Showing papers on "Insulin resistance published in 1975"

Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance

Abstract: Six patients with a unique form of diabetes associated with extreme insulin resistance have markedly reduced insulin binding to specific receptors on their circulating monocytes. When normal insulin receptors were exposed to serum or immunoglobulin fractions from three of these patients in vitro the specific binding defect was reproduced.

Insulin Receptor Deficiency in Genetic and Acquired Obesity

Abstract: We have previously shown that in the insulin-resistant obese hyperglycemic mouse (ob/ob) there is a deficiency in the number of insulin receptor sites on hepatocytes, adipocytes, and thymic lymphocytes. We now find that concentration of insulin receptors on liver plasma membranes is decreased in the db/db mouse, another form of inherited obesity, and in normal mice that became obese after treatment with gold thioglucose, while thin mice, heterozygous for the ob mutation (ob/+), have normal insulin binding. With acute and chronic food restriction of the ob/ob and gold thioglucose obese mice, there is reduction in hyperinsulinemia and an associated increase in the insulin receptor concentration toward normal. In contrast, when fasting ob/ob mice were given exogenous insulin to maintain the hyperinsulinemia, insulin receptors failed to increase. Thus, in all cases, there was a consistent relationship between the degree of hyperinsulinemia and of insulin receptor loss. These findings suggest that decreased insulin binding is a characteristic feature of the insulin resistance of obesity, and that sustained hyperinsulinemia is a major factor in the control of the concentration of insulin receptors on target cells.

Demonstration of insulin resistance in untreated adult onset diabetic subjects with fasting hyperglycemia.

Abstract: We have used a continuous intravenous infusion of glucose (6 mg/kg/min), insulin (80 mU/min), epinephrine (6 mug/min), and propranolol (0.08 mg/min) to directly assess insulin resistance in 14 untreated adult onset diabetics with a mean (plus or minus SE) fasting plasma glucose level of 217 plus or minus 17 mg/100 ml. During the infusion endogenous insulin secretion is inhibited and steady-state plasma glucose and insulin levels are achieved after 90 min. Since similar steady-state levels of plasma insulin are achieved in all subjects, the plasma glucose concentration observed during the steady-state period is a measure of an individual's insulin resistance. Under these conditions, the mean (plus or minus SE) steady-state plasma glucose level of the 14 diabetic patients was 350 plus or minus 16 mg/100 ml, while that of 12 normal subjects was 121 plus or minus 4 mg/100 ml. Additional studies were performed in which control subjects and patients with diabetes had their fasting plasma glucose levels acutely raised or lowered to comparable levels before receiving the basic infusion mixture of glucose, insulin, epinephrine, and propranolol. The results of these studies indicated that differences in initial plasma glucose levels could not account for the different glucose responses of the two groups to the basic infusion. Finally, the mean (plus or minus SE) steady-state plasma glucose level of 104 plus or minus 17 mg/100 ml observed during the same basic infusion in five patients with fasting hyperglycemia (mean plus or minus SE, 142 plus or minus 12 mg/100 ml) secondary to chronic pancreatitis suggested that neither chronic hyperglycemia nor hypoinsulinemia per se necessarily lead to insulin resistance. These results demonstrate that marked insulin resistance exists in adult onset diabetics with fasting hyperglycemia. Since previous studies have documented the presence of insulin resistance in patients with chemical diabetes, the possibility exists that insulin resistance may be characteristic of adult onset diabetes mellitus.

