Biomedical subjects

C A Stuart

Publications and source records attributed to C A Stuart.

At least 55 records · Page 3Linked to original sources

PubMed1989

Prevalence of acanthosis nigricans in an unselected population.

PURPOSE: The intent of this study was to determine, in an unselected population, the prevalence of the hyperinsulinemia-associated skin lesion, acanthosis nigricans. SUBJECTS AND METHODS: The posterior neck of every child in the sixth and eighth grades of the public schools of Galveston, Texas, was personally examined by the investigators during a state-mandated school health survey. A total of 1,412 children were examined. RESULTS: The data for each child examined included the absence or presence of acanthosis nigricans, height, weight, age, sex, and ethnic background. A subset of the children with the skin lesion also had fasting plasma insulin levels measured. Acanthosis nigricans was present in 7.1% of the 1,412 children examined. The skin lesion was equally distributed between boys and girls and was most common among children with severe obesity. The condition was present in two of 440 white non-Hispanics, 19 of 343 Hispanics, and 80 of 601 blacks examined. The fasting plasma insulin concentrations measured in some of these children and in previously evaluated subjects strongly correlate with the presence and severity of the acanthosis nigricans skin lesion. CONCLUSIONS: This skin lesion is much more common than previously believed and has a dramatic ethnic predisposition. We conclude that the high prevalence of this skin lesion further suggests that insulin resistance and hyperinsulinemia, with all of their serious medical implications, are also highly prevalent.

Acanthosis Nigricans↗

PubMed1989

Autophosphorylation of cultured skin fibroblast insulin receptors from patients with severe insulin resistance and acanthosis nigricans.

The severe insulin resistance with acanthosis nigricans seen in young women without insulin-receptor autoantibodies is characterized by hyperinsulinemia and decreased in vivo responsiveness to insulin. We evaluated the potential cellular defects in insulin-receptor binding and autophosphorylation in 12 subjects with this syndrome. When evaluated as a group, insulin binding to freshly isolated monocytes was 55% that of controls. Specific binding of insulin to skin fibroblasts in monolayer culture was 49% that of controls. Maximal insulin-stimulated receptor autophosphorylation was only 27% that of controls. Individual data demonstrated that the diminished autophosphorylation activity was out of proportion to the diminished fibroblast insulin binding in cell lines from most subjects and was less than 50% of the predicted activity in 6 of the 12 studied cell lines. These data are consistent with genetically determined defects leading to diminished numbers of cell surface insulin receptors with intact tyrosine kinase autophosphorylation in many of our cell lines. However, in at least half, there appeared to be an additional defect beyond insulin binding, resulting in a disproportionate decrease in insulin-sensitive phosphorylation of the insulin-receptor beta-subunit.

Acanthosis Nigricans↗

PubMed1988

High affinity antibody from hen's eggs directed against the human insulin receptor and the human IGF-I receptor.

Large quantities of high affinity antibodies directed against the human insulin receptor and the human insulin-like growth factor-I (IGF-I) receptor were obtained from hen's eggs. Hens were immunized with human placental membranes and human liver membranes by intramuscular injections. Specific antibodies to the receptors were demonstrated in serum and egg yolks at 5 weeks and these antibodies presisted for at least 6 months. Antibodies from egg yolks were purified by the polyethylene glycol precipitation technique of Polson et al. The eggs provided the equivalent of about 450 ml of immunized serum per month per bird. The purified antibodies were approximately equally reactive with receptors for insulin or IGF-I. Antibodies immunoprecipitated affinity-labeled receptors, inhibited binding of each ligand, and were capable of stimulating 2-deoxyglucose uptake in rat adipocytes and thymidine incorporation in cultured fibroblasts. The presence of antibodies directed against the IGF-I receptor in those hens immunized with human liver membranes was unexpected, since liver membranes possess little or no IGF-I binding activity. We conclude that antibodies against human antigens may be relatively easily obtained by immunization of hens and purification of those antibodies from eggs.

Animals↗

PubMed1988

Characterization of a novel insulin receptor from stingray liver.

