bluuebunny/crossref_metadata_2025 huggingface dataset:
Stimulation of H-3-Leucine Incorporation into the Proinsulin and Insulin Fraction of Isolated Pancreatic Mouse Islets in the Presence of Glucagon, Theophylline and Cyclic AMP
Authors: Schatz H , Maier V , Hinz M , Nierle C , Pfeiffer E F
Published: December 2014

Incorporation of H-3-leucine into proinsulin and insulin and insulin secretion were determined in isolated pancreatic islets of mice. Batches of forty islets were incubated for three hours at 0, 100 or 300 mg. per cent glucose alone or in the presence of glucagon, theophylline or cyclic AMP. Proinsulin and insulin were separated by gel filtration on columns of Sephadex C50fine in 1 M. acetic acid.

In the absence of glucose, no stimulation of insulin biosynthesis as judged from the incorporation of H-3-leucine was observed with glucagon, cyclic AMP or dibutyryl cyclic AMP; insulin, secretion was not significantly stimulated. At 100 and 300 mg. per cent glucose, both leucine incorporation and insulin secretion were potentiated by the substances tested; the effect of glucagon was pronounced mainly at high concentrations of glucose. However, leucine incorporation and insulin secretion were not stimulated to the same extent in all cases.

Biosynthesis of insulin thus appears to be not always directly linked to insulin secretion. It is suggested that glucagon and the adenylcyclase system, besides regulating insulin secretion, are involved in insulin biosynthesis.
Absorption of Insulin from Perfused Rabbit Small Intestine in Vitro
Authors: Shichiri Motoaki , Etani Nobuaki , Kawamori Ryuzo , Karasaki Kenkichi , Okada Akira , Shigeta Yukio , Abe Hiroshi
Published: December 2014

The intestinal absorption of insulin has been studied in a preparation of isolated rabbit intestine in which artificial plasma is circulated through normal vascular channels. After insulin in doses of 100, 200, and 440 U. was introduced into the intestinal lumen, its appearancein the venous effluent was measured immunologically during perfusion for two hours.

Insulin gradually appeared in the venous effluent and reached a peak fifty to ninety minutes after the perfusion was started. The proportion of insulin absorbed was 6.2 to 9.2 per cent with a dose of 100 U., 5.9 to 15.6 per cent with 200 U., and 8.9 to 15.9 per cent with 440 U. The amount of insulin added significantly correlated with the total amount of insulin absorbed from the intestine. The biologic activity in the fraction absorbed was equivalent to that obtained immunologically. In the venous effluent, insulin component was also identified by the relative mobility similar to crystalline insulin on acrylamide gel electrophoresis.

Although the intestinal absorption in this system does not duplicate physiologic absorption, these results indicate that a considerable portion of insulin can be absorbed from the intestine in a physiologically active form.
Experience with Automation as an Aid in the Management of Diabetes
Authors: Bolinger Robert E , Price Sandra , Kyner Joseph L
Published: December 2014

This study reports experience in the management of eighty-six diabetic patients using a semiautomated system. Input to the system is effected through a teletype terminal and includes information pertaining to commonly used parameters in the regulation of the diabetic patient. Output from the program includes recommendations for short, intermediate and long acting insulins as often as four times per day, oral hypoglycemic agents and dietary regulation. During one phaseof the study management was carried out by a nurse-clinician using the computer as an automated consultation. The current version of the program shows a good correlation for insulin dosage between computer and physician. Because of the necessity of interpreting input information, the user must have some clinical background in the management of diabetes.
Insulin Metabolizing Enzyme Activities in Human Placental Tissue
Authors: Posner Barry I
Published: December 2014

The nature of insulin-degrading activity in the human placenta has been examined. Two soluble enzyme activities, I and II, have been demonstrated, in addition to an activity in the cell debris fraction. Activity I is sulfhydryl dependent and can be partially resolved into two components on C-100 Sephadex chromatography. The minor component chromatographs with activity II in the void volume. The major portion is of smaller molecular weight, as evidenced by its greater elution volume. Activity I has a pH optimum of 7.2 to 7.4 and a broad range of substrate specificity. These properties, along with the demonstration of glutathione-insulin transhydrogenase activity in placental supernatant, raise the possibility that a substantial part of activity I is due to a glutathione-insulin transhydrogenase. Activity II is not sulfhydryl dependent but appears to be stimulated by sulfhydryl and inhibited by p-chloromercuribenzoate. It has a pH optimum of 6.3 to 6.6, shows greater specificity for insulin than does activity I and is less readily inactivated at 60° C. (t1/2, I = 25 min. II = 120 min.). It shows the same elution volume on G-150 Sephadex as rat muscle protease. The characteristics of activity II suggest that it is a sulfhydryl protease similar to that observed in rat skeletal muscle.
Glutamine and Glutamate Metabolism in Normal and Diabetic Subjects
Authors: Felig Philip , Wahren John , Karl Irene , Cerasi Erol , Luft Rolf , Kipnis David M
Published: December 2014

Arteriovenous differences across the leg and across the splanchnic bed were determined for plasma glutamine and glutamate in healthy controls and insulin-dependent diabetics. In both groups glutamine was released from the leg and taken up by the splanchnic bed, while the reverse was observed for glutamate. Arterial glutamine levels were reduced by 25 per cent in the diabetics, but no differences were observed between the diabetics and controls in splanchnic or peripheral glutamine and glutamate metabolism. To assess the contribution of intestinal tissues to splanchnic glutamine uptake, arterio-portal venous differences (A-PV) were determined for plasma glutamine in four nondiabetic patients prior to elective cholecystectomy. A consistently positive A-PV difference was noted indicating net uptake of glutamine by intestinal tissues.

