bluuebunny/crossref_metadata_2025 huggingface dataset:
Embryogenesis of the Human Pancreatic Islets: A Light and Electron Microscopic Study
Authors: Like Arthur A , Orci Lelio
Published: December 2014

The developing pancreases of twenty human embryos and fetuses, 8–23 weeks gestational age, were obtained under conditions optimum for cellular preservation and studied by light and electron microscopy. Primitive pancreatic tubules were the only epithelial structures present at 8 and 8.5 weeks. Alpha cells were first identified at 9 weeks, followed by delta and subsequently beta cells at 10.5 weeks. Endocrine cell progenitors, mixed endocrine cells, or mixed exocrine endocrine cells were not identified. Although potential sampling errors preclude a definitive recitation of the order of islet cell appearance, the alpha and delta cells are numerically the predominant pancreatic endocrine cells during early human embryogenesis. The observation of frequent, well-preserved delta cells and the identification of one undergoing mitotic division support their legitimacy as an independent cell type. Cytoplasmic glycogen was present in primitive tubular cells and differentiated exocrine cells but was excluded from endocrine cells. Other endocrine cells tentatively identified in the developing human pancreas are serotonin, gastrin, epinephrine and norepinephrine cells.
Insulin—Clinical Aspects: The First Fifty Years
Authors: Marble Alexander
Published: December 2014

With the discovery of insulin in 1921 and its general availability in 1922 and 1923, the prevention and successful treatment of diabetic ketoacidosis and coma became possible. As a result of this and the lower mortality from infections, the life expectancy of the diabetic patient has increased steadily, particularly in those with onset of diabetes before the age of twenty years. However, with increased duration of diabetes has come a high frequency of cardiovascular-renal disease as a cause of death (76.6 per cent of 5,009 deaths from 1960 to 1968). Such vascular disease affects both large and small vessels. The cause, prevention and treatment of these complications, including retinopathy, present the major problem and challenge in diabetes today. There is much evidence to suggest that if one could correct the metabolic defect (insulin deficiency) completely and continuously from its inception, the solution of the problem might well be in hand.
New Forms of Insulin
Authors: Galloway John A , Root Mary A
Published: December 2014

This paper reviews some recent developments in insulin purification and formulation. Neutral Regular insulin (unbuffered Regular insulin with pH adjusted to neutrality, designated NRI) maintained nearly full potency when stored at room temperature for twelve months, while the potency of acid Regular (“commercial”) insulin (ARI) had dropped 20 per cent. When NRI and ARI were administered in combination with NPH or Ultralente insulin, comparable time activity responses were elicited. In fasted normal subjects subcutaneous doses of NRI and ARI gave similar blood glucose responses.

Thirty-seven patients with allergy to commercially available insulin were treated with one or both of two highly purified insulins (single peak and single component pork insulin). Improvement occurred in 78 per cent. Single component insulin was usually, but not always, superior to single peak insulin when both were tested in the same patient.

Insulin was administered orally with an absorption promoter, Brij 98, to twenty normal and thirteen diabetic fasted subjects in crossover studies. Under optimum conditions, definite responses were observed in about 50 per cent of subjects. Serum insulin measurements in the normals and diabetics revealed that increased concentrations were not necessarily associated with falls in blood glucose concentrations in spite of delivery of the insulin by the portal route. Because of the amounts of insulin required, the limitations of test conditions, and a high incidence of nausea, this project has been discontinued.
The Circulating Proinsulin-like Components
Authors: Gorden Phillip , Roth Jesse , Freychet Pierre , Kahn Ronald
Published: December 2014

Total plasma insulin as measured by radioimmunoassay can be divided into at least two distinct components by gel fitration. One component is indistinguishable from crystalline pancreatic insulin (insulin component); the second component more closely resembles proinsulin (proinsulin-like component).

The proinsulin-like component may be heterogenous in different disease states. Differences in gel filtration properties have been demonstrated between islet cell tumor patients and nontumor patients.

The percentage proinsulin-like component is highest in the basal state; acute stimulation of insulin release predominantly increases the concentration of the insulin component with a resultant decrease in the percentage proinsulin-like component. The same dynamics are seen both in islet cell tumor patients who have high percentages of proinsulin-like component and in nontumor patients. In severely hypoin-sulinemic patients, the percentage proinsulin-like component increases regardless of the etiology of the hypoinsulinemia.
Practical Developments in Diabetes Research
Authors: Cahill George F , Soeldner J Stuart , Harris Grady W , Foster Richard O
Published: December 2014

A brief survey of current activities in diabetes research suggests that it is feasible in the near future to develop control systems that will closely mimic the normal glucoseinsulin system. A literature survey and preliminary experience in the use of on-line glucose sensing are described, as well as a computer model system applicable to both physiological and pathological studies of fuel homeostasis and to the practical development of an on-line glucose-insulin feedback system (an artificial beta cell).
Some Aspects of “Acute Phase” Insulin Release in Healthy Subjects
Authors: Siegal Alan M , Kreisberg Robert A , Owen W Crawford , Fox Orlando J
Published: December 2014

