Growth hormone stimulating the growth of arterial medial cells in vitro. Absence of effect of insulin

Earlier studies have shown a stimulatory effect of diabetic serum on the growth of rabbit aortic medial cell cultures. Growth media supplemented with normal serum with added insulin (50-2,000 muU./ml. serum) did not enhance the growth of the medial cell cultures. Control media containing serum from recent diabetics with low insulin concentration stimulated the growth (2p less than 0.01). Supplementation of normal serum with human growth hormone (final concentration 1-5 ng./ml. medium) resulted in a significant enhancement of growth (2p less than 0.005). The growth-promoting effect of growth hormone was not detectable with lower concentrations (0.5 ng. and 0.1 ng./ml. medium). The growth effect of the low concentration of growth hormone could not be augmented by increasing the concentration of glucose in the incubation medium. Growth hormone in an amount of 1 ng./ml. medium increased both the number of 3H-thymidine-labeled cells as identified by autoradiography and the number of mitotic bodies (2p less than 0.005 and 2 p less than 0.025). The present results demonstrate that the growth-stimulating factor(s) in diabetic human serum described earlier is not insulin but may well be growth hormone.     

Recurrent goiter, hyperthyroidism, galactorrhea and amenorrhea due to a thyrotropin and prolactin-producing pituitary tumor

A 22-year-old woman with recurrent goiter, hyperthyroidism, galactorrhea, and amenorrhea due to a pituitary tumor is described. She had been treated surgically twice for recurrent goiter with tracheal compression. Despite clinical signs of hyperthyroidism and slightly elevated plasma thyroid hormone levels (T4: 11 mug/dl; T3: 189 ng/dl), without thyroid hormone replacement therapy the basal TSH level was elevated up to 23 muU/ml and could not be suppressed by exogenous thyroid hormones: even when the serum thyroid hormone levels were raised into the thyrotoxic range (T4: 16.2 mug/dl T3: 392 ng/dl), the basal TSH fluctuated between 12 and 29 muU/ml. The basal PRL level was elevated up to 6000 muU/ml. The administration of TRH (200 mug iv) led only to small increments of TSH and PRL levels. Bromocriptin (5 mg p.o.) or l-dopa (0.5 g p.o.) suppressed TSH and PRL values significantly. After transsphenoidal hypophysectomy, TSH and PRL were below normal and the patient development panhypopituitarism. The adenoma showed two cell types which could be identified as lactotrophs and thyrotrophs by electronmicroscopy and immunofluorescence. From these data we conclude that the patient had a pituitary tumor with an overproduction of thyrotropin and prolactin.     

Stimulation by the propranolol-glucagon test of somatotropin secretion in 71 children. Results, statistical study and comparison with the insulin-arginine test

Two tests of stimulation: insulin + arginine and propranolol + glucagon were successively performed in 62 children who were either normal or had essential growth retardation. Average peak value was 10.6 +/- 1.1 ng/ml in the first test and 22.8 +/- 1.4 ng/ml in the second. In 56 cases the response obtained with propranolol + glucagon was higher than that obtained with insulin + arginine. Twenty-four false negative results were obtained employing insulin + arginine, stimulation by propranolol + glucagon resulting in normal values. The determination of the confidence interval at 95% and of the 3rd percentile did not allow to establish the lower threshold for the insulin + arginine test. For the propranolol + glucagon test 7.6 ng/ml for the interval at 95% and 8 ng/ml for 3rd percentile were found as minimal threshold. Therefore, a response below 8 ng/ml should be considered as pathological with the latter test.     

Effect of potassium depletion on mineral appetite in the rat.

Studied potassium appetite in normal female Sprague-Dawley rats and in rats in which the total body potassium had been reduced by 15-20%. Potassium depletion resulted in increased ingestion of solutions of NaCl, KCl, CaCl2, and quinine sulphate in concentrations that were unacceptable to normal Ss. The amount of potassium ingested was related to the degree of potassium depletion and repletion was usually completed within 24 hr. when potassium was offered. Potassium-depleted Ss also drank large quantities of aversive concentrations of sodium chloride. This was preferred to potassium chloride and its ingestion appeared to be unrelated to need. The appetite state was reversed by prior intragastric repletion with potassium but not with sodium salts. (19 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reversal of somatostatin inhibition of insulin and glucagon secretion