The findings indicate that the intestinal tract rather than the liver is the major site of splanchnic glutamine uptake and that removal of glutamine by the splanchnic bed is not augmented in diabetes. The data thus suggest that glutamine is not an important endogenous substrate for hepatic gluconeogenesis.
Carbohydrate Metabolism in Pregnancy: X. Metabolic Disposition of Alanine by the Perfused Liver of the Fasting Pregnant Rat
Authors: Metzger Boyd E , Agnoli Francis S , Hare John W , Freinkel Norbert
Published: December 2014

Hepatocytes from pregnant rats fasted during late gestation are larger and more abundant than in littermate virgin animals and in vivo are exposed to hypoglycemia. To evaluate their intrinsic potential for biosynthetic transformations of alanine, a modified liver perfusion system was employed. Livers from twenty-four hour fasted, nineteenday pregnant and virgin littermate rats were subjected to “wash out” perfusion for twenty-five minutes prior to definitive perfusion for sixty minutes with fresh media containing supramaximal amounts of L-alanine-14-C (17 mM). Under such conditions, livers from pregnant rats displayed an enhanced capacity to assimilate alanine-14-C and to establish concentration gradients for alanine between hepatocytes and perfusion medium. Significantly more alanine carbons were incorporated into glucose, lactate, glyceride-glycerol, and glutamate per hepatocyte by livers of pregnant rats. Clyceride-glycerol formation was disproportionately enhanced suggesting that there may be mechanisms operative during pregnancy for selectively diverting triose phosphates toward the esterification of intrahepatic fatty acids. Despite the augmented disposition of alanine carbons, livers from pregnant animals formed significantly less urea. Instead, a much greater proportion of the nitrogen derived during alanine catabolism was released in a potentially reutilizable form, ammonia.

Thus, hepatocytes from fasted pregnant animals have an enhanced capacity for assimilating “loading” doses of alanine and for incorporating the carbons into glucose, lactate, glyceride-glycerol, and glutamate, while preserving more of the amino nitrogen in a form that can be reutilized.
Hypoglycemic Action of Tryptophan
Authors: McDaniel H G , Boshell B R , Reddy W J
Published: December 2014

These studies were designed to define the mechanism by which the tryptophan metabolite, quinolinic acid, blocks gluconeogenesis and to determine the role it plays in influencing this process under physiologic and pathologic conditions. An alteration in the level of gluconeogenic intermediates occurred at a quinolinic acid content of 43 ng. per gram of liver. At a content of 10 μug. per gram of liver there was no significant change in the level of these intermediates. The concentration of quinolinic acid (3.7 × 10−4 M) which was associated with inhibition of P-enolpyruvate carboxykinase in vivo correlated well with K1 (1 × 10−4 M) derived for ferrous quinolinate in vitro. This level of quinolinic acid was reached by the intraperitoneal administration of approximately one fourth and the intragastric administration of approximately one half the daily dietary intake of L-tryptophan. The content of quinolinic acid in the liver of fasted animals was twenty-five-fold lower than the level required to inhibit the carboxykinase reaction and there was no increase in the quinolinic acid content of the liver on a diet containing the usual amount of tryptophan. The effects of various parameters on the conversion of tryptophan to quinolinic acid were also investigated and the clinical implications of these findings are discussed.
Effect of Phenformin in Hyperglycemic Rats
Authors: Polacek I , Quart J
Published: December 2014

Phenformin administered intraperitoneally in doses of 30 and 100 mg. per kilogram significantly reduced the blood glucose concentration in streptozotocin-diabetic rats, but was virtually inactive in normal healthy rats. Phenformin also antagonized the hyperglycemic effect of an intravenous infusion of epinephrine in normal anesthetized rats and decreased blood glucose concentration of hepatectomized rats infused with glucose. These results are not consistent with hypotheses explaining the biguanide effect as an impairment of the intestinal absorption of sugars and indicate that the liver is not the only site of its action.
Mode of Action of N6-O2′-Dibutyryl Cyclic 3′, 5′ AMP on Fat Cell Metabolism
Authors: Jarett Leonard , Smith Robert M
Published: December 2014

Cyclic nucleotide phosphodiesterase (PDE) activity was measured by a 3H cAMP method on the infranatant portion of the homogenate of adipocytes isolated from rat epididymal fat pads. DBcAMP (0.05 to 1.0 mM.) was found to progressively inhibit the PDE activity. The inhibition was not secondary to dilution of the 3H cAMP by cAMP derived from catabolism of the DBcAMP by deacylase activity in the homogenate. Adipocytes were prelabeled with radiocarbon adenine and the hydrolysis of radiocarbon cAMP was measured in the presence and absence of DBcAMP. Increasing concentrations of DBcAMP prevented the hydrolysis of the radiocarbon cAMP in a dosedependent manner with no breakdown occurring at 1.0 mM., correlating with the complete inhibition of the homogenate PDE activity at 1.0 mM. Kinetic analysis revealed the low Km of the PDE to be 0.8 μM., and this was shifted to 2.5 μM. by 0.05 mM. DBcAMP without a change in Vmax, indicating a competitive-type inhibition which was easily reversible upon removal of the DBcAMP.

