bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Hyperglycemia on the Hexose Monophosphate Shunt in Islets of Langerhans
Authors: Matschinsky F M , Kauffman F C , Ellerman J E
Published: December 2014

The activities of glucose-6-P dehydrogenase, 6-P-gluconate dehydrogenase, ribulose-5-P epimerase, ribulose-5-P isomerase, transketolase and transaldolase were measured in frozen dried specimens of the islets of Langerhans and exocrine cells of the pancreas. Activities of all five enzymes were comparable in the two cell types. The effect of hyperglycemia on the concentration of 6-P-gluconate was also studied. A ten-fold increase in bloodglucose concentration resulted in a thirteen-fold increase in 6-P-gluconate levels in islet tissue but no change in the exocrine portion of the pancreas. The rate of increase of 6-Pgluconate in the islets during hyperglycemia was slower than the rate of increase of either glucose or glucose-6-P. The rise of 6-P-gluconate appears to be too slow a process to serve as a trigger for the insulin release mechanism.
Study of the Relationship Between Glucose and Insulin Responses to an Oral Glucose Load in Man
Authors: Reaven Gerald , Miller Rupert
Published: December 2014

Oral glucose tolerance tests have been performed on 125 patients, and the ensuing changes in plasma glucose and insulin concentrations have been measured. The possible effects of factors which could modify the nature of these responses (obesity, age, sex, family history of diabetes, and indications for performing the tolerance test) have been extensively evaluated. None of these variables were found to have a statistically significant effect on the plasma glucose and insulin responses. Two general relationships between glucose and insulin responses have been defined within the population studied. One, based on the quantitative aspects of the glucose and insulin responses, indicated that there was at first an increase, and then, a decrease in the insulin response to progressive degrees of hyperglycemia. The second relationship was independent of the absolute concentrations of either glucose and insulin, and states that the pattern of glucose response during the three hours of the tolerance test determines the pattern of the insulin response during this same time interval.
Control of Blood Glucose in Normal and in Diabetic Subjects: Studies by Compartmental Analysis and Digital Computer Technics
Authors: Ceresa F , Ghemi F , Martini P F , Martino P , Segre G , Vitelli A
Published: December 2014

A model with two compartments (glucose and insulin) by and a negative feedback has been used to fit the values of blood glucose obtained experimentally by infusing intravenously glucose (0.5 gm. min−1) or insulin (0.055 U. min−1) for about 250 minutes. Glucose was infused to normal ambulatory or hospitalized subjects and to diabetic patients; insulin was infused to normal subjects. The model employed fits the data of all the groups. The SAAM program and a digital computer (IBM 7094) were used. The model cannot be solved completely due to the number of degrees of freedom of the system but values related to the transfer constants of the model can be computed, as the damping constant a, the natural frequency w, the natural period T and the free frequency b of the system, which shows damped oscillations in normal subjects; in diabetic patients the system passes through states of overdamping until no oscillations can be seen in the more severe cases. The effect of ten days of treatment with prednisone (25 mg. m per day, per os) has been evaluated in a group of normal subjects. Discriminant analysis between normal and diabetic subjects and between glucose and insulin infusion has been carried out by using a BMD program and a digital computer.
Diabetes in the Seneca Indians: Plasma Insulin Responses to Oral Carbohydrate
Authors: Frohman Lawrence A , Doeblin Thomas D , Emerling Frank G
Published: December 2014

In a group of adult Seneca Indians living in Western New York, 14 per cent were discovered to have previously diagnosed diabetes, and 20 per cent of the remainder had a plasma glucose of 200 mg. per 100 ml. or greater one hour after oral carbohydrate. This report describes the glucose and insulin responses to oral carbohydrate in fifty of these subjects who were not previously known to have diabetes during initial testing.

On the basis of the results of a two-hour oral glucose tolerance test, forty-six subjects were classified into “diabetic” or “normal” categories. Four persons formed an intermediate group. The diabetics differed from the normals in that (1) they were older and more obese, though even the normal population was significantly obese, and (2) the mean fasting plasma insulin level was three times greater and the insulin response to oral glucose two and one-half times greater than in normals. When diabetics were subdivided on the basis of obesity or degree of glucose intolerance, no significant differences in insulin secretion could be detected. A group of diabetic subjects with a degree of obesity comparable to that of normal subjects still demonstrated two-fold increases in both fasting and postglucose insulin levels.

The elevated insulin levels of diabetics can be explained only in part by co-existent obesity and suggest the presence of insulin resistance associated with diabetes in these Indians.
Plasma Disappearance Rate of Injected Human Insulin in Juvenile Diabetic, Maturity-onset Diabetic and Nondiabetic Subjects
Authors: Orskov Hans , Christensen Niels Juel
Published: December 2014

The half-life in plasma of immunoreactive insulin was determined after the injection of eight units of unlabeled human insulin. Six juvenile diabetics and nine maturityonset diabetics as well as eight and six nondiabetics of comparable ages were investigated. The average T½ for the groups was respectively: 10.0 ± 2.8; 12.9 ± 1.7; 10.6 ± 1.9 and 13.0 ± 2.5 minutes. There is no tendency to any difference in T½ between diabetics and nondiabetics of comparable age. However, the T½ in the older group is significantly longer than T½ in the younger age group.

