Showing papers on "Insulin resistance published in 1973"

A simple method for the determination of serum free insulin levels in insulin-treated patients.

Abstract: A method for the determination of free, active insulin in the sera of insulin-treated diabetics is described. This involved radioimmunoassay after extraction of free insulin with polyethylene glycol. Recovery tests with cold insulin showed 73 per cent recovery of free insulin and no recovery of bound insulin. The fasting free insulin levels were slightly lower in the patients than in normal persons; exceptions were some patients with complications expected to cause insulin resistance at the peripheral tissue level. Free insulin levels did not correlate with total insulin levels, antibody titers, insulin requirements or conditions of insulin treatment. A very slight increase of insulin was observed after glucose loading in insulin-treated patients, but a marked increase of the free insulin level followed by an exaggerated increase in the total insulin level was observed in a patient with the insulin autoimmune syndrome. The diurnal changes of the free insulin suggested the dynamic states of this fraction and its usefulness for determining control of diabetes with insulin.

Amitriptyline, weight gain and carbohydrate craving: a side effect.

Abstract: This paper reports excessive weight gain associated with craving for carbohydrates, occurring as a side effect of treatment with amitriptyline. Subjects were 51 depressed women who had responded to initial treatment with amitriptyline and remained well. Nineteen were maintained on amitriptyline for nine months; 32 had the medication withdrawn after three months. Both groups gained weight during recovery. Subsequently the amitriptyline group continued to gain weight excessively, while the drug withdrawal group did not. This difference was not due to persisting depression. Withdrawal of active drug after nine months treatment was followed by weight loss. Amitriptyline patients also reported a striking and dose-related craving for carbohydrates, developing within one or two months of starting the drug. Fasting insulin and glucose, and intravenous insulin tolerance were not affected, and the mechanism of the side effect is not clear. However, in confirmation of previous work, insulin resistance was found in subjects with minor residual depression.

Relationship between fasting plasma insulin level and resistance to insulin-mediated glucose uptake in normal and diabetic subjects

Abstract: We have previously shown that a significant inverse correlation exists between the height of the plasma insulin concentration and the efficiency of glucose uptake in the fasting state. Subsequently, we devised an infusion technic that provides a more specific measure of cellular resistance to insulin mediated glucose uptake. We have used this technic to study the relationship between fasting plasma insulin level and resistance to insulin mediated glucose uptake in twenty-two patients with normal oral glucose tolerance, fourteen patients with impaired glucose tolerance, and fourteen patients classified as having chemical diabetes mellitus. The results indicate a highly significant positive correlation between the degree of insulin resistance and fasting plasma insulin concentration (r = .69, p

Insulin Receptors in Human Circulating Lymphocytes: Application to the Study of Insulin Resistance in Man

Abstract: 125I-insulin binds to circulating human lymphocytes and is displaced by unlabeled insulin. We have compared the binding and displacement curves of 125I-insulin from the circulating lymphocytes of normal subjects with those of insulin resistant obese and acromegalic patients and insulin sensitive hypopituitary subjects. The initial 125I-insulin binding (maximal percent 125I-insulin bound) for normal subjects had a mean value of 2.9 ng/ml (range 1.9–3.4) per 70 × 106 cells which is not statistically different from the other patient groups. For the normals, the [Insulin]-50% inhibition 125I-insulin bound (that concentration of insulin necessary to inhibit 50% of the maximal binding) had a mean value of 8.4 ng/ml (range 6.0–12.0 ng/ml). This value is significantly different from the obese patients but not from the acromegalic or the hypopituitary subjects. If the circulating lymphocyte mirrors the changes seen in the major metabolic sites of insulin action, these data suggest that an alteration in the insulin...