The cAMP levels were measured in extracts of DBcAMP-treated adipocytes by the protein kinase technic. DBcAMP and O2′ MBcAMP did not affect the assay system until 200 pmoles were present, while N6 MBcAMP was indistinguishable from cAMP in the assay system set for a standard curve of 0.5 to 10 pmoles. A procedure was devised to separate the cAMP from DBcAMP and O2′ MBcAMP such that they would always be at levels too low to interfere with the assay. N6 MBcAMP was shown not to be present in the assayed material since the material was susceptible to PDE digestion and N6 MBcAMP was not. Cellular cAMP levels increased as DBcAMP increased, reaching over fifty times the control at 1.0 mM. DBcAMP. This cAMP was shown to be over 90 per cent of endogenous origin and less than 10 per cent from breakdown of DBcAMP. Lipolysis was stimulated proportional to the increase in cAMP levels but was not maximal until the fiftyfold elevation of cAMP. This suggested that DBcAMP might compete with cAMP in activating the enzymes involved in lipolysis and that the large excess of cAMP is required to overcome this antagonism by DBcAMP.
Effect of Intrapancreatic Injection of Potassium and Calcium on Insulin and Glucagon Secretion in Dogs
Authors: Kuzuya Takeshi , Kajinuma Hiroshi , Ide Takehiko
Published: December 2014

Acute changes in plasma immunoreactive insulin (IRI) and immunoreactive glucagon (IRG) levels in the pancreatic vein of dogs were studied following rapid pulse injections of CaCl2, KCl and glucose into the pancreatic artery. Blood from the pancreatic vein was taken continuously by changing the collection tubes every five seconds. IRI secretion was stimulated by all three agents within thirty seconds, while IRG secretion was stimulated by the injection of KCl but not by CaCl2 or glucose. Detailed comparisons of IRI responses revealed that IRI release occurred most rapidly after the injection of KCl and most slowly after the injection of glucose. Stimulation of IRI and IRG release occurred simultaneously after KCl injection. The data suggest that potassium stimulates α and β cells directly, without increasing calcium influx. The slower insulin-releasing effect of glucose, as compared with the cations, supports the theory that glucose acts by increasing calcium uptake.
A Clinical and Histologic Study of Diabetic Nephropathy in the Pima Indians
Authors: Kamenetzky Stephen A , Bennett Peter H , Dippe Stephen E , Miller Max , LeCompte Philip M
Published: December 2014

The relationship of renal disease to carbohydrate tolerance was examined in the Pima, who are American Indians with a high prevalence of diabetes mellitus. Glucose tolerance, serum creatinine level and urine protein concentration were measured in 1,716 subjects aged fifteen and over, of whom 404 were diabetic. Histologic information was obtained by reviewing autopsy material from forty-three diabetics and sixty-two nondiabetics.

Over 22 per cent of the diabetics and less than 7 per cent of the nondiabetics had proteinuria (p < 0.001). Severe proteinuria aid elevated serum creatinine levels were, respectively, fifteen and nine times more common in the diabetics (p < 0.001). Both the frequency and severity of renal disease increased with duration of diabetes in subjects who were under age sixty-five when examined or when the disease was diagnosed. Above age sixty-five the prevalence of proteinuria was high in all duration groups.

At autopsy, 65 per cent of the diabetics had diffuse glomerulosclerosis. Nodular glomerulosclerosis was found in 56 per cent of the diabetics and in none of the nondiabetics. Arteriolar lesions were also significantly more common in the diabetics. Pyelonephritis was found in 16 per cent of the diabetics and 5 per cent of the nondiabetics; other forms of renal disease were rare in both groups.

Diabetic nephropathy, similar in its clinical and histologic characteristics to that described in other populations, is the predominant form of kidney disease in the Pima Indians, making this population ideal for study of the development and course of diabetic renal disease.
Impaired Leukocyte Function in Patients with Poorly Controlled Diabetes
Authors: Bagdade John D , Root Richard K , Bulger Roger J
Published: December 2014

In order to assess the influence of poor diabetes control on function of leukocytes, polymorphonuclear leukocytes (PMN's) from patients with poorly controlled but nonketotic disease were studied before and after therapy. Before treatment, phagocytosis was significantly reduced (p < .001) and, consequently, the rate of killing the test organism (type 25 pneumococcus) was decreased (p < .01). Following antidiabetes therapy phagocytosis improved significantly; while microbicidal rates also improved, they remained less than control values (p < .01).

Serum from the untreated diabetics uniformly reduced phagocytosis and microbicidal rates of control granulocytes; serum from controls improved phagocytosis by the diabetic PMN's, but restored normal microbicidal rates in only half of the patients. This transferable inhibitory effect of hyperglycemic diabetic serum on control granulocytes was abolished by dilution, and was reproduced in normal serum by the isosmotic addition of glucose. These studies suggest that (1) PMN function may be impaired during periods of poor diabetes control, as has been shown previously in ketoacidosis, and (2) hyperglycemia or a closely related factor may contribute to the defect.
Arginine Infusion in Dogs: Model for the Roles of Insulin and Glucagon in Regulating Glucose Turnover and Free Fatty Acid Levels
Authors: Cherrington A D , Kawamori R , Pek S , Vranic M
Published: December 2014

Arginine administered to normal dogs indicated that glucose production (Ra) and glucose utilization (Rd) increased concomit-antly and plasma free fatty acid (FFA) levels decreased. The present studies were designed to assess the role of the simultaneously released pancreatic hormones in mediation of these responses. The amino add was administered to seven depancreatized insulin-infused dogs during periods when the normal pancreatic hormone response could not occur, and compared with periods during which insulin and glucagon were administered exogenously in patterns resembling the normal endogenous responses.