The effects of acute and chronic dexamethasone administration on insulin binding to isolated rat hepatocytes and adipocytes

Abstract: In an effort to determine the possible relationship between changes in insulin-receptor binding and the glucocorticoid-induced insulin-resistant state, we studied insulin binding to specific receptors located on isolated adipocytes and hepatocytes obtained from dexamethasone (D)-treated rats. Three groups of D-treated rats were studied: (1) acute high-dose treatment (1.5 mgdekg6 days), (2) acute low-dose treatment (0.125 mgkg6days), and (3) chronic low-dose treatment (0.125 mgkg21days). When insulin binding to isolated hepatocytes was studied, we found that binding was only 30%–50% of control values when cells from the D-treated animals were used. This decrease in binding was greatest for cells from the acute high-dose group, indicating a dose-response effect, and least for cells from the chronic group, suggesting a tendency toward return of insulin-receptor binding during chronic treatment. When insulin binding to isolated adipocytes was studied, binding was 50%–60% of control values when cells from both acute D-treated groups were used. While the magnitude of the decrease in insulin binding was not as great as that seen with hepatocytes, the decrease was still greatest using cells from the acute high-dose group as compared to the acute low-dose group. Thus, a dose-response effect was suggested in both tissues. On the other hand, the effects of chronic D treatment on insulin binding were strikingly different in the two cell systems. After chronic D treatment, insulin binding to adipocytes returned to near-normal levels, while a 55% decrease in binding to hepatocytes persisted. Thus, the tendency toward return of insulin binding after chronic D treatment seen with hepatocytes was almost fully expressed by adipocytes. This might be related to the amelioration of the corticosteroid-induced insulin-resistant state which has been reported after chronic corticosteroid administration to humans. In conclusion, (1) a decrease in insulin binding is associated with corticosteroid excess, and it is possible that this decreased binding is related to the insulin resistance which results from corticosteroid administration; (2) the return of insulin binding toward normal after chronic D treatment could well be related to the improvement in insulin resistance seen during chronic corticosteroid administration to humans; and (3) the difference in effects of chronic D treatment on insulin binding to hepatocytes versus adipocytes indicates that changes in insulin binding can be tissue specific.

Lipodystrophy of the extremities. A dominantly inherited syndrome associated with lipatrophic diabetes

Abstract: A female patient with the following symptoms has been observed: complete absence of subcutaneous fat on the arms and legs, well developed adipose tissue on the trunk and face, severe hyperlipidemia, eruptive xanthomas, insulin resistant diabetes mellitus with lack of ketoacidosis, hepatomegaly and elevated basal metabolic rate. The patient thus exhibited all characteristics of lipatrophic diabetes (Lawrence type of diabetes).

Insulin receptor: role in the resistance of human obesity to insulin

Abstract: Large adipocytes from obese subjects have similar receptor numbers and affinities for insulin as small adipocytes from subjects of normal weight. These results indicate that the insulin insensitivity of large fat cells from obese humans occurs after the insulin-receptor interaction and might be explained by either a dilution of receptors over the cell surface or by alterations in intracellular metabolism.

Insulin antibodies and the control of diabetes.

Abstract: Seventy-two insulin-treated diabetic patients were classified on the basis of a clinical evaluation of their control of diabetes. There were 39 stable patients, 23 unstable patients and 10 patients of intermediate degree of control. Four insulin resistant patients were also studied. Serum insulin antibodies were measured in each patient and the concept of insulin buffering by its antibody was developed. Most unstable patients had low concentrations of insulin antibody. Twenty-four of the 39 stable patients had a significant concentration of insulin antibody and 15 patients had low levels of antibody. The insulin resistant patients had hugh levels of antibody. All unstable patients had low antibody buffering and all insulin resistant patients had high antibody buffering. Although many stable patients had buffering antibodies others lacking antibody required a low insulin dose and their stability of diabetic control was attributed to residual pancreatic function.

The role of calcium in insulin action. III. Calcium distribution in fat cells; its kinetics and the effects of adrenaline, insulin and procaine-HCl.

