Sequential studies of glucose tolerance and red blood cell insulin receptors in normal human pregnancy.

Insulin binding to erythrocytes was sequentially studied in 12 healthy pregnant women during the anabolic (11-22 wk) and the catabolic (31-38 wk) gestational phases. For comparison, we studied 12 nonpregnant subjects at mid-luteal and mid-follicular menstrual phases. Oral glucose tolerance tests were also performed during these studies. There was a progressive worsening of the glucose tolerance from the anabolic to the catabolic phase associated with fasting hypoglycemia and hyperinsulinemia. The worsening of glucose tolerance was accompanied by a progressive increment of insulin secretion. Insulin binding to red blood cells increased progressively from the anabolic to the catabolic phase, due to an increased number of receptors per cell, associated with a reduction in the apparent affinity at the low occupancy levels. We concluded that the insulin resistance of pregnancy was not accompanied by an impaired binding of insulin to its receptors, at least in the RBC. The data suggest that the defect of insulin action lies at a site distal to the receptor.

Interferon-alpha therapy increases type I insulin-like growth factor receptors expression on lymphoid cells from patients with chronic myelogenous leukemia.

Aiming to verify if insulin-like growth factor type I and its receptor (IGF-IR) are implicated on pathophysiology of chronic myelogenous leukemia (CML), we studied 35 patients with CML in chronic phase at diagnosis or during interferon-alpha (IFN-A) or hydroxyurea treatments. Cytometry flow analysis and reverse transcription PCR (RT-PCR) molecular assay for IGF-IR expression on peripheral blood cells from CML patients diagnosed didn't show statistical differences from the control group. Hydroxyurea treated patients had lower expression of IGF-IR in granulocytes, lymphocytes and monocytes (P<0.01). We found statistical higher percentage of T and B lymphocytes positive for IGF-IR on IFN-A treated patients (P<0.001). Also an increase of IGF-IR mRNA expression could be detected in this group when compared with patients in hydroxyurea therapy (P<0.05). Our study suggest that IGF-IR is not directly implicated on CML installation and that the increased expression of IGF-IR on lymphoid cells of IFN-A treated patients could contribute to the immune recognition of malignant cell clone by enhancing immunocompetent cell proliferation and action.

Erythrocyte insulin receptor: normalization of binding data for the average cell age by the red cell creatine determination in obese, diabetic and acromegalic patients.

Insulin binding studies performed in erythrocytes (RBC) have been employed in clinical studies assessing the status of insulin receptors at target cell tissues. However, some authors challenged this assumption on the basis of some discrepancies described in comparative studies of other cell types, probably related to populations of different cell age affecting insulin binding to RBC. We evaluated insulin binding to RBC in normal males (n = 10), non-obese diabetic males (n = 13), normal females (n = 15), obese (n = 11) and acromegalic females (n = 5), before and after correction of insulin binding data for creatine concentration in the RBC as a procedure of correction for age, since a negative correlation was described between creatine content and RBC age which also correlates inversely with % insulin binding. Insulin binding in all three groups of patients was not statistically different from corresponding values for normal males and females respectively before correction of data for creatine, but significantly reduced values were found after adjustment for creatine in accordance with published data concerning monocytes. In conclusions, the procedure of correcting insulin binding in erythrocytes by the creatine content in RBC is potentially useful for clinical investigations, since the influence of RBC age is excluded.

Insulin resistance in acromegaly: evaluation by studies of insulin binding to erythrocytes.

Insulin binding to erythrocytes (RBC) was evaluated in 10 acromegalic patients (6 females and 4 males) in comparison to 22 normal subjects (12 females and 10 males) in an attempt to study the insulin resistance of acromegaly. Basal glucose from all acromegalic patients were within the normal range but incremental glucose and insulin curves, respectively, on oGTT were significantly increased in the acromegalic patients suggesting an insulin resistant state. Basal growth hormone concentrations were elevated in all acromegalic patients, but no correlation was observed between insulin and GH levels. The insulin binding studies in the acromegalic patients showed a decreased binding due to a reduction in the receptor number per cell but with no alterations in the affinity state. Correction of data for creatine, as a procedure of normalization of binding data for a standardized RBC cell age, enhanced the reduction of insulin binding of the acromegalic patients in comparison to controls in consequence to the younger population of acromegalic RBC as indicated by their increased creatine concentrations. In conclusion, the insulin resistant state in acromegalics observed in our study is accompanied by a decrease in the insulin binding to the RBC receptor due to a reduction of the receptor concentration as mediated by the compensatory hyperinsulinemia.

Role of obesity and hyperinsulinemia in the insulin resistance of obese subjects with the clinical triad of polycystic ovaries, hirsutism and acanthosis nigricans.

The insulin resistance of 4 nonobese and 8 obese patients with polycystic ovaries, hirsutism and benign acanthosis nigricans, and of 6 'obese normal' apart from obesity and 10 normal female subjects was evaluated by means of an intravenous insulin tolerance test and by measuring basal and insulin responses to an oral glucose load. The patients with polycystic ovaries, hirsutism and acanthosis had a decreased hypoglycemic response to exogenous insulin. The subjects with polycystic ovaries presented a significantly greater mean glucose response area for the same or greater mean insulin response area than the obese or nonobese normal subjects. The insulin resistance in the patient with polycystic ovaries, hirsutism and acanthosis nigricans could not be exclusively ascribed to a reduced receptor number, but also appeared to be due to a simultaneous postbinding defect probably related to the high insulin levels in patients with polycystic ovaries be they obese or not. The elevated plasma androgens and the presence of acanthosis found in these patients are likely also related to the hyperinsulinemia. To evaluate the influence of obesity, obese and nonobese patients with acanthosis nigricans and polycystic ovaries were compared. Higher insulin levels were found in the thin subjects, which could explain their greater insulin resistance and more severe hyperandrogenism. The comparison between obese patients with and those without acanthosis nigricans and polycystic ovaries suggested that, despite similar insulin levels, the greater known duration of obesity (probably also of the hyperinsulinemia) of the former was a possible explanation for their more intense insulin resistance and higher testosterone levels.

Human erythrocyte insulin receptors in normal male and female subjects.

Human red blood cells (RBC) have been shown to have highly specific insulin receptors. We have studied the binding characteristics of insulin to these receptors in erythrocytes from normal male and female subjects on their usual diet and physical activity. There were no significant differences in insulin binding in erythrocytes from females between the two phases of the menstrual cycle. However, the receptor concentration was higher in the 2nd half of the cycle accompanied by a reduction in affinity. Binding curves of 125-I-insulin to RBC from males were higher than females in either phases of the menstrual cycle, primarily due to an increase in receptor concentration when compared to females in the follicular phase and mediated by an increased affinity at low receptor occupancy when compared to females in the luteal phase. We speculated that the differences in the binding characteristics of 125I-insulin to RBC insulin receptors are mediated by differences in the levels of sex hormones.