Evidence from in vitro experiments, as well as from the literature, is presented which points to the fact that iodinated insulin cannot be used for the evaluation of the disappearance rate or secretion rate of endogenous insulin. Furthermore, it is emphasized that protein precipitation with TCA or Na2SO4 cannot be employed for the isolation of undestroyed iodinated insulin.
Chemical and Early Overt Diabetes Mellitus in Children: I. Effect of Glucagon on “Insulin Reserve”
Authors: Murthy D Y N , Guthrie R A , Womack W N , Jackson R L
Published: December 2014

Glucose disappearance rates and serum immunoreactive insulin levels following the infusion of glucose and glucose with glucagon were studied in eleven normal subjects, fortyeight children classified as chemical diabetics, and seventeen children with the recent onset of overt diabetes in the early recovery phase of the disease.

Children with chemical diabetes had significantly lower glucose disappearance rates than the normal controls and significantly higher disappearance rates than the children with overt diabetes. Compared with the normal controls, the change in glucose disappearance rates due to glucagon was significantly reduced in chemical diabetics and absent in overt diabetics.

Normal subjects and chemical diabetics responded to glucose and glucagon infusion by increasing the serum IRI levels. Chemical diabetics formed a heterogeneous group with respect to the serum IRI response to glucagon. Children classified as “late” chemical diabetics, like the overt diabetics, had decreased serum IRI responses to glucagon.

Children with chemical diabetes who have blood sugar values outside the ninety-seventh and third percentiles of the distribution of normal values during an oral glucose tolerance test are already in an advanced (late) stage of chemical diabetes and are likely to have their disease progress rapidly to overt diabetes. Children with “late” chemical diabetes have glucose disappearance rates less than 1.1 per cent per minute, less than +0.3 change in glucose disappearance rates after glucagon stimulation and an impaired serum IRI response to an intravenous infusion of glucose or glucose and glucagon. Identification of children in earlier stages of chemical diabetes is desirable in order to evaluate the feasibility of altering the progressive loss of insulin reserve.
Chemical and Early Overt Diabetes Mellitus in Children: II. Effect of Intravenous Tolbutamide on “Insulin Reserve”
Authors: Murthy D Y N , Guthrie R A , Womack W N , Jackson R L
Published: December 2014

Blood sugar and serum immunoreactive insulin (IRI) response to a rapid intravenous infusion of tolbutamide was studied in twelve normal subjects, forty-four children with chemical diabetes and ten children with overt diabetes mellitus of recent onset.

The diagnosis of chemical diabetes was based on two or more abnormal oral glucose tolerance tests, separated by at least two months' time interval. Of the forty-four children with chemical diabetes, twenty-four children had one or more blood sugar values outside the ninety-seventh or third percentile during oral glucose tolerance tests (“late” chemical diabetes) and had impaired tolbutamide responses at thirty minutes which were significantly different from normal controls and from the children with overt diabetes.

Serum IRI levels were similar in chemical diabetics and normal subjects. Overt diabetics had decreased IRI responses to tolbutamide. The tolbutamide test as performed will not detect children in the earlier stages of chemical diabetes. Until a more sensitive and reliable test is devised, it is necessary to rely on repeated oral glucose tolerance tests to identify children in the earlier stages of chemical diabetes. Longitudinal studies of a large group of children with chemical diabetes are necessary in order to extend our knowledge of the pathophysiology of the disorder and to establish more specific and reliable criteria to define the stages of the disease.
Cotton-wool Spots in Diabetic Retinopathy
Authors: Kohner Eva M , Dollery C T , Bulpitt C J
Published: December 2014

In nineteen patients with diabetic retinopathy the appearance and life history of cotton-wool spots were studied by serial color photographs and fluorescence angiograms.

Cotton-wool spots are a feature of both mild and severe diabetic retinopathy but, while their appearance is similar to that in hypertension, the associated capillary abnormalities are more severe. On fluorescence angiograms cottonwool spots are associated with arteriolar occlusion with an area of capillary closure and are surrounded by abnormal dilated capillaries.

Capillary abnormalities precede the development of arteriolar occlusion which is necessary for the development of cotton-wool spots.

Cotton-wool spots persist for long periods. Their mean half-life is 8.1 months in patients under forty years of age and 17.2 months in patients over the age of forty. Even when cotton-wool spots disappear, capillary closure persists. Following yttrium90 implantation of the pituitary gland the half-life of cotton-wool spots was 2.3 months.
A Rat Pancreas-Small Gut Preparation for the Study of Intestinal Factor(s) and Insulin Release
Authors: Penhos Juan C , Wu Ching-Hui , Basabe Juan C , Lopez Nestor , Wolff Frederick W
Published: December 2014

A technic for in situ perfusion of rat pancreas alone or with a small intestine preparation, which is suitable for studying insulin and/or glucagon secretion and the role intestinal factor(s) has upon it, is described. Krebs- Ringer bicarbonate buffer, containing 4.0 per cent bovine albumin and 80 mg. per 100 ml. glucose with pH adjusted to 7.4, was used as perfusate.

When the pancreas was perfused with a nonrecirculated buffer there was no significant change in the levels of glucose or insulin in the perfusate, while with recirculated buffer, there was a decrease in both measurements.