These studies were designed to elucidate the mechanism of inhibitory action of somatostatin (SRIF) on glucagon (IRG) and insulin (IRI) secretion. Studies were carried out in the unrecirculated isolated rat pancreas perfusion with arginine 19.2 mM and glucose 5.5 mM as stimulus primarily for IRG but also IRI secretion. The effects of excess Ca++ (15.2 mEq./L.) and excess K+ (12.8 mEq./L.) on IRG, IRI, and the SRIF-inhibited pancreas were studied. Ca++ excess in five perfusions strikingly stimulated IRG secretion (+92 per cent) but only stabilized IRI secretion compared with control perfusions. K+ excess (in seven perfusions) markedly inhibited IRG secretion (-39 per cent) while stimulating IRI secretion (+16 per cent). Restoration of normal concentrations of K+ resulted in a rebound of IRG to levels 120 per cent that of controls. SRIF, at concentrations from 0.1-20 ng./ml., produced inhibition of both IRG and IRI. In 11 perfusions, with SRIF at 10 ng./ml., IRG decreased more than IRI (-75.2 per cent IRG and -46.9 per cent IRI). In five perfusions, addition of Ca++ (15.2 mEq./L.) 10 minutes after SRIF was started resulted in a reversal of IRG inhibition to 69.4 per cent and IRI to 73.2 per cent of the arginine controls. The reversal by Ca++ of SRIF effect on IRG was greater at higher concentrations of Ca++, suggesting some form of competition. In four perfusions, excess K+ reversed SRIF-induced IRI inhibition to 79.6 per cent that of controls but had no effect on IRG inhibition. Studies in vitro with isolated islets revealed that SRIF (2 mug./ml.) inhibited 45Ca uptake of islets as did epinephrine (10(-5) M). It was concluded that SRIF-induced inhibition of hormone release appears related to an action on Ca++ uptake.     

Principal component analysis of the elongation of metacarpal and phalangeal bones

The cholesterol-lowering effect of portacaval anastomosis in homozygous familial hypercholesterolemia suggested a study of lipid metabolism in cirrhotic patients after portasystemic anastomoses. Fasting serum cholesterol, triglycerides, insulin, and glucagon levels were obtained in 20 patients with alcoholic cirrhosis and portacaval anastomosis, and in 21 nonshunted subjects with cirrhosis. After 100 g of glucose, given orally, insulin and glucagon levels were measured. In the shunted patients serum cholesterol was higher than in the nonshunted subjects, 240 +/- 15 mg per 100 ml (mean +/- 1 SEM) versus 180 +/- 13 mg per 100 ml, P less than 0.01. Triglycerides were normal in both groups. Fasting insulin was elevated to a greater extent in the shunted patients with cirrhosis (36 +/- 5 muU per ml) than in the nonshunted patients (22 +/- 4 muU per ml), P less than 0.05. Two hours after glucose, insulin levels were also elevated to a greater extent in the shunted subjects (304 +/- 50 muU per ml) than in the nonshunted subjects (167 +/- 29 muU per ml), P less than 0.03. Fasting glucagon (corrected for interference factor) was elevated to a greater extent in the shunted subjects (204 +/- 35 pg per ml) than in the nonshunted subjects (80 +/- 19 pg per ml), P less than 0.01. The explanation for serum cholesterol elevation after surgical shunting in cirrhotics is unknown. Two possible hypotheses--the differential action of insulin and glucagon on cholesterol metabolism and the effects of shunting on the cirrhotic liver--are discussed.     

Chronic exposure of rat fat cells to insulin enhances lipolysis and activation of partially purified hormone-sensitive lipase