The amino add had no effect on glucose turnover in the absence of pancreatic hormone mobilization. However, normal increments in Ra and Rd occurred when extra insulin and glucagon were given concurrently with arginine; in order to maintain a sustained increment in Ra it was necessary to continually decrease the plasma insulin-glucagon (I/G) ratio. The metabolic effectiveness of a given I/G ratio thus varied with time. It appears that in assessing the metabolic significance of the I/G ratio, the duration of the stimulus and the absolute concentrations of the two pancreatic hormones should be considered. Despite pancreatectomy, basal concentrations of immunoreactive glucagon were within normal range prior to glucagon infusion; a nonpancreatic source of this activity is hypothesized. The plasma nonpancreatic glucagon immunoreactiv-ity increased only slightly in response to arginine. A comparable decrease in the FFA level occurred regardless of the presence or absence of extra insulin and glucagon, suggesting a nonpancreatic factor in the arginine associated inhibition of FFA release.

Thus arginine infusion acutely reverses the pattern of fuel utilization characteristic of fasting: glucagon increases glucose production by the liver, insulin increases overall glucose utilization and FFA levels fall. Arginine challenge cannot only reveal metabolic defidendes of insulin lack but also defidendes due to absence of pancreatic glucagon.
Decreased Response of Plasma Renin Activity to Orthostasis in Diabetic Patients with Orthostatie Hypotension
Authors: Christlieb A Richard , Munichoodappa Choodappasetty , Braaten Jan T
Published: December 2014

Plasma renin activity (PRA) was studied in eight patients maintained on a 100 mEq sodium diet who had diabetes mellitus with orthostatie hypotension (OH) and in eight diabetic matched controls without orthostatie hypotension. Signs of neuropathy and nephropathy were more frequent in patients with OH. Supine PRA was 1.2 ± .2 ng./ml. (S.E.M.) in OH and 3.0 ± .9 in controls (P < .1). Following upright posture for one-half hour, patients with OH demonstrated a fall in mean blood pressure from 102 ± 8 mm. Hg. to 72 ± 8 (P < .001). Despite this stimulus for renin release, PRA was 1.5 ± .3, significantly lower than controls, 4.2 ± .8 (P < .01). In patients with OH, mean blood pressures remained lower after four hours of upright posture (80 ± 8) than supine (P < .005). PRA was 2.5 ± .6, again lower than in control diabetic patients (5.6 ± .9) (P < .02). These results contrast with those in ten out of fifteen reported cases of idiopathic orthostatie hypotension who demonstrated an increase in PRA to the stimulus of upright posture. One explanation for decreased renin release in diabetic patients with OH would be defective catecholamine stimulation. In one patient who was given infusions of norepinephrine for one-half hour on two successive days, no increase in PRA was observed. The associated nephropathy in diabetic patients with OH suggests the possibility of defective renal renin stores or renin releasing mechanisms. When combined with other possible defects in blood pressure homeostatic mechanisms such as catecholamine deficiencies and blood volume abnormalities, an inadequate response of the renin-angiotensin system may be etiologically related to the OH in patients with diabetes.
Sustained Insulin Release in Response to Intravenous Infusion of Insulin Releasing Polypeptide (IRP) in the Rat
Authors: Shabaan Ahmad A , Turner Desmond S , Marks Vincent
Published: December 2014

A greatly elevated and sustained insulinemic response was evoked in cats by the intravenous infusion of a solution of IRP in glucose compared with that produced by glucose alone. Larger doses of IRP produced correspondingly greater increases in insulin release.

IRP enhanced glucose disposal up to a finite limit despite higher plasma insulin levels suggesting that there is a maximum rate of glucose disposal under conditions of intense insulin stimulation.
The Posthumous Misfortune of Captain Bligh of the “Bounty”: Hypoglycemia from Blighia
Authors: Mitchell J C
Published: December 2014

The career of William Bligh (1754-1817) was beset by some difficulty in troubled times. He is chiefly remembered for a mutiny on his ship, the Bounty, in the South Seas in 1789. This story is too well known, at least to those who have seen the movies, to require an anecdote. It is less well known that, in 1791, he set out again for Tahiti with another ship and crew and eventually succeeded in landing a cargo of bread-fruit trees, Artocarpus, in the West Indies. As captain of the Director in 1797, he was put ashore when his ship's crew joined the mutiny at the Nore; however, he commanded that ship with distinction at the battle of Camperdown that year, as he did the Glatton at Copenhagen (1801).
Studies on Tryptophan-Niacin Metabolism in Streptozotocin Diabetic Rats
Authors: Akarte Nilkanth R , Shastri Narayan V
Published: December 2014

Streptozotocin diabetic male albino rats were observed to exhibit faulty conversion of tryptophan into niacin. Streptozotocin-injected rats, kept on niacin-deficient diet and given a dose of L-tryptophan (intraperitoneal or oral) excreted comparatively less quantities of niacin and N1-methylnicotinamide in urine than the control nondiabetic rats. Rats continued to show this effect for at least three months after streptozotocin injection. Dietary intake was found to have no influence on the excretory pattern. Streptozotocin diabetic rats were also observed to excrete greater amounts of xanthurenic acid and other tryptophan metabolites on tryptophan administration as compared to the nondiabetic rats.
Effects of Diphenylhydantoin upon Glucose-induced Insulin Secretion in Three Patients with Insulinoma
Authors: Hofeldt Fred D , Dippe Stephen E , Levin Seymour R , Karam John H , Blum M Robert , Forsham Peter H
Published: December 2014

Because diphenylhydantoin (DPH) has been shown to inhibit nontumorous insulin release, we evaluated its effects in patients with insulinoma.