The acute release of insulin in response to graded pulse doses of intravenous glucose was assessed in twelve healthy subjects before and during treatment with tolbutamide, ethanol and tolbutamide plus ethanol. A linear relationship was observed between the mean 3′-5′ insulin increment (ΔIRI) and the glucose dose up to five gm.; thereafter, the response plateaued. Insulin increments over baseline prior to treatment ranged from 12 ± 1.8 μU./ml. for 1.0 gm. to 124 ± 11.3 μU./ml. (mean ± S.E.M.) for 20.0 gm. Pretreatment with tolbutamide, ethanol and tolbutamide plus ethanol resulted in protentiation of the acute phase insulin release and enhanced glucose disappearance with glucose doses of 10 gm. and less. With the 20 gm. glucose dose, no significant potentiation of insulin release nor enhancement of glucose disappearance could be demonstrated. Potentiation of insulin release by tolbutamide pretreatment also required administration of the drug on the day of the test. We suggest that studies involving the effects of agents on the dynamics of acute phase insulin response to glucose be done with glucose doses which produce submaximal β-cell stimulation.
Insulin Content of Fetal Rat Pancreases Grown in Organ Culture and Subsequently Transplanted into Maternal Hosts
Authors: Hegre Orion D , Wells Lemen J , Lazarow Arnold
Published: December 2014

Portions of pancreases from 19.5-day fetal rats were grown in organ culture on two types of liquid media: low glucose, containing 162 to 170 mg. glucose/100 ml.; high glucose, containing 1,031 to 1,073 mg. glucose/100 ml. Following four days of organ culture, the tissues were extracted and assayed for insulin content (immunoassay). Other cultures were transplanted to maternal hosts at two sites: beneath the capsule of the kidney and into the anterior chamber of the eye. Ten days later, the transplants were removed and assayed for insulin content.

Large quantities of immunologically active insulin were present in the culture media following forty-eight and ninety-six hours of incubation. Expiants exhibited a four- to sixfold increase in insulin content following four days in vitro. Pancreatic expiants cultured on the high glucose medium contained less extractable insulin than similar ex-plants cultured on the low glucose medium.

When cultured expiants were transplanted to hosts with normal blood glucose levels, the total extractable insulin content of the grafts was 55 per cent to 130 per cent greater than that at the time of transplantation. When cultures were transplanted to alloxan diabetic hosts, the total extractable insulin content of the grafts was less than that found in grafts to normal hosts.

A small but statistically significant drop in blood glucose level was observed in hyperglycemie diabetic maternal hosts receiving transplants of organ cultured pancreas.

These results indicate the continued growth and functional responsiveness of the islet beta cells during organ culture and following subsequent transplantation.
Opposite Effects of Aminophylline on Arginine-induced Glucagon and Insulin Secretion in Humans
Authors: Marco Josá , Diaz-Fierros Maruxa , Baroja Isabel M , Villanueva Maria L , Valverde Isabel
Published: December 2014

The adenyl cyclase-cyclic AMP system, aside from being a mediator of the actions of several hormones, is believed to play an important role in the secretory mechanism of some of these hormones. In young, healthy, nonobese volunteers, we have studied the effect of a large dose (1 gm.) of a cAMP phosphodiesterase inhibitor (aminophylline) on basal plasma glucagon and insulin levels and on the responses of these two hormones to two different doses of arginine.

With a high (468 mg./kg.) and a low (156 mg./kg.) dose of arginine, similar maximal peaks of glucagon concentration were reached, indicating that the level of aminoacidemia reached with the low dose was sufficient to elicit an almost maximal acute response. Plasma insulin and glucose increased as expected after the arginine doses.

With aminophylline alone, plasma insulin and glucose increased slightly but consistently while the level of circulating glucagon did not change (range of the means, 111 pg./ml. ± 28 to 133 pg./ml. ± 25). Aminophylline pretreatment significantly lowered the glucagon response in the late part of the curve corresponding to the high dose of arginine. This inhibitory effect of the xanthine derivative could be due to: (1) peripheral effects of aminophylline, such as increased mobilization of FFA; (2) enhanced removal of glucagon from plasma; (3) direct suppressor effect of cAMP on the alpha cell secretory mechanism. At any rate, this effect of aminophylline seems to be either a retarded one or only present in the late phase of glucagon secretion.
Abnormal Alpha Cell Function in Diabetics Response to Insulin
Authors: Unger R H , Madison L L , Müller W A
Published: December 2014

The extremely high levels of glucagon recently observed in dogs with severe alloxan-induced diabetes decline promptly and precipitously to normal as soon as exogenous insulin is infused. This suggests that the normal response of the pancreatic alpha cell to hyperglycemia requires the presence of circulating insulin. To determine if the relative hyperglucagonemia of human diabetics responds similarly to insulin repletion, the plasma glucagon response of ten adult-type diabetic patients to a large, predominantly carbohydrate meal was determined with and without the simultaneous forty-five-minute intravenous infusion of glucagonfree insulin (0.12 to 0.2 U./kg.). The glucagon response to the carbohydrate meal during prompt and supernormal hyperinsulinemia resulting from the infusion did not differ from that of the control meal, i.e. normal suppression of glucagon by hyperglycemia was not restored by the abundance of circulating insulin.