The Effect of Adrenalectomy on the Development of the Obese-Hyperglycemic Syndrome in OB/OB Mice

Abstract: Adrenalectomy in the male and female obese-hyperglycemic mouse at 2 months of age significantly lowers blood glucose and body weight. In the ob/ob mouse the response to fasting is appropriate, glucose tolerance is improved, and insulin resistance is significantly reduced after adrenalectomy. {Endocrinology 93: 510, 1973) T^/TANY laboratories have suggested that the •"•'• adrenal plays a role in both the pancreatic islet cell hypertrophy and adiposity seen in some obese hyperglycemic syndromes of laboratory rodents (1,2,3,4,5). Indeed, hyperadrenalcortism is one of the major methods used to produce experimental obesities (6,7,8,9,10). In NH, ob/ob, Aa obese mice, adiposity is associated with some form of adrenal hypertrophy (S). It is of interest that adrenalectomy, before the onset of obesity, prevents both excess weight gain and islet hypertrophy in NH and yellow obese mice (1,3). Intraocular transplantation of adrenals from lean mice maintains excess weight gain in adrenalectomized NH mice (5). Adrenalectomized ob/ob mice gain less weight than controls (11). In the ob/ob mouse the blood glucose is reduced after adrenalectomy, and it is reported (5) that blood sugar levels correlate with adrenal hypertrophy in these mice. In an investigation of the role of the adrenal cortex in the etiology of the obese-hyperglycemic syndrome in ob/ob mice, Hellerstrom et at. (12) found that all zones of the adrenal cortex were markedly hypertrophied in the obese, but not in the lean animals. They also found that the adrenal hypertrophy was directly related to the adiposity, i.e., if the body weight of obese mice was kept within normal ranges by restricted Received August 29, 1972. 1 Supported in part by Grants-in-aid from the National Institutes of Arthritis and Metabolic Diseases (A-2911), National Institutes of Health, U.S. Public Health Service, Bethesda, Maryland; and the fund for Research and Teaching of the Department of Nutrition, Harvard University School of Public Health, Boston, Massachusetts. 2 Present address: Department of Biology, Boston College, Chestnut Hill, Massachusetts, 02167. diet, there was no adrenal enlargement. Age also seems to play a role in the effect of the adrenals on adiposity. In the NH, Aa, and ob/ob mouse adrenal hypertrophy increases with age, as does the adiposity and hyperglycemia (5). Biochemical evidence that the adrenals of ob/ob mice are hyperactive has been shown by increased glucose 6-phosphate dehydrogenase activity (4) and by increased sensitivity to ACTH (13). Thus, the possibility that the adrenals are involved in the expression of the ob/ob genome prompted us to explore the effect of adrenalectomy on young male and female mice. Materials and Methods Male and female C57BL/6J-ob/ob mice obtained from the Jackson Memorial Laboratories were randomized into 2 groups at 2 months of age. Fourteen were bilaterally adrenalectomized; 10 served as unoperated controls. Body weights and blood glucose levels for both groups were obtained one day before, and periodically from 6 to 90 days after the adrenalectomy date. Fourteen lean littermates were similarly randomized into 2 groups: 8 adrenalectomized and 6 unoperated controls. In all groups, body weights and blood sugar levels were determined the day before, and periodically following the adrenalectomy date. All animals were maintained on ad lib food (Purina lab chow) and water. Adrenalectomized animals were also given the choice of 1% salt in drinking water. In order to approximate the functional capacity of the pancreas all animals were fasted overnight 70 days (obese) and 71 days (lean) after adrenalectomy date. A blood sample was obtained from the fasting mice and then 50 mg of glucose ip was administered to the obese mice. Fasting lean mice received 20 mg glucose. Blood samples were drawn 30, 60, and 360 min later to determine glucose tolerance. The insulin sensitivity of adrenalectomized mice and their controls was studied by collecting blood

Glucose Intolerance with Hypokalemia: Failure of Short-term Potassium Depletion in Normal Subjects to Reproduce the Glucose and Insulin Abnormalities of Clinical Hypokalemia