When additional glucose was added to the perfusate, there was an increase of insulin levels, more marked in the pancreas perfusion with recirculated buffer (possibly pancreatic glucagon plus glucose effect) than in nonrecirculated ones (glucose effect).

In pancreas-intestine perfusion with recirculated buffer, there was a decrease of the levels of insulin and glucose, and when additional glucose was added to the perfusate, there was an increase of the levels of insulin and glucose (possibly pancreatic glucagon and glucose effect).

When glucose was passed through the intestine, there was a marked increase of the levels of insulin which was significantly higher than the previous group studied, probably due to the effects of glucose, pancreatic glucagon and intestinal factors.

It may be possible by the results obtained to separate the effects of the three factors on the release of insulin: glucose, glucagon and intestinal factor(s).
Insulin Secretion in Type I Glycogen Storage Disease
Authors: Lockwood Dean H , Merimee Thomas J , Edgar Paul J , Greene Martin L , Fujimoto Wilfred Y , Seegmiller J Edwin , Howell R Rodney
Published: December 2014

Patients with type I glycogen storage disease (glucose-6- phosphatase deficiency) have marked hypoglycemia in infancy but tend to become normoglycemic as they grow older. In addition, these patients characteristically demonstrate abnormal glucose tolerance curves. Since a major mechanism for the maintenance of normal blood glucose levels is lacking in this disease, investigation of the levels of circulating insulin and the regulation of its release in a group of such patients was made.

Three well-known stimuli for secretion of insulin in normal man were studied in two adolescent and three adult patients with type I glycogen storage disease. Basal plasma insulin levels were repeatedly approximately 50 to 60 per cent ot normal. Ingestion of glucose alone, glucose plus prtrteiu Or infusion of arginine monochlorid resulted in significantly less than normal increase in insulin.
Diabetic Diarrhea: A Study of Thirteen Patients with Jejunal Biopsy
Authors: Malins J M , Mayne N
Published: December 2014

Thirteen diabetic patients with chronic diarrhea have been studied clinically and subjected to jejunal biopsy. Eleven conformed to the accepted clinical picture of “diabetic diarrhea,” all showing evidence of gross neuropathy and a normal jejunal mucosa was found in every case. The other two were found to have a flat jejunal biopsy; in one celiac disease had been diagnosed at the age of two, but in the other there was no remote history of gastrointestinal disorder. The diagnosis of “diabetic diarrhea” is one of exclusion and there is no single feature which can be regarded as diagnostic. The nature of the diarrhea is uncertain but the response in some patients to antibiotics suggests an abnormal colonization of bacteria in the intestine though this cannot be demonstrated. The association of diarrhea with diabetic neuropathy is strong.
Insulin-like Activity by Fat Pad Assay and Immunoreactive Insulin: II. Their Occurrence in Fractions by Gel Filtration of Serum
Authors: Kajinuma Hiroshi , Ide Takehiko , Kuzuya Takeshi , Kosaka Kinori
Published: December 2014

In a previous report, serum insulin was extracted with efficient recovery by salt-ethanol extraction.

As the second method of separation of serum insulin gel filtration was adopted. Dog sera obtained from the pancreatic and the femoral veins were separated into two fractions (A and B) with Sephadex G-50. Fractions A and B corresponded respectively to the major peak of serum proteins and the portion where I-131-insulin added to serum was eluted. Insulin-like activity (ILA) was assayed by rat fat pad and immunoreactive insulin (IRI) by a double antibody method. Significant ILA was demonstrated in both fractions. IRI in serum appeared mostly in fraction B. ILA/IRI ratio was closer to 1.0 in fraction B than in serum. Fraction A tended to have fairly uniform ILA irrespectively of origin of serum, often exceeding the ILA of serum. Fraction A from a depancreatized dog serum had similar degree of ILA. Serum and both fractions stimulated various phases of fat pad metabolism similarly to insulin, including glycogen synthesis. Assays based on four different metabolic parameters gave essentially the same ILA values for both serum and fractions. ILA of fraction A differed from insulin in its nonneutralizability with anti-insulin serum, its poor suppressibility by cysteine, and the lack of parallelism of its regression line with that of insulin. Simple dilution and reconcentration of serum resulted in an increase in its ILA. Presumably, fraction B is primarily due to serum insulin with similar immunological and biological activities to pancreatic insulin. Whether or not ILA of fraction A is related to insulin remains unknown.
Studies on the Isolated Goosefish Insulin Secretion Granule
Authors: Sorenson R L , Lindall A W , Lazarow Arnold
Published: December 2014

Goosefish islet secretion granules were isolated from sucrose homogenates by centrifugation. The morphology of the fractions was determined by electron microscopy. Studies on the stability of the secretion granules revealed them to be sensitive to pH and deoxycholate. The secretion granule proteins were subjected to electrophoresis in polyacrylamide gels, and the resultant bands were characterized by a number of stains and by immunoassay of insulin. These procedures showed that the granule fraction had a heterogeneous configuration consisting of lipid, carbohydrate and protein. One band containing much of the insulin activity did not show the ability to stain with aldehyde fuchsin, possibly indicating a different character of insulin.
Preparation and Partial Characterization of Crystalline Human Insulin
Authors: Jackson R L , Shuey E W , Grinnan E L , Ellis R M
Published: December 2014