The insulin receptor from the liver of stingray, a cartilaginous fish, has characteristics which are in marked contrast to those of the mammalian insulin receptor. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of cross-linked, affinity-labeled stingray insulin receptor shows an apparent molecular mass of 210 kDa for the intact receptor. Reduction with mercaptoethanol resulted in no alteration in the apparent size of the stingray insulin receptor. Gel filtration studies of Triton X-100 solubilized stingray insulin receptor demonstrated an apparent Stokes radius of 7.6 nm. Ultracentrifugation sucrose gradient studies of cross-linked affinity labeled stingray receptor resulted in determination of a sedimentation coefficient of 13 S. Both of these parameters were greater than simultaneously obtained data for the human insulin receptor (7.2 nm and 11 S, respectively). Unlabeled insulin competed with binding of 125I-insulin and 125I-insulin growth factor (IGF) I with a half-maximal concentration of 1 nM for either. Unlabeled IGF I and II also competed, but were 4-5-fold less potent than insulin. It was found that not only did IGF I bind to the 210-kDa material, but both insulin and IGF I stimulated phosphorylation of a 210-kDa material which was immunoprecipitable by a polyclonal insulin receptor antibody. Elution of this material from the gel followed by hydrolysis and thin layer chromatography demonstrated that the 210-kDa material was specifically phosphorylated on tyrosine only. These data suggest that the insulin receptor from stingray liver is a dimer made up of 2 identical subunits of about 210 kDa size which contain both binding regions and insulin-stimulated tyrosine kinase. Specificity studies suggest that the stingray insulin receptor may represent a phylogenetic position prior to the evolutionary divergence of insulin and the insulin-like growth factors.

Affinity Labels↗

PubMed1988

Bed-rest-induced insulin resistance occurs primarily in muscle.

Treatment of trauma victims and patients with severe illness may contribute to their metabolic derangements by severely restricting physical activity. We sought to quantitate the impact of absolute bed rest alone on insulin regulation of glucose metabolism in six healthy subjects. Six to seven days of strict bed rest resulted in moderate deterioration in oral glucose tolerance and increased both fasting plasma insulin concentration and the insulin response to an oral glucose challenge by more than 40%. Euglycemic insulin clamp studies demonstrated the development of resistance to insulin's stimulation of whole-body glucose utilization. This change was characterized by a rightward shift of the insulin dose-response curve (insulin concentration at which 50% of maximal stimulation occurred was 45 +/- 3 (SE) microU/mL in the base line period and 78 +/- 8 microU/mL after seven days of bed rest, P less than .01) with little alteration in the maximal response in the rate of glucose uptake (baseline 15.4 +/- 1.4 mg/kg.min and bed rest 14.0 +/- 1.3 mg/kg.min). In contrast to the shift of sensitivity of whole-body glucose utilization to insulin, suppression of hepatic glucose output by insulin was unchanged by seven days of bed rest. Insulin binding to circulating mononuclear cells was not changed by bed rest. These studies demonstrate that the limited physical activity dictated by bed rest for as little as seven days is associated with substantial resistance to insulin's effects on glucose metabolism. Further, the data suggest that these effects occur primarily in skeletal muscle with little change in insulin action on the liver.

Adult↗

PubMed1988

Insulin responsiveness of protein metabolism in vivo following bedrest in humans.

To test the influence of bedrest on insulin regulation of leucine metabolism, six normal young men were subjected to a five-step hyperinsulinemic euglycemic clamp before and after 7 days of strict bedrest. A primed-constant infusion of [1-13C]leucine at 0.12 +/- 0.02 mumol.kg-1.min-1 was used. Before bedrest, the basal rate of appearance (Ra) of intracellular leucine and leucine oxidation were 2.79 +/- 0.17 and 0.613 +/- 0.070 mumol.kg-1.min-1, respectively. Insulin caused a dose-dependent reduction of the intracellular leucine Ra and leucine oxidation to a minimum of 1.64 +/- 0.08 and 0.322 +/- 0.039 mumol.kg-1.min-1, respectively, in nonbedrested subjects (P less than 0.001). Insulin also caused a dose-dependent reduction of plasma leucine concentration from 95 +/- 4 to 38 +/- 2 mumol/l (P less than 0.001). After bedrest, subjects exhibited decreased glucose tolerance and increased endogenous insulin secretion, but basal and insulin-suppressed intracellular leucine Ra and leucine oxidation rates were not different from control. Magnetic resonance imaging of the back and lower extremities revealed a 1-4% decrease in muscle volume and a 2-5% increase in fat volume secondary to bedrest. Bedrest also resulted in a negative nitrogen balance as compared with the control period, with an average cumulative loss of 6.3 g of nitrogen after 6 days. Urinary 3-methyl-L-histidine excretion was unchanged by bed rest. Thus because negative nitrogen balance and skeletal muscle atrophy occurred in six rested subjects in the absence of changes in the two indices of protein breakdown used in this study (3-methyl-L-histidine release and leucine release), it seems likely that muscle protein synthesis was inhibited.