To determine if still higher plasma levels of insulin would overcome the hyposuppressibility of the diabetic alpha cell to hyperglycemia, 0.6 U. per kilogram per hour of insulin was infused at a constant rate for two hours together with 0.6 gm. per kilogram per hour of glucose to prevent hypoglycemia. Insulin levels of more than 1,200 μ,U. per milliliter were thus attained. Under these conditions, plasma glucagon declined from a mean preinfusion level of 97 pg./ml. (SEM ± 11) to a nadir of 75 pg./ml. (SEM ± 10) ninety minutes later. This slow, modest, statistically significant (p < 0.01) decline differed strikingly from the response of eight nondiabetic patients given intravenous glucose alone; in these subjects, at a comparable level of hyperglycemia, glucagon declined from a mean fasting level of 90 pg./ml. (SEM ± 8) to 57 pg./ml. (SEM ± 8) within thirty minutes, despite an insulin rise to only 46 μU./ml.

It was concluded that in human diabetics the acute restoration of plasma insulin, even to supernormal levels, does not promptly restore to normal the alpha cell responsiveness to hyperglycemia. Simple insulin lack may not, therefore, adequately explain the alpha cell abnormality in human diabetes.
Potentiation of Insulin Secretion in Vitro by Serotonin Antagonists
Authors: Feldman Jerome M , Quickel Kenneth E , Lebovitz Harold E
Published: December 2014

The present studies were designed to determine if endogenous pancreatic islet cell monoamines such as serotonin, dopamine and norepinephrine play a physiological role in controlling insulin secretion. With an in vitro rabbit pancreas system, the effects of both serotonin and catecholamine antagonists on basal and stimulated insulin release were studied. Methysergide maleate (Sansert) potentiated both glucose and tolbutamide-stimulated insulin secretion, but alone it had no effect on insulin release. Studies in which exogenous monoamines were added to the incubations demonstrated that methysergide, purported to be a specific serotonin antagonist, blocked inhibition of insulin secretion by dopamine, 1-norepinephrine, 1-epinephrine and 1-isoproterenol. Methysergide differed in action from the alpha adrenergic blocking drug, phenoxybenzamine, for although the latter was a more potent blocker of the inhibitory action of exogenous catecholamines on insulin secretion, it did not potentiate glucose-stimulated insulin secretion. Glucose-mediated insulin secretion was also potentiated by the serotonin antagonists, cinanserin and cyproheptadine. Exogenous serotonin (4 × 10-3 M) had only a weak action in inhibiting insulin secretion from rabbit pancreas. Methysergide (1 × 10-4 M) failed to block this inhibitory action. It is suggested that (1) serotonin antagonists are blocking the inhibitory action of an intracellular compartmentalized serotonin pool, (2) some other endogenous indoleamine is the inhibitory substance that is being blocked by the serotonin antagonists, or (3) the three serotonin antagonists are influencing glucose-mediated insulin release through some unknown mechanism that has nothing to do with serotonin.
Insulin and IgG Complexes: An Immunologic Bypass for Complement Activation
Authors: Cantrell Jerald W , Stroud Robert M , Pruitt Kenneth M
Published: December 2014

Because of prior immunohistochemical findings of insulin, gamma globulin and complement components in diabetic microangiopathy, the in vitro interaction of insulin and IgG was studied. When native insulin and purified IgG were reacted under mild reducing conditions, a precipitate formed which was highly reactive with serum complement. Neither insulin nor IgG alone, reduced under the same conditions, demonstrated significant complement fixing activity. Maximal complement fixing activity was obtained from such a mixture at 30° C. in approximately one hour, the time of appearance of a visible precipitate. The presence of both insulin and IgG in the complement fixing precipitate was demonstrated by Ouchterlony analysis and by use of radio-labeled insulin and IgG. The tracer experiments indicated a precipitate composition of approximately 80 per cent insulin and 20 per cent IgG by weight. The utilization of complement components was similar to that obtained with IgG altered by heat aggregation or reaction with antigen. Complement fixation was not affected by alleviation of the precipitate, indicating that free sulfhydryl groups are not necessary. This interaction of denatured insulin and IgG to form a complement fixing complex offers a possible explanation for the presence of these components in micro-angiopathic lesions and may be a contributing factor to the pathogenesis of diabetic microangiopathy. Although complement is activated by an immunoglobulin insulin complex, this mechanism would be considered an immune bypass since specific antibody to insulin is not required.
Muscle Capillary Basement Membrane Changes Related to Aging and to Diabetes Mellitus
Authors: Kilo Charles , Vogler Nancy , Williamson Joseph R
Published: December 2014

Quantitative electron microscopic studies of muscle capillary basement membrane are reported on 154 control subjects and 151 diabetics. In normal subjects and in diabetics significant thickening of basement membrane is observed as an aging phenomenon in both sexes. Significant age-related sex differences in basement membrane width are evident in normal subjects but not in diabetics. Observations on diabetics suggest that basement membrane width is probably normal in most subjects prior to the onset of carbohydrate intolerance and demonstrate that both the magnitude and incidence of basement membrane thickening increase with longer known duration of carbohydrate intolerance. Basement membrane thickening is demonstrable in a significantly higher percentage of subjects over age fifty (63 per cent) than in subjects under age fifty (25 per cent) who have had the disease for four years' known duration or less. The incidence increases to 90 per cent in subjects with complications of retinopathy and/or nephropathy and to 93 per cent in subjects who have had known disease for twenty years or longer.