Abstract: . The effects of adrenaline, insulin and procaine-HCl on Ca distribution in intact fat cells and on Ca binding to fat cell ghost membranes have been investigated. 1. Fat cells incubated in 45ca containing media till isotopic equilibrium indicated that the exchangeable Ca in these cells averages 25. 7 ± 3. 2 nmol/mg protein, which represents approximately 9. 8 % of their total Ca content. 2. Perifusion of 45Ca prelabelled fat cells gave washout curves whose analysis conformed with three kinetically distinct Ca pools (Fig. 1). The fast exchangeable pool (Compartment A) had an efflux rate constant of 0. 193 ± 0. 013 min. -1. The release of Ca from the second and third pools (Compartments B and C) was much slower with efflux rate constants of 0. 032 ± 0. 0018 min. -l and 0. 0042 + 0. 0006 min. -l respectively. Changing the Ca concentration in the perifusing medium modified the initial fast phase and its rate constant, while added dinitrophenol (DNP) inhibited the efflux rate from the latter compartments. The results suggest that the initial fast component of the 45ca washout represents Ca exchange from an extracellular pool probably present on the outer surface of cell membranes, while the release of Ca during the second and third slow phases represent Ca derived from two distinct intracellular compartments. The rate constant for 45Ca efflux from compartment (B) is of the same order of magnitude as the transmembrane fluxes measured in other cells and presumably represents Ca efflux from the cytoplasmic pool. The efflux of Ca from compartment (C), on the other hand, occurs at a much slower rate and probably reflects the release of Ca from a storage pool bound to the plasma membrane and/or endoplasmic reticulum. 3. Analysis of Ca binding to fat cell ghosts suggests that the membrane structures in these preparations contain two classes to Ca binding sites, a high affinity site with K (assoc) of 1. 4 times 10-6 M and a low affinity site with K (assoc) of 1. 3 × 10-5 M. The maximum amount of Ca that could be stored in these membranes would be approximately 60 nmol/mg protein. 4. In perifused 45Ca prelabelled fat cells adrenaline increased the 45Ca efflux from intracellular compartments prior to its stimulation of lipolysis. Previous perifusion with insulin or procaine-HCl prevented the effects of adrenaline on 45ca efflux and lipolysis. Moreover, both insulin and procaine-HCl decreased the binding of Ca by ghost membranes. The dose response of these effects compared with that for their effects on lipolysis in isolated fat cells. Pretreatment of fat cells with trypsin to delete the insulin receptor abolished the effects of insulin both on Ca binding and on lipolysis while the insulin like response for procain-HCl remained. The experiments suggest that the effects of insulin and procaine-HCl on fat cells could be mediated by increasing mobilisation of Ca from membrane bound stores and inhibition of Ca efflux thereby facilitating an increase in intracellular Ca concentration These effects of insulin require the presence of an intact insulin receptor while procaine-HCl operates beyond the insulin receptor site.

Familial insulin-resistant diabetes, multiple somatic anomalies, and pineal hyperplasia.

Abstract: West, R. J., Lloyd, J. K., and Turner, W. M. L. (1975). Archives of Disease in Childhood, 50, 703. Familial insulin-resistant diabetes, multiple somatic anomalies, and pineal hyperplasia. A syndrome comprising unusual facies, dry skin, acanthosis nigricans, thickened nails, hirsutism, dental precocity and dysplasia, abdominal protuberance, and phallic enlargement is described in 2 sibs. Both have developed diabetic ketoacidosis with insulin resistance. The elder child, a girl, had recurrent septic episodes and died at the age of 7-8 years. At necropsy the pineal gland was hyperplastic, weighing 900 mg. Investigation of the younger sib over a 4-year period has shown decreasing glucose tolerance, and he was frankly diabetic with ketoacidosis by the age of 6-8 years. Serum insulin concentrations have always been grossly raised. Though the mechanism for insulin resistance has not been definitely established, a functional abnormality of the hypothalamus or pituitary is postulated to explain the many endocrine features of the syndrome.

Metabolic effects of increased caloric intake in man.

