of the dumbbell tumor were totally removed during the same surgical session. A laminotomy was performed rather than a laminectomy in order to avoid postoperative spinal column deformation. The authors emphasize the importance of an early diagnosis in preventing irreversible neurosurgical abnormalities and for achieving better surgical results.

Female↗
PubMed1993

Insulin receptor tyrosine kinase activity is reduced in monocytes from non-obese normoglycaemic insulin-resistant subjects.

Insulin sensitivity has been quantified by i.v. insulin tolerance test (0.1 U/kg of body weight) in 18 (11 male/7 female) non-obese (body mass index range 19-25 kg/m2) normoglycaemic subjects. We then compared the tyrosine kinase activity and internalization of insulin receptor in monocytes from the six most insulin-sensitive (group 1) and the six most insulin-resistant (group 3) subjects. Tyrosine kinase activity was measured on immunopurified receptors using 32P-ATP and poly-glutamic acid 4: tyrosine 1, sodium salt (poly-glu-tyr 4:1). Insulin internalization was studied by incubating cells with 1 nmol/l 125I-insulin and measuring total cell-bound and intracellular 125I-insulin by an acid dissociation procedure. Basal (in the absence of insulin) receptor kinase activity was similar in both groups. Maximal (in the presence of 100 nmol/l insulin) kinase activity was 41% lower in group 3 (13.8 +/- 3.6 fmoles 32P-ATP incorporated vs 23.3 +/- 4.0, p = 0.1). Delta increment of receptor kinase activity after insulin stimulation (calculated by subtracting basal from maximal activity) was significantly (p < 0.05) reduced in group 3 (21.3 +/- 3.8 vs 11.1 +/- 2.1) and significantly (p < 0.05) correlated to the in vivo insulin sensitivity. Both total cell-bound (0.70 +/- 0.09% of total radioactivity added vs 0.83 +/- 0.15) and intracellular (0.39 +/- 0.05 vs 0.44 +/- 0.09) 125I-insulin were similar in the two groups. These data suggest that in non-obese, normoglycaemic subjects a defective insulin receptor tyrosine kinase activity may contribute to the development of insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Structural and functional studies of insulin receptors in human breast cancer.

We characterized the structure and the function of insulin receptors isolated from 10 human breast cancer specimens. We observed that the insulin receptor content, as determined by a specific radioimmunoassay, was four fold increased in human breast cancer tissue when compared to normal breast tissues. In both cancer and normal breast tissues, insulin receptor mRNA consisted of two major species of approximately 11.0 and 8.5 kilobases. The size of the insulin receptor alpha subunit was determined by 125I-insulin cross-linking followed by immunoprecipitation and polyacrylamide gel electrophoresis; a value of 135kDa was observed for receptors from both breast cancer and normal breast tissues. The functional binding ability of insulin receptors from cancer tissues was slightly lower as compared to normal tissue derived insulin receptor (% B/T = 2.22 +/- 0.50 per ng of insulin receptor as determined by radioimmunoassay vs. 2.96 +/- 0.49, mean +/- S.E.M.). The concentration of insulin that caused half maximal inhibition of 125I-insulin binding was very similar for both cancer and normal breast receptors (80pM). The size of the insulin receptor beta subunit as determined by receptor autophosphorylation was 95kDa. Basal and maximal insulin (100nM) stimulated receptor tyrosine kinase activity, in terms of both receptor autophosphorylation and phosphorylation of an exogenous substrate, was similar in malignant and normal breast tissue derived insulin receptor. Also, a very similar insulin stimulated Km value for ATP was showed by the tyrosine kinase of insulin receptors from breast cancer and normal breast tissue (11.1 and 10.8 microM ATP, respectively). However, in insulin receptors from breast cancer tissue the average tyrosine kinase sensitivity to insulin, as calculated on the exogenous substrate, was higher, although not significantly, with respect to normal breast tissue (ED50 at 0.28 +/- 0.09 and 1.08 +/- 0.33 nM insulin, respectively). A similarly different sensitivity to insulin was observed also for receptor autophosphorylation. In conclusion, this study demonstrates that breast cancer tissues have an increased number of structurally and functionally normal insulin receptors. In some breast cancer tissues, however, the sensitivity of the receptor tyrosine kinase activity to insulin is greatly increased. These data suggest that, in vivo, the mitogenic effect of insulin may play a role in the biology of certain breast cancers.

Breast Neoplasms↗
PubMed1993

Relationship between insulin receptor tyrosine kinase activity and internalization in monocytes of non-insulin-dependent diabetes mellitus patients.