Abstract: The mechanism by which potassium deficiency per se impairs glucose tolerance was studied in seven subjects who were potassium depleted experimentally (mean depletion = 326 mEq.). In five subjects studied using the oral glucose tolerance test, all showed impairment during the potassium depletion phase compared to the predepletion control period, and four of five subjects showed improvement with potassium repletion. The four subjects with impaired glucose tolerance compared to both control periods showed a delay in the initial phase of total immunoreactive insulin release. None of the five subjects showed a significant variation in the per cent proinsulin-like component from the potassium depletion phase to either control period. Two subjects studied using the intravenous glucose tolerance test showed no impairment of glucose tolerance with potassium depletion, and no evidence of insulin resistance was found following the injection of 0.05 U. per kilogram of insulin. These two subjects did manifest impaired growth hormone responses to the hypoglycemic stimulus, however. Potassium depletion per se impairs glucose tolerance. The defect is mild; severe glucose intolerance, alterations in total immunoreactive insulin, and plasma insulin components seen in clinical hypokalemic states involve a complex interplay between potassium deficiency and the primary disease state.

Immunologic Reactions Against Insulin II. IgE anti-Insulin, Insulin Allergy and Combined IgE and IgG Immunologic Insulin Resistance

Abstract: Immediate or anaphylactic type hypersensitivity to insulin may be detected by in vitro analysis of IgE antibodies against insulin antigenic determinants. A solid phase immunoadsorbent prepared with polystyrene tubes and an IgE anti-IgE matrix provides the method of fixation of serum IgE against radiolabeled insulin. The degree of insulin binding by IgE correlates with the clinical allergic state and declines in parallel with the Prausnitz-Kustner titers of patient9s sera. A more rapid decline in IgE-binding capacity of insulin occurred after therapeutic insulin desensitization or continuous insulin therapy. The occurrence of insulin allergy and immunologic insulin resistance in the same patients was associated with the presence of both IgE and IgG antibodies against insulin. The immunoadsorbent system for detection of IgE antibodies against insulin was used to evaluate cross-reactivity of heterologous insulins or insulin fragments with bovine insulin and is applicable to other IgE-mediated systems.

Effects of adrenalectomy on the obese-hyperglycemic syndrome in mice (gene symbol ob).

Abstract: Mice with the inherited obese-hyperglycemic syndrome (gene symbolob) and their lean litter mates were adrenalectomized and then studied for up to 30–36 weeks with regard to their body weights and the serum glucose and immunoreactive insulin level. Sham operated obese and lean mice were used as controls.-Adrenalectomy did not prevent the excessive weight gain of the obese mice. However, during the first three weeks after adrenalectomy the mean weight increase was some-what smaller than in the sham operated controls. The increase in the body weights of the lean animals was, however, not affected. The most prominent finding after adrenalectomy was a decrease of the serum levels of glucose and insulin in both obese and lean animals.-The results indicate that in the obese mice adrenalectomy decreases the pronounced insulin resistance. It is also suggested that insulin resistance may be dissociated from the development of obesity in these animals.

Immunologic Reactions Against Insulin I. IgG anti-Insulin and Insulin Resistance

Abstract: Antibodies against insulin in three cases of insulin resistant diabetes mellitus were studied. These were IgG antibodies and their insulin-binding capacity was determined by a double antibody precipitation technique. These anti-insulin antibodies were associated in one case with lymphadenopathy, responsive to corticosteroids; anti-insulin activity was detected in an in vitro lymph node culture. In the other two cases, insulin antibodies were associated with an acute viral disease and intermittent insulin resistance of long duration. Although the insulin-binding activity as determined by the double antibody system was reproducible with individual serum samples, serum insulin-binding activity varied markedly on different days. This was presumptively because of variable degrees of free antibody associated with insulin administration; variable amounts of insulin-anti-insulin complexes were present in these sera. Cross-reactivities of insulins and certain insulin fragments from different species were compared by an inhibition technique and they demonstrated the importance of the secondary and tertiary structures in the antigenic determinants of insulin.

Nyctohemeral growth hormone levels in children with growth retardation and inflammatory bowel disease.

