bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of Acid Regular and Neutral Regular Insulin: Responses of Normal Fasted Subjects to Varying Doses of Regular Insulin
Authors: Galloway John A , Root Mary A , Rathmacher Robert P , Carmichael Ralph H
Published: December 2014

Acid Regular insulin (ARI) and neutral Regular insulin (NRI) were compared in normalfasting subjects by means of a Latin-square experimental design. Both blood glucose and serum immunoreactive insulin were measured after the administration of 0.1 and 0.2 U. per kilogram intravenously, and 0.1, 0.2, and 0.3 U. per kilogram subcutaneously. No statistically significant differences were detected between ARI and NRI.

Analysis of blood glucose and serum insulin data pooled from the ARI and NRI treatments disclosed resistance to increasing doses of insulin as the blood glucose fell below 50 to 60 mg. per 100 ml. Thus, relatively small increments in hypoglycemic activity occurred when the intravenous dose was doubled from 0.1 to 0.2 U. per kilogram or the subcutaneous dose increased from 0.2 to 0.3 U. per kilogram in spite of doubling the hypoglycemic effect when the subcutaneous dose was doubled from 0.1 to 0.2 U. per kilogram. In addition, for each 0.1 U. per kilogram of subcutaneouslyadministered insulin the maximum serum levels were approximately 15 to 30 μU. per milliliter andthe duration of effect was extended by one hour. Therefore, following 0.1 U. per kilogram the maximum effect was over by three hours, after 0.2 U. per kilogram by four hours, and 0.3 U. per kilogram by five hours. These results demonstrate the feasibility of studying the time action of insulin in normal subjects and document the conclusion that duration of effect is a function of the dose given.
Influence of Nicotinamide and Pyridine Nucleotides on Streptozotocin and Alloxan Induced Pancreatic B Cell Cytotoxicity
Authors: Lazarus Sydney S , Shapiro Stanley H
Published: December 2014

Pancreas from mice treated with 500 ing. per kilogram of nicotinamide intraperitoneally fifteen minutes before 200 nig. per kilogram of streptozotocin intravenously showed mostly unaltered islet B cells after eight, eighteen or fortyeight hours. Mice pretreated with 1,500 mg. per kilogram of either NAD, NADP or NADPH intraperitoneally showed almost no B cell lesions at eight hours. At eighteen hours some B cell necrohiosis was observed but of lesser extent than that seen after streptozotocin alone at eight hours. At forty-eight hours B cells showed diffuse, uniform necrobiosis only slightly less extensive than that seen in the group treated with streptozotocin alone.

Pretreatment of mice with 500 mg. per kilogram nicotinamide intraperitoneally fifteen minutes before 100 mg. per kilogram alloxan intravenously failed to alter the extent of islet B cell lesions at eighteen hours. When the dosage of nicotinamide administered was increased to 1,000 mg. per kilogram and the time of pretreatment at this dose level increased to sixty minutes there was a slight decrease in the extent of B cell necrosis. Islets from rats pretreated with 1,000 mg. per kilogram nicotinamide intravenously sixty minutes prior to alloxan also showed a general lack of protective influence. Under the same conditions nicotinamide completely protected rats against the B cell cytotoxicity of streptozotocin.

These findings demonstrate the almost specific protective action of nicotinamide against streptozotocin-induced B cell necrosis. While pyridine nucleotides slowed its development they did not prevent B cell necrosis after streptozotocin. The dissimilarity in the action of nicotinamide and pyridine nucleotides makes doubtful the view that streptozotocin-induced B cell necrosis is mediated via lowering of cellular content of NAD or other pyridine nucleotides below critical levels. The minimal protection afforded by nicotinamide against alloxan-induced B cell necrosis, as contrasted with its effectiveness against streptozotocin, confirms the view that the basic mechanisms of action of these drugs are different despite comparable selective B cell cytotoxicity.
Adipose Tissue Cellularity and Metabolism in Newly Diagnosed Juvenile Diabetics
Authors: Ginsberg-Fellner Fredda , Knittle Jerome L
Published: December 2014

Adipose tissue cell number and size were determined in ten juvenile diabetics, ages one to seventeen, four of whom had a history of significant obesity antedating development of symptomatic glucosuria. Studies were performed at the time of diagnosis (before administration of insulin) and two to twenty-five months after institution of therapy. Results were compared with those found in a group of thirtyfour children of normal weight with no blood sugar abnormalities. An increase in adipose cell number was documented while adipose cell size was significantly decreased in the diabetics in both study periods. Weight gain after insulin treatment was due primarily to an increase in total body fat, which was reflected by increased cell size. However, the cells were still significantly smaller than normal. Cell number was not increased by the insulin treatment. In vitro studies of glycerol release revealed blunting of epinephrine-stimulated lipolysis, compatible with diminished adenylcyclase or cyclic AMP activity. However, the effects of in vitro insulin upon glycerol release and upon conversion of glucose l-C-14 to 14-CO2 did not differ from results in normal controls. Baseline values of glycerol release were related to the presence of acidosis, while hormonal responses were unchanged after therapy. Thus, adipose tissue hypercellularity is present at the time of diagnosis of insulin-requiring diabetes mellitus in children and is not accompanied by adipose tissue peripheral “insulin resistance” as measured by two different parameters. A possible role for growth hormone in the development of this hypercellularity, which is also present in childhood obesity, is presented.
Effect of Arginine on Glucose Turnover and Plasma Free Fatty Acids in Normal Dogs
Authors: Cherrington A D , Vranic M
Published: December 2014