Crystalline human insulin was prepared from human pancreas glands in relatively large amounts employing acid-ethanol extraction, fractional precipitation with salts and organic solvents, gel filtration, and crystallization from ammonium acetate buffer. The crystalline insulin had a potency of about 25 International Units per milligram. Polyacrylamide gel electrophoresis showed that the material consisted of a major component and several minor components similar to those usually observed in insulins derived from other species. Amino acid analyses of the crystalline material were consistent with the structure proposed for human insulin by Nicol and Smith.
Insulin Response to Glucagon: The Opposing Effects of Diabetes and Obesity
Authors: Crockford Peter M , Hazzard William R , Williams Robert H
Published: December 2014

Glucose and immunoreactive insulin responses to glucagon were studied in thirty-seven subjects with varying degrees of relative body weight and glucose tolerance. Glucagon was administered intravenously as an infusion (0.5 mg./30 min.), followed by the acute injection of 1.0 mg. Insulin and glucose levels rose concomitantly during the infusion, but only insulin values increased significantly following the acute injection, providing separation of the glycogenolytic and insulinogenic properties of glucagon. During the 30 min. following the glucagon injection, glucose levels fell to normal in the nondiabetic subjects but remained elevated among the diabetics.

Obesity was associated with elevated basal insulin levels related to the degree of adiposity (r = .402, p < .02) but independent of glucose tolerance (r = < .030). In all subjects, the insidin responses to both glucagon infusion and injection were in turn related to the basal insulin values. The insulin response to glucagon, when expressed as per cent increment above basal in order to correct for the effect of varying degrees of insulin sensitivity as reflected in that basal level, was in all subjects related in a reciprocal manner to the degree of glucose intolerance as reflected by fasting glucose values (r = 0.891, p < .001). Thus, progressive glucose intolerance was associated with progressively impaired insulin secretion. Direct comparison of subjects classified on the basis of obesity or diabetes confirmed the exaggerating influence of obesity and the limiting effect of diabetes upon the insulin response to glucagon.
Insulin and Glucagon Release from Isolated Islets of Langerhans: Effect of Enteric Factors
Authors: Buchanan K D , Vance J E , Williams R H
Published: December 2014

The effect of enteric factors on immunoreactive insulin (IRI) and glucagon (IRG) release from isolated islets of Langerhans of the rat was studied. Glucagon caused slight stimulation of IRI release but only at the high concentration of 10 μg. per milligram, and its effect was seen only at aconcentration of glucose of 150 mg. per 100 ml. but not at 30 or 300 mg. per 100 ml. Crude alcohol extracts of intestinal mucosa containing IRG were ineffective in promoting IRI release. Purified pancreozymin and secretin, and a gastrin preparation failed to cause an increase in release of IRI and IRG. Altering the glucose concentration in the media resulted in opposite effects on the release of IRI and IRG; also, IRI release was stimulated by tolbutamide and inhibited by diazoxide, implying that the isolated islet hormone releasing mechanisms are intact. It is suggested that enteric factors may mediate their effects on IRI and IRG release in vivo by indirect means.
Human Fetal Insulin Metabolism Early in Gestation: Response to Acute Elevation of the Fetal Glucose Concentration and Placental Transfer of Human Insulin-I-131
Authors: Adam Peter A J , Teramo Kari , Raiha Niels , Gitlin David , Schwartz Robert
Published: December 2014

Although insulin has been demonstrated in human fetal pancreas as early as thirteen weeks of gestation, the controls of insulin secretion in the human fetus and the magnitude of placental insulin transfer to the fetus are unknown. In pregnant women, scheduled for therapeutic abortions by abdominal hysterolomy at fifteen to twenty weeks of gestation, the fetal plasma insulin response to glucose infusion and insulin transfer across the placenta were studied as follows: (1) glucose was infused to eight fetuses in situ, and (2) insulin-I-131 was infused continuously for four to six hours to eight pregnant women via peripheral vein.

Insulin was measured radioimmunologically and, following the infusion studies, was precipitated quantitatively by a double antibody method. During fasting, no difference was observed between fetal and maternal plasma glucose or in insulin levels. Although glucose administered to the fetus raised the fetal plasma glucose concentration without changing the maternal level, both fetal and maternal plasma insulin concentrations were unchanged at five and ten minutes. Human insulin-I-131 was not transferred across the placenta and no sequestration of insulin-I-131 occurred in the placenta. Early in human gestation the fetal pancreas appears to be the major source of fetal insulin, and the fetal insulin secretion rate may be relatively unresponsive to acute changes in blood glucose concentration. The placenta acts as a barrier to human insulin-I-131 but does not appear to sequester and catabolize insulin-I-131, as was previously demonstrated in human pregnancies at term.
In Vitro Insulinogenic Effect of Two Monoamine-Oxidase Inhibitors
Authors: Hernández Rodolfo Eduardo , Gagliardino Juan José , Rodriguez Ricardo R
Published: December 2014

The stimulatory effect of two monoamine-oxidase inhibitors, nialamide and tranylcypromine, upon insulin secretion was studied using the in vitro rat slice pancreas incubation technic. It was found that these drugs stimulated insulin release in the presence of low levels of glucose. They were also able to enhance the insulin release elicited by high levels of glucose.