Adipose Tissue↗

PubMed1988

A monoclonal antibody to the type 1 insulin-like growth factor and insulin receptors stimulates deoxyribonucleic acid synthesis in human and murine fibroblasts.

Insulin-like growth factor I (IGF-I) and insulin are polypeptide hormones that stimulate their cellular responses by binding to specific cell membrane receptors. These receptors, while chemically distinct, have similar structural and functional characteristics. This manuscript describes the production and characterization of a monoclonal antibody that binds to both type I IGF and insulin receptors. This antibody did not inhibit hormone binding to either receptor type, but stimulated DNA synthesis in both human and murine fibroblasts. Ten BALB/c-BYJ mice were immunized with human placental membrane fragments, and their splenic lymphocytes were fused with SP2 AG0 mouse myeloma cells. Of approximately 3000 hybridoma clones thus obtained, 1 viable clone, designated V3,8 D7, was found to produce an antibody directed against the type I IGF receptor. Solubilized radiolabeled placental membranes immunoprecipitated with affinity-purified antibody and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions revealed bands with relative molecular masses corresponding to the nonreduced intact receptor (approximately 350 x 10(3], the alpha-subunit (130-140 x 10(3], and the beta-subunit (90 x 10(3] of the type I IGF receptor. Clonal supernatant and affinity-purified antibody precipitated solubilized receptors affinity labeled with [125I]IGF-I. Antibody V3,8 D7 also precipitated solubilized placental membranes affinity labeled with [125I]insulin. However, solubilized receptors affinity purified by the monoclonal antibody bound IGF-I much better than insulin, suggesting that this antibody has a higher affinity for the type I IGF receptor than for the insulin receptor. Affinity-purified antibody did not inhibit the binding of IGF-I or insulin to receptors on human placental membranes, suggesting that it is directed against a site on the type I IGF and insulin receptor not involved in hormone binding. However, affinity-purified monoclonal antibody stimulated DNA synthesis in human GM 498 and murine BALB/c-3T3 clone A 31 fibroblasts, as determined by [3H]thymidine incorporation. The combination of IGF-I and affinity-purified antibody did not increase thymidine incorporation above levels observed with either substrate alone, suggesting that these factors may be operating through a common mechanism. These results suggest that antibody V3,8 D7 can stimulate receptor responses by binding to a site on the type I IGF and/or insulin receptors that is not involved in hormone binding. These data support the concept that hormone receptors themselves possess the biological information required for stimulating specific cellular responses.

Animals↗

PubMed1988

Hyperinsulinemia and stromal luteinization of the ovaries in postmenopausal women with endometrial cancer.

Ovarian secretion of testosterone and androstenedione is increased in postmenopausal women with endometrial cancer, and insulin stimulates ovarian stromal androgen synthesis in vitro. We undertook this study to investigate whether women with endometrial cancer have increased serum immunoreactive insulin levels. Ten postmenopausal women with endometrial carcinoma and 10 postmenopausal women without cancer who matched the cancer patients in age, years since menopause, and percentage of ideal body weight were studied. The women with endometrial cancer had significantly higher fasting serum insulin levels than the normal women [mean, 187 +/- 26 (+/- SE) vs. 55 +/- 11 pmol/L; P less than 0.01]. The cancer patients had significantly higher insulin responses after glucose administration than normal women (sum of 1, 2, and 3 h postglucose values, 5545 +/- 1526 vs. 1444 +/- 156 pmol/L; P less than 0.02), even though their glucose responses were similar. Nests of luteinized cells, which were positive for testosterone by immunoperoxidase staining, were found in the ovarian stroma of 8 of the women with endometrial cancer, but in only 1 of those without cancer (P less than 0.01). Specific high affinity insulin receptors were demonstrable in the stroma of the postmenopausal ovaries. These results suggest that the frequency of stromal luteinization is increased in women with endometrial cancer and that insulin may play a role in the pathogenesis of this luteinization.

Adenocarcinoma↗

PubMed1988

Metabolic effects of hydrochlorothiazide and enalapril during treatment of the hypertensive diabetic patient. Enalapril for hypertensive diabetics.