The activity of adipose tissue hormone-sensitive lipase in animals with hyperinsulinemia has been reported to be increased compared with that in control animals. We examined whether this results from a direct effect of insulin on the tissue and whether it is accompanied by alteration in the regulation of lipolysis. When rat epididymal fat pads are incubated in culture medium with bovine serum albumin for 2-4 h with 2 ng/ml or 50 microU/ml of insulin, hormone-sensitive lipase activity in the postmicrosomal supernatant fraction after acid precipitation and activation with ATP-Mg2+ increases significantly compared with preparations from tissues incubated with the vehicle. The specific activities of hormone-sensitive lipase in sonicates of adipocytes after primary culture with insulin at concentrations from 10 to 4000 ng/ml (250 microU to 100 mU/ml) increase in an insulin-dose-related manner. Lipolysis in response to 10(-7) M isoproterenol also increases in an insulin-dose-dependent manner. Enhancement of isoproterenol-mediated lipolysis is not attributable to a difference in the triglyceride content of the cells. Lipolysis caused by the beta-agonist could be completely blocked by the simultaneous presence of insulin in both control and insulin-treated cells reflecting normal responsiveness of both types of cells to the acute effect of insulin. Although an increase in lipolysis is seen with norepinephrine and growth hormone after insulin treatment, other lipolytic agents such as ACTH, thyrotropin, and glucagon evoke similar responses in insulin-treated and control cells. The simultaneous presence of growth hormone and insulin during the 16-h culture results in additive effects on the subsequent response of the cells to 10(-7) M isoproterenol compared with the responses of the cells cultured with each hormone alone. beta-Agonist-mediated cAMP accumulation in the presence of Ro-20.1724, a specific phosphodiesterase inhibitor, is significantly higher in cells cultured in the presence of insulin than in control cells. Forskolin (1-25 microM) increases the lipolytic responses of insulin-treated cells compared with control cells, but the maximal response of the insulin-treated cells to forskolin is lower than that to isoproterenol. We conclude that changes produced by chronic insulin treatment involve more than one site along the lipolytic cascade.     

The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis

PURPOSE: We determined whether intravesical potassium absorption in normal bladders correlates with increased sensory urgency, and corroborated the hypothesis that mucus is important in the regulation of epithelial permeability. We compared sensory nerve provocative ability of sodium versus potassium, and determined whether intravesical potassium sensitivity discriminates patients with interstitial cystitis from normal subjects and those with other sensory disorders of the bladder. MATERIALS AND METHODS: A total of 231 patients with interstitial cystitis and 41 normal subjects underwent intravesical challenge with 40 ml. water and then 40 ml. of 40 mEq./100 ml. potassium chloride. Subjective responses of urgency or pain stimulation were recorded on a scale of 0 to 5. In 19 normal subjects potassium absorption was measured at baseline, after injury of the bladder mucus with protamine, after heparin treatment to reverse mucus damage and then for a final time. These subjects simultaneously recorded the symptoms of sensory urgency and pain at baseline, after protamine and after heparin. Another group of normal volunteers underwent a challenge with sodium versus potassium to determine which cation was more provocative. Patients with bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH), detrusor instability, and acute and chronic urinary tract infection but no current infection were also evaluated for potassium sensitivity. RESULTS: Neither normal subjects nor patients with interstitial cystitis reacted to water administered intravesically. There was marked sensitivity to intravesical potassium in 75% of patients with interstitial cystitis versus 4% of controls (p <0.01). Only 1 patient with BPH responded to potassium and none of the 5 with chronic urinary tract infection responded. All 4 patients (100%) with a current acute urinary tract infection reacted positively to the potassium challenge. Of 16 patients with detrusor instability 25% responded. Normal subjects had minimal sensitivity to potassium before (11%) and markedly increased sensitivity after (79%) protamine treatment, and these symptoms were reversed by heparin in 42%. Potassium absorption directly correlated with symptoms (0.4, 3.0 and 1.3 mEq. before and after protamine, and after heparin reversal, respectively). In regard to sodium versus potassium provocation, potassium was far more provocative for causing urgency after protamine (10 versus 90%). Neither group underwent provocation before protamine. CONCLUSIONS: Chronic diffusion of urinary potassium into the bladder interstitium may induce sensory symptoms, damage tissue and be a major toxic factor in the pathogenesis of interstitial cystitis. Intravesical potassium sensitivity is a reliable method for detecting abnormal epithelial permeability. It discriminates between patients with interstitial cystitis and normal subjects with intact epithelial function, and it is a useful diagnostic test for interstitial cystitis. Potassium sensitivity correlates with increased potassium absorption in normal subjects, and potassium is far more provocative than sodium. Potassium sensitivity is also present in acute urinary tract infection and occasionally detrusor instability but not in BPH or chronic urinary tract infections.     