Arginine infusion is known to increase the plasma levels of both imniunoreactive insulin and glucagon, while it changes the plasma glucose concentration only slightly. In order to clarify the metabolic consequences of glucagon and insulin mobilization induced by arginine, we investigated the effects of this amino acid on the turnover and plasma concentration of glucose, and on the plasma concentration of free fatty acids (FFA) in seven normal dogs. Infusion of arginine hydrochloride induced a biphasic release of insulin, which in turn increased the over-all rate of glucose utilization by 40 per cent. There was, however, only a slight increase in plasma glucose concentration (4 per cent) since the rate of glucose production increased to the same extent as the rate of glucose utilization. We have concluded that the biphasic pattern of insulin release not only reflects the secretory capacity of β cells, but also plays an essential metabolic role in maintaining a balance between the production and utilization of glucose during an arginine challenge. The observed increase in glucose production is attributed to the release of glucagon; this release is essential if normoglycemia is to be maintained. The concentration of FFA in plasma decreased by 50 per cent during infusion of the amino acid. In the dog, arginine infusion rapidly reverses the pattern of fuel utilization characteristic of fasting; the release of free fatty acids from fat depots is inhibited, while the turnover of glucose is enhanced even though normoglycemia is maintained.
Potentiation of Tolbutamide-mediated Insulin Release in Adult Onset Diabetics by Methysergide Maleate
Authors: Baldridge John A , Quickel Kenneth E , Feldman Jerome M , Lebovitz Harold E
Published: December 2014

The effect of placebo or methysergide (2 mg. every six hours) on the plasma glucose and insulin response to 1 gm. of intravenous tolbutamide was studied in eighteen patients with adult onset diabetes mellitus. Neither placebo nor methysergide caused any alteration in the hypoglycemic action of tolbutamide as compared to control tolbutamide studies. Tolbutamide-stimulated insulin secretion after two days of placebo administration was not significantly different from results in the control tolbutamide studies (−6.1 ± 9.8 per cent, mean ± S.E.). Methysergide pretreatment resulted in a significant potentiation of tolbutamide-mediated insulin secretion (39.3 ± 6.1 per cent) as compared to responses in the control tolbutamide studies. The present data indicate that methysergide potentiates tolbutamide – as well as glucose-mediated insulin secretion in patients with adult onset diabetes mellitus.
Hypoglycemia Due to Apparent Autoantibodies to Insulin: Characterization of Insulin-binding Protein
Authors: Ohneda Akira , Matsuda Kiyoshi , Sato Munehiko , Yamagata Shoichi , Sato Toshio
Published: December 2014

A fifty-two year old female, admitted when unconscious, had a blood glucose level of 33 mg./100 ml. Glucose injection restored consciousness, and oral glucose loading revealed a diabetic curve. Hypoglycemic coma was not produced by tolbutamide. Total immunoreactive insulin extracted from fasting plasma ranged from 824 to 1,400 μU. per milliliter. Laparotomy did not reveal adenoma of the pancreas. The specimen of the pancreas contained 3.8 U. of insulin per gram and histologically showed an increase in the numbers of islets.

Her plasma was proved to bind 131-I-insulin by gel filtration, paper chromatography and dextran-coated charcoal methods. The binding protein was identified to be gamma globulin upon paper electrophoresis and was absorbed by anti–human globulin rabbit serum. The gamma globulin was characterized as IgG on immunoelectrophoresis with radioautography. Protein fractions from the patient's plasma, freed from insulin by gel filtration after acidification, reacted with pork, beef or human insulin, and dose response curves were depicted. With bonito insulin, however, it did not show any immunologic reaction. A positive skin anaphylaxis reaction was demonstrated in a guinea pig immunized with the patient's plasma, but no precipitation reaction was observed.

Since the patient had never received insulin injections, the results suggest that the insulin-binding protein contains antibodies which are produced against endogenous insulin.
Insulin Potentiating Action of Synthetic Peptides Relating to the Amino Terminal Sequence of Human Growth Hormone
Authors: Ng Frank M , Bornstein Joseph , Welker Charles , Zimmet Paul Z , Taft Pincus
Published: December 2014

Various synthetic fragments of the amino terminal sequence of human growth hormone (HGH) have been studied with respect to their in vitro action on glucose uptake and in vivo insulin potentiating effects. The results show that the biologic activities so far investigated are confined to sequences containing the octapeptide, Leu-Ser-Arg- Leu-Phe-Asp- Asn-Ala.

There is also a correlation between the in vitro reversal of somantin induced inhibition of glyceraldehyde-3-phosphate dehy-drogenase by the active peptides and their insulin potentiating effect in vivo. The GAPD system provides a convenient and rapid means for monitoring such peptides, but its physiologic significance is at present in doubt.

Large doses (10 mg./kg. body weight) of the active peptide HGH 1-15 do not increase the degree of lowering of blood glucose, but prolong the effect of the peptide and depress plasma immunoreac-tive insulin (IRI) in rabbits.