Abstract: Short stature is a common complication of inflammatory bowel disease. Recently McCaffery, Nasr, Lawrence, and Kirsner (1970) concluded, from blood growth hormone (GH) levels obtained during insulin-hypoglycaemic provocation, that GH deficiency contributed to the retardation in growth observed in subjects with inflammatory bowel disease. Although it was not possible to eliminate the possibility of partial hypopituitarism, this study does not confirm the existence of GH deficiency in six subjects with short stature complicating inflammatory bowel disease. The nyctohemeral (night and day) serum GH is described, and the insulin and glucose levels in these subjects and normal sleep-related GH rises in all are demonstrated. This finding is not compatible with growth hormone deficiency. In one subject the response to arginine provocation was blunted. Three subjects manifested hyperinsulinism and evidence for `insulin resistance'. These findings are unexplained but suggest that insulin resistance may contribute to a blunted GH response to insulin-induced hypoglycaemia. Blunted GH response to both arginine and insulin-induced hypoglycaemia may also result from continuous secretion and reduced pituitary storage of growth hormone. This possibility is suggested by the pattern of raised blood GH levels in one of the subjects.

Glucose tolerance and metabolic changes in human viral hepatitis.

Abstract: 1. Glucose tolerance and metabolic changes after intravenous glucose were studied in fifteen patients with acute viral hepatitis and in eight patients after recovery. In the acute stage glucose tolerance was significantly impaired compared with control subjects or with patients after recovery from hepatitis. 2. Serum insulin concentrations were significantly higher in fasting acute hepatitis patients than in control subjects and the time-integrated serum insulin concentration in the first 5 min after glucose was inappropriately high for the observed glucose disappearance rate, indicating insulin resistance. Serum growth hormone concentrations in male acute hepatitis patients were significantly higher than controls and suppressed poorly. 3. Fasting blood lactate concentrations were significantly elevated and after intravenous glucose there was a variable response. 2-Oxoglutarate, glutamate and glutamine concentrations from blood of fasting subjects, were significantly higher in acute hepatitis patients than controls. 4. There were no significant differences in blood ketones, glycerol and plasma free fatty acid concentrations from fasting subjects, but plasma triglycerides were significantly increased in the acute hepatitis patients. 5. The results indicate that viral hepatitis is associated with glucose intolerance and insulin resistance. After recovery the lactate response after glucose is diminished compared with controls.

Defective Insulin Secretory Response to Glucose in the New Zealand Obese Mouse: Improvement with Restricted Diet

Abstract: Insulin and glucose tolerance tests, and tests of the plasma insulin response to injected glucose were compared in C57B ad libitum fed mice (control strain), NZO ad libitum fed mice, C57B mice with obesity due to induced hyperphagia following gold thioglucose administration, and NZO mice whose weight had been reduced to that of the control strain by dietary restriction. The ad libitum fed NZO mice showed impaired glucose tolerance, increased insulin resistance, basal hyperinsulinemia arid absent rise in plasma insulin in response to glucose injection. The gold thioglucose-treated mice also showed impaired glucose tolerance and insulin resistance, but they demonstrated a rise in plasma insulin in response to glucose injection. The NZO mice whose diet had been restricted showed variable glucose tolerance, improved but not normal insulin sensitivity, and a significant rise in plasma insulin in response to injected glucose. It is concluded that thepancreatic islets of obese NZO mice, although very responsive to arginine, are insensitive to glucose, and with- weight reduction sensitivity to glucose returns.

Metabolic effects in children of a 37 amino acid fragment of bovine growth hormone.

Abstract: The metabolic effects of a 37 amino acid fragment (A-II) from a tryptic digest of bovine growth hormone (bGH) were determined in 4 hypopituitary children and 1 low-birth weight dwarf, and were compared to the effects of human growth hormone (hGH). Responses to the A-II fragment included a decrease in BUN (4 of 5 patients), an increase in calciuria (4 of 5 patients), and a decrease in urinary creatine excretion (2 of 5 patients). A marked increase in insulin resistance occurred in 2 subjects and, to a lesser degree, in 2 other subjects. An increase in fibrinogen and in uric acid occurred in the single patients in whom they were determined. Comparable responses occurred with hGH administration: decrease in BUN (4 of 5 subjects), increase in calciuria (3 of 5 subjects), decrease in urinary creatine excretion (5 of 5 subjects), increased insulin resistance in the 2 patients in whom it was evaluated and a rise in plasma fibrinogen in the 1 patient in whom it was evaluated. Two patients demonstrated de...

