Clinical disorders associated with autoantibodies to the insulin receptor. Simulation by passive transfer of immunoglobulins to rats.

Patients with autoantibodies to the insulin receptor (Anti-R) may exhibit either fasting hypoglycemia or hyperglycemia and extreme insulin resistance. Occasionally, both these phenomena are observed in the same patient at different times in the clinical course. In an effort to understand what determines the patient's response to Anti-R, we developed an animal model of these clinical disorders by passive transfer of Anti-R IgG to rats. IgG fractions from the plasma of Anti-R patients and control subjects were prepared by affinity chromatography with staphylococcal protein A-Sepharose. Anti-R IgG, injected into fasting rats, induced severe and persistent hypoglycemia (plasma glucose 30-60 mg/dl). Rats injected with control IgG maintained a plasma glucose within the range of 75 (fasting) to 165 mg/dl (feeding). In comparison with the effects of insulin, the hypoglycemic response to Anti-R IgG had a slower onset (2-4 h) and lasted longer (8-24 h). Similar, dose-dependent hypoglycemic responses were observed in rats whether the Anti-R IgG was derived from an insulin-resistant or hypoglycemic patient. When Anti-R IgG was administered in sufficiently high doses for several days to fed rats, persistent hyperglycemia (plasma glucose 200-400 mg/dl) developed. Based on these in vivo and previous in vitro studies, we attribute the hypoglycemic response to an insulin-like effect of Anti-R, and the hyperglycemic response to a desensitization of host tissues to the effects of insulin, with more prolonged exposure to higher levels of Anti-R.

Isolation and characterization of aldose reductase from calf brain.

Aldose reductase activity (alditol: NADP+ 1-oxidoreductase, EC 1.1.1.21) from calf brain was separated into two protein fractions by DEAE chromatography. Further purifcation by molecular sieve chromotography and electrofocusing yielding two distinctive enzymes, which were designated AR I and AR II. AR I was purified 646-fold and found to have an isoelectric point of 6.18. AR I was most active as a monomer with a molecular weight of 29 000 and appeared to be in equilibrium with a less active dimer. AR II was purified 425-fold and found to have an isoelectric point of 4.88. The molecular weight of this enzyme was 30 000. Although both enzymes had specificity for aldoses as substrates, AR I had two to three times larger turnover numbers with aromatic aldehydes and hexonates than did AR II. AR I was activated by sulfhydryl compounds and exhibited biphasic double reciprocal plots. AR I was more sensitive to inhibition by high substrate and phenobarbital concentrations than was AR II. AR I and AR II did not have antigenic similarity as tested by Ouchterlony immunodiffusion and counter immunoelectrophoresis. An immunochemical cross-reaction was observed between AR II and lens aldose reductase.

Anomalous glucose and insulin responses in patients with insulinoma. Caveats for diagnosis.

Two patients with insulinomas had unusual glucose and insulin-secretory dynamics in response to prolonged fasting. In patient 1, low insulin values persisted throughout three separate supervised fasts without a steady rise in the insulin-glucose ratio. In patient 2, a rising insulin-glucose ratio during a fast returned to normal after a documented catecholamine surge following a transient hypoglycemic episode. While patient 1 had clearly elevated proinsulin values of 52% to 57%, patient 2 had a near-normal value of 23%. The diagnosis of an insulinoma can usually be made by obtaining simultaneous glucose and insulin values during a prolonged supervised fast. Rarely, however, anomalous results may be obtained during supervised fasts of patients with insulinoma, and a broader range of diagnostic tests will be required to establish the correct diagnosis.

Changes in serum triiodothyronine (T3) kinetics after prolonged Antarctic residence: the polar T3 syndrome.

Humans who live in Antarctica for greater than 5 continuous months demonstrate alterations in the hypothalamic-pituitary-thyroid axis. These changes are characterized by 1) increased pituitary release of TSH in response to iv TRH, 2) increased serum clearance of orally administered T3, and 3) normal serum total, free T4, and unstimulated TSH levels. To clarify the mechanism responsible for these findings, serum kinetic studies of 125I-labeled T4 and T3 were carried out in a group of normal men, first in California, then after 20 and 42 weeks of continuous Antarctic residence. The kinetic parameters were calculated by noncompartmental analysis. The mean T4 residence time (MRT) was not different before and after 42 weeks (5.54 +/- 0.50 and 5.08 +/- 0.43 days). The total T4 volume of distribution (TVd) tended to fall over the same period (4.30 +/- 0.12, 3.56 +/- 0.27 L/m2), but was not significantly different (P = 0.075). In contrast to T4, there was an increase from control values for the T3 MRT from 0.83 +/- 0.03 to 1.10 +/- 0.03 days (P less than 0.002) and a more than doubling of the T3 TVd from 15.55 +/- 0.52 to 47.24 +/- 5.09 L/m2 (P less than 0.002) after 42 wk of Antarctic residence. Energy intake increased approximately 40% throughout the study without a change in body weight. The changes in T3 kinetic parameters may be accounted for by increased extravascular tissue binding. The marked increase in T3 TVd and the small increase in MRT are associated with increased T3 production and clearance and only minor changes in T4 kinetics. This is the first description of a mechanism for the change in thyroid hormone economy occurring with extended residence in Antarctica.