These results would explain, at least in part, the protective role of MAOI in some types of experimental and clinical diabetes.
Plasma Insulin Response to an Oral Carbohydrate Solution
Authors: Genuth Saul M
Published: December 2014

Plasma insulin responses to an oral carbohydrate solution were determined in twenty-one normal subjects. Mean insulin values at fasting, 30, 60, and 120 minutes after the carbohydrate load were 13, 109, 90, and 62 μU. per ml., respectively. Twelve subjects retested with 100 gm. of oral glucose had equivalent insulin responses. In nineteen subjects with moderate diabetes, blood glucose and plasma insulin responses to the carbohydrate solution and to 100 gm. of glucose were also equivalent. It is concluded that this form of carbohydrate loading is an effective and reliable challenge to the pancreas.
Insulin-Resistant Diabetes with Autoantibodies Induced by Exogenous Insulin: Successful Treatment by Insulin Withdrawal
Authors: Karam John H , Grodsky Gerold M , Forsham Peter H
Published: December 2014

An obese woman was studied over a five-year period, during which time she had three episodes of severe insulinresistant diabetes, associated with a high level of insulin antibodies.

During her second hospitalization, there was no evidence of acute stress, suggesting that in addition to obesity, her extremely high levels of antibodies were interfering with the effectiveness of the administered insulin. These antibodies were shown by immunologic methods to bind both circulating exogenous (bovine) and endogenous (human) insulins. With no other specific therapy except the abrupt halt of insulin, her diabetes improved, her antibody liters declined with a half-life of about twenty days, and the capacity of her plasma to bind both exogenous and endogenous insulin decreased. Antibody levels, although much lower, were still detectable more than eighteen months after discontinuing insulin therapy.

The patient's marked clinical improvement on stopping insulin, suggested that the high levels of circulating antibodies were a factor in maintaining her severe insulin resistance. Treatment with insulin in this patient was not only ineffective but apparently had worsened her diabetes. The excellent results obtained during her third hospitalization emphasize the superiority of supervised diet and enforced weight reduction over insulin as a choice of treatment in this type of patient.
Difference in Diabetic and Nondiabetic Fat Distribution Patterns by Skinfold Measurements
Authors: Feldman Robert , Sender A Joseph , Siegelaub A B
Published: December 2014

Fat distribution was assessed by a series of ten skinfold measurements in 7,717 persons voluntarily undergoing a multiphasic health screening examination. From this total, in 360 diabetic and 934 nondiabetic control subjects matched for race, sex, age, height, and weight, fat distribution patterns were compared by direct skinfold measurements, and by triceps ratios and subscapular ratios: thickness of each of the individual's skinfolds relative to his triceps or his subscapular skinfold respectively. Diabetic subjects, especially women, showed a significant shift toward centripetal distribution of fat. The data indicated that centripetal fat distribution is a masculine characteristic. It is suggested that in diabetes there is a disturbance of male/female hormonal balance, responsible for centripetal fat distribution in women, and for exaggeration of centripetal fat distribution in men. Furthermore, the data suggested that persons with diabetes have more total fat than their nondiabetic counterparts.
Changes in Plasma Insulin and Glucose Tolerance in Stable Diabetes in a Young Woman
Authors: Kosaka Kinori , Hagura Ryoko , Saito Reiko , Tsukamoto Fusae , Kuzuya Takeshi
Published: December 2014

In a seventeen-year-old woman with a strong family history of diabetes mellitus, changes in glucose tolerance and plasma insulin response to oral glucose were followed from the early stage of diabetes through exacerbations and remissions of the disease. At the first glucose tolerance test which revealed normal fasting and elevated postprandial blood sugar values, the plasma insulin level at thirty minutes was subnormal but the peak level, which was delayed to ninety minutes, was above normal. During the exacerbation when fasting blood sugar values were elevated, insulin response was markedly diminished. In the stage of improvement following treatment with oral drugs and insulin, plasma insulin response to oral glucose improved remarkably. During the course of subsequent exacerbation and improvement, the degree of plasma insulin response changed in a similar inverse manner with the blood sugar level. The observations suggest that the diminished insulinsecretory capacity in severe diabetes does not always indicate irreversible damage of insulin releasing mechanisms.
Adenosine Triphosphate Levels of Mammalian Pancreatic B Cells after Stimulation with Glucose and Hypoglycemic Sulfonylureas
Authors: Hellman Bo , Idahl Lars-Ake , Danielsson Ake
Published: December 2014

A microchemical technic was applied to elucidate the possible role of ATP in insulin secretion by measuring the levels of this metabolite in pancreatic islets from obese hyperglycemic mice. The β cell content of ATP was markedly reduced within the first minute after interruption of the blood supply. A steady-state level of about 5 mmoles of ATP was noted in islets incubated in the absence of glucose. The corresponding ATP level was twice as high when at least 1 mg./ml. of glucose was present in the incubation medium. While the contents of ATP and glycogen remained constant when the pancreatic islets were incubated with diazoxide, the amounts of both these metabolites were significantly reduced by concentrations of sulfonylurea compounds known to stimulate the insulin release. The sulfonylurea effect on the islet ATP content implies a change in the “phosphate potential” of the β cells, which might stimulate glycogenolysis and increase the glycolytic flux. The sulfonylurea stimulation of insulin release might thus be related to a product of glucose degradation beyond the level of glucose-6-phosphate.
Potentiation of the Plasma Insulin Response to Glucose by Prior Administration of Alcohol: An Apparent Islet-Priming Effect
Authors: Metz Robert , Berger Sheldon , Mako Mary
Published: December 2014