Ritodrine- and terbutaline-induced hypokalemia in preterm labor: mechanisms and consequences

The effects of ritodrine and terbutaline on potassium homeostasis, renal function, and cardiac rhythm were assessed in women treated with these drugs for preterm labor. Timed blood and urine samples were obtained for two hours before and during six hours of intravenous ritodrine (N = 5) and terbutaline (N = 5) administered in pharmacologically equivalent doses. No differences were found in any parameters affecting potassium homeostasis or renal function between these drugs. A decrease in mean plasma potassium of 0.9 mEq/liter occurred after 30 minutes of drug infusion (4.2 +/- 0.1 to 3.3 +/- 0.1 mEq/liter, P < 0.005) before any significant changes in plasma glucose (75.0 +/- 4.7 to 93.7 +/- 6.1 mg/dl, P = NS) or plasma insulin (12.4 +/- 6.0 to 28.4 +/- 5.1 mU/ml, P = NS). The mean plasma potassium after four hours of drug infusion was 2.5 +/- 0.1 mEq/liter. Plasma insulin rose to a level known to induce cellular potassium uptake (39.2 +/- 7.7 mU/ml) after 60 minutes of drug therapy and remained at this level for four hours. Hyperlactatemia occurred at four hours (4.7 +/- 0.8 mmol/liter) and the plasma lactate/pyruvate ratio increased in a 10:1 ratio. Both drugs significantly reduced glomerular filtration rate, sodium, potassium, and chloride excretion and urinary flow rate. Changes in acid-base homeostasis, plasma aldosterone, or renal potassium excretion did not contribute to ritodrine-or terbutaline-induced hypokalemia. In 83 women with preterm labor randomly assigned to ritodrine (N = 42) or terbutaline (N = 41), the maximum decrease in plasma potassium occurred after six hours of drug infusion. During Holter monitoring, 3 of 14 women treated with ritodrine or terbutaline developed symptomatic cardiac arrhythmias at the lowest plasma potassium while no women treated with saline and morphine (N = 12) developed cardiac arrhythmias (P = 0.14). We conclude that ritodrine and terbutaline induce profound hypokalemia by stimulating cellular potassium uptake and both drugs cause significant renal sodium and fluid retention and cardiac arrhythmias. Careful monitoring of electrolytes, fluid balance, and cardiac rhythm should occur during tocolytic therapy with ritodrine or terbutaline.     

Modulation of fatty acid metabolism by glucagon in man. IV. Effects of a physiologic hormone infusion in normal man

This study was done to explore the role of physiologic elevations of glucagon concentration in plasma ketone body concentration in normal man. During the period of hormone elevation, plasma free fatty acids were pharmacologically elevated to ensure adequate free fatty acid substrate delivery to the liver to support hepatic ketogenesis. Eighty-minute infusions of glucagon resulted in a plasma hormone concentration of approximately 300 pg./ml. During the infusion, ketone bodies declined from their basal concentration and remained below basal for the duration of the infusion. An acute heparin-induced pharmacologic elevation of plasma free fatty acid concentration resulted in a transient rise in plasma ketone body concentration, but at no time did it attain the concentration observed during the control saline infusion. Plasma glucose concentration was not altered by glucagon infusion, but plasma insulin concentration rose by approximately 2.5 muU./ml. These results suggest that glucagon is not ketogenic in normal man as has been previously reported in insulin-deficient diabetics. The glucagon-induced rise in plasma insulin concentration may participate in the observed reduction in plasma ketone body concentration.     

beta-cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy

Leptin was overexpressed in the liver of normal Wistar rats by infusing recombinant adenovirus containing the cDNA encoding leptin. Plasma leptin levels rose to 12-24 ng/ml (vs. <2 ng/ml in control rats), and food intake and body weight fell. Visible fat disappeared within 7 days. Plasma insulin fell to <50% of normal in association with hypoglycemia, suggesting enhanced insulin sensitivity. Although beta-cells appeared histologically normal, the pancreases were unresponsive to perfusion with stimulatory levels of glucose and arginine. Since islet triglyceride content was 0, compared with 14 ng/islet in pair-fed control rats, we coperfused a 2:1 oleate:palmitate mixture (0.5 mmol/l). This restored insulin responses to supranormal levels. When normal islets were cultured with 20 ng/ml of leptin, they too became triglyceride-depleted and failed to respond when perifused with glucose or arginine. Perifusion of fatty acids restored both responses. We conclude that in normal rats, hyperleptinemia for 2 weeks causes reversible beta-cell dysfunction by depleting tissue lipids, thereby depriving beta-cells of a lipid-derived signal required for the insulin response to other fuels.     