To determine the effect of enalapril maleate and low-dose hydrochlorothiazide therapy on blood pressure and glucose and lipid homeostasis in hypertensive type II diabetic patients, we treated nine of these patients sequentially with placebo, hydrochlorothiazide (25 mg/d with supplemental potassium chloride), and enalapril (10 to 20 mg/d). Sitting blood pressure fell significantly and to comparable levels with both hydrochlorothiazide and enalapril monotherapy. Enalapril monotherapy was associated with a slight, but not significant, fall in fasting blood glucose levels and with a significant fall in hemoglobin A1c levels. This improved glucose homeostasis could not be explained satisfactorily by changes in peripheral insulin sensitivity or hepatic glucose output, determined with the euglycemic clamp technique, or by changes in fasting serum insulin levels or monocyte insulin binding. In these low doses, hydrochlorothiazide did not worsen glucose homeostasis. Serum total cholesterol levels were significantly lower with enalapril therapy than with hydrochlorothiazide therapy or with placebo, and serum high-density lipoprotein cholesterol and triglyceride levels did not change significantly with either treatment. Thus, by providing effective blood pressure control and beneficial metabolic effects, enalapril therapy appears ideal for treatment of hypertension in diabetic patients. Similarly, low-dose hydrochlorothiazide therapy appears to have fewer metabolic complications in these patients and is, therefore, a logical alternative to substitute for, or add to, enalapril therapy.

Adult↗

PubMed1987

Hyperinsulinemia and hyperandrogenemia: in vivo androgen response to insulin infusion.

The plasma androgen responses to multiple-dose insulin infusions were determined in six normal females, four normal males, five obese females, and in three females with severe insulin resistance, hirsutism, and acanthosis nigricans. During the insulin infusions, the plasma glucose concentrations were maintained at 85 +/- 1 mg/dL by variable infusions of dextrose. Plasma androstenedione was augmented by 27-39% at physiologic insulin concentrations in the normal subjects and the obese group, and by 25% at hyperinsulinemic levels in the insulin-resistant group with acanthosis nigricans. The increased androstenedione concentrations achieved in the normal females and obese females were similar to the hyperandrogenemic levels seen in the acanthotic subjects in the basal state. Plasma cortisol also increased in all groups from 19% in normal females to 135% in obese females during the insulin infusions, but these changes did not reach statistical significance. These studies suggest that hyperinsulinemia may play a pathogenic role in the hyperandrogenemia of polycystic ovarian disease.

Acanthosis Nigricans↗

PubMed1986

Photochemical cross-linking of 125I-hydroxyphenylisopropyl adenosine to the A1 adenosine receptor of rat adipocytes.

Rat adipocyte plasma membranes were incubated with the A1 adenosine receptor agonist, 125I-hydroxyphenylisopropyl adenosine (1 nM) and then treated with the photoactive cross-linking agent, ANB-NOS. The membranes were solubilized and analyzed by SDS-PAGE and autoradiography. A single protein, Mr approx. 38,000, was specifically labeled. Reduction with 2-mercaptoethanol did not affect the apparent Mr of the labeled protein. Labeling was inhibited by the adenosine receptor agonists, HPIA, PIA and NECA, and by the antagonist, theophylline, but was unaffected by inosine. We conclude that the A1 adenosine receptor is a single protein of Mr approx. 38,000.

Adenosine↗

PubMed1986

Physical and hormonal evaluation of transsexual patients: a longitudinal study.

The physical and hormonal characteristics of 60 male-to-female transsexuals and 30 female-to-male transsexuals were measured before or during treatment with commonly used forms and dosages of hormones. Only two patients (both female-to-male) had either a congenital defect in hormonal production or abnormal genital development. Patients were seen at 3- to 6-month intervals for an average of 18 months. The response to therapy was examined over time; physical parameters, hormonal concentrations, liver function tests, lipids, and glucose were measured. Three patients were changed from ethinyl estradiol to conjugated estrogen because of liver enzyme elevations. Ethinyl estradiol (0.1-0.5 mg/day) was equal to conjugated estrogen (7.5-10 mg/day) in its ability to suppress testosterone and gonadotropins and to promote breast growth. Maximum breast growth required 2 years of therapy. During treatment with testosterone, female-to-male transsexuals had a significant mild elevation of cholesterol and triglyceride. The female-to-male transsexuals receiving testosterone cypionate, 200 mg every 2 weeks, ceased to have menstrual periods and became progressively masculinized. A mean maximal clitoral length of 4.6 cm which achieved by 1 year of therapy. Based on the data generated by this study, we recommend as hormonal therapy 0.1-0.5 mg/day of ethinyl estradiol or 7.5-10 mg/day of conjugated estrogen for male-to-female transsexuals, and intramuscular testosterone cypionate, 200 mg every 2 weeks, for female-to-male transsexuals.