Ethyl alcohol which has been reported to be without effect on insulin secretion apparently modifies beta-cell function nevertheless, as indicated by the plasma insulin responses to glucose loading after prior administration of alcohol. Glucose was injected intravenously in nine young adults on three separate occasions at intervals of at least two weeks. During the twelve hours preceding each test the subjects received ethanol either by mouth or by vein or, as a control, no ethanol. Plasma insulin and glucose concentrations were not noticeably affected by the ethanol alone but alcohol pretreatment was followed in all instances by heightened plasma insulin responses to the glycemic pulse stimulus and by accelerated rates of plasma glucose disappearance. The mean plasma insulin response was increased 50 per cent by the alcohol, irrespective of the route of administration. Unlike recognized insulin secretogogues, therefore, ethanol appears to augment insulin secretion only on demand. The route of administration appeared not to be a factor in determining the magnitude of the alcohol effect. Other alcohol effects included blunting of the plasma pyruvate and exaggeration of the plasma lactate elevations after glucose.
Effect of Protein Meals on Plasma Insulin in Mildly Diabetic Patients
Authors: Fajans Stefan S , Floyd John C , Pek Sumer , Knopf Ralph F , Jacobson Mitchell , Conn Jerome W
Published: December 2014

We have reported that in mildly diabetic patients increases in plasma insulin are subnormal in response to infused amino acids while others have reported excessive increases in response to ingested protein. Increases in plasma insulin exhibited by nonobese, mildly diabetic patients in response to the ingest ion of protein meals and to the intravenous administration of a mixture of ten essential amino acids were compared to those of healthy nonobese control subjects. The plasma insulin responses to protein meals were also determined in a group of mildly obese, mildly diabetic patients. The results of these studies indicate that: (1) the mean insulin response of nonobese mildly diabetic patients to protein meals is subnormal and not excessive, (2) mildly obese, mildly diabetic patients respond excessively to protein meals as compared to control subjects of normal weight, and (3) the excessiye insulin response to protein meals reported by others to occur in diabetics is probably the result of a greater degree of adiposity in their diabetics than in their control subjects, rather than of the presence of diabetes mellitus. Unless the degree of adiposity is similar in diabetic and healthy subjects, meaningful comparison of their insulin responses to protein meals or other stimuli cannot be made.
Biological Activities of Tolbutamide and Its Metabolites: A Dissociation of Insulin-releasing and Hypoglycemic Activity
Authors: Feldman Jerome M , Lebovitz Harold E
Published: December 2014

Studies carried out with intact and adrenalectomized mice have demonstrated that modification of the tolbutamide molecule causes a dissociation between its insulinreleasing and hypoglycemic activity. Although tolbutamide and hydroxymethyltolbutamide have the same insulin-releasing effect, hydroxymethyltolbutamide has only 35 per cent of the hypoglycemic potency of tolbutamide. Carboxytolbutamide is devoid of hypoglycemic potency despite a definite, but weaker, insulin-releasing action when compared to tolbutamide. Carboxytolbutamide's insulin-releasing activity was confirmed in in vitro studies with golden hamster pancreas. Thus, insulin release is not the only factor involved in the acute hypoglycemic action of sulfonylureas and, indeed, may not even be the major factor.
Effect of Insulin on the Conversion of Glucose-C-14 to C-14-02 by Normal and Diabetic Fibroblasts in Culture
Authors: Goldstein Samuel , Littlefield John W
Published: December 2014

In an attempt to elucidate the basic genetic defect (s) in diabetes, the acute effect of insulin on the conversion of glucose-C-14 to C-14-02 in cultured human diploid fibroblasts was measured under various conditions. Freshly trypsinized cells did not respond to insulin, but after more than sixteen hours in growth medium, a small but significant stimulation, requiring high concentrations of insulin (0.26 U. per ml.) was observed. Stimulation by insulin in various normal strains ranged from 5 to 45 per cent with a mean of 18 per cent (p < .001). C-14-O2 production was approximately linear with time after an initial lag phase and proportional to the number of cells inoculated. Increasing the concentration of glucose in the medium increased C-14-O2 production, with stimulation by insulin apparent at only very low concentrations and at 250 mg. per 100 ml., the highest concentration studied. Experiments comparing the oxidation of glucose-l-C-14 versus glucose-6-C-14 showed that substantial C-14-O2 production occurred via the hexose monophosphate shunt, but that most of the increase in C-14-O2 production in the presence of insulin occurred via the Krebs cycle.