Three patients with surgically demonstrated insulinomas were tested with oral and intravenous glucose before and after DPH. In two of these patients, we compared the effects of DPH and diazoxide.

Ingestion of DPH for several days did not alter fasting glucose or insulin. Poststimulatory insulin was appreciably reduced in only one patient during treatment with the drug. During diazoxide administration, this patient had increased fasting glucose and decreased fasting insulin, in addition to reduction of poststimulatory insulin. Combined DPH-diazoxide therapy in this patient did not produce greater effects than did diazoxide alone. Neither fasting ingulin or glucose nor poststimulatory insulin secretion were influencse by DPH or diazoxide in the second patient, or affected by DPH alone in the third.

The accepted role of DPH in the treatment of insulinoma involves its ability to alter seizure threshold. It did not influence fasting hypoglycemia in our patients. Reduced insulin secretion after stimuli might reflect effects of DPH on responses of nontumorous endocrine pancreas.
Insulin and Growth Hormone Secretion in Rats with Ventromedial Hypothalamic Lesions Maintained on Restricted Food Intake
Authors: Martin Julio M , Konijnendijk Willem , Bouman Paul R
Published: December 2014

Adult female rats were trained for one week to consume a subnormal amount of food (12 gm.) in two one-hour feeding sessions per day: 4 gm. between 8 and 9 a.m. and 8 gm. between 6 and 7 p.m. At the end of the training period the animals were subjected to either bilateral electrolytic destruction of the ventromedial hypothalamus (VMH) or to a sham operation. The restricted feeding regime was continued for forty-eight hours postoperatively, when comparative studies were made. Plasma insulin response to intravenous Glibenclamide was greater in the rats with VMH lesions than in the pair-fed, sham-operated controls. The former rats also exhibited decreased initial plasma glucose levels, degranulation of the beta cells and reduced pancreatic insulin content. In addition to marked islet enlargement, similar though more severe signs of islet hyper-function were observed in rats with VMH lesions fed ad libitum, which became hyperphagic immediately after the operation.

VMH lesions did not significantly affect the plasma and pituitary levels of growth hormone (GH). The restricted feeding regime, however, caused an increase in plasma GH, responsiveness to hypoglycemic stimulation and a tendency to decreased pituitary GH content both in injured and sham-operated rats.

These findings indicate that VMH lesions per se enhance the responsiveness of the pancreatic islets to insulin secretory stimulation independent of changes in food intake, meal size and meal frequency. The resulting hyperinsulinism might play an essential role in the occurrence of hypothalamic hyperphagia and obesity following VMH injury. In hyperphagic rats with VMH damage, the islet stimulation is magnified, possibly due to the combination of a direct hypothalamic effect plus the secondary effect of increased food intake. Defective secretion of GH does not appear to be primarily involved in the induction of the hypothalamic syndrome.
Glucagon Responses to Arginine in Chronic Pancreatitis: Possible Pathogenic Significance in Diabetes
Authors: Kalk W J , Vinik A I , Bank S , Buchanan K D , Keller P , Jackson W P U
Published: December 2014

The effect of aiginine infusion on pancreatic glucagon, insulin and glucose was studied in fourteen patients with chronic ‘alcoholic’ pancreatitis and seven control patients. There appeared to be two types of pancreatitis, one with concomitant decrease in glucagon and insulin secretion and the other with severe insulinopenia and relative hyperglucagonemia. The bihormonal derangement mimics abnormalities that occur with genetic diabetes. The relative hypersecretion of glucagon in chronic pancreatitis may be a consequence of insulinopenia rather than a primary abnormality.
Plasma Gastrin Responses to Arginine in Chronic Pancreatitis
Authors: Kalk W J , Vinik A I , Bank S , Hayes J R , Ardill J , Buchanan K D , Keller P , Jackson W P U
Published: December 2014

Serum gastrin responses to intravenous L-arginine hydrochloride were measured in insulinopenic and noninsulinopenic patients with chronic pancreatitis and in suitable control subjects. There were no differences between any of the groups studied. Pancreatitis did not impair gastrin responses to arginine nor was gastrin an important determinant of insulin secretion in these patients.
Immunogenicity of “Single Peak” Beef-Pork Insulin in Diabetic Subjects
Authors: Tantillo J J , Karam J H , Burrill K C , Jones M A , Grodsky G M , Forsham P H
Published: December 2014