Both morphologic and statistical evidence indicate that thickening of basement membranes related to aging and to diabetes is essentially segmental in character.
Role of Lipolytic and Glucocorticoid Hormones in the Development of Diabetic Ketosis
Authors: Chernick Sidney S , Clark Charles M , Gardiner Robert J , Scow Robert O
Published: December 2014

Pancreatectomized rats hypophysectomized for one week or longer developed ketosis when given dexamethasone and growth hormone in amounts that were relatively inactive when administered alone. Growth hormone could be replaced by other lipolytic hormones, such as adrenocortico-trophic hormone (ACTH) and thyroxine.

When fasted hypophysectomized rats were made acutely diabetic by injection of mannoheptulose, the plasma concentrations of glucose, ketone bodies, free fatty acids (FFA) and glycerol were increased; injection of growth hormone and dexamethasone further increased the concentrations of these plasma constituents. Injection of these hormones increased lipolysis and decreased glucose metabolism, in vitro, by adipose tissue of mannoheptulose-treated hypophysectomized rats. Uptake of FFA and ketogenesis by perfused livers of fasted hypophysectomized rats were directly related to the concentration of FFA in the perfusing fluid. Growth hormone and glucocorticoid did not have an effect on FFA uptake and ketogenesis in the liver.

It is concluded that lipolytic and glucocorticoid hormones induce diabetic ketosis through their actions on adipose tissue. Lipolytic hormones stimulate lipolysis in adipose tissue while glucocorticoid limits, in the absence of insulin, re-esterification of FFA by suppressing the metabolism of glucose. The resultant increased release of FFA to the blood augments, in turn, the concentration of FFA in plasma, the uptake of FFA by the liver, and the formation of ketone bodies in the liver.
Adrenergic Modulation of Basal Insulin Secretion in Man
Authors: Robertson R Paul , Porte Daniel
Published: December 2014

In normal men of varying degrees of adiposity, alphaadrenergic blockade (one-hour intravenous infusion with phentolamine, 0.5 mg./min.) produced a 31 ± 23 per cent (mean ± S.D.) increase (n = 6, p < .02) over basal insulin levels whereas beta-adrenergic blockade (one-hour intravenous infusion with propranolol, 0.08 mg./min.) produced a 38 ± 15 per cent decrease (n = 6, p < .002) from basal insulin levels; basal glucose did not change during either type of blockade. Epinephrine (two-hour intravenous infusion, 6 /tg./min.) produced a 46 ± 8 per cent decrement in basal insulin by 7 ± 4 min. (n = 12, p < .001). This was followed by a period of recovery during which insulin levels rose to control levels by 46 ± 26 minutes and to 166 ± 36 per cent of control (p < .001) by two hours. The nadir of the decrement correlated, with a high degree of statistical significance, with basal insulin values (r = .99, p < .001), and the amount of time required during the recovery phase for insulin levels to rise to control levels correlated highly with the nadir of the decrement (r = .83, p < .001). The epinephrine-induced decrement from basal insulin did not occur in three subjects pretreated with phentolamine but did occur in four subjects pretreated with propranolol. In the four subjects pretreated with propranolol, the mean recovery time during epinephrine infusion was seventy-two minutes, compared to thirty-six minutes for the group receiving epinephrine alone. In four separate studies, propranolol was superimposed after two hours of a three-hour epinephrine infusion had elapsed, and the elevated insulin levels that had developed by two hours promptly fell below basal levels. It is concluded that (1) endogenous adrenergic activity modulates basal insulin secretion; (2) increases in circulating epinephrine prompt a rapid, marked fall in basal insulin which is alpha mediated; and (3) a slower, beta-mediated recovery phase follows during which insulin surpasses basal levels.
Glucagon Release from Isolated Pancreas in Streptozotocin-treated Rats
Authors: Buchanan K D , Mawhinney W A A
Published: December 2014

Isolated islets (collagenase digestion) and pancreas pieces were prepared from control and insulin-deficient (streptozotocin-treated) rats. Results of experiments were similar with the two pancreas preparations. Glucagon release was increased from islets which were severely insulin-deficient but not from islets showing only moderate insulin deficiency. The normal suppressive effect of glucose on glucagon release was also abolished in the severely insulin-deficient islets. It is suggested that the stimulatory effect of insulin deficiency on glucagon release may be mediated through glucose deprivation in the alpha cell and an alteration in tissue cyclic AMP levels.
Vascular Disease in the Chronic HGH-deficient State
Authors: Merimee Thomas J , Fineberg S Edwin , Hollander William
Published: December 2014

Twenty-four of thirty-one subjects with human growth hormone (HCH) deficiency but otherwise normal pituitary function were studied over a five year period. Metabolic abnormalities in this group included carbohydrate intolerance, with both increased and decreased insulin secretion, hypertriglyceridemia and hypercholesterolemia. Approximately 50 per cent of the total group manifested a type Ha or lib lipoprotein abnormality.

We established previously that despite these metabolic similarities to subjects with diabetes mellitus, the HGHdeficient subjects did not develop diabetic retinopathy or increased thickness of muscle capillary basement membranes. During the past five years, we have gathered objective data regarding involvement of larger arterial vessels in these patients and in age- and sex-matched diabetics and controls. Whereas 12.5 per cent of the dwarfs and 18.5 per cent of the controls consistently exhibited hypertension (> 150/90), 36 per cent of the diabetics were consistently hypertensive. Only one of twenty-four dwarfs followed for five years evidenced coronary artery or peripheral vascular disease, as indicated by studies including electrocardiograms in basal and stress states; 40 per cent of the diabetics and 5.2 per cent of the controls had findings indicating such disease.