Abstract: In order to determine if increased caloric intake could be responsible for the insulin resistance and elevated plasma glucose, insulin, and triglyceride levels commonly associated with obesity, hypercaloric diets were fed for 3 wk to eight normal subjects, and the metabolic consequences of this diet were assessed before significant weight gain had occurred. One wk of increased caloric intake led to statistically significant increases in fasting plasma insulin (22%), glucose (5%), and triglyceride (30%) levels, as well as an increased insulin response (20%) to oral glucose. Since the average weight gain during this period was only 1.6 kg, the observed changes appear to be secondary to increased caloric consumption, not obesity. Most of these changes returned toward baseline values during the succeeding 2 wk of increased caloric intake, but statistically significant elevations of fasting plasma glucose (10%), insulin (8%), and cholesterol (15%) levels were still seen at the end of the hypercaloric dietary period. On the other hand, insulin resistance, as estimated by direct measurement of insulin responsiveness, did not change as a result of 3 wk of increased caloric intake. These results indicate that acute increases in caloric intake can lead to elevated plasma glucose, insulin, cholesterol, and triglyceride levels. These changes occurred before significant weight gain had taken place, and raised the possibility that at least some of the abnormalities of carbohydrate and lipid metabolism attributed to obesity may be due to increased caloric intake. However, this conclusion would not seem to apply to the insulin resistance associated with obesity, as 3 wk of increased caloric intake did not produce any change in the responsiveness of these subjects to insulin's action.

Insulin secretion and glucose tolerance in adults with protein-calorie malnutrition.

Abstract: Glucose tolerance, insulin secretion, and responses to arginine infusion were studied in 17 adults with severe protein-calorie malnutrition (PCM) in Calcutta, India. Patients were selected for the severity of their malnutrition and for absence of other diseases. After 2-4 mo of refeeding there was complete clinical recovery, and control studies were performed. Glucose tolerance, as assessed by intravenous glucose-tolerance test (IVGTT), was reduced in PCM. Insulin response, both to glucose and to arginine infusion, was clearly reduced. The K value of the IVGTT correlated well with the ratio of mean to basal serum insulin during the first 40 min of the test. Basal serum insulin was nearly unchanged in PCM as compared with after recovery, although one patient studied serially showed a temporary drop in basal insulin during the first week of refeeding. In PCM, plasma amino acid levels failed to fall in response to arginine-induced insulin secretion as they did in the control studies. It appears that insulin secretory response is severely reduced in PCM and that a degree of insulin resistance in relation to body weight is present. These changes result in diminished glucose tolerance and probably in a reduced rate of tissue utilization of amino acids. Such alterations may be of adaptive significance in chronic PCM.

Insulin Metabolism in Hypothyroidism

Abstract: Insulin resistance has been invoked to explain the glucose intolerance observed in hypothyroid patients. This possibility was studied by determining fractional and metabolic clearances of intravenously administered porcine crystalline insulin (0.1 U./kg.) and its effect on plasma glucose concentration in ten hypothyroid patients, ten normal subjects, and six treated euthyroid patients. Following administration of porcine insulin, serum immunoreactive insulin concentrations during the period of observation were similar in hypothyroid patients, in normal control subjects, and in treated euthyroid patients. Similarly, no significant differences in the mean half-life, distribution space, or fractional and metabolic clearances of insulin were observed among any of the three groups. In response to insulin administration, plasma glucose concentrations declined to the nadir of 36 +/- 4, 43 +/- 3, and 38 +/- 4 mg. per 100 ml. in hypothyroid patients, normal control subjects, and treated euthyroid patients, respectively. Thereafter, plasma glucose steadily increased and approached the baseline value at ninety minutes in normal subjects and treated euthyroid patients. In contrast, the plasma glucose values remained significantly lower than the baseline for the rest of the procedure in hypothyroid patients. The present study demonstrates that there is no evidence of resistance to the action of insulin in hypothyroid patients. The observation of prolonged hypoglycemic action of exogenously administered insulin in hypothyroid patients might in fact suggest increased sensitivity to insulin action. These findings indicate that glucose intolerance of the hypothyroid state is not characterized by insulin resistance.