Partial and total lipodystrophy: changes in circulating sugar, free fatty acids, insulin and growth hormone following the administration of glucose and of insulin

Abstract: SUMMARY The effect of glucose or insulin administration in a group of five patients with partial lipodystrophy and three with total lipodystrophy was studied. In only one patient was the glucose tolerance curve abnormal. Mean fasting serum insulin, growth hormone, free fatty acids (FFA) and triglycerides were all significantly elevated. The serum insulin response to glucose was grossly elevated. Insulin resistance was present. The serum insulin was shown to be immunologically normal, Exogenous insulin disappeared at a normal rate from the circulation, suggesting that the elevated insulin levels in the fasting state and after glucose were due to hypersecretion. Serum growth hormone levels failed to suppress normally after glucose. Serum FFA fell after glucose or insulin administration. In one patient treated with propranolol unusual insulin responses to the administration of glucose were observed. A working hypothesis capable of explaining the metabolic changes in lipodystrophy is proposed.

Studies of human adipose tissue in culture. II. Effects of insulin and of medium glucose on lipolysis and cell size

Abstract: Explants of human adipose tissue were maintained for one week in vitro and the effect of iodoacetate, insulin and of the medium glucose concentration on cell size determined. In the presence of iodoacetate the mean cell size remained unaltered indicating that the morphologic changes reflect the cellular rates of metabolism. Addition of insulin did not prevent a decrease in mean cell size of explants with a large initial mean offering indirect, morphologic evidence for the insulin resistance in large adipocytes. The data support our previous suggestion that the cellular insulin sensitivity is an important parameter to control adipocyte size and, hence, enlargement of the adipose tissue.

Adipose Tissue Cellularity and Metabolism in Newly Diagnosed Juvenile Diabetics

Abstract: Adipose tissue cell number and size were determined in ten juvenile diabetics, ages one to seventeen, four of whom had a history of significant obesity antedating development of symptomatic glucosuria. Studies were performed at the time of diagnosis (before administration of insulin) and two to twenty-five months after institution of therapy. Results were compared with those found in a group of thirtyfour children of normal weight with no blood sugar abnormalities. An increase in adipose cell number was documented while adipose cell size was significantly decreased in the diabetics in both study periods. Weight gain after insulin treatment was due primarily to an increase in total body fat, which was reflected by increased cell size. However, the cells were still significantly smaller than normal. Cell number was not increased by the insulin treatment. In vitro studies of glycerol release revealed blunting of epinephrine-stimulated lipolysis, compatible with diminished adenylcyclase or cyclic AMP activity. However, the effects of in vitro insulin upon glycerol release and upon conversion of glucose l-C-14 to 14-CO 2 did not differ from results in normal controls. Baseline values of glycerol release were related to the presence of acidosis, while hormonal responses were unchanged after therapy. Thus, adipose tissue hypercellularity is present at the time of diagnosis of insulin-requiring diabetes mellitus in children and is not accompanied by adipose tissue peripheral “insulin resistance” as measured by two different parameters. A possible role for growth hormone in the development of this hypercellularity, which is also present in childhood obesity, is presented.

Iron excess, early glucose intolerance and impaired insulin secretion in idiopathic haemochromatosis.