Highly purified insulins of the “single-component” or “monocomponent” varieties have been previously reported to be nonimmunogenic. Since mass production of insulins with a high degree of purity is not convenient, a “single-peak” insulin with large molecular weight substances removed, has been developed in U-100 concentration. To evaluate its immunogenicity, three groups of diabetic subjects were studied. Seven patients previously untreated with insulin were given single-peak beef-pork insulin for forty-five to 435 days; in undiluted sera, insulin-I131 binding reached a mean of 18 per cent (range, 2 to 46 per cent). In comparison, fifteen diabetics treated with standard USP beefpork insulin for ninety days or more showed a mean insulin-I131 binding of 15 per cent (range, 3.5 to 38 per cent). Six patients who had received USP insulin were treated with the single-peak preparation. Five of these had a mean insulin-I131 binding of 16 per cent (range, 2 to 38 per cent) before single-peak therapy and a mean binding of 27 per cent (range, 6 to 44 per cent) after treatment with single-peak insulin for 105 to 230 days. The sixth patient had severe chronic insulin resistance and required up to 400 U. per day of USP insulin; treatment with single-peak insulin for five weeks produced no fall in antibody titer, and insulin requirements remained high: an initial response to only 50 U. per day of fish (bonito) insulin demonstrated that resistance was due to immunogenicity. U-100 single-peak beef-pork insulin reduces lipoatrophy but does not appear to offer obvious immunologic advantages over standard USP insulin.
Evaluation of Some Commonly Used Semiquantitative Methods for Urinary Glucose and Ketone Determinations
Authors: James Ronald C , Chase Gerald R
Published: December 2014

The 2 Drop Clinitest, 5 Drop Clinitest, Tes-Tape, and Ketodiastix semiquantitative urinary glucose methods were evaluated using 300 urine samples from diabetic patients and comparing the results with those obtained by an AutoAnalyzer-glucose oxidase method. At high levels of glycosuria (above 1,500 mg.'100 ml.) the 2 Drop Clinitest method gave better quantitation than the other methods. In this range the Keto-diastix method often gave falsely low results. At intermediate levels of glycosuria (376 to 1,500 mg.'100 ml.) there appeared to be little or no difference among the methods. The 2 Drop Clinitest method was often insensitive to levels of urinary glucose below 376 mg.'100 ml. In this range the other three methods gave comparable results, with the exception that Tes-Tape was sometimes positive with normal levels (1 to 15 mg.'100 ml.) of glycosuria. Proteinuria and pregnancy had no effect on any of the methods. Acetest was a more sensitive and accurate indicator of urinary ketone levels than Keto-diastix.
Perifusion of Pancreas Fragments: A System for the Study of Dynamic Aspects of Insulin Secretion
Authors: Kikuchi Masatoshi , Rabinovitch Alexander , Blackard William G , Renold Albert E
Published: December 2014

A perifusion system, intermediate in character between perfusion and static incubation, is described for the investigation of the multiphasic aspects of insuiin secretion from pancreas not subjected to separation of endocrine and exocrine tissue. Pancreatic tissue fragments obtained by mechanical chopping with razor blades are placed in small (0.7 ml.) chambers through which medium is pumped and from which effluent is collected at various time intervals for IRI determination. Under the conditions employed, insulin degradation by released proteolytic enzymes is minimal throughout the test period. Dose-dependent glucose-induced insulin release is observed and decreases immediately after cessation of the stimulus. Pancreas from fed animals secretes significantly greater quantities of insulin in response to glucose thata pancreas from fasted animals. Optimal results are obtained when the chopped tissue fragments average (0.5 mm.)3.

The secretion profiles obtained with this system are similar to those reported with pancreatic perfusion. Tolbutamide produced an early insulin response only, whereas glucose and amino acids induced both early and late insulin secretory responses. Among the hexoses tested, only glucose and mannose stimulated insulin secretion, whereas two inhibitors of the early steps of glucose metabolism, mannoheptulose and 2-deoxygIucose, inhibited both the early and late phases of glucose-induced insulin secretion.

The separation between the two phases of insulin secretion is not as sharp and complete with perifusion as with perfusion. This difference is presently attributed to the greater role of tissue diffusion in the minced perifused tissue. Balancing this disadvantage, however, perifusion offers several advantages over perfusion, among which are ease of tissue preparaton and handling, ability to study a number of variables relatively rapidly, comparison of identically prepared and randomly sampled minces of the same pancreas in parallel.

Finally, the preparation is applicable whenever pancreatic perfusion is not possible (for example, in the fetus or for very small animals), or when the isolation of islets of Langerhans presents practical or theoretical disadvantages, as in the study of the influences of exocrine on endocrine tissue.
Further Evidence that Insulin Resistance Exists in Patients with Chemical Diabetes
Authors: Ginsberg Henry , Olefsky Jerrold M , Reaven Gerald M
Published: December 2014

Insulin resistance was estimated in fifty nonobese subjects who were classified as normal (thirty subjects) or as having chemical diabetes (twenty subjects) on the basis of a standard oral glucose tolerance test. Insulin resistance was determined by administering a constant intravenous infusion of epinephrine, propranolol, glucose and exogenous insulin to each subject for 150 minutes and by measuring the resultant steady state plasma glucose levels attained during the last sixty minutes. Under these conditions, endogenous insulin secretion and hepatic glucose output are suppressed, and similar steady state plasma levels of the exogenously infused insulin are achieved in all subjects. Since all patients are challenged with comparable glucose loads, the height of the steady state plasma glucose response becomes a direct measure of an individual's resistance to insulin-mediated glucose uptake. With this approach we found that the mean (± S.E.) steady state plasma glucose level in patients with chemical diabetes was 224 ± 15 mg. per 100 ml. as compared to 126 ± 12 mg. per 100 ml. in control subjects. This difference was statistically significant (p <.001) and could not be attributed to differences in degree of obesity between the two groups. Furthermore, when individual values were examined it was apparent that relatively little overlap existed between steady state plasma glucose levels in normal and diabetic subjects. These results indicate that resistance to insulin-mediated glucose uptake is a characteristic of nonobese patients with chemical diabetes.
Effect of Diphenylhydantoin on Glucose Tolerance in Patients with Hypoglycemia
Authors: Stambaugh John E , Tucker Dale C
Published: December 2014