Size and erosive features of the sella turcica in acromegaly as predictors of therapeutic response to supervoltage irradiation.

Basal growth hormone levels and the sella turcica of patients with acromegaly were evaluated. Fifty of these patients were followed up, with fasting growth hormone levels determined at several intervals within 10 or more years after supervoltage pituitary irradiation. Prior to therapy, basal growth hormone levels were positively correlated with an estimate of tumor size, as reflected by sella abnormalities. Sella abnormality criteria, developed by Hardy et al., were used as the correlating factor. The percentage of fall in growth hormone levels after radiotherapy was indistinguishable in these patients, regardless of sella grade. However, since the larger, more erosive, tumors were associated with higher pre-therapy plasma growth hormone levels, the median growth hormone levels were higher at various intervals after treatment of this group. We suggest that the size and erosive features of the bony sella offer a crude, but possibly useful, predictor of response to supervoltage irradiation in acromegaly.

Partial 3 beta-hydroxysteroid dehydrogenase deficiency presenting as new-onset gynecomastia in a eugonadal adult male.

The postpubertal clinical presentation of 3 beta-hydroxysteroid dehydrogenase deficiency (3B-HSD deficiency) is less well-defined for adult males than for adult females, who often present with hirsutism. We describe a male with normal puberty who presented with new-onset gynecomastia at age 24. Common causes of gynecomastia were excluded. Dehydroepiandrosterone-sulfate (DHEA-S), estradiol, estrone, and 24-hour urinary 17-ketosteroid levels were elevated. A feminizing tumor was considered; biochemical tumor markers, chest x-ray, ultrasound of testes, and abdominal computed tomography (CT) scan were negative. Dexamethasone-suppression testing showed normal suppression of 24-hour urinary adrenal steroids. Cosyntropin-stimulation testing showed normal cortisol, 11-deoxycortisol, 17-OH progesterone (17-OHP), and aldosterone levels, but significant elevations of pregnenolone (preg), 17-OH preg, progesterone, DHEA, and androstenedione (A) levels. The sperm count was high and gonadotropin-releasing hormone (GnRH)-stimulation testing showed a normal increase in testosterone (T) level, suggesting that the defect did not involve the testes. It is concluded that this patient's gynecomastia is due to 3B-HSD deficiency with an associated alteration in sex hormone ratios. To our knowledge, this is the first well-described adult male with normal gonadal function presenting with postpubertal gynecomastia due to 3B-HSD deficiency. This defect may be a frequently unrecognized cause of gynecomastia.

Interpretive reporting of laboratory data: proposed criteria to qualify as a high-quality, limited clinical pathology consultation.

OBJECTIVE: To present recommended criteria designed to improve the computer-based interpretation of laboratory test results. METHODS: Guidelines for providing high-quality test interpretations and an outline for incorporating such criteria into a program for interpretive reporting are presented. RESULTS: Traditionally, when a laboratory reports a test result, the clinician interprets it within the clinical context. More recently, even in the absence of clinical information about the patient, laboratories that report test results, including biochemical thyroid function tests, have begun to insert "informative" statements about the test. These statements fail to provide an adequate limited pathology consultation that merits the CPT code 80500. Such interpretations can be improved by making them optional, specific for the test result, considerations rather than recommendations, and accompanied, on request, by an expanded list of differential diagnoses and an itemization of drugs known to affect the test result. CONCLUSION: High-quality interpretations of laboratory tests should improve patient care, avoid unnecessary costs, and prompt appropriate referrals to specialists.

Combined injury syndrome in space-related radiation environments.