Effects of Burn Injury on Insulin Secretion and on Sensitivity to Insulin in the Rat in vivo

Abstract: Both insulin resistance and impairment of insulin secretion are know to occur in man after injury. The relative importance of these effects was studied in rats 2 h after a non-lethal 20 percent dorsal scald. No impairment of insulin secretion was found after this injury. Concentrations of both blood glucose and plasma insulin were elevated in scalded rats. Scalded rats responded to intravenous glucose injection (1-0 g/kg) with a further rise in plasma insulin concentration, which remained normal for the prevailing blood glucose concentration. However, marked impairment of glucose tolerance was observed, indicating the presence of insulin resistance. After intravenous insulin injection (1-0 U/kg) the initial rate coefficient for fall of blood glucose concentration was significantly lower (p less than 0-02) in scalded (mean 3-9 percent min.(-1) than in control rats (mean 6-3 percent min.(-1). The minimum in blood glucose concentration after insulin injection was reached at 10 min. in control rats, but not until 60 min. after injection in scalded rats. This difference was due to a delay in compensation for the hypoglycaemia in the scalded rats, since the rate of disappearance of insulin measured by injection of a tracer of 125I-labelled bovine insulin was not decreased after this injury. It was concluded that the impairment of glucose utilization in scalded rats (Heath and Corney, 1973) is due to decreased sensitivity to insulin rather than to suppression of insulin release.

Plasma glucagon levels in normal women during pregnancy.

Abstract: Increased plasma pancreatic glucagon concentrations have been reported during various states of decreased glucose tolerance.In vitro studies have demonstrated that human somatomammotropin stimulates glucagon release. The present investigation aimed at evaluating the role of plasma glucagon in the insulin resistance associated with normal pregnancy. Postprandial samples of plasma were obtained from 156 pregnant women between the 5th and the 40th week of pregnancy and were assayed for blood glucose, plasma insulin, glucagon and free fatty acids. Plasma insulin showed a gradual increase during pregnancy, and reached its maximal values during the last trimester. A moderate but significant increase in plasma glucagon was present between the 16th and the 28th week of gestation, whereas during the first and the last trimester of pregnancy its concentration was similar to that in non pregnant women. Intravenous glucose tolerance was performed during the last trimester and in a group of non pregnant control women. The slight decrease in glucose tolerance and the marked hyperinsulinemia associated with late pregnancy were accompanied by a more rapid and more pronounced decrease in plasma glucagon. A rapid and sustained decrease in glucagon was also observed when plasma FFA were raised by the intravenous administration of a triglyceride emulsion and heparin. These data suggest that glucagon is not involved in the insulin resistance associated with normal human pregnancy.

Relation of insulin receptors to insulin resistance.

Abstract: The status of insulin-receptor interactions in a variety of insulin-resistant states is reviewed. Utilizing large adipocytes from adult rats and small fat cells from young rats, we have conducted a series of in vitro experiments in an attempt to determine the cellular alteration(s) responsible for the insulin resistance associated with obesity. Stimulation of glucose oxidation by insulin is reduced in large cells. Studies using a mimicker of insulin action, spermine, as well as measurements of 125I-insulin binding to large and small cells indicate that receptor number and affinity are not responsible for hormone resistance. Furthermore, when rapid and direct measurements of sugar uptake were made, insulin stimulation was virtually identical in both cell types. These findings indicate that large adipocytes have an efficient insulin-responsive D-glucose transport system and suggest that the apparent hormone resistance may be due to alterations in intracellular glucose metabolism. It has been proposed that altered insulin-receptor interaction underlies the insulin resistance of human obesity. We have investigated this particular aspect of insulin action by 125I-insulin binding studies. Similar numbers of insulin receptors per cell and affinity for insulin were observed in adipocytes obtained from normal weight subjects and morbidly obese patients. Thus, the initial step in insulin action is unaltered in human obesity.