Clinical characteristics and EPS-guided therapy in 142 cases of sustained ventricular tachycardia

In order to characterize an alternative animal model for the study of diabetes mellitus type II onset, we compared the effects of a diet containing 8% of protein (LPD) and a normal diet containing 25% of protein supplied to the dams during the first 12 days of lactation. We studied in the pups the growth evolution and, when they develop into adults (60 days), the glucose tolerance test (GTT) and the insulin secretion, in response to stimulatory concentrations of glucose. The weight of the two groups were significantly different at 60 days of age (LPD = 179 +/- 19 g; NPD = 186 +/- 18 g). The GTT ten minutes after iv glucose administration showed a significant increase of blood glucose concentration of the LPD group (LPD = 550 +/- 17 mg/dl; NPD = 425 +/- 13 mg/dl, p < 0.001). The insulin secretion, four minutes after stimulation was found reduced in the LPD group (LPD = 1.1 +/- 0.08 muU/islet/min; NPD = 1.85 +/- 0.2 muU/islet/min.). The present study indicates insulin secretory and/or resistance impairment due to early undernutrition. Also, the data taken together suggest that undernutrition during early lactation can be used as an alternative model to study particular characteristics of the onset of diabetes mellitus type II.     

Primary aldosteronism with uncommon complications

In a patient who had primary aldosteronism and severe total-body potassium depletion muscular tonic contractures developed during induction of anesthesia. After correction of the potassium deficit, the patient underwent uneventful anesthesia and transabdominal right adrenalectomy. Neither serum potassium level nor EKG seems to provide a reliable index of correction of potassium deficit. Measurement of potassium balance provided a method of quantitating the potassium depletion and of determining when the potassium deficit had been corrected. Balance studies should be utilized preoperatively when long-term potassium loss is suspected to reduced complication secondary to hypokalemia.     

Effect of sodium restriction and angiotensin II infusion in Bartter's syndrome

Five patients with Bartter's syndrome were investigated. Sodium restriction (less than 10 mEq/day for at least 5 days) showed a renal sodium wastage in only two patients (I and II) in spite of increased aldosterone secretion rate (from 151-427 to 680-842 mug/day). The effect of angiotensin II (A II) 80ng/kg/min for 30-180 min, on plasma renin activity (PRA), plasma aldosterone, and urinary sodium excretion was compared with the effect of a previous infusion of 5% dextrose given at the same rate, 0.5 ml/min for 1 hr. A II infusion resulted in increased plasma aldosterone levels: from 236-330 pg/ml to 800-881 pg/ml in 30 min. This increase was also observed in patient II (from 139 to 600 pg/ml). PRA was decreased by A II infusion (from 1,142-2,462 to 121-1,625 ng/liter/min). In patient IV, this decrease in PRA was also observed when he was on a salt-restricted diet (from 1,934 to 370 ng/liter/min); but the minimal PRA was still higher (370 ng/liter/min) than with a normal diet (121 ng/liter/min). In no case could normal PRA level be obtained. A II infusion induced an increase in urinary sodium excretion only in the two patients with renal sodium wastage (from 80-90 to 265-230 muEq/min in 30 min). Urinary sodium excretion decreased in the other patients from (37.5-213 to 4.30-46 muEq/min) and fractional sodium excretion was reduced in patient V (from 0.56% to 0.45% at 30 min and to 0.29% at 120 min). No significant change with A II infusion was observed in patient IV when he was on a sodium-restricted diet (from 1 to 2.5 muEq/min in 30 min). Urinary potassium excretion was similar to sodium excretion. No change was observed in plasma potassium and sodium.     