The data would be consistent with an hypothesis that a chronic deficiency of HGH deters the development of both microangiopathic and macroangiopathic pathologic changes to a clinically detectable state. The protective effect may result from an inability of protein synthesis to proceed at normal rates when HCH is absent.
Tests for Glucosuria: An Analysis of Factors That Cause Misleading Results
Authors: Feldman Jerome M , Lebovitz Francine L
Published: December 2014

The incidence of potentially erroneous tests for urinary glucose was studied. Each urine specimen collected was tested with Clinitest, Clinistix, Diastix, and Tes-Tape before and after addition of glucose to produce a urine glucose concentration of 1/2 per cent. There was a 23 per cent incidence of falsely high (>1/ 2 per cent) and a 33 per cent incidence of falsely low (<1/2 per cent) results in the 513 specimens examined. Underreading, frequently caused by urinary metabolites of common medications, was seen only with Clinistix and Diastix. Overreading had a distinct relationship to dilute urine and was most frequent with Clinitest (65 per cent). The patient's habits (medications taken and water ingestion) should be considered carefully when a urine testing method is selected. Periodic plasma glucose measurements are recommended to confirm impressions obtained from urine tests for glucose.
Increased Growth Hormone in Partial and Total Lipoatrophy
Authors: Tzagournis Manuel , George Jack , Herrold Joyce
Published: December 2014

Since some clinical and metabolic features of lipoatrophy suggest increased human growth hormone (HGH) activity, we studied HGH responses in five patients with partial or total lipoatrophy. Two patients with total lipoatrophy had elevated basal levels of HGH of 80 and 25 ng. per milliliter, while two with partial lipoatrophy had abnormally high levels after arginine stimulation. The elevated levels seemed to correlate with the clinical activity of the disease. In one of the patients there was a slowing of the growth rate and a moderate weight gain after long-term chlorpromazine therapy decreased HGH levels; a comparison of the immunoreactive HGH in her serum with that from a normal patient by serial dilution technics suggested that the two were immunologically identical, and chromatographic mobilities were also identical. Oral glucose suppressed elevated HGH in all of the patients. These studies suggest that HGH levels are elevated intermittently in lipoatrophic patients and that the increase may contribute to some features of the disease.
A Simple Method for the Determination of Serum Free Insulin Levels in Insulin-treated Patients
Authors: Nakagawa Shoichi , Nakayama Hidetaka , Sasaki Takashi , Yoshino Koichi , Yu Yune Ying , Shinozaki Kenjiro , Aoki Shin , Mashimo Keimei
Published: December 2014

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.
Enhanced Release of Insulin by Prostaglandins in Isolated Pancreatic Islets
Authors: Johnson David G , Fujimoto Wilfred Y , Williams Robert H
Published: December 2014

The effects of several prostaglandins on insulin release were studied during incubation of isolated pancreatic islets from the rat. The glucose-stimulated release of insulin into medium containing 300 mg. per cent glucose and 1.0 mM. theophylline was increased approximately twofold by PGE1, PGE2, and PGF2α. The effect of PGE1was apparent at doses as low as 10−8 M. and progressively increased with concentrations up to 10−5 M. PGA1 did not affect insulin release. Inhibition of insulin release by norepinephrine (10−5 M.) was partially reversed by both PGE1 and PGE2. None of the prostaglandins affected the small basal release of insulin into medium containing 30 mg. per cent glucose. PGE1 (10−5 M.) increased the accumulation of cyclic AMP formed from labeled precursor by pancreatic islets incubated in media containing 10 mM. theophylline and either 30 mg. per cent or 300 mg. per cent glucose.

These results indicate that prostaglandins can enhance the release of insulin from beta cellsin response to glucose. This action is antagonistic to the inhibitory effect of norepinephrine on insulin release and may be mediated through effects on adenyl cyclase activity.
Personality Disorder and Reactive Hypoglycemia: A Quantitative Study
Authors: Anthony Dick , Dippe Stephen , Hofeldt Fred D , Davis John W , Forsham Peter H
Published: December 2014

Thirty-seven previously diagnosed reactive hypoglycemic patients (HP) were evaluatedand classified according to blood glucose nadir and plasma cortisol response to the nadir. We found eight definite, ten probable, and thirteen possible HP. Six patients were vaguely symptomatic without chemical evidence of hypoglycemia. Underlying etiology for the HP included nine diabetics, seven alimentary, thirteen idiopathic, one hypothyroid, and one with liver disease.

The Minnesota Multiphasic Personality Inventory (MMPI) was given to all the patients and to twenty-one patients with various endocrine disorders without hypoglycemic symptoms. HP had mean scores two standard deviations above normal on hypochondriasis and hysteria scales with all other scales within normal limits. Definite, probable, and possible HP did not differ significantly from each other. HP differed significantly from mixed endocrine patients on the Hs and Hy scales (p < .001) and from vaguely symptomatic patients on the Hy scale (p < .05). The latter groups were normal on all scales.