The mechanism of action of the active sequence has not been established at present, and the physiological significance is not yet known.
Work Absenteeism in Diabetics
Authors: Moore Robert H , Buschbom Ray L
Published: December 2014

A new study of work absentee statistics was made of 108 employed diabetics, observed for an average of 4.3 years. The individuals in this group were absent on an average of 6.3 days per work year. The diabetic study group, age-matched to other studies of absenteeism in nondiabetics, compared favorably with the non-diabetics.
Impotence and Diabetes: Histological Studies of the Autonomic Nervous Fibers of the Corpora Cavernosa in Impotent Diabetic Males
Authors: Faerman Isaac , Glocer Leticia , Fox Dora , Jadzinsky Mauricio N , Rapaport Mauricio
Published: December 2014

Normal androgenic function has already been reported elsewhere as a fact in impotent diabetic males. Many of these patients show some type of visceral or peripheral diabetic neuropathy. Looking for a possible neurological origin for impotence in diabetic men, we have undertaken the present study, analyzing the autonomic nervous fibers of the corpora cavernosa of the penis by means of light microscopy.

In five autopsies of impotent diabetics, mean age 51, with an average duration of diabetes of 9.6 years, the following stainings were made: hematoxylin-eosin, P.A.S. and silver impregnations. Out of five cases, four showed morphological alterations of varying degrees (hyperargentophilia, beaded thickening, spindle shaped thickening, and argentophilic spherical swellings).

No correlations were found with diabetic microangiopathy. Only one of the diabetics did not show any lesion. The control group, five non-impotent, nondiabetic patients of similar age, did not show alterations at all.

This first study of the autonomic nervous system in the corpora cavernosa of impotent diabetics lends strong support to the idea that their sexual impotence is due to a neurological lesion of the nerve fibers that control erection.
Circadian Variation of the Blood Glucose, Plasma Insulin and Human Growth Hormone Levels in Response to an Oral Glucose Load in Normal Subjects
Authors: Aparicio Néstor J , Puchulu Félix E , Gagliardino Juan J , Ruiz Maximino , Llorens Jóse M , Ruiz Jorge , Lamas Aldo , Miguel Raul De
Published: December 2014

Circadian variations in blood glucose, plasma insulin and human growth hormone response were studied in six healthy males who received 100 gm. oral glucose loads at 6 a.m., noon, 6 p.m., and midnight. The tests were conducted at seven day intervals, and each was preceded by a ten hour fast. During the three days before each test the subjects received meals containing no less than 300 gm. carbohydrate per day. Blood samples were drawn at 0, 15, 30, 60, 90, 120, and 180 minutes. A clear circadian variation occurred in the blood glucose levels, with lower values in the morning and higher values at 6 p.m. and midnight. The insulin profiles showed a trend toward lower afternoon and night values, with a noon peak. The afternoon insulin-glucose ratios were significantly lower. HGH values were inconsistent and tended toward higher afternoon and night basal levels. The results confirm the existence of a circadian variation in the blood glucose response to oral glucose loads in healthy men. This might in turn result from a circadian variation in the insulin response, probably secondary to changes in the pancreatic β cell sensitivity to glucose. This basic mechanism is believed to sustain the conditioning influence of other hormones, HGH being one of them.
Effect of a Fat Free, High Carbohydrate Diet on Diabetic Subjects with Fasting Hyperglycemia
Authors: Brunzell John D , Lerner Roger L , Porte Daniel , Bierman Edwin L
Published: December 2014

Fasting plasma glucose levels and glycosuria were measured in untreated diabetic subjects on basal and on fat free, high carbohydrate diets. On the high carbohydrate diet the mean fasting plasma glucose was slightly, but not significantly, increased by 15 mg./100 ml. and the twenty-four hour excretion of glucose was increased by 56 gm./24 hr. (p < .02). Five of these subjects were restudied following insulin or oral sulfonylurea therapy, and four similar patients were studied only while on this therapy. In these treated diabetic subjects receiving the high carbohydrate diet, fasting plasma glucose was significantly decreased by 22 mg./100 ml. plasma (p < . 0 2); glycosuria did not change. Thus, among diabetics, only those who remain untreated have worsened glucose tolerance on fat free, high carbohydrate diets.
Treatment of Streptozotocin Diabetes with Di-isopropylammonium Dichloroacetate (DIPA)
Authors: Eichner Harvey L , Stacpoole Peter W , Forsham Peter H
Published: December 2014

Streptozotocin-diabetic rats were treated with di-isopropylammonium dichloroacetate (DIPA) via an orogastric tube in doses of 25 or 50 mg./l kg. twice daily for one week. In nonketotic animals, mean blood glucose concentration decreased significantly during treatment with either DIPA or its acid moiety, sodium dichloroacetate. Neither di-isopropylammonium hydrochloride nor saline reduced hyperglycemia in the diabetic rats. There was no change in the blood glucose of nondiabetic rats in response to DIPA. In ketotic diabetes produced by streptozotocin, 63 per cent of DIPA-treated animals survived after one week, compared to 24 per cent of those given saline. DIPA did not influence glucose absorption in isolated everted jejunal sacs from diabetic and normal rats, while phenformin inhibited transport by more than 50 per cent Thus DIPA, which only partially mimics insulin in its actions and does not stimulate insulin release as do the sulfonylureas, also fails to duplicate the effects of phenformin and appears to have a unique mode of action. DIPA is an effective oral hypoglycemic agent in streptozotocin-diabetic rats.
Portal and Peripheral Vein Immunoreactive Glucagon Concentrations After Arginine or Glucose Infusions
Authors: Blackard William G , Nelson Norman C , Andrews Samuel S
Published: December 2014