Interaction of endogenous growth hormone, cortisol, and catecholamines with blood glucose in children with brittle diabetes mellitus.

Abstract: Hormonal balance was studied in eight insulin-treated diabetic children who had excessive glycosuria. Glucose, growth hormone, and cortisol in plasma were determined every 0.5 hr for 48 hr. Total catecholamines and glucose were measured and tests for ketones done in 2-hourly collections of urine. Intermittent hypoglycemia as low as 20 mg/100 ml and swings of the blood sugar curve by 200-300 mg/100 ml within 2-4 hr were documented in most patients. Peaks of growth hormone concentration in plasma (8-78 ng/ml) followed almost every sharp fall in blood glucose; these peaks were usually followed by abrupt rises of glucose and prolonged hyperglycemia. Cortisol concentration was usually within the high normal range; there was no consistent relationship to the concentration of glucose. Urinary excretion of catecholamines in most patients was between 1 and 6 mug/hr; three patients excreted up to 8-23 mug/hr during short periods and up to 190 mug in 24 hr. The causes for the high excretion of catecholamines are unknown and may not have included hypoglycemia.

Resistance of gluconeogenic and glycogenic pathways in obese-hyperglycemic mice

Abstract: The genetically obese-hyperglycemic mouse, C57 BL/6J-ob, exhibits hyperglycemia and hyperinsulinemia. We have investigated the in vivo hepatic response to a glucose load in female obese mice and their lean littermates. Within 15 min after the administration of glucose (1.5 g/kg) to fasted lean mice, gluconeogenesis from [14C]alanine markedly decreased, endogenous hepatic levels of alanine and other gluconeogenic precursors increased, and glycogen synthetase was activated by virtue of an increase in the precent of synthetase I. These changes persisted up to 60 min and then returned to fasting values. In contrast, obese mice did not produce any of the above changes when given a similar glucose load. Failure to activate glycogen synthetase occurred despite the presence of synthetase D phosphatase activity. In lean mice [14C]glucose synthesis from [14C]glycerol exceeded that from [14C]alanine and was not suppressed by glucose administration, indicating the site of control of gluconeogenesis to be below the triose phosphate step. Insulin resistance in obese mice may involve the liver, as well as peripheral tissues studied by others.

Lipoatrophy produced in mice and rabbits by a fraction prepared from the urine from patients with congenital generalized lipodystrophy

Abstract: Urine from 5 patients with congenital generalized lipodystrophy has been fractionated by protein precipitation and Sephadex gel filtration. A fraction with a molecular weight in the range of 1000 was observed to be metabolically active in mice, rats, and rabbits. Hypophysectomized rats got hypoglycaemia following an injection, and the lipolytic-hyperglycaemic effect of ACTH was reduced after injection into intact mice. This effect was probably due to insulin release, because no insulin-like activity was observed on isolated fat cells in vitro. Persistant changes were observed in the animals after 3 weeks of daily injections of the urinary fraction. Adult mice and rabbits developed lipoatrophy with decrease of body weight in spite of a doubling of the food consumption. The metabolic rate and the body temperature were raised. Infantile animals developed a lipodystrophic state with increased growth velocity, and 50 per cent increase of the body weight, although no fat depots were observed. The treated animals got hyperglycaemia, hypertriglyceridaemia, hyperinsulinaemia, and insulin resistance. The rabbits developed manifest diabetes. The corresponding fraction prepared from the urine from the lipoatrophic rabbits produced lipoatrophy after injection into the mice. It is suggested that the lipodystrophic urinary fraction is of hypothalamic origin, and that it acts through the pituitary gland. The fraction is still heterogenous, and was observed to contain thyrotrophin releasing activity.