Sustained reduction in urinary calcium during long-term treatment with slow release neutral potassium phosphate in absorptive hypercalciuria

PURPOSE: We tested whether UroPhos-K, a new slow release neutral form of potassium phosphate (155 mg. phosphate, 8 mEq. potassium per tablet) in a dose of 4 tablets twice daily would produce a sustained hypocalciuric response and maintain bone mass in patients with absorptive hypercalciuria, a major cause of nephrolithiasis characterized by excessive intestinal calcium absorption accompanied in some patients by excessive bone loss. MATERIALS AND METHODS: A total of 25 patients with absorptive hypercalciuria were studied in a 4-year, prospective, open trial with UroPhos-K at yearly intervals during a 4-day inpatient physiological study with a constant metabolic diet containing 400 mg. calcium, 100 mEq. sodium and 800 mg. phosphate daily. RESULTS: Treatment with UroPhos-K caused a sustained, marked reduction in urinary calcium (264 to 181 mg. daily). Fractional 47calcium absorption decreased modestly (74.0 to 64.6%) commensurate with a reduction in serum 1,25-dihydroxyvitamin D (42 to 34 pg./ml.). Intact parathyroid hormone increased within the normal range (30 to 42 pg./ml.). Bone mineral density was stable at the lumbar spine, femoral neck and distal third of the radius. CONCLUSIONS: UroPhos-K may provide a long-term alternative for hypercalciuric patients in whom thiazide therapy fails.     

Diet-induced alterations of hGH secretion in man

Studies were designed to determine whether variations in diet composition could modify the secretion of human growth hormone. Eight men and seven women ingested experimental diets for 10-12 days. Each experimental diet was preceded by a control diet for five days. Experimental diets studied in men were a) 2300 calorie, 80% carbohydrate (8 men); b) 2300 calorie, 75% high-fat (7 men); c) 2300 calorie, 70% high-protein (5 men); d) 3600 calorie, "control" (40% carbohydrate, 40% fat, 20% protein) (5 men); and e) 3600 calorie, 80% high-carbohydrate (5 men). A control diet and a high-carbohydrate (5 men). A control diet and a high-carbohydrate diet at the 2300 calorie level were studied in women. Each diet study was terminated by a 72 hour fast. Serum samples were collected hourly for 24 hours after each control period, on the eigth, ninth, or tenth day of each study, and during the final day of each fast. High-carbohydrate diets at the 2300 calorie level caused a significant decrease of growth hormone values in serum in each of eight men (sign test of significance, P less than .01). The mean figures were likewise significantly decreased. Isocaloric diets of high fat and high protein did not alter growth hormone concentrations in serum. A high-caloric diet similar to the control diet in composition was without effect on growth hormone secretion in men; however, a high-carbohydrate diet at the higher caloric level again depressed growth hormone values in plasma. On the third day of a 72 hour fast, growth hormone values in serum increased 287% in men, from a mean control serum concentration of 4.4 +/- 0.8 ng/ml to 11.9 +/- 5.0 ng/ml (P less than .01). Women, unlike men, had no significant decrease in growth hormone concentrations in serum over a 24 hour period after the high-carbohydrate diet, and the increase after starvation was significantly less than that in men, achieving significance only when evaluated by paired analysis. Growth hormone values in serum after the infusion of arginine followed a similar pattern, i.e., decreased after high carbohydrate but unaffected by other diets in men; high carbohydrate diets did not alter the growth hormone response of women to arginine.     

Establishment of functional human pituitary tumor cell cultures

Five primary human pituitary tumor cell cultures were initiated from adenoma fragments obtained from patients with prolactin-secreting adenomas and acromegaly. Functional cell cultures were maintained and propagated in monolayer or suspension culture for up to 9 months. Optimal cell viability and growth were achieved using Ham's F10 medium enriched with 20% fetal bovine serum, although cells from a patient with acromegaly also grew in serum-free, defined, hormone-containing medium. Bromocriptine (100 ng/ml) did not alter the growth curve of replicating cells derived from a patient with acromegaly. These cells initially secreted 5.5 micrograms human growth hormone/10(6) cells, and hormone production diminished after 6 wk. Prolactin secretion by cells derived from prolactinomas (0.5 to 1.3 micrograms/10(6) cells/24 h) was stimulated by thyrotropin-releasing hormone (10 ng/ml) in two of the cultures. Both dopamine (10 ng/ml) and nickel chloride (1 mM) suppressed PRL secretion. These studies demonstrate that responsive human pituitary tumor cell cultures can be initiated and maintained.     