HP of varying etiology (diabetic, alimentary, or idiopathic) show the same MMPI pattern. Thispattern differs from that shown in previous MMPI studies of diabetic patients and patients with gastric surgery without hypoglycemia. Thus, a relationship between hypoglycemia, of whatever origin, and this specific personality pattern is suggested.
Effects of Comparative Perfusions of Equimolar, Single Component Insulin and Proinsulin in the Human Forearm
Authors: Fineberg S Edwin , Merimee Thomas J
Published: December 2014

The human forearm was used as a model system for testing the biological activity of proinsulin (PI) upon peripheral adipose tissue and muscle. Contrasts were made with equimolar perfusions of single component insulin (SCI) in a mean venous perfusion concentration of 263 μU per milliliter and also with SCI perfusions giving venous concentrations of 83 or 47.7 μU permilliliter. Mean venous concentration of PI when perfused alone was equivalent on a molar basis to SCI at 281 μU. per milliliter. PI, at a molar excess of 26:1 (PI:endogenous insulin), shut off lipolysis and promoted potassium uptake but was only slightly effective in promoting glucose uptake. PI was quantitatively similar in effect to 47.7 or 83 μU. per milliliter of insulin upon K flux and blockade of lipolysis but less effective than 47.7 μU. per milliliter in promotion of glucose uptake. When PI and SCI were simultaneously perfused in a molar ratio of 1:1, PI neither augmented nor inhibited SCI actions.
Antilipolytic Action of Tolbutamide in Isolated Fat Cells of the Rat
Authors: Allen Donald O , Largis Elwood E , Ashmore James
Published: December 2014

Concentrations of tolbutamide from 0.25 to 4.0 mg. per milliliter were found to inhibit epinephrine-stimulated lipolysis in isolated fat cells of the rat. At a concentration of 1 mg. per milliliter, tolbutamide also inhibited lipolysis stimulated by ACTH or dibutyryl cyclic AMP. At the same concentration it failed to alter basal lipolysis, basal or epinephrine-stimulated cyclic AMP levels. Basal and epinephrine-stimulated adenylate cyclase and glycogen phosphorylase as well as binding of cyclic AMP to protein kinase were unaltered. These data are discussed in relation to the antilipolytic mechanism of tolbutamide.
Glucose Metabolism in Rat Skeletal Muscle at Rest: Effect of Starvation, Diabetes, Ketone Bodies and Free Fatty Acids
Authors: Goodman Michael N , Berger Michael , Ruderman Neil B
Published: December 2014

The influence of starvation, diabetic ketoacidosis, ketone bodies and free fatty acids on glucose metabolism in resting skeletal muscle was studied in the isolated perfused rat hindquarter perparation and in intact rats. In the hindquarter preparation, the provision of 1.3 mM oleate, 1 mM octanoate or 2 mM acetoacetate did not alter the uptake of glucose in the presence of insulin. In contrast, glucose uptake in the presence of insulin was significantly depressed in hindquarters of rats with diabetic ketosis. In fed, fasted and diabetic rats the distribution space of glucose in skeletal muscle in vivo ranged between 15 to 20 per cent (extracellular space, 18 to 20 per cent), indicating that transport into the cell and not phosphorylation was rate-limiting for glucose uptake. The administration of glucose and insulin did not increase the glucose distribution space in fed or fasted rats; however, it caused a marked increase in tissue lactate in the fasted group, suggesting inhibition of pyruvate oxidation. The concentrations of hexose monophosphates in skeletal muscle freeze-clamped in vivo were very similar in the three groups, indicating phosphofructokinase was not inhibited in the fasted or diabetic rats. There were also no major differences in the concentrations of citrate, glycerolphosphate, ATP, ADP and AMP: the concentration of acetyl CoA was increased in both forty-eight hour fasted and diabetic rats and free CoA was diminished in the diabetic rats. Tissue glycogen waslower in fasted and diabetic than in fed rats. The data suggest that in resting skeletal muscle there is no inhibition of glucose metabolism by exogenous fatty acids and ketone bodies anaiagous to that which occurs in heart and diaphragm. The rate limiting step in glucose uptake appears to be its transport into the cell which is inhibited in rats with diabetic ketosis. Glucose metabolism at the level of pyruvate dehydrogenase may be inhibited in skeletal muscle during fasting and diabetes as a result of changes in the concentrations of acetyl CoA and CoA.
Insulin Response to Glucose and Tolbutamide in “Essential” versus “Pancreatic” Mild Glucose Intolerance
Authors: Vague Philippe , Ramahandridona Georges , Gerolami André
Published: December 2014

In order to determine whether the symptom of “mild glucose intolerance” is associated with functional β cell abnormalities, differing depending on their etiology, the insulin response to intravenously injected glucose was compared with that to intravenous tolbutamide in three homogeneous groups of subjects. Normal weight (NW) subjects comprised one group; chronic pancreatitis (CP) patients'another and obese subjects (O) the other. Each group included both nondiabetic and chemical diabetic subjects.

A. In nondiabetic subjects the early insulin response to glucose (0-10' post glucose insulin area) was similar to that to tolbutamide (NW:310N/ml. x mn. versus 343-CP:299 versus 318-O:576 versus 600).

B. In all the diabetics the early insulin response to glucose was diminished compared to their nondiabetic counterparts (NW:114 versus 310; CP:120 versus 299; O:320 versus 576.