Evaluation of Insulin Resistance in Patients with Primary Hyperparathyroidism

Abstract: Increased plasma insulin levels, both in the fasting state and in response to glucose loads have been reported in patients with primary hyperparathyroidism (1). In this study surgical correction of the hyperparathyroidism was associated with a decrease in plasma insulin levels. However, since glucose tolerance in these patients was similar before and after surgery, it appears that a state of insulin resistance coexisted with the hyperparathyroidism. Documentation of these findings would add hyperparathyroidism to the list of pathologic states associated with antagonism to the action of insulin (2). Furthermore, since hyperin-sulinemia and insulin resistance are often associated with hypertriglyceridemia (3), patients with primary hyperparathyroidism might have an increased incidence of elevated plasma triglyceride levels. In order to evaluate these possibilities, we have measured plasma levels of glucose, insulin, triglyceride, and cholesterol, and directly estimated insulin resistance in a group of patie...

Metabolic responses to monocomponent human insulin infusions in normal subjects and patients with liver and endocrine disease.

Abstract: Hypoglycaemic and growth hormone responses were studied at different steady-state plasma insulin concentrations during a graded infusion of monocomponent human insulin. The control group consisted of ten volunteer subjects. The other groups studied included women taking oral contraceptives and patients with obesity, thyrotoxicosis, myxoedema, acromegaly, diabetes mellitus (moderate and severe) and liver disease. The hypoglycaemic response was measured in two ways: (i) the percentage reduction in plasma glucose below basal, and (ii) the rate of fall of plasma glucose (Kg-%/min). Insulin sensitivity was greatest in the normal subjects and in the other groups decreased in the order thyrotoxicosis greater than oral contraceptive greater than obesity greater than myxoedema greater than acromegaly greater than liver disease. Insulin sensitivity was difficult to assess in the diabetic patients because basal plasma glucose concentrations were elevated. At any given insulin concentration, the diabetics metabolized approximately the same amount of glucose as the normal subjects but the fact that this rate of glucose turnover occurred at higher plasma glucose concentrations probably indicated insulin resistance. Within each group Kg at each dose level of insulin correlated with the steady state plasma insulin concentration during the same infusion period. Diminishing sensitivity to insulin was reflected in an increasing fasting plasma insulin and insulin/glucose ratio except in patients with diabetes. GH responses to insulin infusion in normal subjects reflected the pattern of fall of plasma glucose. In the diabetic patients GH secretion appeared to be related to the infusion of insulin and occurred before plasma glucose had fallen to hypoglycaemic levels. GH secretory patterns were within normal limits in women taking oral contraceptives and in seven of eleven patients with liver disease but were impaired in three of seven patients with thyrotoxicosis and four of five patients with myxoedema. Four obese patients had a markedly delayed but eventually normal GH response.

The role of calcium in insulin action. IV. Mechanism of insulin resistance in adipose tissue of obese (ob/ob) mice and old Wistar rats.

Abstract: The in-vitro antilipolytic response to insulin and procaine hydrochloride by adipose tissue from young rats (150 - 180 g) and lean mice has been compared with that from aged Wistar rats (600 g) and obese (ob/ob) hyperglycaemic mice. 1. The adipose tissue from the obese mice showed diminished responsiveness to insulin and to procaine hydrochloride. Response to these agents, however, was restored by prewashing the tissue, suggesting that the apparent resistance in this tissue reflected saturation of the insulin receptors to endogenous insulin. 2. In adipose tissue of old Wistar rats the antilipolytic effect of insulin was also impaired, but this was not restored after extensive washing. Unlike adipose tissue ghosts prepared from young rats, insulin did not decrease the binding of calcium to ghost membrane preparations from old rats. Neither did insulin inhibit the adrenaline stimulated 45 calcium efflux from perifused isolated fat cells prepared from old rats. These results suggest that the insulin response of fat cells from old rats is impaired because of a defect either in their insulin receptors or in their post-receptor responses. 3. Procaine-hydrochloride, however, when added to the medium perifusing fat cells of these old rats inhibited the adrenaline stimulated lipolysis, reduced the Ca efflux and decreased the binding of Ca to fat cell ghosts; as it did with similar preparations of young rats. Thus the cells from old rats still show full post-receptor responsiveness to an insulin-like stimulus, provided the stimulus for such a response is given at a point beyond the insulin receptor itself. The results suggest that the insulin resistance observed in old rat fat cells may be related to some by deficiency in the insulin receptors, possibly due to their lower replacement with age.