Reduced insulin receptor tyrosine kinase activity and internalization have been reported in non-insulin-dependent diabetes mellitus (NIDDM) patients. To clarify whether in NIDDM the defective internalization is caused by the defective kinase activity, we studied receptor tyrosine kinase activity and internalization in monocytes from eight lean control and six obese subjects and 10 obese NIDDM patients. Receptor internalization was also stimulated by an anti-insulin receptor antibody (MA-10) that is unable to stimulate receptor kinase activity. Basal exogenous tyrosine kinase activity was not different in monocytes from the three groups of subjects. As compared with control subjects (2,690 +/- 637 fmol 32P incorporated), insulin (100 nmol/L)-stimulated tyrosine kinase activity was lower in NIDDM patients (1,262 +/- 318, P < .05), but not in obese subjects (2,640 +/- 731). Basal receptor autophosphorylation did not differ between the three groups, whereas insulin-stimulated autophosphorylation in comparison to that in control subjects was reduced in NIDDM patients (P < .05), but not in obese subjects. In NIDDM patients, receptor internalization induced by both insulin and MA-10, was lower (P < .05) than that in control and obese subjects. No correlation was found between receptor internalization and exogenous tyrosine kinase activity (r = .30, NS) or autophosphorylation (r = .08, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Comparison of combined therapies in treatment of secondary failure to glyburide.

OBJECTIVE: To compare the effectiveness of alternative combined treatments in patients with non-insulin-dependent diabetes mellitus (NIDDM) with secondary failure to sulfonylureas. RESEARCH DESIGN AND METHODS: A crossover study was carried out by randomly assigning 16 NIDDM patients to a combined treatment with the addition of either a single low-dose bedtime injection of 0.2 U/kg body wt NPH insulin or an oral three times a day administration of 1.5 g/day metformin to the previously ineffective glyburide treatment. RESULTS: Both combined therapies significantly (P less than 0.01) reduced fasting plasma glucose (FPG), postprandial plasma glucose (PPPG) and percentage of HbA1. The addition of metformin was more effective than the addition of insulin (P less than 0.01) in improving PPPG in the 8 patients with higher post-glucagon C-peptide levels. In contrast, the efficacy of neither combined therapy was related to patient age, age of diabetes onset, duration of the disease, percentage of ideal body weight, and FPG. The addition of insulin but not metformin caused a significant (P less than 0.01) increase of mean body weight. Neither combined treatment caused changes in serum cholesterol and triglyceride levels. No symptomatic hypoglycemic episode was reported in any of the 16 patients. CONCLUSIONS: The addition of bedtime NPH insulin or metformin was effective in improving the glycemic control in most NIDDM patients with secondary failure to glyburide. The combination of metformin and sulfonylurea was more effective in reducing PPPG and did not induce any increase of body weight.

Blood Glucose↗
PubMed1991

Treatment of NIDDM patients with secondary failure to glyburide: comparison of the addition of either metformin or bed-time NPH insulin to glyburide.

In this study we compared, in 12 NIDDM patients with secondary failure to glyburide, the effect of adding either a single, low-dose bed time NPH insulin injection (0.2 U/Kg) or an oral metformin administration (500 mg x 3) to the previously ineffective sulfonylurea treatment. The addition of both insulin and metformin treatment significantly improved fasting plasma glucose, post-prandial plasma glucose and %HbA1. The effect of both combined therapies was already evident and maximal after 2 weeks of treatment. The addition of bed-time NPH insulin caused a greater decrease of fasting plasma glucose, although the difference with the addition of metformin was not significant. In contrast, the average post-prandial plasma glucose decrease was significantly greater after metformin addition. The addition of bed-time NPH insulin caused a significant increase in average body weight, while after metformin addition, average body weight was unchanged; no change in the average cholesterol and triglyceride level was observed after either combined therapies.

Adult↗
PubMed1990

Insulin down-regulates insulin receptor number and up-regulates insulin receptor affinity in cells expressing a tyrosine kinase-defective insulin receptor.