Catheterization of the portal vein via the umbilical vein was performed under local anesthesia in eight nondiabetic subjects before exploratory laparotomy for a variety of conditions. Levels of immunoreactive glucagon (IRG) and immunoreactive insulin (IRI) were determined in simultaneously obtained portal and peripheral vein plasma before, during and after a fifteen minute arginine infusion (30 gm.) in five subjects. The mean portal vein to peripheral vein glucagon ratio in the postabsorptive state was 1.7 ± 0.5. A biphasic portal vein IRG response to arginine was observed, with the initial glucagon peak occurring within one minute of the beginning of the infusion. Peripheral IRG concentrations did not reflect the biphasic response. The portal vein IRI response to arginine was also mildly biphasic, and the first phase occurred before a detectable increase in blood glucose. The portal vein IRG peak either preceded or coincided temporally with the portal vein IRI peak. In three nondiabetic subjects, portal vein IRG decreased rapidly to its nadir within two minutes after a two minute glucose infusion (25 gm.) was started.
Insulin Receptors in Human and Animal Placental Tissue
Authors: Posner Barry I
Published: December 2014

The existence of polypeptide hormone receptors in the human placenta was evaluated by studying the specific binding of 125-I-labeled insulin, human growth hormone (hGH), human pro lac tin (hPRL) and glucagon to a defined placental membrane fraction. Only insulin showed specific binding to placental membranes. The binding of 125-I-insulin was time and temperature dependent. Its dissociation from the membrane was first order with a half time, at 24° C, of twenty minutes. Specific binding was readily observed at a concentration of 5 × 10−11 (7.5 μU./ml.). Inhibition of 125-I-insulin binding by unlabeled insulin was 30 per cent at 10−9 M, and >90 per cent at 10−9 M. Desalanine insulin was equally effective in inhibiting the binding of 125-I-insulin. Proinsulin was about twenty times less effective, and desoctapeptide insulin was even less effective. Structurally unrelated polypeptide hormones were without significant inhibitory effect. Binding sites of relatively high affinity (K1 = 4.2 × 108 M−1) and low capacity could be distinguished from those of lower affinity (K2 = 0.7 × 108M−1) and higher capacity. Insulin degrading activity was shown to be present in the placental membranes. Under standard binding assay conditions, less than 20 per cent of the 125-I-insulin present was degraded. The 125-I-insulin could be eluted from the membranes and appeared intact by several criteria. Specific binding was augmented by Ca++ and other divalent cations but was unaffected by high sodium chloride concentrations. Binding was greatly reduced by pretreatment of membranes with proteolytic enzymes. Incubation with phospholipase C, RNase and neur-aminidase had relatively little effect on binding.

Insulin binding was unaffected by maternal diabetes but was reduced in membranes from early gestational placentas. There was considerable species variation in insulin binding, with the placental membranes of the guinea pig and monkey having the highest and those of the rat having the lowest binding.

The characteristics of the insulin binding sites in the human placenta are similar to those in established insulin target tissues.
Reticuloendothelial System Phagocytosis in Diabetes Mellitus
Authors: Berken Arthur , Sherman Abraham A
Published: December 2014

Phagocytosis of the reticuloendothelial system, measured by clearance of radioiodinated microaggregated human serum albumin, was not significantly different among diabetics, with or without retinopathy, and nondiabetics. The findings are compatible with those of other studies that fail to demonstrate defective antibacterial defense mechanisms in the nonketotic diabetic. Review of tnese studies suggests that any decrease in resistance to infection in the nonketotic diabetic may be due to pronounced hyperglycemia, a remediable factor.
Nonketotic Hyperosmolar Coma and Frusemide Therapy
Authors: Lavender S , McGill R J
Published: December 2014

Nonketotic hyperosmolar diabetic coma developed in a patient with congestive cardiac failure who was treated with frusemide. With the introduction of large doses of frusemide for resistant edema the authors suggest that particular care be taken to exclude the development of diabetes mellitus. Hyperglycemia in a patient with an already established diuresis may lead to lethal hyperosmolar coma.
Diazoxide Modification of Streptozotocin-induced Diabetes in Rats
Authors: Culbert S , Sharp R , Rogers M , Felts P , Burr I M
Published: December 2014

Diazoxide was found to modify streptozotocin-induced diabetes in rats when given twelve hours and one hour before streptozotocin. In contrast to rats treated with streptozotocin alone, rats treated with diazoxide, 15 or 30 mg./kg., plus streptozotocin, 30 mg./kg., did not become clinically diabetic and had fasting blood glucose levels within the normal range. Diazoxide pretreatment protected against streptozotocin-induced glucose intolerance as defined by response to intraperitoneal glucose. Further, the immunoreactive insulin response to intraperitoneal glucose in the rats treated with both diazoxide and streptozotocin differed from the control value only at sixty minutes. It is possible that the protective effect of diazoxide is mediated through the adrenergic-like activity of diazoxide on the β-cell.
Enzymes of Glucose Metabolism in Liver of Subjects with Adult-onset Diabetes
Authors: Belfiore Francesco , Romeo Francesco , Napoli Elena , Vecchio Luigi Lo
Published: December 2014

An enzyme study was made on needle biopsy specimens of liver from thirty-two subjects with adult-onset diabetes and normal body weight and thirty-two controls. The enzyme pattern in the patients with diabetes was different from that seen with alloxan diabetes.