The risk of combined injury (CI) to space travelers is a function of exposure to anomalously large surges of a broad spectrum of particulate and photon radiations, conventional trauma (T), and effects of weightlessness including decreased intravascular fluid volume, and myocardial deconditioning. CI may occur even at relatively low doses of radiation which can synergistically enhance morbidity and mortality from T. Without effective countermeasures, prolonged residence in space is expected to predispose most individuals to bone fractures as a result of calcium loss in the microgravity environment. Immune dysfunction may occur from residence in space independent of radiation exposure. Thus, wound healing would be compromised if infection were to occur. Survival of the space traveler with CI would be significantly compromised if there were delays in wound closure or in the application of simple supportive medical or surgical therapies. Particulate radiation has the potential for causing greater gastrointestinal injury than photon radiation, but bone healing should not be compromised at the expected doses of either type of radiation in space.

Changes in triiodothyronine mark severe pain syndrome: a case report.

Non-thyroidal illness is classically associated with a low total triiodothyronine (T3) level. Episodes of severe recurrent dental pain unassociated with fever or systemic infection in a patient was marked 2 to 3 weeks later by low T3 levels (56 ng/ml). Other thyroid and metabolic tests were normal. T3 levels returned to normal on resolution of pain. Recurrence of a transient, mild episode of pain was not associated with a low T3 2 weeks after its onset. We suggest that T3 levels may be markers for severe pain and suffering or disturbances responsible for pain and suffering in patients receiving analgesics.

Assessment of desmopressin-enhanced cognitive function in a neurosurgical patient.

The vasopressin analog desmopressin (DDAVP) is known to enhance memory in animals and man but its precise mechanism of action is uncertain. We report the case of a patient who experienced chronic memory dysfunction with impaired job performance following transsphenoidal resection of a pituitary adenoma. A prospective double-blind, placebo-controlled trial of the effects of DDAVP was performed. Memory storage and recall improved with DDAVP treatment and declined within 1 week after drug withdrawal both by subjective and objective criteria. The Buschke Selective Reminding Test was clearly the most responsive out of a battery of standard memory testing paradigms employed to track the presence or absence of DDAVP treatment.

McCune-Albright syndrome: how many endocrinopathies can one patient have?

In this one patient with McCune-Albright syndrome are seen a multitude of endocrinopathies--more than in any case previously described. Only fibrous dysplasia with café-au-lait spots and/or endocrine hyperfunction are required for the diagnosis of the syndrome. Our patient has polyostotic fibrous dysplasia, café-au-lait spots, and at least four primary endocrinopathies. She had shown precocious puberty (with an ovarian follicular cyst later requiring resection), hyperthyroidism due to toxic nodular thyroid disease, primary hyperparathyroidism, and hyperprolactinemia (with associated hypogonadotropic hypogonadism and premature menopause). With this many organs involved in the same patient, it is hard to imagine that a genetic defect will not soon be identified as the unifying cause of the entire syndrome.

Impaired 6-phosphofructokinase activity in mononuclear leukocytes from patients with type II diabetes mellitus.

Seven cytoplasmic enzyme activities were measured in extracts of mononuclear leukocytes (lymphocytes plus monocytes) obtained from 19 type II diabetic humans and 10 healthy control subjects. 6-Phosphofructokinase activity was significantly decreased in cell extracts from diabetics, while other enzyme activities were similar in diabetics and controls. Since the effects of starvation on enzyme activities are sometimes similar to the effects of diabetes, the studies were repeated in 5 control subjects after a 2-day fast. This short period of starvation did not mimic the effect of diabetes on 6-phosphofructokinase activity. The decreased enzyme activity was not correlated with percent specific insulin binding to monocytes in the same cell preparations nor to clinical variables such as obesity or the broad range of fasting plasma glucose values encountered among the diabetics. We conclude that 6-phosphofructokinase activity in mononuclear leukocytes, as in other tissues, may be a marker for a postreceptor lesion associated with the insulin resistance found in type II diabetes mellitus.

The effect of endurance training on serum triiodothyronine kinetics in man: physical conditioning marked by enhanced thyroid hormone metabolism.