Adolescent↗

PubMed1986

Insulin resistance with acanthosis nigricans: the roles of obesity and androgen excess.

The roles of hyperandrogenemia and obesity in the syndrome of severe insulin resistance with acanthosis nigricans were evaluated in studies of 11 females with this condition. Our results in these subjects were compared to evaluations of control subjects matched for degree of androgen excess or obesity. Fasting insulin levels were 3-, 5-, and 15-fold higher in the obese (OB), hyperandrogenemic (HO), and acanthosis nigricans (AN) groups, respectively, when compared to normal females. Responsiveness to a standard bolus of exogenous insulin was 78% of normal in the OB group, 40% of normal in the HO group, and 30% of normal in the AN group. Insulin binding to monocytes from both the OB group, and the HO group was modestly diminished primarily due to decreased receptor number. As a group, AN subjects when compared to either normal or weight-matched controls, demonstrated a significant decrease in monocyte insulin binding predominantly due to a decrease in receptor number. However, two patients in the AN group had normal insulin binding suggesting a postreceptor mechanism for the insulin resistance in at least some of these subjects. In vivo glucose utilization insulin dose response curves were determined in 3 acanthotic subjects using the euglycemic clamp technique. All 3 of these subjects had a right shift of the curve and diminished maximal utilization, consistent with combined receptor and postreceptor defects in insulin action. In evaluating the relationship between hyperandrogenemia, insulin resistance, and acanthosis nigricans, significant correlations among basal levels of plasma insulin, and both testosterone and androstenedione were demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Acanthosis Nigricans↗

PubMed1986

Acanthosis nigricans and obesity: acquired and intrinsic defects in insulin action.

Six obese, severely acanthotic females were evaluated for insulin resistance by an oral glucose tolerance test, intravenous insulin tolerance test, and insulin binding to freshly isolated monocytes, as well as studies of cultured skin fibroblasts. After baseline studies were obtained, the acanthotic subjects were maintained for 14 days on a 500 calorie diet, and the evaluations were repeated. Initial evaluation demonstrated normal glucose tolerance, but marked fasting hyperinsulinemia (57 +/- 5 microU/mL) and dramatically blunted response to exogenous insulin (KITT, 2.0%/min) when compared with five nonacanthotic weight-matched controls (insulin, 15 +/- 2 microU/mL; KITT, 5.2%/min). Monocyte insulin binding for the acanthotic group (0.251 +/- 0.050%/10(6) cells) was only 56% of the binding seen in the obese controls (0.447 +/- 0.108%). After the acanthotic females dieted for 14 days, their hyperinsulinemia and monocyte insulin binding improved, but failed to normalize. The response to exogenous insulin was unchanged and remained drastically blunted. In contrast to the normal insulin binding found in the cultured fibroblasts from the nonacanthotic obese controls, insulin binding to fibroblasts from the acanthotic group was decreased by 40%, suggesting that an intrinsic defect in insulin binding was present. Thus, we conclude that this cohort of acanthotic obese females are considerably more insulin-resistant than nonacanthotic weight-matched females. Furthermore, these studies suggest that the severe insulin resistance results from a combination of an acquired defect related to obesity and an inherent cellular defect in insulin action at, or beyond, the receptor.

Acanthosis Nigricans↗

PubMed1986

Phylogenetic distance from man correlates with immunologic cross-reactivity among liver insulin receptors.

The hepatic insulin receptors from evolutionarily diverse species were evaluated to determine their ability to bind human insulin and their immunologic cross-reactivity with the human insulin receptor. We found that the liver membranes of each species possessed insulin receptors with remarkably similar affinities for human insulin. An immunoassay specific for human insulin receptor showed that the amount of shared antigenic determinants differed widely among the species tested and in general decreased as the phylogenetic distance from man increased. These data suggest that the ability to bind insulin has been highly conserved during evolution despite considerable variation in the primary structure of the insulin receptor.

Animals↗

PubMed1986

Urinary cyclic AMP:creatinine ratio and nephrogenous cyclic AMP as indicators parathyroid functional status.