Five patients with symptomatic hypoglycemia unresponsive to dietary management were treated orally with 600 mg. of diphenylhydantoin (DPH) daily administered in three divided doses. Treatment with DPH resulted in both subjective and objective improvement in all cases. Serum glucose and insulin levels were determined before and after DPH therapy, and the changes observed after treatment correlated with the clinical response. DPH treatment resulted in an over-all increase of 31 per cent in mean plasma glucose values and an over-all decrease of 76 per cent in plasma insulin levels. These changes are in accord with those previously reported in normal subjects, and they appear to reflect a direct effect of the drug.
Cell-mediated Immunity to Human Pancreas in Diabetes Mellitus
Authors: MacCuish A C , Jordan Jennifer , Campbell C J , Duncan L J P , Irvine W J
Published: December 2014

Cellular hypersensitivity to an extract of human pancreas, using the leucocyte migration test (LMT), was found in twenty-nine of 101 diabetic and eight of fifty normal control subjects. However, the difference in response between diabetics and controls was confined to young insulin-dependent patients, there being no distinction between normal subjects and older diabetics treated by diet or oral hypoglycemic agents. The use of rat liver mitochondria and bovine insulin as antigens in the LMT did not induce inhibition of leucocyte migration in diabetics or controls.
Effect of Glucagon: Insulin Ratios on Hepatic Metabolism
Authors: Parrilla R , Goodman M N , Toews C J
Published: December 2014

Glucagon (1.7 × 10−9M) stimulated gluconeogenesis, ureogenesis, lactate production, ketogenesis, proteolysis and glycogenolysis in the isolated perfused rat liver. Insulin at relatively low concentrations (10-100 μU/ml.) suppressed these metabolic effects of glucagon. When a molar glucagon:insulin ratio (2.6 or 26) was selected, which partially suppressed the stimulatory effects of glucagon and the inhibitory effects of insulin, a 100-1,000 fold change in insulin and glucagon concentration at a constant glucagon:insulin ratio, did not alter the rate of gluconeogenesis, ketogenesis, ureogenesis, glycogenolysis or lactate production. These results indicate that glucagon and insulin are complete competative antagonists in the perfused liver. This suggests that it is the glucagon:insulin ratio and not the absolute concentration of either hormone that determines their metabolic events in liver.
Generalized Hypersensitivity Reaction and Visceral Arteritis with Fatal Outcome During Glibenclamide Therapy
Authors: Clarke B F , Campbell I W , Ewing D J , Beveridge G W , MacDonald M K
Published: December 2014

A severe generalized hypersensitivity reaction with toxic erythema, cholestatic jaundice and eosinophilia complicated by bronchopneumonia and renal failure with fatal outcome is described in a sixty-seven-year-old male diabetic patient treated with the recently introduced sulfonylurea, glibenclamide. Autopsy findings included the demonstration of a necrotizing angiitis with associated granulomatous changes in the spleen and kidneys.
Effects of Small Intravenous Doses of Epinephrine on Serum Insulin, Glucose Tolerance and Serum Free Fatty Acids
Authors: Cardon P V , Weiss J L , Mueller P S
Published: December 2014

Eighteen intravenous glucose tolerance tests (IVGTT) were carried out in six young, normal subjects while they were receiving normal saline or epinephrine (E) intravenously at the low rates of 0.1 and 0.3 μgm. per minute. The lower dose of E caused changes in the rate of urinary excretion of free E similar to those caused by caffeine; the higher dose caused changes similar to those reported to occur during various moderate to severe stresses. The higher dose of E augmented the insulin response to IVGTT. Glucose tolerance was not significantly decreased, resulting in relatively low glucose-insulin ratios following glucose injection. Serum free fatty acids were unaffected.
A Six-minute Test with Glucagon-free Insulin As a Guide to Treatment of Diabetes
Authors: Anderson George E , Fribourg M
Published: December 2014

In the treatment of diabetes, the ability of the organism to respond to insulin has not been accorded the attention it merits. This is especially true since it has been demonstrated that in normal individuals responsiveness to insulin is largely contingent on dietary habits. Therapeutic efforts have been centered about attaining a reasonably “normal” blood glucose level, whatever may be the method of arriving at this quasi-ideal state. Spot blood glucose readings have been the basis for determining such “normalcy”. Certainly, in the diabetic these isolated readings do not necessarily reflect a true picture of the status of insulin function. They can at best present only snapshots of blood glucose status at given instants rather than a dynamic picture of what is actually happening to a function which is probably never static. They portray the end result of an action rather than the mechanism of the action producing it. For example, a patient receiving insulin who shows a blood glucose value of 130 or more mg. per 100 cc. may be in far better glucose economy than is one with a value of only 80 mg. The latter's supernormal level may well represent an artifact of normal suggesting improved insulin efficiency in the individual, a picture which, however, is not at all dependent on improved intrinsic insulin function but rather on a forced and unphysiologic lowering of blood sugar resulting from massive dosage of extrinsic insulin. The ideal reading may well represent a mass stoicheiometric effect of insulin from without rather than the more normal functional role of the hormone, which should act as a delicate and sensitive catalyst even in small dosage.
Charles F. Bolduan: His Role in the Attack on Diabetes As a Public Health Problem
Authors: Mosenthal Herman O
Published: December 2014