We examined the effect of insulin treatment on HTC cells transfected with large numbers of either normal insulin receptors (HTC-IR) or insulin receptors defective in tyrosine kinase (HTC-IR/M-1030). In both HTC-IR and HTC-IR/M-1030 cells, 20 h of insulin treatment (1 microM) at 37 degrees C resulted in a 65% decrease in the number of binding sites with a reciprocal 6-fold increase in affinity. In contrast, treatment with 10 nM insulin (20 h, 37 degrees C) also increased receptor affinity but had a smaller effect on the number of binding sites. 125I-Insulin binding to soluble receptors from HTC-IR and HTC-IR/M-1030 cells pretreated with insulin showed results similar to those obtained in intact cells. In both HTC-IR and HTC-IR/M-1030 cells, insulin enhanced insulin receptor degradation. In HTC-IR/M-1030 cells a 1-h incubation with insulin did not change receptor number and had only a small effect on receptor affinity; also there was no effect of insulin after a 20-h incubation at 15 degrees C. Inhibiting protein synthesis by pretreatment with cycloheximide (100 microM) did not block either the decrease in receptor number or the increase in receptor affinity. Both HTC-IR and HTC-IR/M-1030 cells exhibited a very slow rate of insulin and insulin receptor internalization and no differences were seen in this parameter when HTC-IR cells were compared to HTC-IR/M-1030 cells. These studies indicate, therefore, that in cells expressing kinase-defective insulin receptors, insulin down-regulates insulin receptor number via enhanced receptor degradation, and up-regulates receptor affinity. These effects were time- and temperature-dependent, but not dependent on new protein synthesis, and suggest that activation of tyrosine kinase may not be a prerequisite for certain mechanisms whereby insulin regulates its receptor.

Animals↗
PubMed1990

Improvement with metformin in insulin internalization and processing in monocytes from NIDDM patients.

This study investigated the relative effect of obesity alone and in combination with non-insulin-dependent diabetes mellitus (NIDDM) on the intracellular processing of insulin and evaluated the effect of metformin therapy on this process. Monocytes from 11 obese hyperinsulinemic subjects, 13 obese hyperinsulinemic NIDDM patients, and 7 nondiabetic control subjects were incubated with A14-125I-labeled insulin for 60 min at 37 degrees C, and intracellular insulin degradation was characterized by high-performance liquid chromatography. Total cell-associated insulin (insulin binding) and internalized and degraded insulin were decreased in obese subjects and significantly decreased in obese NIDDM patients compared with nondiabetic control subjects. In NIDDM patients, intracellular insulin degradation was inversely correlated with fasting plasma glucose (P less than 0.01). Eight obese subjects and 9 obese NIDDM patients were restudied after 4 wk of therapy with metformin (850 mg twice a day). Plasma levels of the drug were superimposable in the two groups. Metformin therapy did not change glucose and insulin levels in obese subjects but caused a decrease in blood glucose in obese NIDDM patients. Total cell-associated radioactivity (insulin binding) significantly increased in both groups (P less than 0.01). On the contrary, internalized radioactivity increased (0.83 +/- 0.3 vs. 1.31 +/- 0.35%, P less than 0.01), and similarly, insulin degradation was enhanced (54.6 +/- 8.9 vs. 74.22 +/- 9.15%, P less than 0.01) only in monocytes from obese NIDDM patients. However, the levels of these parameters were still lower than in control subjects (internalization, 2.94 +/- 0.68%; degradation, 93.03 +/- 3.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Transport↗
PubMed1989

Endocytosis, recycling, and degradation of the insulin receptor. Studies with monoclonal antireceptor antibodies that do not activate receptor kinase.

The endocytosis, recycling, and degradation of the insulin receptor were studied in IM-9 cells and U-937 cells by employing two monoclonal antibodies directed at the alpha subunit of the human insulin receptor, antibodies MA-5 and MA-10. Antibody MA-5 is an insulin agonist and MA-10 is an insulin antagonist (Forsayeth, J., Caro, J.F., Sinha, M.K., Maddux, B.A., and Goldfine, I.D. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 3448-3451). Both monoclonal antibodies, like insulin, induced the endocytosis of the insulin receptor within 15 min. Upon removal of extracellular ligand the internalized receptor recycled to the cell surface. At this time there was no degradation of the receptor as measured by a sensitive insulin receptor radioimmunoassay. After 20 h of incubation, insulin and MA-5, but not MA-10, induced significant receptor degradation as measured by both insulin receptor radioimmunoassay and metabolic labeling studies. These studies demonstrated, therefore, that: 1) internalization and recycling of the receptor can be induced by antireceptor monoclonal antibodies that are either insulin agonists or insulin antagonists; 2) enhanced receptor degradation can be induced by monoclonal antibodies that are insulin agonists; and 3) the process of receptor internalization does not necessarily lead to enhanced receptor degradation. Since prior studies have indicated that neither MA-5 nor MA-10 enhance insulin receptor kinase activity, the present studies also suggest that insulin receptor endocytosis and degradation induced by ligands different than insulin can occur without activation of this process.

Antibodies, Monoclonal↗