C. The early response to tolbutamide, compared with that of their nondiabetic counterparts, was similar for the diabetic subjects in the normal-weight (333 to 343 for the controls) and overweight, having or not having a family history of diabetes, (779 and 752 respectively to 600) groups but lower for the diabetics in the chronic pancreatitis group (120 to 318). While in the chemical diabetes of chronic pancreatitis patients the lower response to glucose seems due to a reduction in the functional mass of the cells, in essential diabetes of normal weight as well as obese subjects it is related to an insensitivity of the pancreas to glucose. Estimation of the latter by comparison with the response to tolbutamide in a given individual allows one to dispense with the necessity of referring to a control group and to eliminate the influence of hyperinsulinism.
Dietary and Drug Treatment of Hyperlipidemia in Diabetes
Authors: Albrink Margaret J
Published: December 2014

Diabetics have increased risk of ASCVD and patients with ASCVD have increased incidence of diabetes. Patients with diabetes are susceptible to hypertriglyceridemia, particularly if they are obese maturity-onset diabetics. Elevated plasma triglycerides may constitute a greater risk factor for ASCVD than elevated plasma cholesterol in diabetics.

The classification of hyperlipidemia can be made on the basis of plasma cholesterol and triglyceride concentration measured in the fasting state. Hypercholesterolemia (type II) or hypertriglyceridemia with or without hypercholesterolemia (type IV) will comprise the great majority of hyperlipidemias.

The treatment of hyperlipidemia in diabetics is uncertain because most dietary and drug studies have centered about cholesterol rather than Trigrycerides, and most such studies have excluded diabetics. It is necessary, then, to assume that treatment ppropriate for nondiabetics is also appropriate for diabetics.

The first order of treatment is restoration of body weight to ideal, as Is usually the case, it exceeds ideal weight.

If weight reduction fails to bring about normal lipids, modest reduction of total dietary fat, of saturated fat, and slight increase in nsaturated fat and decrease in dletary cholesterol is worth a trial regardless of type of lipidemia. Although this diet is aimed chiefly at reduction of cholesterol it either does not change or may even decrease the plasma triglyceride concentration. Carbohydrates should be in the complex form with high fiber content.

If hypertriglyceridemia persists despite the above measures, limited evidence suggests that restriction of dietary carbohydrate to 40 or 30 per cent of calories with a corresponding increase in fat may be effective. If the added fat is polyunsaturated the cholesterol will nort increase. If chylomicronemia is present a very low fat diet may be necessary.

Only when diet fails are drugs justified. Only two drugs are of practical usefulness: cholestyramine for the treatment of pure hypercholesterolemia (type II) and clofibfate for the treatment of hypertriglyceridemia (types III, IV and V). Clofibrate is probably worth trying also in hypercholesterolemia.

There is as yet no firm evidence that lowering lipids by whatever means reduces the risk of ASCVD, though several studies give cause for optimism. Diabetics have been excluded from most such studies. There is need for long-range diet and drug studies of diabetics.
Cationic Environment and Dynamics of Insulin Secretion: II. Effect of a High Concentration of Potassium
Authors: Henquin Jean-Claude , Lambert Andre E
Published: December 2014

The effects of 24 mM K+ upon the dynamics of immunoreactive insulin (IRI) release were studied in perifused rat islets in the absence of glucose and in its presence at concentrations of 50 and 300 mg. per 100 ml. Raising external K+ to 24 mM in the absence or in the presence of glucose (50 mg. per 100 ml.) was rapidly followed by a transient discharge of IRI. This rapid secretory phase was markedly inhibited in a medium containing 1 mM Na+ and was totally obliterated in a Ca2+-free medium.

The early IRI response to a simultaneous increase of glucose to 300 mg. per 100 ml. and of K+ to 24 mM was enhanced while the late response was not significantly modified. In contrast, the same rise in glucose concentration after a twenty-five minute perifusion in a medium containing 24 mM K+ provoked markedly diminished early and late phases of IRI release. Under both experimental conditions, the effect of glucose was almost completely abolished in a medium containing 1 mM Na+. The stimulant action of glucose was not restored when K+ concentration was lowered from 24 to 6 mM at the time of glucose increase, but was normal if this diminution of K+ occurred ten minutes earlier.

It is hypothesized that modifications in IRI secretion rate induced by 24 mM K+ result from changes in membrane permeability for Ca2+.
Mortality of Diabetic Patients Treated Surgically for Lower Limb Infection and/or Gangrene
Authors: Kahn Otto , Wagner William , Bessman Alice N
Published: December 2014

A retrospective study was made to ascertain the mortality rate among 100 consecutive patients with diabetes mellitus who had undergone lower limb amputations for infection and/or gangrene in the combined medical-orthopedic service of a county hospital. The medical and orthopedic staffs functioned as equal members, and combined decision-making conferences were held regularly. The over-all mortality rate was 9 per cent, a substantial decrease from the 22 to 25 per cent previously reported in similar studies. The mortality rate among patients with below-knee procedures was 1 per cent versus the 7 to 9 per cent reported by others. Close medical-surgical liaison on a service specializing in the care of these often fragile patients with diffuse multisystem disease results in decreased mortality.
Racial Differences in Serum and Urine Glucose after Glucose Challenge
Authors: Dales Loring G , Siegelaub Abraham B , Feldman Robert , Friedman Gary D , Seltzer Carl C , Collen Morris F
Published: December 2014