The clinical utility of the urinary cyclic AMP:creatinine ratio in assessing parathyroid function was evaluated in 33 hypercalcemic patients and compared this with the determination of the renal component of urinary cyclic AMP. We found the discriminatory value of urinary cyclic AMP:creatinine ratio to be slightly superior and to have additional advantages. Not only did the urinary cyclic AMP:creatinine ratio show empirically somewhat better discrimination between normals and patients with primary hyperparathyroidism, but it is technically simpler than the determination of the nephrogenous cyclic AMP. Our urinary cyclic AMP excretion data show 90% discrimination of primary hyperparathyroid subjects from normals. Among all hypercalcemic patients studied who had both elevated urinary cyclic AMP and elevated parathyroid hormone (PTH) levels by radioimmunoassay (RIA), 77% had primary hyperparathyroidism, and 23% had malignancy-associated hypercalcemia. Of those patients with malignant tumors and hypercalcemia, half had elevated urinary cyclic AMP and two thirds had elevated PTH by RIA. These data suggest that these tests have little discriminatory value in differentiating primary hyperparathyroidism from malignancy-associated hypercalcemia. No hypercalcemic patient who had both serum PTH and urine cyclic AMP in the normal range was found to have primary hyperparathyroidism. This suggests that further observation and evaluation is indicated in such patients before exploratory surgery is undertaken.

Calcium↗

PubMed1986

Insulin receptor proliferation: a mechanism for tumor-associated hypoglycemia.

A 30-yr-old man was found to have intractable hypoglycemia associated with colon carcinoma metastatic to the liver. Analysis of glucose requirements before death revealed a level of glucose turnover in excess of 12.9 mg/kg X min, consistent with maximally stimulated whole body glucose utilization. This high level of glucose turnover was present at a time when plasma immunoreactive insulin was very low. Insulin binding was measured in freshly isolated circulating mononuclear cells before death and in plasma membranes prepared from several tissues obtained at autopsy. A 3- to 5-fold increase in insulin receptor number was found in the mononuclear cells and liver and muscle plasma membranes. In contrast, skin fibroblasts maintained in tissue culture demonstrated no increase in insulin binding, thus suggesting that the increase in insulin receptors in freshly isolated tissues was acquired rather than intrinsic. Antibodies directed against the insulin receptor were not present. The patient's serum concentration of insulin-like growth factor I was low, but the serum level of nonsuppressible insulin-like protein was elevated. Serum bioassayable insulin-like activity was decreased. Based on tumor bulk at autopsy and in vitro analysis of glucose transport by his tumor cells maintained in monolayer tissue culture, it was estimated that his tumor could directly account for less than one third of the whole body glucose requirement. These data suggest that the increased tissue utilization of glucose in this hypoglycemic patient was caused by proliferation of insulin receptors in liver and muscle induced by his nonislet cell tumor through an unknown humoral mechanism(s).

Adenocarcinoma↗

PubMed1986

Functional characteristics of decreased insulin receptors on fibroblasts obtained from a subject with severe insulin resistance and acanthosis nigricans.

In a patient with severe insulin resistance and acanthosis nigricans, a decrease in the number of insulin receptors has been found on freshly isolated monocytes and cultured fibroblasts compatible with a primary or genetic decrease in cell-surface insulin receptors. To determine the functional characteristics of the remaining receptors on these cells, insulin-stimulated glucose uptake, insulin internalization, and insulin-induced receptor loss were evaluated in monolayer fibroblasts obtained from this subject. Maximal insulin stimulation of 2-deoxyglucose was markedly blunted, compatible with abnormal insulin responsiveness due to a functional impairment of the remaining receptors. In the presence of chloroquine, the acanthotic subject's fibroblasts internalized more insulin per available receptor compared with the normal cell line, suggesting an accelerated rate of insulin internalization. When the rate of insulin internalization was more directly determined by assessing the rate of appearance of acid-resistant, cell-associated radioactivity at 37 degrees C, a similar increase in insulin internalization rate was evident. When downregulation was assessed, insulin's ability to induce receptor loss in the acanthotic subject's cell line was augmented. Thus, a primary or genetic decrease in insulin receptors on cultured fibroblasts from a patient with acanthosis nigricans and insulin resistance is associated with functional impairment of the remaining receptors leading to significant alterations in ligand processing and subsequent insulin action.

Acanthosis Nigricans↗