A comparison of basal and insulin-stimulated C-14-O2 production in normal and diabetic fibroblasts revealed no significant differences. Possible explanations for the failure to distinguish between the two groups are discussed.
Early Insulin Synergistic Activity of Growth Hormone
Authors: Mahler Richard J , Szabo Olga
Published: December 2014

Intravenous injection of growth hormone to the intact rat (0.2 mg./100 gm.) causes significant reduction in the blood sugar within twenty minutes of injection. To determine the influence of CH upon insulin destruction, BGH was injected into intact animals and the animals were sacrificed ten minutes later with removal and incubation of kidney and liver slices in I-131-insulin. There resulted a marked reduction in the rate of insulin degradation. In addition, kidney slices and hemidiaphragms obtained from animals injected with BGH ten minutes previously demonstrated enhanced sensitivity to the in vitro effect of insulin upon glucose uptake and glycogen content.

These observations allow the suggestion that the early hypoglycemic activity of growth hormone may be mediated by a transitory impairment of insulin degradation with consequent metabolic effects upon specific tissues.
Effect of Alloxan on the Enzyme Activity of Microdissected Mammalian Pancreatic Islets
Authors: Dixit Padmakar K , Lazarow Arnold
Published: December 2014

Quantitative histochemical methods have been used for the assay of 6-phosphogluconic dehydrogenase (6-PGDH), isocitric dehydrogenase (ICDH), peptidase (PEPT), and adenosine triphosphatase (ATPase) in the microdissected islets and acinar tissue obtained from normal and alloxan diabetic rats.

6-PGDH activity of the islets following alloxanization showed an increase at twelve hours; maximal change was observed at seventy-two hours. There was no consistent and significant increase in the enzyme activity of the acinar tissue following alloxanization.

ICDH activity of rat islet was increased significantly at twelve hours but decreased at twenty-four hours after alloxanization. At forty-eight and seventy-two hours the enzyme activity of the islet returned to normal. Enzyme activity of the acinar tissue showed no particular trend, although at twenty-four hours following alloxanization it was significantly lower than in the controls.

Changes in islet peptidase activity were more marked. Following alloxanization the islet enzyme activity decreased significantly up to twenty-four hours; at forty-eight hours it showed marked increase and was between two- and threefold that of the value at twenty-four hours. It should be noted that this increase in the islet peptidase activity coincides with the period of disappearance of the beta cells.

No immediate effect of alloxan injection was noted on the ATPase activity of the rat islet tissues during the first two hours. This is contrary to the reports of some earlierworkers.
Immunological Properties of Bovine Proinsulin and Related Fractions
Authors: Rubenstein Arthur H , Steiner Donald F , Cho Sooja , Lawrence Ann M , Kirsteins Lidia
Published: December 2014

The immunological interrelationships of bovine proinsulin, its related fractions and insulin are described. Proinsulin has been iodinated and the labeled material purified and characterized. Proinsulin and its intermediate fractions, which could be converted to desalanyl insulin by trypsin, reacted more strongly than insulin or the “nonconvertible” insulin-like material with antiserum to purified proinsulin. The order of reactivity was reversed in favor of insulin when an insulin antiserum was used. Preincubation of the antiserum to purified proinsulin with large quantities of insulin allowed the preferential measurement of bovine proinsulin, and the assay was unaffected by further addition of insulin. The isolated C-peptide from proinsulin was effective in displacing I-131-proinsulin from this antibody.

Human and porcine proinsulin reacted weakly with antisera to bovine proinsulin. The immunological differences between proinsulins are far greater than among the corresponding insulins, and imply that the C-peptide of proinsulin contains major antigenic determinants. It is probable that specific antisera will be needed for the optimal assay of each species of proinsulin.
Some Effects of 1-Methyl-4-(3-Methyl-5-Isoxazolyl) Pyridinium Chloride and Phenformin on Carbohydrate and Lipid Metabolism in Mice
Authors: Blickens D A , Riggi S J
Published: December 2014

1-Methyl-4-(3-methyl-5-isoxazolyl)pyridiniuni chloride (I) was previously reported to be a potent oral hypoglycemic agent in normal and alloxan diabetic animals. The present studies were undertaken to define the effects of I on carbohydrate and lipid metabolism. A comparison with phenformin was also made. Hypoglycemia induced in mice after acute or chronic administration of I was associated with increased skeletal muscle glycogen concentration and lactacidemia. Hepatic glycogen decreased after a single dose of I while increased or unaltered liver glycogen concentration was observed after chronic treatment. The data suggest that compound I may cause hypoglycemia in mice by increasing the uptake of glucose by skeletal muscle. Hypoglycemia, unaltered hepatic glycogen and increased blood lactate and muscle glycogen concentration were observed after a single oral dose of phenformin. Hepatic and plasma triglyceride, sterol and phospholipid levels were unaltered after chronic treatment with I. Phenformin induced a decrease in plasma triglyceride while plasma sterol and phospholipid and liver lipids were unchanged after chronic treatment. These data suggest that I may have clinical utility as an oral hypoglycemic agent.
Cortical Sponge Kidneys Induced in Rats by Alloxan
Authors: Vargas L , Friederici H H R , Maibenco H C
Published: December 2014