OBJECTIVE: We studied the relationship between endurance training, aerobic capacity, and T3 metabolism in healthy euthyroid men. DESIGN: T3 kinetic studies performed on two groups of subjects differentiated on the basis of physical activity status and aerobic capacity. SUBJECTS: Five endurance-trained athletes and five sedentary controls (mean +/- SD VO2 max = 48.2 +/- 7.1 vs 23.2 +/- 4.5 ml/kg/min, respectively) matched for age, body surface area, lean body mass, and baseline thyroid function. MEASUREMENTS: Kinetic analysis performed using serial serum T3 levels measured following oral T3 administration. Metabolic clearance rate, total volume of distribution, disposal rate, and total body pool calculated using non-compartmental analysis. RESULTS: When normalized for lean body mass, all kinetic parameters were 25-38% greater in the athletic group compared to controls (P < 0.05). Total volume of distribution, disposal rate, and total body pool were positively correlated with aerobic capacity (r = +0.69 to +0.79; P < 0.05). Metabolic clearance rate was positively correlated to a non-significant degree. CONCLUSIONS: These results confirm the findings of prior studies that thyroid hormone metabolism is altered by physical conditioning. In addition, we demonstrated a positive correlation between aerobic capacity and several parameters of T3 kinetics. Differences in absolute lean body mass cannot explain these findings; rather it appears that there is something qualitatively different in the way endurance-trained tissue processes thyroid hormone, compared to untrained tissue. The study was not designed to elucidate these differences at the cellular level; however, it does support a link between muscle physiology and T3 activity and may suggest a physiological role for thyroid hormone in physical conditioning.

The insulin receptor is an age-dependent integral component of the human erythrocyte membrane.

Human erythrocytes were separated according to age to determine whether there is heterogeneity in the specific binding of 125I-insulin to red cells. The mean cell age of erythrocyte isolates was determined from the cumulative distribution frequency of the cells in an isotonic (290 milliosmolar) density gradient and confirmed by assay for pyruvate kinase, an age-dependent red cell enzyme. An IBM 2997 centrifugal cell separator was used to obtain larger quantities of younger erythrocytes from normal subjects. 125I-insulin binding to red cells including reticulocytes was found to decrease exponentially as a function of their mean cell age in 8 normal subjects. A change in receptor number rather than affinity appeared to account for the observed change in 125I-insulin binding. An exponential, age-dependent change in binding of a hormone to its cell membrane bound receptor has not previously been observed. Consistent with these results is the possibility that regulation of the red cell insulin receptor concentration takes place only in the younger red cells.

Insulin receptors in normal and disease states.

The binding of insulin to its receptor has been studied under various physiological and pathological conditions. Quantitative studies have involved human circulating cells such as monocytes and erythrocytes, adipocytes, placental cells, and cultured cells such as fibroblasts and transformed lymphocytes. In animals, other target tissues such as liver and muscle have been studied and correlated with the human studies. Various physiological conditions such as diurnal rhythm, diet, age, exercise and the menstrual cycle affect insulin binding; in addition, many drugs perturb the receptor interaction. Disease affecting the insulin receptor can be divided into five general categories: (1) Receptor regulation--this involves diseases characterized by hyper- or hypoinsulinaemia. Hyperinsulinaemia in the basal state usually leads to receptor 'down' regulation as seen in obesity, type II diabetes, acromegaly and islet cell tumours. Hypoinsulinaemia such as seen in anorexia nervosa or type I diabetes may lead to elevated binding. (2) Antireceptor antibodies--these immunoglobulins bind to the receptor and competitively inhibit insulin binding. They may act as agonists, antagonists or partial agonists. (3) Genetic diseases which produce fixed alterations in both freshly isolated and cultured cells. (4) Diseases of receptor specificity where insulin may bind with different affinity to its own receptor or related receptors such as receptors for insulin-like growth factors. (5) Disease of affinity modulation where physical factors such as pH, temperature, ions, etc. may modify binding. In this review, we have considered primarily abnormality in insulin receptor binding. There are numerous other functions of the receptor such as coupling and transmission of the biological signal. These mechanisms are frequently referred to as postreceptor events, but more properly should be referred to as postbinding events since the receptor subserves other functions in addition to recognition and binding of insulin.

PIP: This article reviews the literature on insulin receptor binding under various physiologic and pathologic conditions. Quantitative studies have involved human circulating cells such as monocytes and erythrocytes, adipocytes, placental cells, and cultured cells such as fibroblasts and transformed lymphocytes. Insulin binding is affected by physiologic conditions such as diurnal rhythm, age, diet, exercise, and the menstrual cycle. In addition, many drugs disturb the receptor interaction. Oral contraceptives, for example, appear to abolish the normal variation in insulin binding during the menstrual cycle due to reduced receptor concentration. Diseases affecting the insulin receptor can be divided into 5 categories: 1) receptor regulation, including diseases characterized by hyper or hypoinsulinemia; 2) antireceptor antibodies that bind to the receptor and competitively inhibit binding; 3) genetic diseases that produce fixed alterations in both freshly isolated and cultured cells; 4) diseases of receptor specificity where insulin may bind with different affinity to its own receptor or related receptors; and 5) diseases of affinity modulation, where physical factors such as pH, temperature and ions modify binding.