The activities of the two glucose phosphorylating enzymes tested were changed in opposite directions, hexokinase being enhanced and glucokinase moderately decreased. Total glucose phosphotransferase activity remained unchanged.

Phosphofructokinase had a reduced activity, which suggested depressed glycolysis, especially if considered together with the enhanced activity of the opposing enzyme, fructose-1, 6-diphosphatase. Normal activity was found for most other glycolytic enzymes, as well as for key gluconeogenic enzymes, including glutamic oxalacetic and glutamic pyruvic transaminases, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. The finding suggests normal glucose release.

Glucose-6-phosphate- and 6-phosphogluconate dehydrogenase activity was elevated. This would indicate an increased metabolism of glucose through the oxidative pathway and, therefore, increased formation of NADPH. This metabolic condition, which is known to favor fatty acid synthesis, might contribute to fatty liver changes. On the other hand, NADP-isocitrate dehydrogenase, which does not provide NADPH for fatty acid synthesis, was little changed.
Assessors of Fetal Perinatal Mortality in Diabetic Pregnancy: Analysis of 1,332 Pregnancies in the Copenhagen Series, 1946–1972
Authors: Pedersen Jøhrgen , Mølsted-Pedersen Lars , Andersen Bjørn
Published: December 2014

In a series of 1,332 pregnancies in women with diabetes, perinatal fetal mortality varied in a statistically significant degree, with maternal factors and pregnancy complications expressed respectively, by the White and PBSP classifications. Also, mortality declined steadily over the years 1946 to 1972. Fatal congenital malformation was the most important single cause of perinatal death in recent years.

A controlled trial must take into account the year of admission as well as the White and PBSP classifications; with the prevailing low and decreasing mortality, even large centers may be unable to fulfill the requirements as to sample size within a few years. Therefore, criteria other than perinatal mortality may be needed to assess the value of changes in treatment.
An Artificial Endocrine Pancreas
Authors: Albisser A M , Leibel B S , Ewart T G , Davidovac Z , Botz C K , Zingg W
Published: December 2014

In order to regulate the blood sugar in the intact depancreatized dog as precisely as that accomplished by its normal pancreas, specific equipment has been devised to deliver insulin or glucose continuously and establish normoglycemia both in the fasting and glucose-loaded states. A minicomputer was programmed to respond to the constantly monitored whole blood glucose by injecting appropriate insulin or glucose intravenously to maintain or restore the normal blood sugar.

Standardized glucose challenges consisting of uniform infusions of 10 mg. glucose per kg. min. for sixty minutes were applied to assess the performance of the artificial pancreas. Direct control which relates insulin dosage to the level of the circulating blood sugar results in a response to the challenge resembling mild maturity-onset diabetes both in the abnormally high blood sugar response to glucose loading and in the large amount of insulin required to effect a return to normoglycemia. In contrast, control based on projected (predicted) values of blood sugar not only prevents the abnormal rise but consumes in some cases only 10 per cent of the insulin used for the same glucose load. The performance of the system parallels that of the normal pancreas and lends support to the hypothesis that biphasic insulin responses to glucose challenges are essential for the economy of insulin and the precision of regulation seen in healthy subjects.
Metabolic Effects of Sodium Bicarbonate in Management of Diabetic Ketoacidosis
Authors: Assal Jean-Ph , Aoki Thomas T , Manzano Francisco M , Kozak George P
Published: December 2014

Biochemical analyses of blood and cerebrospinal fluid of nine patients with diabetic ketoacidosis and impaired levels of consciousness were performed before and after four hours of intravenous therapy with insulin, saline, and bicarbonate. A comparison with previously reported data from a similar group of patients treated with insulin and saline alone revealed no significant differences in blood or cerebrospinal fluid with the following exceptions. First, the fall in CSF osmolality was significantly less after insulinsaline-bicarbonate therapy than in patients receiving only insulin and saline. Second, CSF pH values declined in both groups with therapy but were significantly lower in the group receiving insulin-saline-bicarbonate. Definite and progressive clinical improvement was noted in all nine patients from admission to discharge. It was concluded that the use of sodium bicarbonate did not discernibly alter the clinical course of the nine patients studied except for the unexplained slower decline in CSF osmolality. The use of NaHCO3 appears to be indicated primarily in situations in which prompt correction of metabolic acidosis is essential, e.g., to improve cardiovascular function.
Relationship Between Insulin Response During the Intravenous Glucose Tolerance Test, Rate of Fractional Glucose Removal and the Degree of Insulin Resistance in Normal Adults
Authors: Reaven Gerald M , Olefsky Jerrold M
Published: December 2014

We studied the relationship between the absolute insulin response during the intravenous glucose tolerance test (IVGTT) and both the fractional glucose disposal rate (KG) during the IVGTT and the degree of insulin resistance as measured by a separate infusion study, the pancreatic suppression test (PST), in normal adults. Insulin response during the IVGTT was analyzed in four ways: (1) early (area under the one, three and five minute response curve); (2) middle (ten minute insulin value); (3) late (area under the twenty to sixty minute response curve); and (4) total (area under the entire response curve). Only weak to modest correlations existed between the four measures of insulin response and KG, and the only statistically significant correlation (r = .39, p < .05) existed between the middle insulin response and KG. However, significant correlations were found between the degree of insulin resistance measured during the PST and the early (r = .40, p < .05), middle (r = .59, p < .005), late (r = .71, p < .001) and total (r = .66, p < .001) insulin responses. Whereas the height of the insulin response during an IVGTT has only a modest correlation with the KG, it correlates quite well with the degree of insulin resistance.
Glucose Oxidation (14-CO2 Production) and Insulin Secretion by Pancreatic Islets Isolated from Hyperglycemic and Normoglycemic Rats
Authors: Cole Edward H , Logothetopoulos John
Published: December 2014