A study was made of serum glucose response to oral glucose challenge in 88,000 white, 12,000 black, and 4,300 oriental adults undertaking routine health checkups. It was found that serum glucose levels one hour after glucose ingestion were markedly lower in the black group than was the case for the whites and orientals. Glycosuria at one hour was also less common in the blacks than in the whites, while it was distinctly more common among the orientals. Racial differences in age, height, weight, triceps skinfold thickness, completeness of glucose load ingestion, length of time since last eating, time of day when the test was performed, thiazide usage, educational level, and cigarette smoking history did not explain these findings.
A Study of Glucose Tolerance and Insulin Response in Partially Depancreatized Dogs
Authors: Sun A M , Coddling J A , Haist R E
Published: December 2014

The effects of a standard glucose tolerance test (GTT) and of pretreatment with aminophylline (AM) were examined in dogs with a reduced reserve of islet function prepared by partial removal of the pancreas and in normal intact dogs. Serum glucose, free fatty acid and insulin levels were measured. No significant differences were found before and after partial pancreatectomy when less than 50 per cent of the pancreas was removed or after sham operation. When AM was infused prior to the GTT, serum insulin levels were elevated to almost twice those obtained during a standard GTT. Dogs with less than 50 per cent of the pancreas remaining showed deterioration in GTT two weeks after operation, although the fasting blood sugar was normal except in one animal. The deterioration in GTT response progressed with time. Maintaining the animal on a high protein diet improved the GTT response. In chow-fed dogs with less than 50 per cent of the pancreas but no glucosuria or fasting hyperglycemia, prior AM infusion significantly improved the GTT and increased insulin secretion. In one dog with fasting hyperglycemia, AM did not cause improvement.
Effect of Moderate Alcohol Intake on Control of Diabetes
Authors: Walsh C H , O'Sullivan D J
Published: December 2014

The effect of moderate amounts of alcohol on control of diabetes has been studied in twenty patients. No deterioration in control occurred after alcohol. Two subjects became severely hypoglycemic following alcohol. The implications of the use of alcohol by diabetic patients are discussed.
Studies with (+)—Octanoylcarnitine in Experimental Diabetic Ketoacidosis
Authors: McGarry J Denis , Foster Daniel W
Published: December 2014

The ability of (+)-decanoylcarnitine to inhibit ketogenesis in perfused livers from severely ketotic alloxan diabetic rats and to cause the rapid reversal of ketoacidosis in intact animals was shown not to be the result of a detergent action of this compound, since no such effects were seen when similar experiments were carried out with (−)-decanoylcarnitine.

Comparison of the hexanoyl, octanoyl and decanoyl esters of (+)-carnitine for their antiketogenic capacity in perfused Hvers from alloxan diabetic rats revealed that the eight- and ten-carbon homologues were equally effective, with the six-carbon species having less inhibitory properties. When tested in vivo, both in the presence and absence of insulin, the eight-carbon species exhibited the greatest hypoketoiemic potential.

Further studies with (+)-octanoyIcarnitine showed that (a) its potent effects in the rat are completely reversible; (b) it is not metabolized in this animal species and is rapidly excreted by the kidneys; (c) it has a far lower hemolytic capacity than (+)-decanoylcarnitine; and (d) it is capable of reversing severe ketoacidosis when administered orally, although the doses required using this procedure are much greater than those needed when the agent is given intravenously.

It is concluded that (+)-acylcarnitines are useful tools for studies of metabolic regulation both in vitro and in vivo. In this regard the compound of choice would seem to be (+)-octanoylcarnitine.
Insulin Binding to Isolated Human Adipocytes
Authors: Olefsky Jerrold M , Jen Phyllis , Reaven Gerald M
Published: December 2014

In order to study the binding of insulin to insulin-sensitive human tissue, we isolated adipocytes from surgically obtained human fat tissue. Our data demonstrate that insulin readily and specifically binds to isolated adipocytes. The time course of this reaction indicates that steady state binding conditions occur at forty-five minutes, with a subsequent decline in binding later. There is no appreciable insulin or receptor degradation before forty-five minutes, suggesting a true equilibrium. After forty-five minutes the decline in binding can be accounted for by insulin plus receptor degradation. At 3 × 10−11 M 125-I-insulin and 2 × 105 cells per milliliter, 1.8 to 2.4 per cent of the 125-I-insulin was bound. The specificity of this binding reaction is demonstrated by the high concentrations of thyroid stimulating hormone and human growth hormone that are without effect on binding, while proinsulin and desalanine insulin inhibit binding in proportion to their biologic activity. On the other hand, binding can be readily inhibited by porcine insulin at physiologic concentrations, i.e. binding is 13 per cent inhibited at 1 ng. per milliliter and 50 per cent inhibited at 8.6 ng. per milliliter. The kinetic behavior of this reaction can be approximated by Scatchard analysis, which indicates 50,000 high affinity sites per cell with a dissociation constant (Kd) of 1.9 × 10−9 M per liter and 250,000 low affinity sites per cell with a Kd of 8 × 10−9 M per liter.

In conclusion, these studies demonstrate and characterize the binding of insulin to normal isolated human adipocytes; they indicate that the study of insulin-adipocyte binding is a possible means to gain further insight into the mechanism of altered response to insulin in human disease states.