How or why Charles F. Bolduan first became interested in diabetes I have never found out. He began his active work in this field while he was Director of the Bureau of Health Education of the Department of Health of the City of New York. In this capacity, he was editor of the Quarterly Bulletin published by the Health Department and in its pages he frequently presented information regarding diabetes. Then in 1930 he arranged to have a communication submitted by the Health Department to the New York Academy of Medicine. He stated that at that time there were about 2,000 diabetes deaths registered annually in the city of New York, that the diabetes death rate was about 50 per cent higher than it had been 20 years previously and that these facts called for some remedial effort.
Atherosclerotic Lesions in Diabetes
Authors: Bevans Margaret
Published: December 2014

Since arteriosclerosis accounted for 69.4 per cent of deaths in a series of diabetic subjects in the five-year period from 1944 to 1949, it seems appropriate to reassess our knowledge of this serious complication of diabetes in the last trimester of 1954.

“Atherosclerotic lesions” I have interpreted as meaning those lesions, primarily intimal, which occur in the large and medium-size arteries of the body. Within the limitations of this paper the term “atherosclerosis” will be considered to be synonymous with arteriosclerosis of the intimal type. I propose to discuss atherosclerosis from the pathologist's point of view, to consider the relationship between this disease and diabetes, and to summarize some of the problems that confront investigators in the field of arteriosclerosis.
Present-day Concept of Diabetic Retinopathy
Authors: Givner Isador
Published: December 2014

The interpretation of the pathogenesis of diabetic retinopathy has changed so much in the past twenty-five years that it is of interest to consider how and why this volution has occurred. In part the method of sectioning retinas on the flat and the newer staining and injection procedures have given a better picture of the vascular changes. In addition, ophthalmologists have always tried to determine whether findings in related specialties have an application to their problems, and thus advances made in pathology in general have suggested to thinkers in ophthalmology the possibility of applying such knowledge to their own field. We are indebted for much of our present-day concept of diabetic retinopathy to Friedenwald, Becker, Rich, McManus, Ballantyne, Loewenstein, and Ashton.

In recent years diabetic retinopathy has been on the increase, and if we are to get at the basic cause we must seek the reasons for the vascular involvement that is the basis of its development. The lengthening in life expectancy and the stress of present-day living probably do contribute to the increased incidence of visual loss, but if we are to gain in the prevention of blindness from diabetes we must try to remove or neutralize the fundamental pathology; namely, the involvement of the capillaries and venules which is the beginning of the trouble.

The characteristic vascular lesion of diabetic retinopathy consists of great numbers of minute saccular aneurysms in the retinal capillaries. Often the aneurysms are hyalinized. Two possibilities come to mind in regard to their formation: increased capillary pressure or histochemical changes that allow for the development of these aneurysms. In regard to the former, Friedenwald noted in studying histologic specimens of diabetic retinopathy that localized retinal venous occlusions were associated with abundant newly formed capillary collaterals. Aneurysms were not seen in these newly formed vessels, suggesting that increased capillary pressure is not in itself sufficient to cause the aneurysmal dilations.
Prosthetic Technics in the Aftercare of Diabetic Gangrene
Authors: Downie Ewen , O'Connor Maida
Published: December 2014

This paper describes an appliance, modified from the original design of Charlesworth, which in our hands has found particular application to problems which have arisen from the conservative management of infection or gangrene in the feet of diabetic patients. These are complications of an aging population which has suffered peculiar nervous and vascular damage ofttimes for years before any typical symptoms or signs of trouble develop.

In recent years the introduction of antibiotic drugs has provided a choice of potent weapons to combat infections which previously were impossible to control except by drastic and radical surgery. In consequence conservative surgical procedures may now be undertaken which, without the help of these drugs, would still be unthinkable. It is important to realize that the treatment of the traumatic injuries of youth or early adult life differs sharply from that of the elderly diabetic. In the young adult loss of a leg below the knee can be almost completely compensated by the fitting of an adequate artificial limb, but in our experience very few patients over the age of sixty years will tolerate an artificial leg satisfactorily. This being so, a crutch is an inadequate and precarious substitute for a human limb. One fall from inexperience and the patient, losing confidence, prefers to spend the rest of his life in a wheel chair.
Experimental Diabetic Glomerulosclerosis
Authors: Bloodworth J M B , Hamwi George J
Published: December 2014

With the advent of adequate replacement therapy for diabetes mellitus and the subsequent prolongation of life, degenerative vascular disease has become a problem of paramount importance. Unfortunately the study of degenerative vascular disease is complicated by its chronicity. The nodular glomerular lesions described by Kimmelstiel and Wilson in 1936 remain obscure in origin, but—if critical histologic criteria are met—represent a form of degenerative vascular disease seen only in patients with diabetes mellitus. The study of these lesions as well as of degenerative vascular disease in general would benefit greatly by the availability of an experimental method for the rapid production of diabetic glomerulosclerosis. In 1951 Rich et al reported that rabbits treated with cortisone for three weeks developed nodular glomerular lesions. Following this report we undertook the study of glomerular changes produced by the administration of various adrenal CQrtical steroids in the hope that we might produce typical diabetic glomerulosclerosis.