Pancreatic islets from glucose-infused rats retained a “memory” of the hyperglycemic environment, (a) They oxidized (14-CO2 production) glucose-U-14-C and glucose-6-14-C at rates three to four times higher than islets from normoglycemic rats. Inhibitors of insulin secretion and synthesis did not affect the rates of 14-C2 production. In contrast, ouabain (1 mM) decreased glucose oxidation by nearly 50 per cent, (b) They secreted insulin in vitro at rates similar to those of islets of control rats, in spite of the heavy degranulation of their beta cells.
Plasma Proinsulin: Comparison of Insulin Specific Protease and Gel Filtration Assays
Authors: Cresto Juan C , Lavine Robert L , Fink Gloria , Recant Lillian
Published: December 2014

Our laboratory has had a good experience using the gel filtration assay for proinsulin. Since the proteolytic enzymatic assay for proinsulin has the reported advantage of being simpler and requiring less plasma per assay, a comparison was made of the enzyme and gel filtration assays for plasma proinsulin. The proteolytic enzyme was prepared from rat muscle and a 30 to 60 per cent ammonium sulfate fraction was used. The kinetics of the enzyme were characterized with regard to substrate concentration (proinsulin and insulin), enzyme concentration, time of incubation and effect of plasma. The studies of enzyme using labeled substrates revealed identical behavior as with cold substrates. The Km for insulin was .476 × 10−6M and for proinsulin was .956 × 10−6M. Lineweaver-Burk plot showed competitive inhibition between insulin and proinsulin. A noncompetitive inhibitor of the enzyme was identified in a plasma sample from a “normal” human subject.

The plasma proinsulin assay was performed as described by Kitabchi et al. with the modification that each plasma had an internal control incubated with labeled insulin or proinsulin. It was seen that the activity of the enzyme was somewhat variable in different plasmas. In noninsulinoma samples of plasma, the per cent proinsulin varied between 0 and 72 per cent. In the insulinoma plasmas, the values were 30 to 143 per cent. Twenty-one samples were compared with the gel filtration assay for proinsulin. This latter procedure utilizes G-50 Sephadex columns with size separation of proinsulin and insulin. Enzymatic assay values appeared consistently higher but still had a degree of correlation with those obtained by column. However, the enzyme assay has significant limitations both in screening of normal subjects as well as in diagnosing insulinomas, since false high proinsulin values may be found.

Gel filtration appears at this point in time to be the most reliable method for assay of plasma proinsulin-like material.
Effect of Alloxan on Insulin Secretion in Isolated Rat Islets Perifused in Vitro
Authors: Tomita Tatsuo , Lacy Paul E , Matschinsky Franz M , McDaniel Michael L
Published: December 2014

Isolated rat islets were maintained in vitro in a simple perifusion system and the rate of insulin secretion was maintained throughout the period of perifusion. Exposure of the perifused islets to alloxan (20 mg. per cent) for a period of five minutes produced complete inhibition of subsequent glucose-induced insulin secretion with retention of basal secretion. Glucose, mannose and 3-0 methyl glucose provided complete or almost complete protection of the perifused islets from the inhibitory effect of alloxan on glucose-induced insulin release. The order of potencies of various hexoses to protect against alloxan toxicity in vitro was glucose (100 ⋝ 3−0 methyl glucose ⋝ mannose > 2-deoxyglucose > galactose > fructose ≫ L-glucose (0). Mannoheptulose diminished but did not abolish the protective effect of glucose against alloxan. The first phase of tolbutamide-induced secretion was retained after exposure to alloxan. This finding indicated that the beta cells were still viable and suggests that a separate receptor or transport site for tolbutamide may exist on the beta cell. The possible mechanisms by which the hexoses protect the beta cells from alloxan are discussed.
Effects of Different Prostaglandins on Glucose Kinetics in the Rat
Authors: Sacca L , Perez G , Rengo F , Condorelli M
Published: December 2014

The primed constant infusion of glucose-2−3H was used to study the influence of prostaglandins (PGs) infusion (2μg./min.) on glucose turnover in intact rats in the postabsorptive state. While PGA1 did not exert any appreciable effect on glucose production by the liver and on plasma glucose levels, prostaglandins of E-series significantly increased hepatic glucose output and consequently plasma glucose levels. In this regard, PGE1 appeared more effective than PGE2. In some experiments PGE1 was infused for two hours at the dose of 1.5μg./xmin.: glucose concentration rose to a maximum of 127 per cent above the control values and glucose production reached during the second hour of the infusion a level twice the base line (from 8.1 ±0.5 to 16.9±0.5 mg./kg. body weight/min.). These changes were paralleled by a proportional increase in glucose uptake by peripheral tissues which reached a level very near to that of hepatic output toward the end of the infusion.
Insulin and Glucagon Degradation by the Same Enzyme
Authors: Duckworth William C , Kitabchi Abbas E
Published: December 2014

An insulin-degrading enzyme has been previously isolated from rat skeletal muscle and highly purified by a series of procedures including affinity chromatography on insulin-agarose. Glucagon-degrading activity was also found in each of the purification steps including the final highly purified material. Insulin- and glucagon-degrading activities were associated with the same band on polyacrylamide gel and both activities were obtained from affinity chromatography on glucagon-agarose.