Abstract: . The relationship between iron storage and glucose metabolism was studied in 21 relatives of 4 patients with idiopathic haemochromatosis and in 10 healthy control subjects. In all individuals, plasma iron and iron binding capacity were measured and liver function was assessed. In addition, intravenous and oral glucose tolerance tests (IVGTT, OGTT), as well as tolbutamide (TTT) and insulin tolerance tests (ITT), were performed. Serum insulin (IRI) was measured. Liver biopsies were performed on the 21 relatives only. In the relatives of patients with haemochromatosis, glucose tolerance was impaired and insulin secretion in response to hyperglycaemia diminished and/or delayed. Glucose intolerance increased with age but did not depend on abnormal liver function or excessive iron storage. Insulin release in response to tolbutamide was normal and insulin tolerance test failed to reveal insulin resistance. The results suggest that: 1. There is an early glucose intolerance in healthy relatives of patients suffering from idiopathic haemochromatosis. 2. The glucose intolerance seems unrelated to measurable anomalies in iron metabolism. 3. The delayed insulin secretion in response to glucose resembles that observed in common maturity-onset diabetes mellitus. 4. The results obtained are compatible with the hypothesis that haemochromatosis and diabetes mellitus might be two distinct but genetically linked entities.

Effects of Glucocorticoid and Aminophylline on Glucose Intolerance of Adrenalectomized Rats

Abstract: Eighteen—hr—fasted male normal (N) and adrenalectomized (Adrx) rats (used after the fourth postoperative day) were subjected to an intravenous glucose tolerance test (IVGTT, 25% glucose, 1.0 ml/100 g bw). Adrx rats exhibited both abnormal insulin release pattern and glucose intolerance which were restored to normal with cortisone (C) treatment (5 mg/100 g bw/day for 4 days). Aminophylline (A) administration (10 mg/100 g bw) before the IVGTT to N animals resulted in severe glucose intolerance and higher insulin values. Same treatment in Adrx animals resulted in increased insulin values with minimal changes in the glucose tolerance. The lipolytic effect of A was only seen in N animals and in Adrx treated with C. Combined A—C treatment with Adx and N rats resulted in very marked glucose intolerance in the presence of extremely high insulin levels. Aminophylline produces a syndrome of insulin resistance in Adrx animals as well as N. The quantitative difference in glucose tolerance between these groups can be ...

Anti-glucagon antibodies in diabetes mellitus.

Abstract: Anti-insulin antibodies appear in the sera of patients treated with insulin lastingly. A high anti-insulin antibody level results in the development of insulin resistance. Most of the insulin preparations available on the market contain also glucagon as an impurity. It was therefore to be expected that in part of the patients, who had been treated with insulin lastingly, antibodies would be produced also against glucagon, and the presence of these was actually demonstrated. It is to be assumed that the anti-glucagon antibodies play a role in the pathomechanism of diabetes mellitus, mainly in its labile form. The possible presence of anti-glucagon antibodies must be taken into account when the glucagon concentration in the sera of diabetics is to be determined by means of radioimmunoassay (RIA). The specific antibodies in the serum give false results in the quantitative determination of glucagon. We have tested the sera of 10 diabetics who had been treated with insulin for at least 6 years. All patients were given protamine zinc and crystalline insulin preparations.

Circulating ‘big’ insulin in protein-energy malnutrition

Abstract: 1. The ‘big’ insulin content of the serums from ten children with protein–energy malnutrition was estimated before, during and after 3–6 weeks of treatment. The values for immunoreactive insulin (IRI) after intravenous injections of glucose were almost normal, with one exception, although tolerance was impaired. In addition, total body potassium content (TBK) was measured for three of the children on each test day.2. In nine of twenty-three estimations ‘big’ insulin content was slightly more than 20% of the total IRI. However, there was a wide fluctuation in the values and no change was noted after treatment.3. The amount of ‘big’ insulin did not correlate with either the magnitude of insulin secretion, the insulin:glucose ratio or TBK. There was a barely significant negative correlation between ‘big’ insulin content and degree of glucose intolerance, with some individual exceptions.

The Decline in Pancreatic Insulin Release During Hemorragic Shock in the Baboon

Abstract: Hyperglycemia has been noted in man and animal during hemorrhagic shock. Studies in the dog demonstrated that this hyperglycemia is accompanied by elevated levels of serum immunoreactive insulin, suggesting increased insulin resistance (2). However, recent shock studies by Carey (3) in man, and from our laboratory in the baboon (6) have shown a different pattern. Insulin levels have been depressed despite hyperglycemia, suggesting suppression of insulin release rather than increased insulin resistance.