The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog

The aim of the present experiments was to determine the role of insulin and glucagon in the regulation of basal glucose production in dogs fasted overnight. A deficiency of either or both pancreatic hormones was achieved by infusin somatostatin (1 mug/kg per min), a potent inhibitor of both insulin and glucagon secretion, alone or in combination with intraportal replacement infusions of either pancreatic hormone. Infusion of somatostatin alone caused the arterial levels of insulin and glucagon to drop rapidly by 72+/-6 and 81+/-8%, respectively. Intraportal infusion of insulin and glucagon at rates of 400 muU/kg per min and 1 ng/kg per min, respectively, resulted in the maintenance of the basal levels of each hormone. Glucose production was measured using tracer (primed constant infusion of [3-3H]glucose) and arteriovenous difference techniques. Isolated glucagon deficiency resulted in a 35+/-5% (P less than 0.05) rapid and sustained decrease in glucose production which was abolished upon restoration of the plasma glucagon level. Isolated insulin deficiency resulted in a 52+/-16% (P less than 0.01) increase in the rate of glucose production which was abolished when the insulin level was restored. Somatostatin had no effect on glucose production when the changes in the pancreatic hormone levels which it normally induces were prevented by simultaneous intraportal infusion of both insulin and glucagon. In conclusion, in the anesthetized dog fasted overnight; (a) basal glucagon is responsible for at least one-third of basal glucose production, (b) basal insulin prevents the increased glucose production which would result from the unrestrained action of glucagon, and (c) somatostatin has no acute effects on glucose turnover other than those it induces through perturbation of pancreatic hormone secretion. This study indicates that the opposing actions of the two pancreatic hormones are important in the regulation of basal glucose production in the postabsorptive state.     

Treatment of diabetic ketoacidosis in dogs by continuous low-dose intravenous infusion of insulin

In a prospective clinical trial, low-dose, continuous, IV infusion of insulin (dosage, 2.2 U/kg of body weight, q 24 h) was used to treat 21 dogs with diabetic ketoacidosis. Mean (+/- SD) blood glucose concentration at the onset of treatment was 550 +/- 150 mg/dl and after 6 hours, was 350 +/- 106 mg/dl, with a mean decline of 34 +/- 16 mg/dl/h. By 12 hours, mean blood glucose was 246 +/- 85 mg/dl, with a mean decline of 28 +/- 14 mg/dl/h during the second 6 hours of treatment. Mean duration of treatment required to reach a blood glucose concentration < or = 250 mg/dl was 10 +/- 4 hours, with a range of 4 to 24 hours. Ketonuria was observed for 26 +/- 14 hours (range, 6 to 72 hours). Hypoglycemia developed in 3 of 21 dogs during treatment, but responded to IV administration of a glucose solution and to a reduction in rate of insulin delivery. Potassium supplementation was required in 15 of 21 dogs. Mean bicarbonate concentration was 11.6 +/- 3.4 mEq/L before treatment and was 18.2 +/- 0.7 mEq/L after 24 hours. Fifteen of 21 dogs (71%) survived to be discharged. Mean duration of treatment with the insulin infusion was 50 +/- 30 hours (range, 7 to 124 hours). In this series of dogs, continuous, low-dose, IV infusion of insulin provided a gradual and consistent reduction in blood glucose concentration while ketoacidosis, electrolyte balance, and dehydration were corrected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transient diabetes mellitus in a neonate. Evaluation of insulin, glucagon, and growth hormone secretion and management with a continuous low-dose insulin infusion

This neonate developed marked hyperglycemia four days after birth and required insulin therapy for eight weeks. During the acute phase of the disease, immunoreactive insulin was undetectable in portal venous serum. Neither tolbutamide nor theophylline administration significantly triggered insulin secretion. Somatostatin infusion inhibited growth hormone release but had no effect on plasma glucagon or blood glucose concentrations. At 2 1/2 months, two weeks after insulin withdrawal, the infant was still intolerant to an oral glucose load, insulin response was markedly delayed, and growth hormone secretion was paradoxical. At five months, the insulin, glucagon, and growth hormone responses to glucose and to somatostatin were normalized. Thus, in this patient, insulin secretion was transiently deficient. Peculiarities of glucagon and growth hormone secretion were also present but are more characteristic of this age group than of diabetes. The hyperglycemic state was managed by intraportal infusion of 0.1 to 0.2 IU regular insulin/kg/hour. This mode of insulin administration proved efficient, secure, and easy to manage.