Lipodystrophy of limbs associated with insulin resistance.

Abstract: Austin, J. (1973). Metachromatic leukodystrophy (sulphatide lipidosis). Lysosomes and Storage Diseases, p. 411. Ed. by H. G. Hers and F. Van Hoof. Academic Press, New York. Greene, H., Hug, G., and Schubert, W. (1967). Arylsulfatase A. in the urine and metachromatic leukodystrophy. 3'ournal of Pediatrics, 71, 709. Melchior, J. C., and Clausen, J. (1968). Metachromatic leucodystrophy in early childhood. Treatment with a diet deficient in vitamin A. Acta Paediatrica Scandinavica, 57, 2. Moosa, A., and Dubowitz, V. (1971). Late infantile metachromatic leucodystrophy Effect of a low vitamin A diet. Archives of Disease in Childhood, 46, 381. Percy, A. K., and Kaback, M. M. (1971). Infantile and adult-onset metachromatic leukodystrophy. Biochemical comparisons and predictive diagnosis. New England Journal of Medicine, 285, 785. Sundaresan, P. R. (1966). Vitamin A and the sulphate-activating enzymes. Biochimica et Biophysica Acta, 113, 96. Wiesman, U. N., Rossi, E. E., and Herschkowitz, N. N. (1972). Correction of the defective sulfatide degradation in cultured fibroblasts from patients with metachromatic leucodystrophy. Acta Paediatrica Scandinavica, 61, 296.

Effects of Theophylline on Glucose Kinetics in Normal and Sympathectomized Rats

Abstract: The influence of intraperitoneal administration of aminophylline on the rate of hepatic glucose production and peripheral uptake (Ra and Rd) was studied in normal and in adrenodemedullated and reserpinized rats by using the primed constant infusion of Glucose-2-3H. In normal rats, the dose of 100 mg. per kilogram of aminophylline produced a marked increase of Ra and Rd. Since Ra rose more rapidly than Rd did initially, hyperglycemia developed. Thereafter, glucose production and uptake increased to nearly the same extent, and a new steady state was reached at plasma glucose levels almost twice those of the baseline. Smaller and transient modifications were observed after the administration of 20 mg. per kilogram of aminophylline. With the higher dose, insulin levels markedly rose (reaching a tenfold peak above the basal value) while minor increments were observed with the lower dose. In a group of normal rats which were given glucose (10 mg. per kilogram per minute) in order to achieve a degree of hyperglycemia comparable to that brought about by the higher dose of aminophylline, an almost identical enhancement of glucose uptake was recorded. However, insulin levels were much higher in aminophylline-treated rats as compared to normal rats. From these finding it was concluded that aminophylline induces resistance to insulin effect. When aminophylline was injected into demedullated rats pretreated with reserpine, at the dose of 100 mg. per kilogram, a marked enhancement of Ra, and consequently of glycemia, was recorded initially; later, severe hypoglycemia developed depending on both a progressive exhaustion of hepatic glucose production and a marked increase of glucose utilization. Insulin levels dramatically increased in these experiments. These results suggest that aminophylline directly increases glucose production by the liver and insulin secretion. The simultaneous activation of the sympathetic system blunts the insulin response and counteracts the restraining effect of insulin on the liver and the stimulatory effect of insulin on overall glucose uptake as well.