Renal changes were studied in rats with short and long-term alloxan diabetes. In the first few days, there was necrosis of cells lining the distal portion of the proximal convoluted tubules, with focal involvement of distal convoluted tubules, and was especially marked at the cortico-medullary junction. Not all tubules were equally affected. Disruption of the tubular basement membrane led to the formation of interstitial granulomas. Regenerating tubular epithelial cells were frequently abnormal, with basophilic cytoplasm and lacking a brush border. Regenerating cells were often flat or cuboidal, and sometimes they formed prominent clusters projecting into the dilated tubular lumen. Cystic tubular dilatation ensued in about 70 per cent of the cases and was very prominent in most of them, leading to a spongy appearance of the cortex. Tubular dilatation was probably due both to abnormal tubular cells and to incomplete tubular obstruction. These changes are different from chronic interstitial nephritis with which they were probably confused in the past. This lesion can be attributed to alloxan directly, with diabetes probably playing a secondary role by interfering with normal tubular regeneration.
Adrenergic Regulation of Insulin Secretion During Fasting in Normal Subjects
Authors: Misbin Robert I , Edgar Paul J , Lockwood Dean H
Published: December 2014

It is well known that a prolonged period of fasting produces, in normal subjects, a “diabetic-like” condition manifested by glucose intolerance and diminished insulin secretion. Administration of the alpha adrenergic blocking agent, phentolamine (Regitine), to healthy fasting subjects caused hyperinsulinemia in response to an intravenous glucose load without amelioration of glucose intolerance. These observations indicate that (1) reversal of hypoinsu-linemia does not acutely alter those factors which cause fasting glucose intolerance, and (2) the increase in sympathetic tone observed during starvation is responsible for the suppression of insulin release. The latter suggests that the autonomic nervous system plays an important physiological role in the regulation of the glucose-insulin axis.
Two-stage Procedure for Total Pancreatectomy in the Rat
Authors: Mieliorini R H
Published: December 2014

A method is described for pancreatectomizing rats in two stages. In the first, most of the gland is excised, including the difficult to remove pancreatic lobes along the bile duct. A small portion, sufficient to prevent the appearance of diabetes, is left near the spleen. In the second stage, performed several weeks later, the remaining pancreas is extirpated rapidly, with minimal surgical trauma and immediate onset of severe diabetes. The time course of the changes in the levels of blood glucose, plasma free fatty acids, acetoacetate and triglycerides within the first twenty-four hours after the operation was studied. The results show that this preparation is very suitable for studying the metabolic effects of acute insulin deprivation in the rat.
Comparison of Different Methods for the Evaluation of the Oral Glucose Tolerance Test
Authors: Kobberling J , Creutzfeldt W
Published: December 2014

Among 746 first degree relatives of diabetics we have performed oral glucose tolerance tests (GTT) very similar to the recommendations of the Committee on Statistics of the American Diabetes Association. The number of pathologic cases according to our method was 223 (or 29.9 per cent), according to the Wilkerson Point System 95 (or 12.7 per cent), according to the criteria of Fajans and Conn 213 (or 28.6 per cent) and after the University Group Diabetes Program 196 (or 26.3 per cent). For subgroups of different sex, age and body weight the relations were similar. The main difference between the four methods consists in a different sensitivity in finding pathologic test results. In addition the different methods of evaluation do not indicate the same subjects as being diabetic. 20 to 25 per cent of the diabetics with one method are nondiabetic with another despite the same over-all number of diabetics found. A fifth method is proposed which seems to be superior to all the other methods because the sum of those cases which are positive or negative only with this method is the lowest. According to this method a person is diabetic if the sum of the one-hour and the two-hour values of the GTT is 300 mg./100 ml. or more. Two hundred and forty-six (or 33.0 per cent) of our probands were diagnosed diabetic with this method. Onlyby followup studies will a decision be possible as to which method of evaluation of the GTT givesthe best results, i.e., the lowest number of false positive and false negative cases.
Synthesis of Liver Glycogen in Starved Alloxan Diabetic Rats
Authors: Hornbrook K Roger
Published: December 2014

Alloxan diabetic rats are considered unable to synthesize liver glycogen because of a low activity of glycogen synthetase. The present report shows, however, that livers of alloxan diabetic rats have activities of the I-form of glycogen synthetase intermediate between those of starved normal or adrenalectomized rats, and can synthesize substantial amounts of liver glycogenafter refeeding of a chow diet or administration of hydrocortisone. Neither glycogenic procedure, increased the activity of glycogen synthetase in livers of starved alloxan diabetic rats. In contrast, both normal and adrenalectomized rats had increased activities of the I-form of glycogen synthetase three hours after refeeding.

After twenty-four hours of access to food, normal and adrenalectomized rats had liver glycogen contents similar to those found in nonstarved rats, and a markedly decreased activity of synthetase I. Alloxan diabetic rats refed for twenty-four hours also had lowered activity of synthetase I, but the concentration of glycogen was not higher than that found after three hours of refeeding.

These results show that livers of alloxan diabetic rats have sufficient glycogen synthetase activity to synthesize glycogen rapidly, but the ability to accumulate larger amounts of glycogen is limited by an alteration in the control of glycogen synthetase activity by the content of liver glycogen. Also, the effect of hydrocortisone on the activity of glycogen synthetase in normal or adrenalectomized rats is the result of insulin release; however, not all the changes in glycogen metabolism produced by adrenalectomy can be explained by insulin deficiency.