Insulin- and glucagon-degrading activities could not be differentiated by the effect of sulfhydryl reagents, pH, or by heat inactiva-tion. Insulin served as a competitive inhibitor of glucagon degradation (Ki = 1.5 × 10−8M) and glucagon was a competitive inhibitor of insulin degradation (Ki = 5.3 × 10−6M).

On the basis of these studies it appears that insulin and glucagon can be degraded by the same enzyme which is found in the soluble fraction of rat skeletal muscle homogenate.
Electrocardiogram as a Guide to Potassium Replacement in Diabetic Ketoacidosis
Authors: Soler N G , Bennett M A , Fitzgerald M G , Malins J M
Published: December 2014

Twenty-three patients in severe diabetic ketoacidosis were followed by continuous electrocardiographic monitoring using Lead II of the electrocardiogram throughout their course of treatment. Frequent serum potassium determinations were carried out and correlated with the ECG changes. On admission to hospital the electrocardiogram of ketoacidotic patients showed varied T wave patterns often with little correlation to the serum potassium, but the two patients who were initially hypokalemic were identified from the ECG appearances. Following the infusion of fluids alone the serum potassium fell with accompanying T wave and ST segment changes while the administration of potassium reversed these abnormalities. Although the electrocardiogram is not a substitute for serum potassium determinations, it is a useful guide to potassium replacement in diabetic ketoacidosis. In the successful management of this diabetic emergency the achievement and maintenance of a normal ECG, by means of early and continuous administration of potassium in the infused fluids, should be an important objective of treatment.
Changes in Immunospecificity and Biologic Activity of Bovine Insulin Due to Subsequent Removal of the Amino Acids B1, B2 and B3
Authors: Kerp L , Steinhilber S , Kasemir H , Han J , Henrichs H R , Geiger R
Published: December 2014

The influence of splitting off the N-terminal amino acids B1, B2 and B3 of bovine insulin on the binding of these derivatives to antibodies raised with bovine insulin in guinea pigs and on biologic insulin activities is investigated.

In comparison with bovine insulin the standard free energies −ΔF°1 for complex formation between high affinity antibodies Ak1 and des-PheB1-insulin or des-(Phe-Val)B1-2-insulin are reduced to 77 per cent and 76.3 per cent respectively, with a further decrease to 68 per cent for des-(Phe-Val-Asn)B1-3-[PyrB4] insulin.

The standard free energy -ΔF°2 for complex formation between low affinity antibodies Ak2 and des-PheB1-insulin drops to 48.4 per cent. Further splitting off of the N-terminal amino acids B2 and B3 completely abolishes the antigen binding to Ak2.

The ability of both des-PheB1-insulin and des-(Phe-Val)B1-2-insulin to lower the in vivo blood sugar level does not differ significantly from bovine insulin, whereas the in vivo activity of des-(Phe-Val-Asn)B1-3-[PyrB4] insulin decreases to 70±7 per cent.

The in vitro biologic activity, tested on isolated fat cells, is slightly reduced to 89±9 per cent for des-PheB1-insulin, to 86±3 per cent for des-(Phe-Val)B1-2-insulin and to 68±6 per cent for des-(Phe-Val-Asn) B1-3-[PyrB4] insulin.
Pancreatic Islet Transplantation: Effects on the Glomerular Lesions of Experimental Diabetes in the Rat
Authors: Mauer S Michael , Sutherland David E R , Steffes Michael W , Leonard Robert J , Najarian John S , Michael Alfred F , Brown David M
Published: December 2014

Diabetes was induced in Lewis rats with streptozotocin. Six to nine months later glomeruli showed significant mesangial matrix thickening; by immunofluorescent microscopy large quantities of IgG, (β1C and in some instances, IgM were seen in a mesangial distribution. Sustained normoglycemia was then achieved in nine of these animals by successful pancreatic islet isotransplantation. Three months following transplantation five of these animals had decreased mesangial matrix while four had no further progression of glomerular lesions. All had a marked decrease in IgG, IgM and β iC in the mesangium. In contrast, untreated diabetic rats, over the same time period, demonstrated progressive mesangial thickening and focal tuft sclerosis. Immunoglobulins and complement were in the mesangium in quantities equal to or greater than seen in earlier biopsies. Thus, successful pancreatic islet transplantation in the rat results in regression or arrest of the diabetic glomerular lesion.
Kidney Size in Diabetes Mellitus
Authors: Kahn Charles B , Raman P G , Zic Zeljiko
Published: December 2014

Kidneys were found to be significantly enlarged both by radiographic examination and by weight at autopsy in diabetic patients. No correlation was found between kidney size and the duration of diabetes which indicates that kidneys remain large late in the course of the disease. The possible mechanisms for the kidney enlargement are discussed.
Banting Memorial Lecture, 1954: Hormones of the Pituitary Posterior Lobe
Authors: Dale Henry
Published: December 2014

This lecture commemorates Frederick Grant Banting, his life and his work, bringing once again into the focus of our immediate attention the achievement for which the world will always keep his name in honor. There is no need, of course, for me to remind you, the members of a Diabetes Association, of this special reason for keeping him in grateful memory. There is no possibility that you will ever forget the enterprise which, some 33 years ago now, he led with such vigor and insistence, and with a youthful enthusiasm unblunted by experience. And there are others, of course, whose work we think of with Banting's, and who are still alive, to know that we remember. There is Charles Best, Banting's younger comrade and his full partner in the work which gave the first clear proof that insulin had a real existence, and that its extraction on a practical scale ought not to be beyond the reach of conservative methods, when these could be developed in detail. It is good to know that Professor Best, still at the height of his powers, is leading an eager team of his colleagues and pupils in Toronto, and fulfilling the brilliant promise of that early triumph, when he shared with Banting in the great discovery which we commemorate. There is J. B. Collip, too, whose work did much to speed the developments required to bring insulin within the range of practical and regular production, from ordinary, slaughterhouse pancreas. Professor Collip, we rejoice to know, is also still fully active, leading his own research team, and carrying an administrative burden for the new generation, as Dean of the Medical Faculty in London, Ontario. And there was J. J. R. Macleod, head of the Physiological Department in Toronto when the early work on insulin was done there, who was prompt to organize men of his own training into a team to hasten its practical development, as well as to begin the study of its significance for normal and fundamental physiology. Professor Macleod, however, afflicted by ill-health, returned later to his native Scotland, where he died some years ago.
Diabetes Mellitus at the Massachusetts General Hospital from 1824 to 1898: A Study of the Medical Records
Authors: Fitz Reginald H , Joslin Elliott P
Published: December 2014

Dr. Elliott P. Joslin laid the foundation for his lifetime interest in diabetes at the beginning of his medical career. The results of his careful study of the early medical records of the Massachusetts General Hospital published in collaboration with Dr. Fitz 57 years ago reveal information of interest from the viewpoint of the medical historian. The paper is also instructive from two other points of view. The importance of careful observation and sound evaluation of clinical data is illustrated. The progress which has been made in the therapy of diabetes since its initial publication represents a challenge to the future.
Management of the Diabetic with Vascular Disease
Authors: Mulholland Henry B
Published: December 2014

Vascular disease and its devastating end-results constitute one of the major problems faced by the medical profession today. The steadily increasing duration of life, with large numbers of the population living to sixty-five years of age and over, is bringing in an era in which degeneration of all systems must constitute a challenge. The diabetic too must pay the price of living longer by being more likely to develop degenerative disease and its complications.

The remarkable contributions in the field of vascular disease during the last three decades have added to the insight into these disorders. It is commonly considered that involvement of the vascular system is inevitable in the diabetic, provided he lives long enough. One does see, however, a few individuals with diabetes of many years’ duration who seem to have escaped the ravages of time and have no demonstrable changes in their vascular tree.

That arteriosclerosis in diabetes increases with the duration of the disease is evidenced by the figures quoted by Root, who noted that this process as a cause of death increased from 17 per cent at an average age of 44.5 to 70 per cent at an average age of 65.3.

As will be discussed below, diabetics seem to have a greater incidence of arteriosclerosis and atherosclerosis than does the general population. Although these conditions appear to differ in no respect from those found in nondiabetics, nevertheless, there is evidence that certain vascular changes, particularly in the retina and kidneys, may well be peculiar to the complicated metabolic disturbance found in diabetes mellitus. In many organs of the diabetic, vascular lesions are found with special frequency. They will be more fully described as the individual anatomic units are discussed. White, who studied juvenile diabetics who had lived twenty years or more after developing the disease, noted some evidence of vascular disease in 92 per cent, an astounding figure.

Factors playing a role in this increasing incidence, such as an inheritance of a defective vascular tree, seem to have some influence. Nutrition in a broad sense, infection (which is notoriously more frequent in the diabetic), so-called toxic factors, hormone imbalance, and capillary fragility all may play a part, although one cannot justifiably accuse any one of these.
Insulin Treatment of Juvenile Diabetes Observations on the Combined Use of Intermediate and Regular Insulins
Authors: McArthur James A , Jackson Robert L
Published: December 2014

For many years the management of diabetes mellitus at the Pediatric Clinic of the State University of Iowa has had as its objective to attain and maintain physiologic control. To accomplish this end we have found the administration of insulin on a percentage distribution basis practicable.

Under the standard conditions of quantitative diet and exercise in the hospital, we obtained normoglycemic diurnal curves when four doses of regular insulin were distributed as 35, 22, 28, and 15 per cent of the total daily dosage, the injections being given one-half hour before meals and once during the night. This pattern of distribution, in keeping with the generally acceptable three-meal plan of the child, has guided us when modifying our regimen as new types of insulin have become available. We found it impossible to attain our objective using protamine-2inc insulin. In 1944, when globin insulin with zinc was made available, we started to use it in a regimen which we had developed in our clinic. In this plan, one dose of globin insulin with zinc given one hour before the evening meal replaced the evening and night doses of regular insulin. In 1953, when NPH insulin was made available, we studied its use in place of globin insulin and observed no significant differences in the diurnal blood sugar curves for groups of well regulated diabetic children.

The purpose of this study is to present the development of a satisfactory two-injection regimen employing mixtures of an intermediate insulin and regular insulin as the morning injection and an intermediate insulin as the evening injection. The intermediate insulins employed are NPH and globin insulin with zinc.